.jpg)
When tomorrow starts without me,
and I'm not there to see;
If the sun should rise
and find your eyes,
all filled with tears for me;
I wish so much you wouldn't cry,
the way you did today,
while thinking of the many things,
we didn't get to say.
I know how much you love me,
as much as I love you,
and each time that you think of me,
I know you'll miss me too;
But when tomorrow starts without me,
please try to understand,
that an Angel came
and called my name,
and took me by the hand,
and said my place was ready,
in heaven far above,
and that I'd have to leave behind,
all those I dearly love.
But as I turned to walk away,
a tear fell from my eye,
for all life, I'd always thought,
I didn't want to die.
I had so much to live for,
so much yet to do;
it seemed almost impossible,
that I was leaving you.
I thought of all the yesterdays,
the good ones and the bad,
I thought of all the
love we shared,
and all the fun we had.
If I could relive yesterday,
just even for awhile,
I'd say goodbye and kiss you
and maybe see you smile.
But then I fully realized,
that this could never be,
for emptiness and memories,
would take the place of me.
And when I thought of worldly things,
I might miss come tomorrow,
I thought of you, and when I did,
my heart was filled with sorrow.
But when I walked
through heaven's gates,
I felt so much at home.
When God looked down
and smiled at me,
from His great golden throne,
He said, "This is eternity,
and all I've promised you".
Today for life on earth is past,
but here it starts anew.
I promise no tomorrow,
but today will always last,
and since each day's the same day,
there's no longing for the past.
But you have been so faithful,
so trusting and so true.
Though there were times
you did some things,
you knew you shouldn't do.
But you have been forgiven
and now at last you're free.
So won't you take my hand
and share my life with me?
So when tomorrow starts without me,
don't think we're far apart,
for every time you think of me,
I'm right here, in your heart.
All rights reserved
Copyrighted ©David M. Romano
Saturday, May 30, 2009
Thursday, May 28, 2009
Circumcision helps reduce HIV @ Penile Cancer
Phimosis, Adult Circumcision, and Buried Penis
Author: Richard A Santucci, MD, FACS, Chief of Urology, Detroit Receiving Hospital; Specialist-in-Chief of Urology, Detroit Medical Center; Chief of Urologic Trauma Surgery, Sinai Grace Hospital; Director, The Center for Urologic Reconstruction; Clinical Professor of Urology, Michigan State College of Medicine
Coauthor(s): Ryan P Terlecki, MD, Clinical Instructor in Reconstructive Urology, Department of Urology, Division of Surgery, University of Colorado
Contributor Information and Disclosures
Updated: Apr 15, 2009
Print ThisEmail This
Overview
Treatment
Follow-up
Multimedia
References
Keywords
Introduction
Phimosis
Phimosis is defined as the inability of the prepuce (foreskin) to be retracted behind the glans penis in uncircumcised males.
Nearly all males are born with congenital phimosis, a benign condition that resolves in the overwhelming majority of infants as they transition into childhood. In 1949, Douglas Gairdner showed that only 4% of infants had a fully retractable foreskin at birth but that 90% did by age 3 years. Contemporary work demonstrates that only 1% of males aged 17 years still have an unretractable foreskin. Adult phimosis (ie, pathologic or true phimosis) may be caused by poor hygiene or an underlying medical condition (eg, diabetes mellitus).
Uncomplicated pathologic phimosis is usually amenable to conservative medical treatment. Failure of medical treatment warrants surgical intervention, usually in the traditional form of a circumcision or preputioplasty.
Although phimosis is the most common indication for adult circumcision, other reported indications include paraphimosis, balanitis without phimosis, condyloma, redundant foreskin, Bowen disease, carcinoma, trauma, disease prophylaxis (eg, HIV infection), and patient choice.
Buried penis
Buried penis was described in the early 20th century as a penis of normal size that lacks an appropriate sheath of skin and is located beneath the integument of the abdomen, thigh, or scrotum. This condition is more common in children, usually presenting in neonates or obese prepubertal boys; however, it can also be seen in adults and has been observed in both circumcised and uncircumcised individuals. Marginal cases may not be diagnosed until adulthood, when increased fat deposition accentuates the problem.
Several classification systems of buried penis have been proposed, although none has been universally adopted in the literature. Maizels et al (1986) differentiated among the terms concealed (before circumcision), trapped (cicatricial [scarred] after circumcision), and buried (associated with adolescence and obesity).1
In most congenital pediatric cases, the buried penis is self-limited. In untreated adults, however, the condition tends to worsen as the abdominal pannus continues to grow.
History of the Procedure
Circumcision and adult circumcision
Circumcision is one of the earliest elective operations known to man. Historically, this procedure has been performed for various religious reasons, social reasons, or both. The practice is considered a commandment in Jewish law and a rule of cleanliness in Islam, although it is not mentioned in the Quran. In biblical times, mothers were responsible for circumcising their newborn sons, with mohels gradually taking over. Priests in ancient Egypt would perform the procedure with their gold-impregnated thumbnail. Female circumcision, which is likely better termed "genital mutilation," has been practiced for centuries by some cultures but is an unacceptable practice and without medical benefit.
Adult circumcision for phimosis is described in textbooks dating from the early 19th century. Alternative procedures for adult phimosis were described as early as 1900 by Cloquet. Surgical attempts to restore the prepuce are also well documented, going as far back as the Old Testament. However, potential psychological and surgical complications have led to closer scrutiny of routine neonatal circumcision. Currently, the American Academy of Pediatrics (AAP) neither recommends nor condemns routine neonatal circumcision.
Studies suggest that circumcised boys are at a lower risk of urinary tract infections (UTIs). To put this in perspective, the approximate likelihood of a UTI occurring in the first year of life is 1 in 100 in uncircumcised boys and 1 in 1000 in circumcised boys. A lower risk of malignancy is also reported in studies of circumcised men, although the incidence is also rare in uncircumcised men. Of note, this decreased risk seems to be associated only with infant circumcision and not with adult procedures.
The theory that circumcision contributes to prevention of sexually transmitted diseases (STDs) was encouraged by a 19th-century report of lower rates of syphilis in Jewish men. Van Howe et al (1999), in an earlier literature review, found no clear evidence that circumcision prevents STDs.2 However, studies have demonstrated that human papillomavirus (HPV) infection, including oncogenic HPV infection, is more prevalent in uncircumcised men, regardless of demographics and sexual history.3 Citing a link between the intact prepuce and sexually transmitted infection, some authorities have gone as far as suggesting that circumcision protects against prostate cancer.4
A recent meta-analysis of 3 randomized controlled trials in South Africa,5 Kenya,6 and Uganda7 has demonstrated that circumcision decreases the risk of HIV infection among heterosexual men by nearly 60%.8 Data from a mathematical model suggest that routine circumcision in southern sub-Saharan Africa could prevent 2 million HIV infections over 10 years.9 The results of the African randomized trials have sparked speculative interest in male circumcision to reduce HIV infection in the United States, especially in areas such as New York City.10 Pask et al (2008) have suggested that the protective benefit of circumcision against HIV infection may result from removal of Langerhans cells and that enhanced keratinization conferred by topical estrogen may therefore represent an alternative to circumcision.11
Surgical correction of buried penis
The first description of the buried penis was in 1919 by Keyes. The first attempted surgical correction of this problem was by Schloss in 1959; in 1968, successful correction was performed in an adult by Glanz. Since then, numerous techniques to correct buried penis have been developed.
Problem
Phimosis
Phimosis is defined as a condition in which the foreskin cannot be retracted behind the head of the penis. Depending on the situation, this condition may be considered either physiologic or pathologic.
Physiologic, or congenital, phimosis is a normal condition of the newborn male. In 90% of cases, natural separation allows the foreskin to retract by age 3 years. However, phimosis persisting into late adolescence or early adulthood need not be considered abnormal.
The entity of pathologic, or true, phimosis is far less common and can affect children or adults. This is associated with cicatricial scarring of the prepuce that is often white in appearance. Phimosis may occur after circumcision if redundant inner prepuce slides back over the glans, with subsequent cicatricial scarring and contraction.
Buried penis
Buried penis is a true congenital disorder in which a penis of normal size lacks the proper sheath of skin and lies hidden beneath the integument of the abdomen, thigh, or scrotum. The literature, on occasion, also refers to this condition as a hidden or concealed penis. Trapped penis is a condition in which the penis becomes inconspicuous secondary to a cicatricial scar, usually after overzealous circumcision. Webbed penis is characterized by obscuration of the penile shaft by scrotal skin webs at the penoscrotal junction. Micropenis (also known as microphallus) represents a penis less than 2 standard deviations below the mean in length when measured in the stretched state. Diminutive penis is a penis that is small, malformed, or both secondary to epispadias, exstrophy, severe hypospadias, chromosomal abnormalities, or intersex conditions.
Frequency
Phimosis
Nearly all males are born with physiologic phimosis. Data have shown that the foreskin is retractable in 90% of boys by age 3 years. Only 1% of boys have physiologic phimosis that persists until age 17 years. Thus, most healthy adult men should not have phimosis; the presence of the disorder in an adult male should raise the suspicion of balanitis (infection of the foreskin), balanoposthitis (infection of glans and foreskin), diabetes, or malignancy.
Approximately 1 in 6 men in the world are circumcised. In the United States, circumcision is the fifth most common procedure; in 1992, the foreskin was removed in 62% of newborn males in the United States.
Buried penis
Congenital buried penis is uncommon. The incidence of buried penis in adulthood is unknown, but it is highly likely that many cases go unreported.
Etiology
Phimosis
Physiologic phimosis is the rule in newborn males. Formation of the prepuce is complete by 16 weeks' gestation. The inner prepuce and glans penis share a common, fused mucosal epithelium at birth. This epithelium separates via desquamation over time as the proper hormonal and growth factors are produced. Thus, neonatal circumcision is a surgical treatment of normal anatomy.
Pathologic, or true, phimosis has several different etiologies. The most common cause is infection, such as posthitis, balanitis, or a combination of the two (balanoposthitis). Diabetes mellitus may predispose to such infections.
Adult circumcision is most commonly performed to correct phimosis. When circumcision is performed for phimosis, 25%-46% of removed foreskins are histologically normal. Other indications for adult circumcision include balanitis xerotica obliterans (BXO), infection without phimosis; paraphimosis; Bowen disease; carcinoma; condylomas (warts); trauma; religious or social reasons; disease prophylaxis (eg, HIV infection); and personal preference.
Buried penis
Various etiologic factors have been proposed to explain congenital buried penis. Recent literature favors dysgenetic dartos tissue with abnormal attachments proximally and to the dorsal cavernosum. A prominent prepubic fat pad is also a common primary factor, in addition to dysgenetic dartos fascia. Secondary buried penis may be the result of an overzealous circumcision with subsequent cicatricial scar (trapped penis), a large hernia, or a hydrocele.
Adults with buried penis are commonly obese and often have a history of trauma or surgery. Adults with this condition may have undergone abdominoplasty with overzealous release of attachments between the Scarpa and dartos fasciae, penile-lengthening procedures, or other genitoinguinal surgeries.
Pathophysiology
Phimosis
The foreskin of an uncircumcised child should not be forcefully retracted. This may result in significant bleeding, as well as glanular excoriation and injury. Consequently, dense fibrous adhesions may form during the healing process, leading to true pathologic phimosis.
Circumcision has been promoted as a means of reducing the risk of UTIs, which are more common in uncircumcised males younger than 6 months. The risk in circumcised infants is approximately 1 in 1000, whereas the risk in uncircumcised infants is about 1 in 100. Some researchers contend that the risk of UTI in these children is not high enough to warrant mandatory circumcision. Interestingly, nongonococcal urethritis (NGU) may be more common in circumcised men. However, a multicenter study suggested that, if a child has associated vesicoureteral reflux (VUR), the benefit of reduced infection risk may be valid support for surgery.12
Another cited indication for circumcision is prevention of STDs. Numerous case-control studies concerning the relationship between the foreskin and HIV infection have been published, with inconsistent results and no definite link. Therefore, it seems that STD prevention is not a justification for routine circumcision. Of note, of the developed nations, the United States has one of the highest rates of STDs, HIV infection, and male circumcision.
Infant circumcision seems to decrease the risk of penile cancer,13 whereas later circumcision does not. Penile cancer is a rare disease in the United States, with an incidence of 1.5 per 100,000 people. In developing countries, the incidence is higher and accounts for up to 10% of malignancies in some African and South American nations. Although primarily a disease of older men, penile cancer has been reported in children. The lowest incidence has been reported in Jews, with a similar incidence in Muslims; both groups have high rates of neonatal circumcision.
Daling et al performed a population-based case-control study in 2005 that examined the importance of circumcision in patients with penile cancer. Preputial status was not found to be a statistically significant factor in penile cancer. The investigators concluded that the role of circumcision in penile cancer prevention is unclear.14 Several studies suggest that poor hygiene may be a stronger risk factor than circumcision status. Although smegma has been implicated as a carcinogenic agent, definitive evidence is lacking.
Adult phimosis may be caused by repeated episodes of balanitis or balanoposthitis. Such infections are commonly due to poor personal hygiene (failure to regularly clean under the foreskin).
Phimosis may be a presenting symptom of early diabetes mellitus. When the residual urine of a patient with diabetes mellitus becomes trapped under the foreskin, the combination of a moist environment and glucose in the urine may lead to a proliferation of bacteria, with subsequent infection, scarring, and eventual phimosis.
Buried penis
The penis is properly formed by 16 weeks' gestation. Congenital buried penis is caused by a developmental anomaly in which the dartos fascia has not developed into the normal elastic configuration to allow the penile skin to move freely over the deeper tissues of the penile shaft. Instead, the dartos layer is inelastic, which prevents the forward extension of the penis and holds it buried under the pubis.
Other possible contributing factors to congenital buried penis include excess prepubic fat, scrotal webbing, deficient penile skin, loose skin, an abnormally low position at which the crura separate, abnormal attachments between the Buck fascia and the tunica albuginea, and insufficient attachment of dartos fascia and skin to the Buck fascia.
The pathophysiology of buried penis in adults differs from that in children and includes iatrogenically induced scar contracture with concurrent descent of the abdominal fat pad. Because the penis is suspended from the pubis by the suspensory ligament, it remains fixed, unlike the prepubic fat. As fat descends over the penis, excessive moisture and bacterial overgrowth may occur. Chronic infection may lead to skin maceration and more scar contracture, further aggravating the problem. In many children, this condition is self-limited. However, in adults, total body fat content typically increases with age, causing the buried penis to worsen over time.
Presentation
Phimosis
Congenital or physiologic phimosis is clinically asymptomatic so is not a cause for concern. It is often associated with "ballooning" of the foreskin during voiding. This is a self-limited phenomenon that, in the absence of pathologic phimosis, does not indicate urinary tract obstruction. Pathologic, or true, phimosis is far less common. Symptoms include skin irritation, dysuria, bleeding, and occasionally enuresis or urinary retention. Physical examination usually reveals white cicatricial scarring at the preputial ring. Meuli et al (1994) devised the following scoring system to rate the severity of phimosis:15
Grade I - Fully retractable prepuce with stenotic ring in the shaft
Grade II - Partial retractability with partial exposure of the glans
Grade III - Partial retractability with exposure of the meatus only
Grade IV - No retractability
Pathologic phimosis may be due to BXO, a genital form of lichen sclerosus et atrophicus. This condition affects both men and boys and represents an absolute indication for circumcision, which may be curative. The etiology of BXO is unknown, and it may represent a premalignant state. Clinically, it presents as severe phimosis and possibly meatal stenosis, glanular lesions, or both.
In older men, when the phimosis is severe, the distal foreskin often appears swollen and erythematous with cracked fissures (see Image 1). Men who are affected report pain and discomfort during sexual activity or when they attempt to retract the foreskin. Unlike in the pediatric population, lower urinary tract voiding symptoms are absent. In older men, acquired phimosis is often associated with poor hygiene but may be a product of diabetes mellitus.
Phimotic foreskin. The distal foreskin is edematous, with cracked fissures. The patient was unable to retract the foreskin.
[ CLOSE WINDOW ]
Phimotic foreskin. The distal foreskin is edematous, with cracked fissures. The patient was unable to retract the foreskin.
All uncircumcised adult men should have the foreskin retracted to exclude occult carcinoma as a part of a complete urologic examination. Squamous cell carcinoma of the penis may manifest as an ulcerated fungating mass of the glans or the prepuce. Alternatively, carcinoma in situ or penile carcinoma may appear as a velvety macular lesion of the glans (erythroplasia of Queyrat) or the penile shaft (Bowen disease).
Buried penis
Most pediatric cases of buried penis present in neonates or prepubertal boys. The most common age range of patients at presentation is 6 months to 1 year. Adolescents who present with buried penis are usually obese, and weight loss should be advised. Patients may be uncircumcised or circumcised; the latter complicates repair. One series found that 77% of children presenting with buried penis had been previously circumcised, emphasizing a need for pediatric urologists to educate primary care physicians.
The reasons for presentation vary. Often, parents are concerned because they are unable to see the penis, which may also complicate proper hygiene. Occasionally, they may witness ballooning of the foreskin with voiding, and children may be persistently wet if they are voiding into the preputial sac.
Adolescents may report dysuria, dribbling between voids, trouble directing their urinary stream because of difficulty holding the penis, or embarrassment in the locker room. Some patients have a history of balanitis and balanoposthitis, and some have undergone a radical circumcision or even multiple circumcisions.
In addition to some of the symptoms seen in children, adults may present with sexual complaints. These include painful erection, sexual embarrassment, and difficulty with vaginal penetration, especially if the tip of the glans does not project past the male escutcheon. This condition may lead to the inability to void in a standing position and may cause the patient to soil himself while urinating in the seated position. Obesity and diabetes mellitus are commonly associated comorbidities.
On physical examination, the penis may be concealed because it is buried in prepubic tissues; buried and enclosed in scrotal tissue (penis palmatus); trapped by phimosis, traumatic scar tissue, or postcircumcision cicatrix; or hidden secondary to a large hernia or hydrocele. A smooth transition from prepubic to penile skin indicates a buried penis. Trapped penis demonstrates a circumferential groove at the base of the penis. Only Maizels (1986)1 and Burkholder (1983)16 have noted an association between buried penis and renal anomalies. Other genitourinary anomalies have not been associated with this condition.
Indications
Phimosis
The main medical indication for circumcision in children is pathologic phimosis. In a prospective long-term study, 40% of boys treated for phimosis were found to have BXO, which has been linked to the development of penile squamous cell carcinoma (SCC).17 Although potent topical steroids may allow improvement and slow progression, total circumcision is the treatment of choice for BXO and may be curative.
Recurrent balanoposthitis, which affects 1% of boys, is also considered a relative indication for circumcision. However, this condition tends to be self-limited, and even if balanoposthitis is recurrent, preputioplasty and topical steroids represent alternatives to circumcision.18,19,20,21 In patients with balanoposthitis who are sufficiently troubled to warrant surgical intervention, circumcision is always curative.
Paraphimosis results from abuse or accident, not disease, of the foreskin and can be seen at any age. It represents the second most common indication for adult circumcision. Infants may present with paraphimosis if their parents have retracted the prepuce and failed to pull it forward thereafter. Reduction of the foreskin under sedation is almost always possible. However, in some situations, a dorsal slit or circumcision is required (see Paraphimosis). Unrecognized chronic paraphimosis or delay in diagnosis may result in urinary retention or even penile autoamputation.
Other indications for circumcision that are less common include small preputial tumors, multiple preputial cysts or condylomas, and penile lymphedema. A reasonable case may be made for circumcising boys with VUR who suffer from UTIs. In addition, the foreskin may be removed to perform a biopsy of lesions hidden under the prepuce or for definitive radiation therapy for penile cancer.
Occasions arise in which urethral instrumentation—in the form of a cystoscopy or Foley catheterization—is necessary. This may be quite problematic in an adult affected by severe phimosis. In such instances, an emergency bedside dorsal slit can be performed safely and expeditiously. After being discharged, the patient may proceed to undergo formal circumcision.
Many circumcisions are performed for social or religious reasons. Interestingly, only 1 out of 6 schools of Islamic law consider circumcision obligatory, whereas others feel it is to be recommended. Among religious Jews, circumcision is felt to be a commandment from their creator.
In summary, common indications for circumcision include the following:
Phimosis
Paraphimosis
Recurrent balanitis or balanoposthitis
Social or religious reasons
Buried penis
The primary reason that children are referred for correction of the buried penis is cosmesis. In the neonate, observation seems to be a viable option. Children younger than 3 years have a 58% chance of spontaneous resolution. Some pediatric urologists insist that this condition is a developmental stage that will resolve by puberty and feel that correction should therefore be deferred. Evidence has shown, however, that spontaneous resolution does not always occur. Also, in men and adolescents, measures such as diet and exercise are unlikely to be effective.
Other authors feel that, after age 3 years, buried penis requires correction. The primary reason cited is the importance of being able to void while standing during the period of toilet training. There are numerous other indications for repair. For example, a concealed penis can hamper proper hygiene, trap urine, and complicate voiding. This can lead to repeated infections, secondary phimosis, or even urinary retention. In addition, numerous investigators feel that children with buried penis are at risk for psychological and social trauma, even from an early age. Obese boys with a buried penis may be ostracized by their peers and withdraw socially. Surgery often relieves anxiety and may improve self-image.
In adults, buried penis tends to worsen over time as they accumulate more fat. The cicatricial scar does not loosen on its own over time. Urinary and sexual complications can greatly affect daily life. Therefore, surgery is likely necessary in these patients.
Relevant Anatomy
The penis is composed of paired corpora cavernosa, the crura of which are attached to the pubic arch, and the corpus spongiosum (see Image 16). The proximal portion of the corpus spongiosum is referred to as the bulb of the penis, and the glans represents the distal expansion. The urethra traverses the corpus spongiosum to exit at the meatus. The cavernosal bodies produce the male erection when they are engorged with blood.
Cross-section through the body of the penis.
[ CLOSE WINDOW ]
Cross-section through the body of the penis.
The fascial layers of the penis are continuous with the fascial layers of the perineum and lower abdomen. Dartos fascia represents the superficial penile fascia. Deep to this lies the Buck fascia, which covers the tunica albuginea of the penile bodies. Proximally, the Buck fascia is in continuity with the suspensory ligament of the penis, which attaches to the symphysis pubis.
The penis is supplied by a superficial system of arteries that arise from the external pudendal arteries and a deep system of arteries that stem from the internal pudendal arteries. The superficial blood supply lies in the superficial penile fascia and supplies the penile skin and prepuce. The internal pudendal artery, which arises from the hypogastric artery, gives rise to the penile artery. The penile artery then gives rise to the bulbourethral artery, the urethral artery, and the cavernous artery (deep artery of the penis) before terminating as the dorsal artery of the penis (see Images 14-15).
The arterial blood supply of the penis arises from the internal pudendal artery. The internal pudendal artery gives off branches to the bulbar artery, cavernosal artery, and dorsal penile artery. The bulbar artery continues on as the bulbourethral artery to supply the urethra. The cavernosal artery gives rise to the helicine arteries that are end arteries. The dorsal artery of the penis gives branches off to the circumflex arteries.
[ CLOSE WINDOW ]
The arterial blood supply of the penis arises from the internal pudendal artery. The internal pudendal artery gives off branches to the bulbar artery, cavernosal artery, and dorsal penile artery. The bulbar artery continues on as the bulbourethral artery to supply the urethra. The cavernosal artery gives rise to the helicine arteries that are end arteries. The dorsal artery of the penis gives branches off to the circumflex arteries.
Dorsal view of the arterial and venous blood supply of the penis.
[ CLOSE WINDOW ]
Dorsal view of the arterial and venous blood supply of the penis.
Somatic nerve supply to the penis comes by way of the pudendal nerves, which eventually produce the dorsal nerves of the penis on each side. Although cutaneous innervation to the penis is primarily from branches of the pudendal nerve, the proximal portion is supplied by the ilioinguinal nerve after it leaves the superficial inguinal ring. The prepuce has somatosensory innervation by the dorsal nerve of the penis and branches of the perineal nerve. The glans is primarily innervated by free nerve endings and has poor fine-touch discrimination.
Contraindications
Circumcision is generally not performed in children born prematurely or those with blood dyscrasias. It should not be performed in children with congenital penile anomalies such as the following:
Hypospadias
Epispadias
Chordee
Penile webbing
Buried penis
Author: Richard A Santucci, MD, FACS, Chief of Urology, Detroit Receiving Hospital; Specialist-in-Chief of Urology, Detroit Medical Center; Chief of Urologic Trauma Surgery, Sinai Grace Hospital; Director, The Center for Urologic Reconstruction; Clinical Professor of Urology, Michigan State College of Medicine
Coauthor(s): Ryan P Terlecki, MD, Clinical Instructor in Reconstructive Urology, Department of Urology, Division of Surgery, University of Colorado
Contributor Information and Disclosures
Updated: Apr 15, 2009
Print ThisEmail This
Overview
Treatment
Follow-up
Multimedia
References
Keywords
Introduction
Phimosis
Phimosis is defined as the inability of the prepuce (foreskin) to be retracted behind the glans penis in uncircumcised males.
Nearly all males are born with congenital phimosis, a benign condition that resolves in the overwhelming majority of infants as they transition into childhood. In 1949, Douglas Gairdner showed that only 4% of infants had a fully retractable foreskin at birth but that 90% did by age 3 years. Contemporary work demonstrates that only 1% of males aged 17 years still have an unretractable foreskin. Adult phimosis (ie, pathologic or true phimosis) may be caused by poor hygiene or an underlying medical condition (eg, diabetes mellitus).
Uncomplicated pathologic phimosis is usually amenable to conservative medical treatment. Failure of medical treatment warrants surgical intervention, usually in the traditional form of a circumcision or preputioplasty.
Although phimosis is the most common indication for adult circumcision, other reported indications include paraphimosis, balanitis without phimosis, condyloma, redundant foreskin, Bowen disease, carcinoma, trauma, disease prophylaxis (eg, HIV infection), and patient choice.
Buried penis
Buried penis was described in the early 20th century as a penis of normal size that lacks an appropriate sheath of skin and is located beneath the integument of the abdomen, thigh, or scrotum. This condition is more common in children, usually presenting in neonates or obese prepubertal boys; however, it can also be seen in adults and has been observed in both circumcised and uncircumcised individuals. Marginal cases may not be diagnosed until adulthood, when increased fat deposition accentuates the problem.
Several classification systems of buried penis have been proposed, although none has been universally adopted in the literature. Maizels et al (1986) differentiated among the terms concealed (before circumcision), trapped (cicatricial [scarred] after circumcision), and buried (associated with adolescence and obesity).1
In most congenital pediatric cases, the buried penis is self-limited. In untreated adults, however, the condition tends to worsen as the abdominal pannus continues to grow.
History of the Procedure
Circumcision and adult circumcision
Circumcision is one of the earliest elective operations known to man. Historically, this procedure has been performed for various religious reasons, social reasons, or both. The practice is considered a commandment in Jewish law and a rule of cleanliness in Islam, although it is not mentioned in the Quran. In biblical times, mothers were responsible for circumcising their newborn sons, with mohels gradually taking over. Priests in ancient Egypt would perform the procedure with their gold-impregnated thumbnail. Female circumcision, which is likely better termed "genital mutilation," has been practiced for centuries by some cultures but is an unacceptable practice and without medical benefit.
Adult circumcision for phimosis is described in textbooks dating from the early 19th century. Alternative procedures for adult phimosis were described as early as 1900 by Cloquet. Surgical attempts to restore the prepuce are also well documented, going as far back as the Old Testament. However, potential psychological and surgical complications have led to closer scrutiny of routine neonatal circumcision. Currently, the American Academy of Pediatrics (AAP) neither recommends nor condemns routine neonatal circumcision.
Studies suggest that circumcised boys are at a lower risk of urinary tract infections (UTIs). To put this in perspective, the approximate likelihood of a UTI occurring in the first year of life is 1 in 100 in uncircumcised boys and 1 in 1000 in circumcised boys. A lower risk of malignancy is also reported in studies of circumcised men, although the incidence is also rare in uncircumcised men. Of note, this decreased risk seems to be associated only with infant circumcision and not with adult procedures.
The theory that circumcision contributes to prevention of sexually transmitted diseases (STDs) was encouraged by a 19th-century report of lower rates of syphilis in Jewish men. Van Howe et al (1999), in an earlier literature review, found no clear evidence that circumcision prevents STDs.2 However, studies have demonstrated that human papillomavirus (HPV) infection, including oncogenic HPV infection, is more prevalent in uncircumcised men, regardless of demographics and sexual history.3 Citing a link between the intact prepuce and sexually transmitted infection, some authorities have gone as far as suggesting that circumcision protects against prostate cancer.4
A recent meta-analysis of 3 randomized controlled trials in South Africa,5 Kenya,6 and Uganda7 has demonstrated that circumcision decreases the risk of HIV infection among heterosexual men by nearly 60%.8 Data from a mathematical model suggest that routine circumcision in southern sub-Saharan Africa could prevent 2 million HIV infections over 10 years.9 The results of the African randomized trials have sparked speculative interest in male circumcision to reduce HIV infection in the United States, especially in areas such as New York City.10 Pask et al (2008) have suggested that the protective benefit of circumcision against HIV infection may result from removal of Langerhans cells and that enhanced keratinization conferred by topical estrogen may therefore represent an alternative to circumcision.11
Surgical correction of buried penis
The first description of the buried penis was in 1919 by Keyes. The first attempted surgical correction of this problem was by Schloss in 1959; in 1968, successful correction was performed in an adult by Glanz. Since then, numerous techniques to correct buried penis have been developed.
Problem
Phimosis
Phimosis is defined as a condition in which the foreskin cannot be retracted behind the head of the penis. Depending on the situation, this condition may be considered either physiologic or pathologic.
Physiologic, or congenital, phimosis is a normal condition of the newborn male. In 90% of cases, natural separation allows the foreskin to retract by age 3 years. However, phimosis persisting into late adolescence or early adulthood need not be considered abnormal.
The entity of pathologic, or true, phimosis is far less common and can affect children or adults. This is associated with cicatricial scarring of the prepuce that is often white in appearance. Phimosis may occur after circumcision if redundant inner prepuce slides back over the glans, with subsequent cicatricial scarring and contraction.
Buried penis
Buried penis is a true congenital disorder in which a penis of normal size lacks the proper sheath of skin and lies hidden beneath the integument of the abdomen, thigh, or scrotum. The literature, on occasion, also refers to this condition as a hidden or concealed penis. Trapped penis is a condition in which the penis becomes inconspicuous secondary to a cicatricial scar, usually after overzealous circumcision. Webbed penis is characterized by obscuration of the penile shaft by scrotal skin webs at the penoscrotal junction. Micropenis (also known as microphallus) represents a penis less than 2 standard deviations below the mean in length when measured in the stretched state. Diminutive penis is a penis that is small, malformed, or both secondary to epispadias, exstrophy, severe hypospadias, chromosomal abnormalities, or intersex conditions.
Frequency
Phimosis
Nearly all males are born with physiologic phimosis. Data have shown that the foreskin is retractable in 90% of boys by age 3 years. Only 1% of boys have physiologic phimosis that persists until age 17 years. Thus, most healthy adult men should not have phimosis; the presence of the disorder in an adult male should raise the suspicion of balanitis (infection of the foreskin), balanoposthitis (infection of glans and foreskin), diabetes, or malignancy.
Approximately 1 in 6 men in the world are circumcised. In the United States, circumcision is the fifth most common procedure; in 1992, the foreskin was removed in 62% of newborn males in the United States.
Buried penis
Congenital buried penis is uncommon. The incidence of buried penis in adulthood is unknown, but it is highly likely that many cases go unreported.
Etiology
Phimosis
Physiologic phimosis is the rule in newborn males. Formation of the prepuce is complete by 16 weeks' gestation. The inner prepuce and glans penis share a common, fused mucosal epithelium at birth. This epithelium separates via desquamation over time as the proper hormonal and growth factors are produced. Thus, neonatal circumcision is a surgical treatment of normal anatomy.
Pathologic, or true, phimosis has several different etiologies. The most common cause is infection, such as posthitis, balanitis, or a combination of the two (balanoposthitis). Diabetes mellitus may predispose to such infections.
Adult circumcision is most commonly performed to correct phimosis. When circumcision is performed for phimosis, 25%-46% of removed foreskins are histologically normal. Other indications for adult circumcision include balanitis xerotica obliterans (BXO), infection without phimosis; paraphimosis; Bowen disease; carcinoma; condylomas (warts); trauma; religious or social reasons; disease prophylaxis (eg, HIV infection); and personal preference.
Buried penis
Various etiologic factors have been proposed to explain congenital buried penis. Recent literature favors dysgenetic dartos tissue with abnormal attachments proximally and to the dorsal cavernosum. A prominent prepubic fat pad is also a common primary factor, in addition to dysgenetic dartos fascia. Secondary buried penis may be the result of an overzealous circumcision with subsequent cicatricial scar (trapped penis), a large hernia, or a hydrocele.
Adults with buried penis are commonly obese and often have a history of trauma or surgery. Adults with this condition may have undergone abdominoplasty with overzealous release of attachments between the Scarpa and dartos fasciae, penile-lengthening procedures, or other genitoinguinal surgeries.
Pathophysiology
Phimosis
The foreskin of an uncircumcised child should not be forcefully retracted. This may result in significant bleeding, as well as glanular excoriation and injury. Consequently, dense fibrous adhesions may form during the healing process, leading to true pathologic phimosis.
Circumcision has been promoted as a means of reducing the risk of UTIs, which are more common in uncircumcised males younger than 6 months. The risk in circumcised infants is approximately 1 in 1000, whereas the risk in uncircumcised infants is about 1 in 100. Some researchers contend that the risk of UTI in these children is not high enough to warrant mandatory circumcision. Interestingly, nongonococcal urethritis (NGU) may be more common in circumcised men. However, a multicenter study suggested that, if a child has associated vesicoureteral reflux (VUR), the benefit of reduced infection risk may be valid support for surgery.12
Another cited indication for circumcision is prevention of STDs. Numerous case-control studies concerning the relationship between the foreskin and HIV infection have been published, with inconsistent results and no definite link. Therefore, it seems that STD prevention is not a justification for routine circumcision. Of note, of the developed nations, the United States has one of the highest rates of STDs, HIV infection, and male circumcision.
Infant circumcision seems to decrease the risk of penile cancer,13 whereas later circumcision does not. Penile cancer is a rare disease in the United States, with an incidence of 1.5 per 100,000 people. In developing countries, the incidence is higher and accounts for up to 10% of malignancies in some African and South American nations. Although primarily a disease of older men, penile cancer has been reported in children. The lowest incidence has been reported in Jews, with a similar incidence in Muslims; both groups have high rates of neonatal circumcision.
Daling et al performed a population-based case-control study in 2005 that examined the importance of circumcision in patients with penile cancer. Preputial status was not found to be a statistically significant factor in penile cancer. The investigators concluded that the role of circumcision in penile cancer prevention is unclear.14 Several studies suggest that poor hygiene may be a stronger risk factor than circumcision status. Although smegma has been implicated as a carcinogenic agent, definitive evidence is lacking.
Adult phimosis may be caused by repeated episodes of balanitis or balanoposthitis. Such infections are commonly due to poor personal hygiene (failure to regularly clean under the foreskin).
Phimosis may be a presenting symptom of early diabetes mellitus. When the residual urine of a patient with diabetes mellitus becomes trapped under the foreskin, the combination of a moist environment and glucose in the urine may lead to a proliferation of bacteria, with subsequent infection, scarring, and eventual phimosis.
Buried penis
The penis is properly formed by 16 weeks' gestation. Congenital buried penis is caused by a developmental anomaly in which the dartos fascia has not developed into the normal elastic configuration to allow the penile skin to move freely over the deeper tissues of the penile shaft. Instead, the dartos layer is inelastic, which prevents the forward extension of the penis and holds it buried under the pubis.
Other possible contributing factors to congenital buried penis include excess prepubic fat, scrotal webbing, deficient penile skin, loose skin, an abnormally low position at which the crura separate, abnormal attachments between the Buck fascia and the tunica albuginea, and insufficient attachment of dartos fascia and skin to the Buck fascia.
The pathophysiology of buried penis in adults differs from that in children and includes iatrogenically induced scar contracture with concurrent descent of the abdominal fat pad. Because the penis is suspended from the pubis by the suspensory ligament, it remains fixed, unlike the prepubic fat. As fat descends over the penis, excessive moisture and bacterial overgrowth may occur. Chronic infection may lead to skin maceration and more scar contracture, further aggravating the problem. In many children, this condition is self-limited. However, in adults, total body fat content typically increases with age, causing the buried penis to worsen over time.
Presentation
Phimosis
Congenital or physiologic phimosis is clinically asymptomatic so is not a cause for concern. It is often associated with "ballooning" of the foreskin during voiding. This is a self-limited phenomenon that, in the absence of pathologic phimosis, does not indicate urinary tract obstruction. Pathologic, or true, phimosis is far less common. Symptoms include skin irritation, dysuria, bleeding, and occasionally enuresis or urinary retention. Physical examination usually reveals white cicatricial scarring at the preputial ring. Meuli et al (1994) devised the following scoring system to rate the severity of phimosis:15
Grade I - Fully retractable prepuce with stenotic ring in the shaft
Grade II - Partial retractability with partial exposure of the glans
Grade III - Partial retractability with exposure of the meatus only
Grade IV - No retractability
Pathologic phimosis may be due to BXO, a genital form of lichen sclerosus et atrophicus. This condition affects both men and boys and represents an absolute indication for circumcision, which may be curative. The etiology of BXO is unknown, and it may represent a premalignant state. Clinically, it presents as severe phimosis and possibly meatal stenosis, glanular lesions, or both.
In older men, when the phimosis is severe, the distal foreskin often appears swollen and erythematous with cracked fissures (see Image 1). Men who are affected report pain and discomfort during sexual activity or when they attempt to retract the foreskin. Unlike in the pediatric population, lower urinary tract voiding symptoms are absent. In older men, acquired phimosis is often associated with poor hygiene but may be a product of diabetes mellitus.
Phimotic foreskin. The distal foreskin is edematous, with cracked fissures. The patient was unable to retract the foreskin.
[ CLOSE WINDOW ]
Phimotic foreskin. The distal foreskin is edematous, with cracked fissures. The patient was unable to retract the foreskin.
All uncircumcised adult men should have the foreskin retracted to exclude occult carcinoma as a part of a complete urologic examination. Squamous cell carcinoma of the penis may manifest as an ulcerated fungating mass of the glans or the prepuce. Alternatively, carcinoma in situ or penile carcinoma may appear as a velvety macular lesion of the glans (erythroplasia of Queyrat) or the penile shaft (Bowen disease).
Buried penis
Most pediatric cases of buried penis present in neonates or prepubertal boys. The most common age range of patients at presentation is 6 months to 1 year. Adolescents who present with buried penis are usually obese, and weight loss should be advised. Patients may be uncircumcised or circumcised; the latter complicates repair. One series found that 77% of children presenting with buried penis had been previously circumcised, emphasizing a need for pediatric urologists to educate primary care physicians.
The reasons for presentation vary. Often, parents are concerned because they are unable to see the penis, which may also complicate proper hygiene. Occasionally, they may witness ballooning of the foreskin with voiding, and children may be persistently wet if they are voiding into the preputial sac.
Adolescents may report dysuria, dribbling between voids, trouble directing their urinary stream because of difficulty holding the penis, or embarrassment in the locker room. Some patients have a history of balanitis and balanoposthitis, and some have undergone a radical circumcision or even multiple circumcisions.
In addition to some of the symptoms seen in children, adults may present with sexual complaints. These include painful erection, sexual embarrassment, and difficulty with vaginal penetration, especially if the tip of the glans does not project past the male escutcheon. This condition may lead to the inability to void in a standing position and may cause the patient to soil himself while urinating in the seated position. Obesity and diabetes mellitus are commonly associated comorbidities.
On physical examination, the penis may be concealed because it is buried in prepubic tissues; buried and enclosed in scrotal tissue (penis palmatus); trapped by phimosis, traumatic scar tissue, or postcircumcision cicatrix; or hidden secondary to a large hernia or hydrocele. A smooth transition from prepubic to penile skin indicates a buried penis. Trapped penis demonstrates a circumferential groove at the base of the penis. Only Maizels (1986)1 and Burkholder (1983)16 have noted an association between buried penis and renal anomalies. Other genitourinary anomalies have not been associated with this condition.
Indications
Phimosis
The main medical indication for circumcision in children is pathologic phimosis. In a prospective long-term study, 40% of boys treated for phimosis were found to have BXO, which has been linked to the development of penile squamous cell carcinoma (SCC).17 Although potent topical steroids may allow improvement and slow progression, total circumcision is the treatment of choice for BXO and may be curative.
Recurrent balanoposthitis, which affects 1% of boys, is also considered a relative indication for circumcision. However, this condition tends to be self-limited, and even if balanoposthitis is recurrent, preputioplasty and topical steroids represent alternatives to circumcision.18,19,20,21 In patients with balanoposthitis who are sufficiently troubled to warrant surgical intervention, circumcision is always curative.
Paraphimosis results from abuse or accident, not disease, of the foreskin and can be seen at any age. It represents the second most common indication for adult circumcision. Infants may present with paraphimosis if their parents have retracted the prepuce and failed to pull it forward thereafter. Reduction of the foreskin under sedation is almost always possible. However, in some situations, a dorsal slit or circumcision is required (see Paraphimosis). Unrecognized chronic paraphimosis or delay in diagnosis may result in urinary retention or even penile autoamputation.
Other indications for circumcision that are less common include small preputial tumors, multiple preputial cysts or condylomas, and penile lymphedema. A reasonable case may be made for circumcising boys with VUR who suffer from UTIs. In addition, the foreskin may be removed to perform a biopsy of lesions hidden under the prepuce or for definitive radiation therapy for penile cancer.
Occasions arise in which urethral instrumentation—in the form of a cystoscopy or Foley catheterization—is necessary. This may be quite problematic in an adult affected by severe phimosis. In such instances, an emergency bedside dorsal slit can be performed safely and expeditiously. After being discharged, the patient may proceed to undergo formal circumcision.
Many circumcisions are performed for social or religious reasons. Interestingly, only 1 out of 6 schools of Islamic law consider circumcision obligatory, whereas others feel it is to be recommended. Among religious Jews, circumcision is felt to be a commandment from their creator.
In summary, common indications for circumcision include the following:
Phimosis
Paraphimosis
Recurrent balanitis or balanoposthitis
Social or religious reasons
Buried penis
The primary reason that children are referred for correction of the buried penis is cosmesis. In the neonate, observation seems to be a viable option. Children younger than 3 years have a 58% chance of spontaneous resolution. Some pediatric urologists insist that this condition is a developmental stage that will resolve by puberty and feel that correction should therefore be deferred. Evidence has shown, however, that spontaneous resolution does not always occur. Also, in men and adolescents, measures such as diet and exercise are unlikely to be effective.
Other authors feel that, after age 3 years, buried penis requires correction. The primary reason cited is the importance of being able to void while standing during the period of toilet training. There are numerous other indications for repair. For example, a concealed penis can hamper proper hygiene, trap urine, and complicate voiding. This can lead to repeated infections, secondary phimosis, or even urinary retention. In addition, numerous investigators feel that children with buried penis are at risk for psychological and social trauma, even from an early age. Obese boys with a buried penis may be ostracized by their peers and withdraw socially. Surgery often relieves anxiety and may improve self-image.
In adults, buried penis tends to worsen over time as they accumulate more fat. The cicatricial scar does not loosen on its own over time. Urinary and sexual complications can greatly affect daily life. Therefore, surgery is likely necessary in these patients.
Relevant Anatomy
The penis is composed of paired corpora cavernosa, the crura of which are attached to the pubic arch, and the corpus spongiosum (see Image 16). The proximal portion of the corpus spongiosum is referred to as the bulb of the penis, and the glans represents the distal expansion. The urethra traverses the corpus spongiosum to exit at the meatus. The cavernosal bodies produce the male erection when they are engorged with blood.
Cross-section through the body of the penis.
[ CLOSE WINDOW ]
Cross-section through the body of the penis.
The fascial layers of the penis are continuous with the fascial layers of the perineum and lower abdomen. Dartos fascia represents the superficial penile fascia. Deep to this lies the Buck fascia, which covers the tunica albuginea of the penile bodies. Proximally, the Buck fascia is in continuity with the suspensory ligament of the penis, which attaches to the symphysis pubis.
The penis is supplied by a superficial system of arteries that arise from the external pudendal arteries and a deep system of arteries that stem from the internal pudendal arteries. The superficial blood supply lies in the superficial penile fascia and supplies the penile skin and prepuce. The internal pudendal artery, which arises from the hypogastric artery, gives rise to the penile artery. The penile artery then gives rise to the bulbourethral artery, the urethral artery, and the cavernous artery (deep artery of the penis) before terminating as the dorsal artery of the penis (see Images 14-15).
The arterial blood supply of the penis arises from the internal pudendal artery. The internal pudendal artery gives off branches to the bulbar artery, cavernosal artery, and dorsal penile artery. The bulbar artery continues on as the bulbourethral artery to supply the urethra. The cavernosal artery gives rise to the helicine arteries that are end arteries. The dorsal artery of the penis gives branches off to the circumflex arteries.
[ CLOSE WINDOW ]
The arterial blood supply of the penis arises from the internal pudendal artery. The internal pudendal artery gives off branches to the bulbar artery, cavernosal artery, and dorsal penile artery. The bulbar artery continues on as the bulbourethral artery to supply the urethra. The cavernosal artery gives rise to the helicine arteries that are end arteries. The dorsal artery of the penis gives branches off to the circumflex arteries.
Dorsal view of the arterial and venous blood supply of the penis.
[ CLOSE WINDOW ]
Dorsal view of the arterial and venous blood supply of the penis.
Somatic nerve supply to the penis comes by way of the pudendal nerves, which eventually produce the dorsal nerves of the penis on each side. Although cutaneous innervation to the penis is primarily from branches of the pudendal nerve, the proximal portion is supplied by the ilioinguinal nerve after it leaves the superficial inguinal ring. The prepuce has somatosensory innervation by the dorsal nerve of the penis and branches of the perineal nerve. The glans is primarily innervated by free nerve endings and has poor fine-touch discrimination.
Contraindications
Circumcision is generally not performed in children born prematurely or those with blood dyscrasias. It should not be performed in children with congenital penile anomalies such as the following:
Hypospadias
Epispadias
Chordee
Penile webbing
Buried penis
Early EPO Use Increased SVR Rates and Reduced Discontinuation Rate
EASL 44th Annual Meeting
April 22-26, 2009
Copenhagen, Denmark Back
Early EPO Use Increased SVR Rates and Reduced Discontinuation Rate !
EASL April 23-26 2009 Copenhagen Denmark Reported by Jules Levin
These findings are important because most studies to date have reported NOT finding that EPO improved SVR rates, but this was always implausiable to me so I always doubted the previous findings, I was convinced that EPO provided benefit and improved SVR rates. The EPO finding may need further study in a randomized prospective study but the association found here that early EPO use within the first 8 weeks of starting Peg/RBV appears to be the key. I don't think any previous studies examined the question this way, which underscores how common it see that we see poorly conducted studies in HCV: HALT-C and EPO studies. The problem now is that my understanding is that the FDA placed a Black Box on EPO saying it was restricted in HCV use and we know there are concerns about toxicities associated with EPO use. So what will Schering do with regards to to their approval application for boceprevir to the FDA, they will I think request the FDA to allow EPO use but how will the FDA respond? In addition, I don't know if EPO is being used in Vertex's phase 3 studies but it wasn't used in their phase 2 studies so this is another intetesting aspect of this story. In the SPRINT-1 boceprevir phase 2 results reported at EASL anemia was higher among study patients receiving boceprevir+peg/RBV than patients receiving peg/RBV alone 34% vs 54%, and EPO use was higher among the boceprevir group than those receiving only peg/RBV (7% vs 15%). In the Vertex telaprevir study in treatment-experienced reported at this EASL anemia rate was reported as 8% in the peg/RBV group, 8% in the telaprevir/peg group without ribavirin, and 26% in the telaprevir 12 week/peg/rbv 24 week group, and 27% in the telaprevir 24 week/peg/RBV 48 week group. So the anemia rates I think need to be better characterized in its association with both boceprevir and telaprevir.
Jules Levin
April 22-26, 2009
Copenhagen, Denmark Back
Early EPO Use Increased SVR Rates and Reduced Discontinuation Rate !
EASL April 23-26 2009 Copenhagen Denmark Reported by Jules Levin
These findings are important because most studies to date have reported NOT finding that EPO improved SVR rates, but this was always implausiable to me so I always doubted the previous findings, I was convinced that EPO provided benefit and improved SVR rates. The EPO finding may need further study in a randomized prospective study but the association found here that early EPO use within the first 8 weeks of starting Peg/RBV appears to be the key. I don't think any previous studies examined the question this way, which underscores how common it see that we see poorly conducted studies in HCV: HALT-C and EPO studies. The problem now is that my understanding is that the FDA placed a Black Box on EPO saying it was restricted in HCV use and we know there are concerns about toxicities associated with EPO use. So what will Schering do with regards to to their approval application for boceprevir to the FDA, they will I think request the FDA to allow EPO use but how will the FDA respond? In addition, I don't know if EPO is being used in Vertex's phase 3 studies but it wasn't used in their phase 2 studies so this is another intetesting aspect of this story. In the SPRINT-1 boceprevir phase 2 results reported at EASL anemia was higher among study patients receiving boceprevir+peg/RBV than patients receiving peg/RBV alone 34% vs 54%, and EPO use was higher among the boceprevir group than those receiving only peg/RBV (7% vs 15%). In the Vertex telaprevir study in treatment-experienced reported at this EASL anemia rate was reported as 8% in the peg/RBV group, 8% in the telaprevir/peg group without ribavirin, and 26% in the telaprevir 12 week/peg/rbv 24 week group, and 27% in the telaprevir 24 week/peg/RBV 48 week group. So the anemia rates I think need to be better characterized in its association with both boceprevir and telaprevir.
Jules Levin
BMS-790052 is a First-in-class Potent Hepatitis C Virus (HCV)
59th Annual Meeting of the American Association
for the Study of Liver Diseases
(AASLD)
Oct 31-Nov 1 2008
San Francisco, CA Back
BMS-790052 is a First-in-class Potent Hepatitis C Virus (HCV) NS5A Inhibitor for Patients with Chronic HCV Infection: Results from a Proof-of-concept Study
Reported by Jules Levin
AASLD Nov 3 2008, San Francisco, CA
This morning was the Late Breaker HCV new drugs poster session, where new data for several new drugs were presented. This new class of drug, the BMS NS5A inhibitor, attracted quite a lot of discussion because of it potent viral load reduction of -3.6 logs, after one dose in 48 hours. This is the first data publicly reported and obviously it is very early. Also presented was the Tibotec protease inhibitor TMC435, the new Pfizer NNRTI, Roche/Pharmasset's R7128, Anadys' NNRTI, Schering's HCV protease inhibitor boceprevir data, and a few others. The Pfizer drug and the Tibotec drug looked potent and promising. Merck wil be presenting this afternoon early patient data from their HCV protease inhibitor. And tomorrow Vertex's telaprevir data, Boerhinger Ingleheim's protease inhibitor, and several others interesting and promising new drug data will be reported.
AUTHOR CONCLUSIONS
BMS-790052 is a potent NS5A inhibitor that:
- was safe and well tolerated in single doses up to 100 mg
- has a PK profile that potentially supports once-daily dosing
- produced a robust decline in HCV RNA (-3.6 logs after 48 hours from a single 100 mg) dosefollowing a single dose in patients chronically infected with HCV genotype 1
Multiple ascending dose trials are ongoing
Richard E Nettles1, Caly Chien1, Ellen Chung1, Anna Persson1, Min Gao1, Makonen Belema1, Nicholas Meanwell1, Michael DeMicco2, Thomas Marbury3, Ronald Goldwater4, Patrick G Northup5, John Coumbis1, Walter K Kraft6, Michael Charlton7, Juan Carlos Lopez-Talavera1, Dennis M Grasela1 1Bristol-Myers Squibb, Research and Development, Princeton, NJ; 2Advanced Clinical Research Institute, Anaheim, CA; 3Orlando Clinical Research Center, Orlando, FL; 4PAREXEL International, Baltimore, MD; 5University of Virginia, Charlottesville, VA; 6Thomas Jefferson University, Philadelphia, PA; 7Mayo Clinic, Rochester, MN
BACKGROUND
NS5A is an essential component of the hepatitis C virus (HCV) replication complex
BMS-790052 is a first-in-class, highly selective, oral HCV NS5A inhibitor
BMS-790052 has broad genotype coverage and exhibits picomolar in vitro potency against genotypes 1a and 1b
BMS-790052 has additive to synergistic effects in combination with interferon and other HCV inhibitors in vitro
In a single ascending dose study in healthy non-HCV infected patients
(Protocol AI444-001), BMS-790052:
- was safe and well tolerated
- had a pharmacokinetic (PK) profile suggesting the possibility of once-daily dosing
METHODS
Study Design
⋅ Double-blind, placebo-controlled, single ascending dose study
⋅ Patients were randomized to receive 1, 10 or 100 mg of BMS-790052 or placebo
- Six patients per dose (active:placebo=5:1)
⋅ Enrollment criteria
- Male or female
- 18 to 49 years of age
- HCV genotype 1
- Treatment naïve or experienced
- Body mass index (BMI) of 18-35 kg/m2
- HCV RNA ≥105 IU/mL at screening
- Documented FibroTestTM score of ≦0.59 and AST to platelet ratio index (APRI) ≦2
-- Non-cirrhotic compensated liver disease
Study Objectives
Primary
- To assess the safety and tolerability of a single oral dose of 1, 10 and 100 mg of BMS-790052 in patients with chronic genotype 1 HCV infection
Secondary
- To assess the single-dose PK of BMS-790052
- To assess the effect of a single dose of BMS-790052 on plasma HCV RNA dynamics
Study Assessments
⋅ Safety and tolerability
- Assessed by physical examination, vital sign measurements, ECGs, clinical laboratory tests and adverse event (AE) reporting
⋅ Bioanalytical methods
- LC/MS/MS (tandem mass spectrometry)
- LLOQ=0.05 ng/mL for BMS-790052
- QC deviations within +/- 15% for BMS-790052
⋅ PK analysis
- PK parameters were calculated by non-compartmental analysis using Kinetica ⋅ HCV RNA was measured with the Roche COBAS® TaqMan® HCV Test, v2.0
- LLOQ=25 IU/mL
⋅ Statistical analysis
- PK parameters and changes in HCV RNA from baseline (in log10 IU/mL) were calculated and summarized by dose (baseline HCV RNA defined as log10 IU/mL prior to dosing)
RESULTS
⋅ Eighteen patients were randomized into the study
- One patient randomized to the placebo arm received active drug (1 mg) due to a dosing error
- One patient in the 10 mg cohort withdrew from the study 8 hours after study drug administration due to personal, non-drug related reasons
Safety
⋅ There were no serious adverse events (SAEs) or AE-related study discontinuations
⋅ There were 15 AEs in total
- Headache was the most common AE (n=4)
⋅ Incidence was not dose-related
- No other AE occurred in more than one patient
- All AEs were mild except for one event of moderate headache that began prior to receipt of BMS-790052 and deemed as unrelated by the Principal Investigator ⋅ No clinically relevant impact on vital signs, physical examinations, ECGs or laboratory tests
⋅ Single doses of 1, 10 and 100 mg of BMS-790052 were generally safe, well tolerated and had a safety profile similar to that of placebo
Pharmacokinetics
(grey circles) Normal healthy volunteer (NHV) (blue circles) HCV-infected patient (HCV) Following oral administration in HCV-infected patients, BMS-790052:
- was readily absorbed
- exhibited more than dose-proportional increases in exposures over the dose range of 1 to 100 mg
- produced exposures comparable to those observed in a previous study in healthy volunteers (Protocol AI444-001)
-- had C24 above the protein binding-adjusted (PBA) EC90 derived in replicon for both genotypes 1a and 1b at doses ≥1 mg
⋅ Mean decline in HCV RNA 24 hours after a single dose of BMS-790052 was:
- 1.8 log10 IU/mL (range 0.18-3.0 log10) for 1 mg
- 3.2 log10 IU/mL (range 2.9-4.0 log10) for 10 mg
- 3.3 log10 IU/mL (range 2.7-3.6 log10) for 100 mg
⋅ The 100 mg dose of BMS-790052 resulted in a mean decline in HCV RNA of 3.6 log10 IU/mL (range 3.0-4.1 log10 IU/mL) observed at 48 hours after dosing, which was maintained at 144 hours
⋅ All active drug recipients had at least a 0.5 log10 decrease from baseline HCV RNA
⋅ Eight of 16 (50%) active drug recipients achieved at least a 3 log10 IU/mL decrease in HCV RNA
⋅ One active drug recipient achieved HCV RNA
for the Study of Liver Diseases
(AASLD)
Oct 31-Nov 1 2008
San Francisco, CA Back
BMS-790052 is a First-in-class Potent Hepatitis C Virus (HCV) NS5A Inhibitor for Patients with Chronic HCV Infection: Results from a Proof-of-concept Study
Reported by Jules Levin
AASLD Nov 3 2008, San Francisco, CA
This morning was the Late Breaker HCV new drugs poster session, where new data for several new drugs were presented. This new class of drug, the BMS NS5A inhibitor, attracted quite a lot of discussion because of it potent viral load reduction of -3.6 logs, after one dose in 48 hours. This is the first data publicly reported and obviously it is very early. Also presented was the Tibotec protease inhibitor TMC435, the new Pfizer NNRTI, Roche/Pharmasset's R7128, Anadys' NNRTI, Schering's HCV protease inhibitor boceprevir data, and a few others. The Pfizer drug and the Tibotec drug looked potent and promising. Merck wil be presenting this afternoon early patient data from their HCV protease inhibitor. And tomorrow Vertex's telaprevir data, Boerhinger Ingleheim's protease inhibitor, and several others interesting and promising new drug data will be reported.
AUTHOR CONCLUSIONS
BMS-790052 is a potent NS5A inhibitor that:
- was safe and well tolerated in single doses up to 100 mg
- has a PK profile that potentially supports once-daily dosing
- produced a robust decline in HCV RNA (-3.6 logs after 48 hours from a single 100 mg) dosefollowing a single dose in patients chronically infected with HCV genotype 1
Multiple ascending dose trials are ongoing
Richard E Nettles1, Caly Chien1, Ellen Chung1, Anna Persson1, Min Gao1, Makonen Belema1, Nicholas Meanwell1, Michael DeMicco2, Thomas Marbury3, Ronald Goldwater4, Patrick G Northup5, John Coumbis1, Walter K Kraft6, Michael Charlton7, Juan Carlos Lopez-Talavera1, Dennis M Grasela1 1Bristol-Myers Squibb, Research and Development, Princeton, NJ; 2Advanced Clinical Research Institute, Anaheim, CA; 3Orlando Clinical Research Center, Orlando, FL; 4PAREXEL International, Baltimore, MD; 5University of Virginia, Charlottesville, VA; 6Thomas Jefferson University, Philadelphia, PA; 7Mayo Clinic, Rochester, MN
BACKGROUND
NS5A is an essential component of the hepatitis C virus (HCV) replication complex
BMS-790052 is a first-in-class, highly selective, oral HCV NS5A inhibitor
BMS-790052 has broad genotype coverage and exhibits picomolar in vitro potency against genotypes 1a and 1b
BMS-790052 has additive to synergistic effects in combination with interferon and other HCV inhibitors in vitro
In a single ascending dose study in healthy non-HCV infected patients
(Protocol AI444-001), BMS-790052:
- was safe and well tolerated
- had a pharmacokinetic (PK) profile suggesting the possibility of once-daily dosing
METHODS
Study Design
⋅ Double-blind, placebo-controlled, single ascending dose study
⋅ Patients were randomized to receive 1, 10 or 100 mg of BMS-790052 or placebo
- Six patients per dose (active:placebo=5:1)
⋅ Enrollment criteria
- Male or female
- 18 to 49 years of age
- HCV genotype 1
- Treatment naïve or experienced
- Body mass index (BMI) of 18-35 kg/m2
- HCV RNA ≥105 IU/mL at screening
- Documented FibroTestTM score of ≦0.59 and AST to platelet ratio index (APRI) ≦2
-- Non-cirrhotic compensated liver disease
Study Objectives
Primary
- To assess the safety and tolerability of a single oral dose of 1, 10 and 100 mg of BMS-790052 in patients with chronic genotype 1 HCV infection
Secondary
- To assess the single-dose PK of BMS-790052
- To assess the effect of a single dose of BMS-790052 on plasma HCV RNA dynamics
Study Assessments
⋅ Safety and tolerability
- Assessed by physical examination, vital sign measurements, ECGs, clinical laboratory tests and adverse event (AE) reporting
⋅ Bioanalytical methods
- LC/MS/MS (tandem mass spectrometry)
- LLOQ=0.05 ng/mL for BMS-790052
- QC deviations within +/- 15% for BMS-790052
⋅ PK analysis
- PK parameters were calculated by non-compartmental analysis using Kinetica ⋅ HCV RNA was measured with the Roche COBAS® TaqMan® HCV Test, v2.0
- LLOQ=25 IU/mL
⋅ Statistical analysis
- PK parameters and changes in HCV RNA from baseline (in log10 IU/mL) were calculated and summarized by dose (baseline HCV RNA defined as log10 IU/mL prior to dosing)
RESULTS
⋅ Eighteen patients were randomized into the study
- One patient randomized to the placebo arm received active drug (1 mg) due to a dosing error
- One patient in the 10 mg cohort withdrew from the study 8 hours after study drug administration due to personal, non-drug related reasons
Safety
⋅ There were no serious adverse events (SAEs) or AE-related study discontinuations
⋅ There were 15 AEs in total
- Headache was the most common AE (n=4)
⋅ Incidence was not dose-related
- No other AE occurred in more than one patient
- All AEs were mild except for one event of moderate headache that began prior to receipt of BMS-790052 and deemed as unrelated by the Principal Investigator ⋅ No clinically relevant impact on vital signs, physical examinations, ECGs or laboratory tests
⋅ Single doses of 1, 10 and 100 mg of BMS-790052 were generally safe, well tolerated and had a safety profile similar to that of placebo
Pharmacokinetics
(grey circles) Normal healthy volunteer (NHV) (blue circles) HCV-infected patient (HCV) Following oral administration in HCV-infected patients, BMS-790052:
- was readily absorbed
- exhibited more than dose-proportional increases in exposures over the dose range of 1 to 100 mg
- produced exposures comparable to those observed in a previous study in healthy volunteers (Protocol AI444-001)
-- had C24 above the protein binding-adjusted (PBA) EC90 derived in replicon for both genotypes 1a and 1b at doses ≥1 mg
⋅ Mean decline in HCV RNA 24 hours after a single dose of BMS-790052 was:
- 1.8 log10 IU/mL (range 0.18-3.0 log10) for 1 mg
- 3.2 log10 IU/mL (range 2.9-4.0 log10) for 10 mg
- 3.3 log10 IU/mL (range 2.7-3.6 log10) for 100 mg
⋅ The 100 mg dose of BMS-790052 resulted in a mean decline in HCV RNA of 3.6 log10 IU/mL (range 3.0-4.1 log10 IU/mL) observed at 48 hours after dosing, which was maintained at 144 hours
⋅ All active drug recipients had at least a 0.5 log10 decrease from baseline HCV RNA
⋅ Eight of 16 (50%) active drug recipients achieved at least a 3 log10 IU/mL decrease in HCV RNA
⋅ One active drug recipient achieved HCV RNA
"Using a new palette of treatment options for HCV
"Using a new palette of treatment options to paint the portrait of cure for patients infected with hepatitis C on our clinical canvas."
EASL 2009 Copenhagen April 23-26 2009
Robert Gish MD
CPMC- Department of transplantation and Division of Hepatology and Complex GI, California Pacific Medical Center, San Francisco, CA
INTRODUCTION: Current treatment of hepatitis C is both exciting and fraught with frustrations. The current cure rate, after a course of pegylated interferon therapy, is between 40 and 90% and is dependent on many factors, including hepatitis C virus (HCV) genotype, treatment tolerance, the use of full doses of pegylated interferon and optimal doses of ribavirin, as well as completion of treatment with full adherence and compliance with the recommended treatment instructions as per treatment guidelines. Key factors in predicting who will have further on-treatment response and who will ultimately obtain a sustained viral response (SVR) include baseline viral load, and the level of fibrosis prior to therapy, as well as on-treatment viral response at 4 weeks. Currently, we comfortably use the phrase “SVR” synonymously with a cure in most patients, recognizing that there are a few manuscripts in the literature where this question of "cure" is being further investigated. Importantly, most clinicians, practitioners and researchers believe that most patients with this RNA virus, which does not integrate into the host genome, is capable of being cleared from all compartments of infection within the human body.
EASL 2009: The recent meeting in Copenhagen was blessed with clear skies, favorable weather, and blooming trees and flowers as well as a panoply of new therapeutic options that were either entering the pre-clinical stage or phase I, II or III trials for hepatitis C. The purpose of this review is to place the general groups of new treatment options into perspective and discuss specific new therapies as well as to place these emerging treatments into a structure where we can map out how to manage your patients over the next 3-5 years. We also, hopefully, can communicate to our colleagues and patients that there is substantial hope for increasing cure rates, providing a shorter duration of therapy, or both with only a modest (if any) increase in toxicity, side effects or complexity of care. We are currently hearing the song “Should I stay or should I go” with the revised lyrics “Should I stay on course and plan on immediate therapy or should I delay treatment and wait for future treatment options that may evolve in the next 2-5 years?”. Clearly, for some patients, treatment will eventually progress toward both interferon- and ribavirin-free therapy. I do believe, however, as do most clinical investigators, that interferon will be here for the short and intermediate term, although we may be able to bring about incremental dose reductions in interferon and ribavirin as powerful new targeted therapies enter our armamentarium. Each day in the clinic, we are having dialogue with both our patients and our colleagues regarding whether we should "warehouse the patient” pending emergence of these new treatment options, or should instead treat in the near term and then assess treatment responses at 4 weeks (or less) in order to determine whether to terminate therapy or to continue. This rapid virological response (RVR) rule allows us to accurately select many patients who can obtain a substantial chance at SVR. Bringing this treatment rule into a new perspective was a paper by Holland that measured virus at 48 hours to predict RVR. Motivated patients with advanced disease (stage 3-6 by Ishak fibrosis score) and no evidence of liver decompensation clearly form a subset of patients who will be more interested in initiating therapy immediately with the current standard of care. When offered very early stopping rules, patients often gain even further motivation based on their understanding that they will not be faced with 24 or 48 weeks of therapy that may end up being futile. This early response rule provides an immediate motivation to start therapy for many patients. Conversely, we have been offering slow responders to therapy the option to continue therapy for as long as 72 weeks in order to increase cure rates, based on multiple past publications. An important paper by Buti, et. al., at this meeting demonstrated that prolonged therapy to 72 weeks did not result in an increased SVR rate and brought into question whether we should be continuing therapy for 72 weeks, even in patients who have mid to late on-treatment response. Also, from the EPIC 3 study, presented by Bruix et al, we gained further confirmation (complementing the HALT- C study) that maintenance therapy has minimal or no role in treating patients in general who are non-responders.
NEW SMALL MOLECULES:
As was highlighted at this meeting by NATAP, there are over 25 STAT-C medications in clinical development. The two small molecules in the STAT-C group that are likely to reach clinical practice by 2011 are telaprevir (Vertex) and boceprevir (Schering-Plough). The next group of protease inhibitors includes the compound R7227 (also known as ITMN-191) which Roche is developing with InterMune. Further adding to the Roche armamentarium is the nucleoside polymerase inhibitor R7128 which is being developed with Pharmasset. In the late breaker session at EASL, Gane et al presented results of the phase I study INFORM-1, showing that the combination of these two oral medications (the protease R7227 with the polymerase nucleoside R7128) resulted in significant HCV viral load reduction. This was an important proof-of-concept study, showing at least short-term efficacy and safety with an exclusively oral combination.
[Gane EJ, Roberts SK, Stedman C, et al. First-in-man demonstration of potent antiviral activity with a nucleoside polymerase (R7128) and protease (R7227/ITMN-191) inhibitor combination in HCV: safety, pharmacokinetics, and virologic results from INFORM-1. 44th Annual Meeting of the European Association for the Study of the Liver (EASL 2009). Copenhagen, Denmark. April 22-26, 2009. Late-breaker Abstract 1046.]
If other compounds, such as PSI 7851, Pharmasset?s second generation nucleotide polymerase inhibitor, could be brought forth early and quickly, as well, we will have even more options by 2014 or sooner. Additional protease compounds such as Merck?s MK-7009, Boehringer Ingelheim?s BI 201355, and Schering-Plough?s SCH 900518 all showed substantial possibilities of therapeutic benefit in either animal models or early phase I studies. Abbott and Enanta are moving towards a model of once-a-day therapy, as is the current standard for HIV treatment, with their protease inhibitors EA-058 and EA-063. Tibotec?s TMC435 is in early study in patients and is also once-daily.
Additional polymerase NRTI/NNRTI inhibitors are in development by a number of companies, including Pfizer, Idenix, Anadys, Vertex/ViroChem, ViroPharma/Wyeth, Boehringer Ingelheim, Merck, GeneLabs/GSK, and Gilead, using either every 12 or every 24 hour dosing, with what appears in early development to be more favorable side effects profiles with less resistance and predictors of non-overlapping resistance profiles.
Advances in immunomodulation include a series of new compounds that are being looked at that enhance one or more components of the human immune response that targets HCV infection. These new compounds have the potential for similar or improved side effect profiles and less frequent dosing. These molecules include pegylated lambda interferon, a controlled release interferon (Locteron), and an interferon variant, albinterferon alfa-2b (Albuferon), a genetic fusion polypeptide of albumin and interferon alfa-2b. Albuferon has completed large phase III studies, known as ACHIEVE 1 and ACHIEVE 2/3, in which albinterferon alfa-2b given every two weeks was compared to weekly peginterferon alfa-2a, both in combination with ribavirin. The data reported at EASL showed non-inferiority and similar adverse events with the two drugs, and submission for approval by the FDA is expected in the near term. Biolex Therapeutics? Locteron, a controlled-release interferon alpha 2b, has completed its phase 2a PLUS trial in which it was compared to PEG-Intron. Locteron was given on a once-every-two week dosing schedule compared to the once weekly schedule for PEG-Intron, with both drugs accompanied by ribavirin. The initial trial results reported at EASL showed comparable viral load suppression. Flu-like symptoms were reported to be less frequent and milder in patients receiving Locteron. ZymoGenetics reported results on its phase 1a trial with PEG-interferon lambda. Neither fever, fatigue, insomnia, irritability, injection site pain, nor significant hematologic changes, including neutropenia, were observed at any dose level tested. Reversible liver enzyme and bilirubin increases were noted at higher doses. There is ongoing research with other medications with immunomodulating effects, including nitazoxanide, IV silibinin (a silymarin derivative) and cyclophilin inhibitors, such as Debio 025, NIM811 and SCY-635. With further product improvement and teasing out key clinical information, these products may also enter into partnerships with STAT-C molecules and decrease or eliminate the need for interferon/ribavirin-based therapies. Importantly, if we can obtain profound suppression with minimal resistance with 2 oral STAT-C medications, these newer immunomodulatory medications may be able to arrive on the "scene" of the infected hepatocyte while also attacking in extrahepatic locations of replication or sanctuaries, thus performing a "mop-up" of viral infection and allowing high SVR rates. Hopefully, these compounds will ultimately allow us to clear virus in a great majority of patients, with a much lower impact on quality of life that will allow for high rates of full employment and maintenance of normal activities of daily living. Ribavirin and oral ribavirin analogues that allow increased exposure in the hepatocyte compartment would allow lower systemic blood levels and lower rates of anemia. Taribavirin is such a molecule and data at EASL demonstrated the potential role this medication may have in sparing patients anemia and possibly allowing for a beneficial partnership with STAT-C molecules. This may be particularly important for STAT-C molecules that demonstrated significant bone marrow suppression with anemia such as boceprevir.
Additional classes of medications include the Progenics? entry inhibitor PRO206 and Bristol-Myers Squibb?s BMS-790052, a first-in-class NS5A inhibitor. Such medications are going to potentially provide further enhancement of our arsenal of weapons to fight hepatitis C. Studies using various combinations of direct nucleoside polymerase inhibitors, non “nuke” polymerase inhibitors and other small molecules targeted at the HCV protease protein, both NS3 and NS3-4A, may lead to further exciting advances for managing our hepatitis C patients, hopefully, by 2015.
NATAP: EASL 44th Annual Meeting (European Association for the Study of the Liver)
April 22-26, 2009
Copenhagen, Denmark
REGULATORY ENVIRONMENT:
Within our new millennium of drug development, in the U.S. and worldwide, dialogue with regulatory authorities emphasizes an almost zero tolerance for risks with an emphasis on the highest possible safety level while still espousing the need for an accelerated approach to medication development. The potential for conflict between these two goals has led to a substantial level of drug development, including combination therapy, moving off shore. With 2 oral medications appearing to dominate the new concept of drug development for HCV, it is disappointing that all of these studies are being performed outside the U.S. The INFORM-1 study was an example of this new development and was probably the most exciting abstract presented at EASL in the clinical domain. As mentioned above, this study, in process in New Zealand, showed very high on-treatment response rates at two weeks using a protease and polymerase inhibitor as a pair without any interferon or ribavirin exposure.
The natural history of hepatitis C is a rainbow disease state that includes many individuals who never develop advanced disease in their lifetimes and thus, are never at risk of developing cirrhosis or cancer or of needing a liver transplant. There is a subset of these HCV-infected patients who are symptomatic based on the presence of circulating hepatitis C immune complexes or other inflammatory reactions. These HCV-related effects are difficult to quantify and documenting the association level between hepatitis C and somatic symptoms has been difficult and elusive. Thus, the impression that HCV treatment is non-urgent inhibits the energy at a regulatory level to support accelerated drug discovery, research and regulatory approval. Unfortunately, 40,000 people die of endstage liver disease each year in the US, with HCV being a major contributor to this mortality rate. Nearly 7,000 patients undergo costly liver transplants in the U.S. each year, with more than half of the adults receiving these transplants requiring them as the result of chronic hepatitis C infection. The current and predicted costs of HCV infection have been well documented in the medical literature. Rates of hepatitis C-induced cirrhosis and liver cancer are accelerating as the disease matures, and these patients are much more difficult to treat. The challenge in managing these patients includes a lower SVR rate, enhanced symptoms and enhanced toxicity. This is a very important group that should be at the forefront of activities and activism to signal the regulatory authorities that we are spending huge amounts of money on managing liver failure, liver transplants and liver cancer each year, much of which might be avoided with early and effective HCV treatment. In the near term, the cycle needs to be broken. Other special groups include African-Americans, who appear to have a lower response rate to interferon-based therapies, and hepatitis C/HIV coinfected individuals and other immunosuppressed individuals who also have a lower response rate to interferon/ribavirin therapy, with higher toxicity. Importantly, after liver transplant, more than half of patients have cirrhosis in 10 years. This is double the rate of cirrhosis in a non-transplant population and decreases the time period to develop cirrhosis by 50-80% because of the immunosuppressed setting and probable interactions with the allograft and host immune system. This is an urgent medical problem that should support accelerated drug development in the US to parallel other efforts worldwide.
A discussion about the U.S. hepatitis C burden also took place during the EASL meeting and looked at individuals who are infected and undiagnosed, diagnosed and untreated, actively being treated, and defined as treatment failures. Although many publications estimate the current infection rate in the U.S. as 5,000,000, this publication started with a much more conservative estimate of 2.7 million infected and then derived their model that identified that nearly 600,000 individuals have failed pegylated interferon/ribavirin treatment in the US patient population. This study by Jang and his colleagues at Johnson & Johnson highlighted that the reduction of infections by the introduction of STAT-C molecules would markedly decrease the incidence of new cases of chronic hepatitis C infection, as well as decrease the prevalence of current HCV disease, thus markedly decreasing the development of advanced liver disease incidence over time and ultimately culminating in a marked decrease in mortality. This data provides an even greater motivation for developing and rapidly bringing to market new therapies for hepatitis C.
The treatment boneyard
A variety of compounds including NM283, which was stopped due to GI toxicity and R1626, which was stopped due to bone marrow suppression, highlight the hazards of drug development. VX796 treatment was stopped due to the documented risk of hepatotoxicity, as was a Gilead polymerase compound that led to renal problems, identifying that there may be a variety of “class effects” for drug toxicity that may include bone marrow toxicity, renal toxicity, as well as GI problems that may present as pancreatitis, A variety of both new and known side effects are being identified in phase I and II studies with the new HCV compounds. These toxicities are concerns that will add additional complexities to managing our HCV patients over time. Hopefully, with appropriate clinical and pre-clinical homework, the graveyard for hepatitis C small molecules and other classes of compounds will remain relatively small, and the majority of medications will be able to reach our clinical practice within the next decade.
Back to the Future
Painting an exceptionally bright picture was easy for the field of HCV treatment as we place the many colors of treatment on our art easel. We hope to move from the current “still life” to an active 3 D movie where we can continue our “Battle for the Terra of HCV infections” I think that with all of these compounds in development, it behooves us to enhance the education of all of our colleagues who are managing hepatitis C in the liver disease space, because as we add new compounds, hepatitis C management will become ever more complex due to demands that arise from patient's concerns, from colleagues? fear of treatment toxicity and from the current safety-focused regulatory environment at the US FDA. An active educational process about new options in HCV treatment will enable us to retain the large number of hepatitis C “treaters” worldwide, including a large number of infectious disease experts and gastroenterologists. Conversely, focusing patient treatment in specialty liver centers has been proposed by a number of experts in the U.S. and worldwide. Challenges to such a specialty setting would be long travel times for many patients since they would have to be taken care of in a “face-to-face” clinic setting that might be a long distance from their homes. Whether there is actually a need for treatment of patients only by specialized individuals with extensive experience in managing hepatitis C and knowledge of the smorgasbord of new compounds remains to be proven. One major advantage of managing liver disease in such a specialty liver center would be to provide financial support by regulatory authorities and insurance companies as well as governmental insurance-run plans to pay for patients to be managed by video conferencing. In addition, an extensive amount of care could take place via email and telephone, with infrequent face-to-face visits. These clinic visits could be reserved for special adverse events and for patients requiring a special clinic setting. This new and innovative system would allow the distribution of liver disease expertise over broad regional areas while saving time, fuel and energy in this new green era where each of us is trying to enhance medical care but minimize our carbon footprint.
Robert Gish, M.D.
Medical Director
Liver Transplant Program
Robert Gish, M.D.
Medical Director
Liver Transplant Program
EASL 2009 Copenhagen April 23-26 2009
Robert Gish MD
CPMC- Department of transplantation and Division of Hepatology and Complex GI, California Pacific Medical Center, San Francisco, CA
INTRODUCTION: Current treatment of hepatitis C is both exciting and fraught with frustrations. The current cure rate, after a course of pegylated interferon therapy, is between 40 and 90% and is dependent on many factors, including hepatitis C virus (HCV) genotype, treatment tolerance, the use of full doses of pegylated interferon and optimal doses of ribavirin, as well as completion of treatment with full adherence and compliance with the recommended treatment instructions as per treatment guidelines. Key factors in predicting who will have further on-treatment response and who will ultimately obtain a sustained viral response (SVR) include baseline viral load, and the level of fibrosis prior to therapy, as well as on-treatment viral response at 4 weeks. Currently, we comfortably use the phrase “SVR” synonymously with a cure in most patients, recognizing that there are a few manuscripts in the literature where this question of "cure" is being further investigated. Importantly, most clinicians, practitioners and researchers believe that most patients with this RNA virus, which does not integrate into the host genome, is capable of being cleared from all compartments of infection within the human body.
EASL 2009: The recent meeting in Copenhagen was blessed with clear skies, favorable weather, and blooming trees and flowers as well as a panoply of new therapeutic options that were either entering the pre-clinical stage or phase I, II or III trials for hepatitis C. The purpose of this review is to place the general groups of new treatment options into perspective and discuss specific new therapies as well as to place these emerging treatments into a structure where we can map out how to manage your patients over the next 3-5 years. We also, hopefully, can communicate to our colleagues and patients that there is substantial hope for increasing cure rates, providing a shorter duration of therapy, or both with only a modest (if any) increase in toxicity, side effects or complexity of care. We are currently hearing the song “Should I stay or should I go” with the revised lyrics “Should I stay on course and plan on immediate therapy or should I delay treatment and wait for future treatment options that may evolve in the next 2-5 years?”. Clearly, for some patients, treatment will eventually progress toward both interferon- and ribavirin-free therapy. I do believe, however, as do most clinical investigators, that interferon will be here for the short and intermediate term, although we may be able to bring about incremental dose reductions in interferon and ribavirin as powerful new targeted therapies enter our armamentarium. Each day in the clinic, we are having dialogue with both our patients and our colleagues regarding whether we should "warehouse the patient” pending emergence of these new treatment options, or should instead treat in the near term and then assess treatment responses at 4 weeks (or less) in order to determine whether to terminate therapy or to continue. This rapid virological response (RVR) rule allows us to accurately select many patients who can obtain a substantial chance at SVR. Bringing this treatment rule into a new perspective was a paper by Holland that measured virus at 48 hours to predict RVR. Motivated patients with advanced disease (stage 3-6 by Ishak fibrosis score) and no evidence of liver decompensation clearly form a subset of patients who will be more interested in initiating therapy immediately with the current standard of care. When offered very early stopping rules, patients often gain even further motivation based on their understanding that they will not be faced with 24 or 48 weeks of therapy that may end up being futile. This early response rule provides an immediate motivation to start therapy for many patients. Conversely, we have been offering slow responders to therapy the option to continue therapy for as long as 72 weeks in order to increase cure rates, based on multiple past publications. An important paper by Buti, et. al., at this meeting demonstrated that prolonged therapy to 72 weeks did not result in an increased SVR rate and brought into question whether we should be continuing therapy for 72 weeks, even in patients who have mid to late on-treatment response. Also, from the EPIC 3 study, presented by Bruix et al, we gained further confirmation (complementing the HALT- C study) that maintenance therapy has minimal or no role in treating patients in general who are non-responders.
NEW SMALL MOLECULES:
As was highlighted at this meeting by NATAP, there are over 25 STAT-C medications in clinical development. The two small molecules in the STAT-C group that are likely to reach clinical practice by 2011 are telaprevir (Vertex) and boceprevir (Schering-Plough). The next group of protease inhibitors includes the compound R7227 (also known as ITMN-191) which Roche is developing with InterMune. Further adding to the Roche armamentarium is the nucleoside polymerase inhibitor R7128 which is being developed with Pharmasset. In the late breaker session at EASL, Gane et al presented results of the phase I study INFORM-1, showing that the combination of these two oral medications (the protease R7227 with the polymerase nucleoside R7128) resulted in significant HCV viral load reduction. This was an important proof-of-concept study, showing at least short-term efficacy and safety with an exclusively oral combination.
[Gane EJ, Roberts SK, Stedman C, et al. First-in-man demonstration of potent antiviral activity with a nucleoside polymerase (R7128) and protease (R7227/ITMN-191) inhibitor combination in HCV: safety, pharmacokinetics, and virologic results from INFORM-1. 44th Annual Meeting of the European Association for the Study of the Liver (EASL 2009). Copenhagen, Denmark. April 22-26, 2009. Late-breaker Abstract 1046.]
If other compounds, such as PSI 7851, Pharmasset?s second generation nucleotide polymerase inhibitor, could be brought forth early and quickly, as well, we will have even more options by 2014 or sooner. Additional protease compounds such as Merck?s MK-7009, Boehringer Ingelheim?s BI 201355, and Schering-Plough?s SCH 900518 all showed substantial possibilities of therapeutic benefit in either animal models or early phase I studies. Abbott and Enanta are moving towards a model of once-a-day therapy, as is the current standard for HIV treatment, with their protease inhibitors EA-058 and EA-063. Tibotec?s TMC435 is in early study in patients and is also once-daily.
Additional polymerase NRTI/NNRTI inhibitors are in development by a number of companies, including Pfizer, Idenix, Anadys, Vertex/ViroChem, ViroPharma/Wyeth, Boehringer Ingelheim, Merck, GeneLabs/GSK, and Gilead, using either every 12 or every 24 hour dosing, with what appears in early development to be more favorable side effects profiles with less resistance and predictors of non-overlapping resistance profiles.
Advances in immunomodulation include a series of new compounds that are being looked at that enhance one or more components of the human immune response that targets HCV infection. These new compounds have the potential for similar or improved side effect profiles and less frequent dosing. These molecules include pegylated lambda interferon, a controlled release interferon (Locteron), and an interferon variant, albinterferon alfa-2b (Albuferon), a genetic fusion polypeptide of albumin and interferon alfa-2b. Albuferon has completed large phase III studies, known as ACHIEVE 1 and ACHIEVE 2/3, in which albinterferon alfa-2b given every two weeks was compared to weekly peginterferon alfa-2a, both in combination with ribavirin. The data reported at EASL showed non-inferiority and similar adverse events with the two drugs, and submission for approval by the FDA is expected in the near term. Biolex Therapeutics? Locteron, a controlled-release interferon alpha 2b, has completed its phase 2a PLUS trial in which it was compared to PEG-Intron. Locteron was given on a once-every-two week dosing schedule compared to the once weekly schedule for PEG-Intron, with both drugs accompanied by ribavirin. The initial trial results reported at EASL showed comparable viral load suppression. Flu-like symptoms were reported to be less frequent and milder in patients receiving Locteron. ZymoGenetics reported results on its phase 1a trial with PEG-interferon lambda. Neither fever, fatigue, insomnia, irritability, injection site pain, nor significant hematologic changes, including neutropenia, were observed at any dose level tested. Reversible liver enzyme and bilirubin increases were noted at higher doses. There is ongoing research with other medications with immunomodulating effects, including nitazoxanide, IV silibinin (a silymarin derivative) and cyclophilin inhibitors, such as Debio 025, NIM811 and SCY-635. With further product improvement and teasing out key clinical information, these products may also enter into partnerships with STAT-C molecules and decrease or eliminate the need for interferon/ribavirin-based therapies. Importantly, if we can obtain profound suppression with minimal resistance with 2 oral STAT-C medications, these newer immunomodulatory medications may be able to arrive on the "scene" of the infected hepatocyte while also attacking in extrahepatic locations of replication or sanctuaries, thus performing a "mop-up" of viral infection and allowing high SVR rates. Hopefully, these compounds will ultimately allow us to clear virus in a great majority of patients, with a much lower impact on quality of life that will allow for high rates of full employment and maintenance of normal activities of daily living. Ribavirin and oral ribavirin analogues that allow increased exposure in the hepatocyte compartment would allow lower systemic blood levels and lower rates of anemia. Taribavirin is such a molecule and data at EASL demonstrated the potential role this medication may have in sparing patients anemia and possibly allowing for a beneficial partnership with STAT-C molecules. This may be particularly important for STAT-C molecules that demonstrated significant bone marrow suppression with anemia such as boceprevir.
Additional classes of medications include the Progenics? entry inhibitor PRO206 and Bristol-Myers Squibb?s BMS-790052, a first-in-class NS5A inhibitor. Such medications are going to potentially provide further enhancement of our arsenal of weapons to fight hepatitis C. Studies using various combinations of direct nucleoside polymerase inhibitors, non “nuke” polymerase inhibitors and other small molecules targeted at the HCV protease protein, both NS3 and NS3-4A, may lead to further exciting advances for managing our hepatitis C patients, hopefully, by 2015.
NATAP: EASL 44th Annual Meeting (European Association for the Study of the Liver)
April 22-26, 2009
Copenhagen, Denmark
REGULATORY ENVIRONMENT:
Within our new millennium of drug development, in the U.S. and worldwide, dialogue with regulatory authorities emphasizes an almost zero tolerance for risks with an emphasis on the highest possible safety level while still espousing the need for an accelerated approach to medication development. The potential for conflict between these two goals has led to a substantial level of drug development, including combination therapy, moving off shore. With 2 oral medications appearing to dominate the new concept of drug development for HCV, it is disappointing that all of these studies are being performed outside the U.S. The INFORM-1 study was an example of this new development and was probably the most exciting abstract presented at EASL in the clinical domain. As mentioned above, this study, in process in New Zealand, showed very high on-treatment response rates at two weeks using a protease and polymerase inhibitor as a pair without any interferon or ribavirin exposure.
The natural history of hepatitis C is a rainbow disease state that includes many individuals who never develop advanced disease in their lifetimes and thus, are never at risk of developing cirrhosis or cancer or of needing a liver transplant. There is a subset of these HCV-infected patients who are symptomatic based on the presence of circulating hepatitis C immune complexes or other inflammatory reactions. These HCV-related effects are difficult to quantify and documenting the association level between hepatitis C and somatic symptoms has been difficult and elusive. Thus, the impression that HCV treatment is non-urgent inhibits the energy at a regulatory level to support accelerated drug discovery, research and regulatory approval. Unfortunately, 40,000 people die of endstage liver disease each year in the US, with HCV being a major contributor to this mortality rate. Nearly 7,000 patients undergo costly liver transplants in the U.S. each year, with more than half of the adults receiving these transplants requiring them as the result of chronic hepatitis C infection. The current and predicted costs of HCV infection have been well documented in the medical literature. Rates of hepatitis C-induced cirrhosis and liver cancer are accelerating as the disease matures, and these patients are much more difficult to treat. The challenge in managing these patients includes a lower SVR rate, enhanced symptoms and enhanced toxicity. This is a very important group that should be at the forefront of activities and activism to signal the regulatory authorities that we are spending huge amounts of money on managing liver failure, liver transplants and liver cancer each year, much of which might be avoided with early and effective HCV treatment. In the near term, the cycle needs to be broken. Other special groups include African-Americans, who appear to have a lower response rate to interferon-based therapies, and hepatitis C/HIV coinfected individuals and other immunosuppressed individuals who also have a lower response rate to interferon/ribavirin therapy, with higher toxicity. Importantly, after liver transplant, more than half of patients have cirrhosis in 10 years. This is double the rate of cirrhosis in a non-transplant population and decreases the time period to develop cirrhosis by 50-80% because of the immunosuppressed setting and probable interactions with the allograft and host immune system. This is an urgent medical problem that should support accelerated drug development in the US to parallel other efforts worldwide.
A discussion about the U.S. hepatitis C burden also took place during the EASL meeting and looked at individuals who are infected and undiagnosed, diagnosed and untreated, actively being treated, and defined as treatment failures. Although many publications estimate the current infection rate in the U.S. as 5,000,000, this publication started with a much more conservative estimate of 2.7 million infected and then derived their model that identified that nearly 600,000 individuals have failed pegylated interferon/ribavirin treatment in the US patient population. This study by Jang and his colleagues at Johnson & Johnson highlighted that the reduction of infections by the introduction of STAT-C molecules would markedly decrease the incidence of new cases of chronic hepatitis C infection, as well as decrease the prevalence of current HCV disease, thus markedly decreasing the development of advanced liver disease incidence over time and ultimately culminating in a marked decrease in mortality. This data provides an even greater motivation for developing and rapidly bringing to market new therapies for hepatitis C.
The treatment boneyard
A variety of compounds including NM283, which was stopped due to GI toxicity and R1626, which was stopped due to bone marrow suppression, highlight the hazards of drug development. VX796 treatment was stopped due to the documented risk of hepatotoxicity, as was a Gilead polymerase compound that led to renal problems, identifying that there may be a variety of “class effects” for drug toxicity that may include bone marrow toxicity, renal toxicity, as well as GI problems that may present as pancreatitis, A variety of both new and known side effects are being identified in phase I and II studies with the new HCV compounds. These toxicities are concerns that will add additional complexities to managing our HCV patients over time. Hopefully, with appropriate clinical and pre-clinical homework, the graveyard for hepatitis C small molecules and other classes of compounds will remain relatively small, and the majority of medications will be able to reach our clinical practice within the next decade.
Back to the Future
Painting an exceptionally bright picture was easy for the field of HCV treatment as we place the many colors of treatment on our art easel. We hope to move from the current “still life” to an active 3 D movie where we can continue our “Battle for the Terra of HCV infections” I think that with all of these compounds in development, it behooves us to enhance the education of all of our colleagues who are managing hepatitis C in the liver disease space, because as we add new compounds, hepatitis C management will become ever more complex due to demands that arise from patient's concerns, from colleagues? fear of treatment toxicity and from the current safety-focused regulatory environment at the US FDA. An active educational process about new options in HCV treatment will enable us to retain the large number of hepatitis C “treaters” worldwide, including a large number of infectious disease experts and gastroenterologists. Conversely, focusing patient treatment in specialty liver centers has been proposed by a number of experts in the U.S. and worldwide. Challenges to such a specialty setting would be long travel times for many patients since they would have to be taken care of in a “face-to-face” clinic setting that might be a long distance from their homes. Whether there is actually a need for treatment of patients only by specialized individuals with extensive experience in managing hepatitis C and knowledge of the smorgasbord of new compounds remains to be proven. One major advantage of managing liver disease in such a specialty liver center would be to provide financial support by regulatory authorities and insurance companies as well as governmental insurance-run plans to pay for patients to be managed by video conferencing. In addition, an extensive amount of care could take place via email and telephone, with infrequent face-to-face visits. These clinic visits could be reserved for special adverse events and for patients requiring a special clinic setting. This new and innovative system would allow the distribution of liver disease expertise over broad regional areas while saving time, fuel and energy in this new green era where each of us is trying to enhance medical care but minimize our carbon footprint.
Robert Gish, M.D.
Medical Director
Liver Transplant Program
Robert Gish, M.D.
Medical Director
Liver Transplant Program
Safety, Tolerability, and Pharmacokinetic Data Following Single- and Multiple-Dose Administration of MK-7009
59th Annual Meeting of the American Association
for the Study of Liver Diseases
(AASLD)
Oct 31-Nov 1 2008
San Francisco, CA Back
Safety, Tolerability, and Pharmacokinetic Data Following Single- and Multiple-Dose Administration of MK-7009, a Hepatitis C Virus Non-structural 3/4a Protease Inhibitor, to Healthy Male Subjects (1910)
Reported by Jules Levin
AASLD Nov 4 2008
Duncan Hamish Wright, Jutta Miller, Ilse Verlinden, Caroline Cilissen, John Valentine, Peng Sun, Marina De Smet, Jan de Hoon, Marleen Depré, Luc Cavens, Jeffrey Chodakewitz, John Wagner
Whitehouse Station, NJ; Antwerp, Brussels and Leuven, Belgium
Copyright 2008 Merck & Co., Inc., Whitehouse Station, New Jersey, USA, All Rights Reserved.
Author Summary & Conclusion
Pharmacokinetics
SD
-- Plasma AUC0-∞ and Cmax values increase greater than dose proportionally.
-- Short apparent terminal half-life in plasma, averaging ~ 4-5 hours.
-- High-fat meal has no overall effect on plasma PK.
-- Renal excretion of unchanged drug plays a minimal role in the elimination of MK-7009 in man.
MD
-- Geometric mean accumulation ratios (GMR) of AUC0-12hr exposure (Day 14 vs. Day 1): ~1.66.
-- AUC0-12hr and Cmax both appear to increase greater than dose proportionally.
-- Steady state PK rapidly achieved by second b.i.d. dose in all panels.
Safety
-- Single doses of MK-7009 ≦1300 mg and multiple doses of MK-7009 ≦800 mg q.d. over 14 days were generally well tolerated.
-- AEs: mild to moderate in intensity; all resolved spontaneously.
Author Conclusions
MK-7009 is generally safe and well-tolerated when administered at single and multiple doses that correlate with plasma pharmacokinetics, which are multiples over the in vitro measured EC50s and the extrapolated EC90s derived from these data.
MK-7009 exhibits plasma pharmacokinetics which permit once or twice daily dosing.
This profile permits further clinical evaluation of MK-7009, including in HCV-infected patients.
ABSTRACT
Background:
MK-7009 is a rapidly reversible non-covalent competitive inhibitor of the nonstructural 3/4A protease of the hepatitis C virus.
It exhibits good inhibitory potency against genotypes 1 and 2 (replicon EC50 values = 17 and 7 nM for genotypes 1b and 2a, in the presence of 50% human serum and 10% fetal calf serum, respectively).
Initial studies were conducted to evaluate the safety, tolerability and pharmacokinetics following single-dose (SD) and multiple-dose (MD) administration of MK-7009 to healthy male subjects.
Methods:
SD: 16 healthy males received single doses of 10-825 mg MK-7009/placebo in the fasted state, with 80 mg single doses of MK-7009/placebo also evaluated in the fed state, in an alternating panel, multiple period, dose escalation study.
Single doses of 1000-1300 mg MK-7009/placebo were evaluated in the fasted state in a separate group of 16 healthy males.
MD: 40 healthy males received multiple doses of 100-800 mg MK-7009/ placebo for 14 days (once daily doses on days 1 and 14, twice daily doses on days 2-13) in a serial-panel study.
Clinical safety evaluations were performed throughout each study. Plasma and urine samples for MK-7009 pharmacokinetic data were collected.
Results:
There were no serious adverse experiences (AEs) reported, nor were there any discontinuations due to AEs.
Additionally, there were no dose-dependent patterns with respect to the frequency or the intensity of the AEs observed after SD and MD administration of MK-7009.
SD: Following oral administration, AUC0-∞ and Cmax values increased greater than dose proportionally. The apparent terminal half-life averaged ~ 4-5 h. SD administration of 80 mg of MK-7009 with a high-fat meal did not have a meaningful effect on plasma pharmacokinetics of MK-7009. Data suggest that renal excretion of unchanged drug plays a minimal role in the elimination of MK-7009 in man.
MD: Accumulation occurred over the 14-day period in all subjects, as evidenced by geometric mean ratios (Day 14/Day 1) for AUC0-12hr (1.5-1.8), Cmax (1.4-1.9) and C12hr (1.2-1.9). The apparent terminal half-lives stayed constant (~3.8-5.1 hours), regardless of dose, and were consistent with previously identified values collected after SD administration.
Conclusions:
MK-7009 is generally safe and well-tolerated, and exhibits plasma pharmacokinetics which permit once or twice daily dosing. This profile permits further clinical evaluation of MK-7009, including in HCV-infected patients.
Background - MK-7009
In vitro
-- Rapidly reversible non-covalent competitive inhibitor of hepatitis C virus (HCV) NS3/4A protease.
-- Sub-nM inhibitor of GT1a and 1b proteases, low nM potency against GT2a and 2b and potent activity in cell-based HCV replicon assay (GT1b & GT2a EC50s = 17 & 7 nM with 50% human serum & 10% fetal calf serum, respectively).
In vivo
-- Good plasma PK across preclinical species.
-- Liver concentrations maintained at a significant multiple of the cell-based replicon activity over 12-24 h following moderate oral doses (5-10 mg/kg) of MK-7009.
-- Dosing of MK-7009 (5 mg/kg, b.i.d) to a protease inhibitor naive GT1b chronically HCV-infected chimpanzee resulted in a highly significant 4.4 log10 drop in plasma viral load.
Based on this overall profile, MK-7009 was selected for clinical development.
Premise
SD
-- Evaluate safety and tolerability of single-rising oral doses of MK-7009 in healthy young male volunteers.
-- Obtain preliminary plasma PK (e.g., area under the plasma concentration versus time curve [(AUC0-∞)], maximum concentration of drug in the plasma [Cmax], plasma concentrations at 12 hours postdose [C12hr], time to reach Cmax [Tmax], and apparent terminal half-life[t1/2] of MK-7009 in the fasted state and following a standard high-fat meal.
-- Obtain preliminary data on urinary excretion of intact drug following administration of single oral doses of MK-7009.
MD
-- Evaluate safety and tolerability of MK-7009 administered for a 14 day period. -- Assess single-dose and steady-state plasma PK of MK-7009 (e.g., area under the plasma concentration versus time curve [AUC0-12hr, AUC0-24hr, and AUC0-∞ as appropriate on Day 1, and AUC0-12hr on Day 14], Cmax, trough concentration of drug in the plasma [Ctrough; C12hr after b.i.d. dosing], Tmax, T1/2 and accumulation ratio).
Methods
Study Design - Protocol 001 (PN001)
· Double-blind, placebo-controlled, alternating-panel, multiple-period, single-rising dose study in 16 healthy male volunteers.
· 2 panels (Panels A & B), 8 subjects (6 active/2 placebo), alternating rising single oral doses of MK-7009/placebo over 5 Periods.
· Panel A: 10, 40, 160, 350, and 825 mg MK-7009 or placebo.
· Panel B: 20, 80, 240, and 550 mg MK-7009 or placebo.
· Period 5, Panel B: 80 mg MK-7009 or placebo (identical assignment to that of Period 2 ) following a high-fat meal.
· Clinical safety evaluation (AEs, VS, ECG, laboratory safety) throughout the study.
· Plasma & urine samples for PK collected throughout the study.
Study Design - Protocol 002 (PN002) · Double-blind, randomized, placebo-controlled, staggered incremental dose study in 48 healthy male volunteers.
· 6 successive panels (Panels A, B, C, D, E and F), 8 subjects (6 active/2 placebo).
· Panels A, B, C & F (100, 200, 400 and 800 mg of MK-7009 or placebo): q.d. on Day 1 & Day 14, b.i.d. doses over 12 day MD period (Days 2-13).
· Panel D: 1200 mg SD MK-7009 or placebo, 7 day washout, 600 mg q.d. MK-7009 or placebo on Day 1 & Day 14, b.i.d. doses over 12 day MD period (Days 2-13).
· Panel E: 1000 mg SD MK-7009 or placebo, 7 day washout, 1300 mg SD MK 7009 or placebo, 7 day washout, 1300 mg SD MK-7009 or placebo.
· Clinical safety (AEs, VS, ECG, laboratory safety) evaluated and plasma & urine
samples for PK collected throughout the study.
No notable differences observed between treatment groups or between subjects who received active treatment versus placebo.
Safety & Tolerability - Blinded Assessment
PN001
PN001: 15 subjects reported 73 adverse experiences (AEs), 23 determined to be drug-related by the investigator.
Most common drug-related AE: headache.
PN002
PN001: 43 subjects reported 111 AEs, 70 drug-related.
Most common drug-related AEs: loose stools, headache, & stomach discomfort.
PN001 & PN002
All AEs resolved, no subjects discontinued due to an AE, no serious AEs.
No apparent relationship between dose of MK-7009 and frequency or intensity of any AE.
No consistent, clinically relevant, treatment- or dose-related effects of MK-7009 on ECGs, VS (blood pressure/heart rate) or laboratory safety tests.
for the Study of Liver Diseases
(AASLD)
Oct 31-Nov 1 2008
San Francisco, CA Back
Safety, Tolerability, and Pharmacokinetic Data Following Single- and Multiple-Dose Administration of MK-7009, a Hepatitis C Virus Non-structural 3/4a Protease Inhibitor, to Healthy Male Subjects (1910)
Reported by Jules Levin
AASLD Nov 4 2008
Duncan Hamish Wright, Jutta Miller, Ilse Verlinden, Caroline Cilissen, John Valentine, Peng Sun, Marina De Smet, Jan de Hoon, Marleen Depré, Luc Cavens, Jeffrey Chodakewitz, John Wagner
Whitehouse Station, NJ; Antwerp, Brussels and Leuven, Belgium
Copyright 2008 Merck & Co., Inc., Whitehouse Station, New Jersey, USA, All Rights Reserved.
Author Summary & Conclusion
Pharmacokinetics
SD
-- Plasma AUC0-∞ and Cmax values increase greater than dose proportionally.
-- Short apparent terminal half-life in plasma, averaging ~ 4-5 hours.
-- High-fat meal has no overall effect on plasma PK.
-- Renal excretion of unchanged drug plays a minimal role in the elimination of MK-7009 in man.
MD
-- Geometric mean accumulation ratios (GMR) of AUC0-12hr exposure (Day 14 vs. Day 1): ~1.66.
-- AUC0-12hr and Cmax both appear to increase greater than dose proportionally.
-- Steady state PK rapidly achieved by second b.i.d. dose in all panels.
Safety
-- Single doses of MK-7009 ≦1300 mg and multiple doses of MK-7009 ≦800 mg q.d. over 14 days were generally well tolerated.
-- AEs: mild to moderate in intensity; all resolved spontaneously.
Author Conclusions
MK-7009 is generally safe and well-tolerated when administered at single and multiple doses that correlate with plasma pharmacokinetics, which are multiples over the in vitro measured EC50s and the extrapolated EC90s derived from these data.
MK-7009 exhibits plasma pharmacokinetics which permit once or twice daily dosing.
This profile permits further clinical evaluation of MK-7009, including in HCV-infected patients.
ABSTRACT
Background:
MK-7009 is a rapidly reversible non-covalent competitive inhibitor of the nonstructural 3/4A protease of the hepatitis C virus.
It exhibits good inhibitory potency against genotypes 1 and 2 (replicon EC50 values = 17 and 7 nM for genotypes 1b and 2a, in the presence of 50% human serum and 10% fetal calf serum, respectively).
Initial studies were conducted to evaluate the safety, tolerability and pharmacokinetics following single-dose (SD) and multiple-dose (MD) administration of MK-7009 to healthy male subjects.
Methods:
SD: 16 healthy males received single doses of 10-825 mg MK-7009/placebo in the fasted state, with 80 mg single doses of MK-7009/placebo also evaluated in the fed state, in an alternating panel, multiple period, dose escalation study.
Single doses of 1000-1300 mg MK-7009/placebo were evaluated in the fasted state in a separate group of 16 healthy males.
MD: 40 healthy males received multiple doses of 100-800 mg MK-7009/ placebo for 14 days (once daily doses on days 1 and 14, twice daily doses on days 2-13) in a serial-panel study.
Clinical safety evaluations were performed throughout each study. Plasma and urine samples for MK-7009 pharmacokinetic data were collected.
Results:
There were no serious adverse experiences (AEs) reported, nor were there any discontinuations due to AEs.
Additionally, there were no dose-dependent patterns with respect to the frequency or the intensity of the AEs observed after SD and MD administration of MK-7009.
SD: Following oral administration, AUC0-∞ and Cmax values increased greater than dose proportionally. The apparent terminal half-life averaged ~ 4-5 h. SD administration of 80 mg of MK-7009 with a high-fat meal did not have a meaningful effect on plasma pharmacokinetics of MK-7009. Data suggest that renal excretion of unchanged drug plays a minimal role in the elimination of MK-7009 in man.
MD: Accumulation occurred over the 14-day period in all subjects, as evidenced by geometric mean ratios (Day 14/Day 1) for AUC0-12hr (1.5-1.8), Cmax (1.4-1.9) and C12hr (1.2-1.9). The apparent terminal half-lives stayed constant (~3.8-5.1 hours), regardless of dose, and were consistent with previously identified values collected after SD administration.
Conclusions:
MK-7009 is generally safe and well-tolerated, and exhibits plasma pharmacokinetics which permit once or twice daily dosing. This profile permits further clinical evaluation of MK-7009, including in HCV-infected patients.
Background - MK-7009
In vitro
-- Rapidly reversible non-covalent competitive inhibitor of hepatitis C virus (HCV) NS3/4A protease.
-- Sub-nM inhibitor of GT1a and 1b proteases, low nM potency against GT2a and 2b and potent activity in cell-based HCV replicon assay (GT1b & GT2a EC50s = 17 & 7 nM with 50% human serum & 10% fetal calf serum, respectively).
In vivo
-- Good plasma PK across preclinical species.
-- Liver concentrations maintained at a significant multiple of the cell-based replicon activity over 12-24 h following moderate oral doses (5-10 mg/kg) of MK-7009.
-- Dosing of MK-7009 (5 mg/kg, b.i.d) to a protease inhibitor naive GT1b chronically HCV-infected chimpanzee resulted in a highly significant 4.4 log10 drop in plasma viral load.
Based on this overall profile, MK-7009 was selected for clinical development.
Premise
SD
-- Evaluate safety and tolerability of single-rising oral doses of MK-7009 in healthy young male volunteers.
-- Obtain preliminary plasma PK (e.g., area under the plasma concentration versus time curve [(AUC0-∞)], maximum concentration of drug in the plasma [Cmax], plasma concentrations at 12 hours postdose [C12hr], time to reach Cmax [Tmax], and apparent terminal half-life[t1/2] of MK-7009 in the fasted state and following a standard high-fat meal.
-- Obtain preliminary data on urinary excretion of intact drug following administration of single oral doses of MK-7009.
MD
-- Evaluate safety and tolerability of MK-7009 administered for a 14 day period. -- Assess single-dose and steady-state plasma PK of MK-7009 (e.g., area under the plasma concentration versus time curve [AUC0-12hr, AUC0-24hr, and AUC0-∞ as appropriate on Day 1, and AUC0-12hr on Day 14], Cmax, trough concentration of drug in the plasma [Ctrough; C12hr after b.i.d. dosing], Tmax, T1/2 and accumulation ratio).
Methods
Study Design - Protocol 001 (PN001)
· Double-blind, placebo-controlled, alternating-panel, multiple-period, single-rising dose study in 16 healthy male volunteers.
· 2 panels (Panels A & B), 8 subjects (6 active/2 placebo), alternating rising single oral doses of MK-7009/placebo over 5 Periods.
· Panel A: 10, 40, 160, 350, and 825 mg MK-7009 or placebo.
· Panel B: 20, 80, 240, and 550 mg MK-7009 or placebo.
· Period 5, Panel B: 80 mg MK-7009 or placebo (identical assignment to that of Period 2 ) following a high-fat meal.
· Clinical safety evaluation (AEs, VS, ECG, laboratory safety) throughout the study.
· Plasma & urine samples for PK collected throughout the study.
Study Design - Protocol 002 (PN002) · Double-blind, randomized, placebo-controlled, staggered incremental dose study in 48 healthy male volunteers.
· 6 successive panels (Panels A, B, C, D, E and F), 8 subjects (6 active/2 placebo).
· Panels A, B, C & F (100, 200, 400 and 800 mg of MK-7009 or placebo): q.d. on Day 1 & Day 14, b.i.d. doses over 12 day MD period (Days 2-13).
· Panel D: 1200 mg SD MK-7009 or placebo, 7 day washout, 600 mg q.d. MK-7009 or placebo on Day 1 & Day 14, b.i.d. doses over 12 day MD period (Days 2-13).
· Panel E: 1000 mg SD MK-7009 or placebo, 7 day washout, 1300 mg SD MK 7009 or placebo, 7 day washout, 1300 mg SD MK-7009 or placebo.
· Clinical safety (AEs, VS, ECG, laboratory safety) evaluated and plasma & urine
samples for PK collected throughout the study.
No notable differences observed between treatment groups or between subjects who received active treatment versus placebo.
Safety & Tolerability - Blinded Assessment
PN001
PN001: 15 subjects reported 73 adverse experiences (AEs), 23 determined to be drug-related by the investigator.
Most common drug-related AE: headache.
PN002
PN001: 43 subjects reported 111 AEs, 70 drug-related.
Most common drug-related AEs: loose stools, headache, & stomach discomfort.
PN001 & PN002
All AEs resolved, no subjects discontinued due to an AE, no serious AEs.
No apparent relationship between dose of MK-7009 and frequency or intensity of any AE.
No consistent, clinically relevant, treatment- or dose-related effects of MK-7009 on ECGs, VS (blood pressure/heart rate) or laboratory safety tests.
Safety, Tolerability, and Pharmacokinetics after Single and Multiple Doses of MK-3281
Safety, Tolerability, and Pharmacokinetics after Single and Multiple Doses of MK-3281 in Healthy Subjects
EASL April 23-26 2009 Copenhagen Denmark
Reported by Jules Levin
D.M. Brainard,1 D. H. Wright,1 K. Sneddon,2 C.E. Cummings,2 P. Sun,1 J. Valentine,3 M.S. Anderson,1 S. Warrington,4 B. Sanderson,5 J.A. Chodakewitz,1 J.A. Wagner1 1Merck & Co., Inc., Whitehouse Station, NJ; 2Merck, Sharp & Dohme Ltd, Hoddesdon, England; 3Merck & Co., Inc., Whitehouse Station, NJ, - current address Bristol Myers Squibb, Princeton, NJ;4Hammersmith Medicines Research, London, England; and 5Chiltern (Early Phase) Limited, Dundee, Scotland
AUTHOR SUMMARY
Single Dose Pharmacokinetics
MMean AUC· 0-∞, Cmax and C12hr values appear to increase dose proportionally through 200 mg and less than dose proportionally at doses greater than 200 mg. PPeak plasma concentrations at ~3.0 hours. TTerminal half-life of ~16.5 hours. HHigh-fat meal has no clinically meaningful effect on pharmacokinetic parameters.
Multiple Dose Pharmacokinetics
DDay 10/Day 1 geometric mean accumulation ratios of AUC 0-12hr: 2.3 to 3.6, Cmax: 1.7 to 2.8.
AAUC 0-12hr, Cmax and C12hr appear to increase less than dose proportionally. SSteady state was achieved after 4-5 days regardless of dose.
Safety
Single doses of MK-3281 up to 2250 mg and multiple doses of MK-3281 up to 800 mg b.i.d. over 10 days were generally well tolerated.
AUTHOR CONCLUSIONS
MMK-3281 is generally well tolerated when administered as single and multiple doses.
MMK-3281 exhibits plasma pharmacokinetics which permit twice daily dosing.
This profile permits further clinical evaluation of MK-3281 including in Hepatitis C infected patients.
ABSTRACT
Background: MK-3281 is a novel non-nucleoside hepatitis C virus (HCV) polymerase inhibitor. MK-3281 has potent and selective in vitro activity against the genotype 1 hepatitis C virus (genotype 1b replicon assay, EC90 = 241 nM in 50% human serum). Pharmacokinetic (PK) and safety data were collected after single-dose (SD) and multiple-dose (MD) administration in healthy subjects.
Methods:
Single Dose: Alternating panel, multiple period, dose escalation study in 16 healthy males who received 25 to 2250 mg single doses of MK-3281 or placebo in the fed or fasted state.
Multiple Dose: Serial-panel study in 32 healthy males who received 100 to 800 mg MK-3281 or placebo q12 hr for 10 days.
Safety evaluations were performed throughout the studies. Plasma samples for MK-3281 concentration determination and pharmacokinetics were collected.
Results:
There were no serious adverse experiences (AEs) reported and no discontinuations due to adverse experiences.
Single Dose: Following oral administration, MK-3281 increased in plasma with median Tmax values of 2.5 - 3.5 hours. Thereafter, concentrations declined in a biphasic manner with mean terminal t· ~14.3 - 18.6 hours. Administration of 800 mg with a high-fat meal had no clinically meaningful effect on the pharmacokinetic parameters. Mean AUC0-∞, Cmax and C12hr values appeared to increase in a dose proportional fashion through 200 mg and in a less than dose proportional manner at doses greater than 200 mg.
Multiple Dose: Steady state was achieved after 4-5 days. Accumulation over the 10-day period occurred in all subjects for AUC0-12hr (geometric mean ratio (GMR) 2.3-3.6), Cmax (GMR 1.7-2.8) and C12hr (GMR 2.5 - 2.7). In general, AUC0-12hr, Cmax and C12hr appeared to increase less than dose proportionally on Day 1 and on Day 10. The apparent terminal half-life on Day 10 following multiple twice daily doses in the present study (e.g., ~17 hours) was consistent with values from the single dose study.
Conclusions: MK-3281 is generally well tolerated and exhibits a pharmacokinetic profile supportive of twice daily dosing.
BACKGROUND MK-3281
MK-3281 is a selective non-nucleoside inhibitor of HCV polymerase.
MK-3281 is a selective non-nucleoside inhibitor of HCV NS5B polymerase.
Potent in vitro activity against HCV genotypes 1 and 3. In cell-based genotype 1b replicon assay, the EC50 and EC90 in 50% human serum are 120 and 241 nM, respectively.
Approximate one log reduction in activity against viral isolates belonging to genotype 2.
Studies in HCV-infected humanized mice and chimpanzees have demonstrated preclinical in vivo efficacy of MK-3281.
MK-3281 is being developed as an antiviral drug for the treatment of chronic infection with HCV genotypes 1.
STUDY OBJECTIVES
Single Dose
Evaluate the safety and tolerability of single rising oral doses of MK-3281 in healthy young male volunteers.
Evaluate plasma PK profile of single doses of MK-3281 in the fasted state and following a high-fat meal. (e.g., AUC0-∞, Cmax, C12hr, Tmax, apparent t1/2).
Multiple Dose
Evaluate the safety and tolerability of MK-3281 orally administered twice-daily for a 10 day period in healthy young male volunteers.
Evaluate plasma PK profile of multiple doses of MK-· 3281 (e.g., AUC0-12hr, Cmax, C12hr, Tmax, apparent t1/2 and accumulation ratios).
STUDY DESIGN
Single Dose
- Double-blind, randomised, placebo-controlled, alternating panel, multiple-period, single rising dose study in 16 healthy male volunteers.
- 2 panels (A & B), 8 subjects per panel (6 active, 2 placebo), alternating rising single oral doses ofMK-3281/placebo over 5 periods.
- Identical assignment of MK-3281/placebo for panel B periods 2 and 4.
- Clinical safety evaluation (AEs, vital signs, ECG, laboratory safety) throughout the study.
- Plasma and urine samples for PK throughout the study.
Multiple Dose
- Double-blind, randomised, placebo-controlled, serial panel multiple rising dose study in 32 healthy male volunteers.
- 4 successive panels (A, B, C & D), 8 subjects per panel (6 active, 2 placebo).
- MK-3821 or placebo given b.i.d. (q12 hours) for 10 consecutive days (AM & PM) with AM dosing only on day 10.
- Clinical safety evaluation (AEs, vital signs, ECG, laboratory safety) throughout the study.
- Plasma and urine samples for PK throughout the study
Safety & Tolerability - Blinded Assessment
Single Dose
- 11 subjects reported 23 AEs, 10 considered drug related by the Investigator.
- Most common drug related AE: headache.
Multiple Dose
26 subjects reported 64 AEs, 8 considered drug related by the Investigator.
Most common drug related AEs: elevated ALT, muscle spasm.
Integrated Summary (Single and Multiple Dose)
- All AEs resolved, no subjects discontinued due to an AE, no serious AEs.
- No apparent relationship between dose of MK-3281 and frequency or intensity of any AE.
- No consistent, clinically relevant, treatment- or dose-related effects of MK-3281 on ECGs, vital signs or laboratory safety tests.
Single Dose Pharmacokinetics
EASL April 23-26 2009 Copenhagen Denmark
Reported by Jules Levin
D.M. Brainard,1 D. H. Wright,1 K. Sneddon,2 C.E. Cummings,2 P. Sun,1 J. Valentine,3 M.S. Anderson,1 S. Warrington,4 B. Sanderson,5 J.A. Chodakewitz,1 J.A. Wagner1 1Merck & Co., Inc., Whitehouse Station, NJ; 2Merck, Sharp & Dohme Ltd, Hoddesdon, England; 3Merck & Co., Inc., Whitehouse Station, NJ, - current address Bristol Myers Squibb, Princeton, NJ;4Hammersmith Medicines Research, London, England; and 5Chiltern (Early Phase) Limited, Dundee, Scotland
AUTHOR SUMMARY
Single Dose Pharmacokinetics
MMean AUC· 0-∞, Cmax and C12hr values appear to increase dose proportionally through 200 mg and less than dose proportionally at doses greater than 200 mg. PPeak plasma concentrations at ~3.0 hours. TTerminal half-life of ~16.5 hours. HHigh-fat meal has no clinically meaningful effect on pharmacokinetic parameters.
Multiple Dose Pharmacokinetics
DDay 10/Day 1 geometric mean accumulation ratios of AUC 0-12hr: 2.3 to 3.6, Cmax: 1.7 to 2.8.
AAUC 0-12hr, Cmax and C12hr appear to increase less than dose proportionally. SSteady state was achieved after 4-5 days regardless of dose.
Safety
Single doses of MK-3281 up to 2250 mg and multiple doses of MK-3281 up to 800 mg b.i.d. over 10 days were generally well tolerated.
AUTHOR CONCLUSIONS
MMK-3281 is generally well tolerated when administered as single and multiple doses.
MMK-3281 exhibits plasma pharmacokinetics which permit twice daily dosing.
This profile permits further clinical evaluation of MK-3281 including in Hepatitis C infected patients.
ABSTRACT
Background: MK-3281 is a novel non-nucleoside hepatitis C virus (HCV) polymerase inhibitor. MK-3281 has potent and selective in vitro activity against the genotype 1 hepatitis C virus (genotype 1b replicon assay, EC90 = 241 nM in 50% human serum). Pharmacokinetic (PK) and safety data were collected after single-dose (SD) and multiple-dose (MD) administration in healthy subjects.
Methods:
Single Dose: Alternating panel, multiple period, dose escalation study in 16 healthy males who received 25 to 2250 mg single doses of MK-3281 or placebo in the fed or fasted state.
Multiple Dose: Serial-panel study in 32 healthy males who received 100 to 800 mg MK-3281 or placebo q12 hr for 10 days.
Safety evaluations were performed throughout the studies. Plasma samples for MK-3281 concentration determination and pharmacokinetics were collected.
Results:
There were no serious adverse experiences (AEs) reported and no discontinuations due to adverse experiences.
Single Dose: Following oral administration, MK-3281 increased in plasma with median Tmax values of 2.5 - 3.5 hours. Thereafter, concentrations declined in a biphasic manner with mean terminal t· ~14.3 - 18.6 hours. Administration of 800 mg with a high-fat meal had no clinically meaningful effect on the pharmacokinetic parameters. Mean AUC0-∞, Cmax and C12hr values appeared to increase in a dose proportional fashion through 200 mg and in a less than dose proportional manner at doses greater than 200 mg.
Multiple Dose: Steady state was achieved after 4-5 days. Accumulation over the 10-day period occurred in all subjects for AUC0-12hr (geometric mean ratio (GMR) 2.3-3.6), Cmax (GMR 1.7-2.8) and C12hr (GMR 2.5 - 2.7). In general, AUC0-12hr, Cmax and C12hr appeared to increase less than dose proportionally on Day 1 and on Day 10. The apparent terminal half-life on Day 10 following multiple twice daily doses in the present study (e.g., ~17 hours) was consistent with values from the single dose study.
Conclusions: MK-3281 is generally well tolerated and exhibits a pharmacokinetic profile supportive of twice daily dosing.
BACKGROUND MK-3281
MK-3281 is a selective non-nucleoside inhibitor of HCV polymerase.
MK-3281 is a selective non-nucleoside inhibitor of HCV NS5B polymerase.
Potent in vitro activity against HCV genotypes 1 and 3. In cell-based genotype 1b replicon assay, the EC50 and EC90 in 50% human serum are 120 and 241 nM, respectively.
Approximate one log reduction in activity against viral isolates belonging to genotype 2.
Studies in HCV-infected humanized mice and chimpanzees have demonstrated preclinical in vivo efficacy of MK-3281.
MK-3281 is being developed as an antiviral drug for the treatment of chronic infection with HCV genotypes 1.
STUDY OBJECTIVES
Single Dose
Evaluate the safety and tolerability of single rising oral doses of MK-3281 in healthy young male volunteers.
Evaluate plasma PK profile of single doses of MK-3281 in the fasted state and following a high-fat meal. (e.g., AUC0-∞, Cmax, C12hr, Tmax, apparent t1/2).
Multiple Dose
Evaluate the safety and tolerability of MK-3281 orally administered twice-daily for a 10 day period in healthy young male volunteers.
Evaluate plasma PK profile of multiple doses of MK-· 3281 (e.g., AUC0-12hr, Cmax, C12hr, Tmax, apparent t1/2 and accumulation ratios).
STUDY DESIGN
Single Dose
- Double-blind, randomised, placebo-controlled, alternating panel, multiple-period, single rising dose study in 16 healthy male volunteers.
- 2 panels (A & B), 8 subjects per panel (6 active, 2 placebo), alternating rising single oral doses ofMK-3281/placebo over 5 periods.
- Identical assignment of MK-3281/placebo for panel B periods 2 and 4.
- Clinical safety evaluation (AEs, vital signs, ECG, laboratory safety) throughout the study.
- Plasma and urine samples for PK throughout the study.
Multiple Dose
- Double-blind, randomised, placebo-controlled, serial panel multiple rising dose study in 32 healthy male volunteers.
- 4 successive panels (A, B, C & D), 8 subjects per panel (6 active, 2 placebo).
- MK-3821 or placebo given b.i.d. (q12 hours) for 10 consecutive days (AM & PM) with AM dosing only on day 10.
- Clinical safety evaluation (AEs, vital signs, ECG, laboratory safety) throughout the study.
- Plasma and urine samples for PK throughout the study
Safety & Tolerability - Blinded Assessment
Single Dose
- 11 subjects reported 23 AEs, 10 considered drug related by the Investigator.
- Most common drug related AE: headache.
Multiple Dose
26 subjects reported 64 AEs, 8 considered drug related by the Investigator.
Most common drug related AEs: elevated ALT, muscle spasm.
Integrated Summary (Single and Multiple Dose)
- All AEs resolved, no subjects discontinued due to an AE, no serious AEs.
- No apparent relationship between dose of MK-3281 and frequency or intensity of any AE.
- No consistent, clinically relevant, treatment- or dose-related effects of MK-3281 on ECGs, vital signs or laboratory safety tests.
Single Dose Pharmacokinetics
MK-7009 Significantly Improves Rapid Viral Response (RVR)
MK-7009 Significantly Improves Rapid Viral Response (RVR) in Combination with Pegylated Interferon Alfa-2a and Ribavirinin Patients with Chronic Hepatitis C (CHC) Genotype 1 Infection
EASL April 23-26 2009 Copenhagen Denmark
Reported by Jules Levin
Michael P. Manns,1 Edward Gane,2 Maribel Rodriguez-Torres,3 Albrecht Stoehr,4 Chau-Ting Yeh,5 Richard T. Wiedmann,6 Peggy M. Hwang,7 Erin Quirk,6 Jeffrey Silber,6 and Andrew W. Lee6 1Medical School of Hannover, Hannover, Germany, 2Auckland Clinical Studies, Auckland, New Zealand, 3Fundacion de Investigacion de Diego, San Juan, and Ponce School of Medicine, Ponce, Puerto Rico, 4ifi-institute for interdisciplinary medicine, Hamburg, Germany,5Liver Research Unit, Chang Gung Medical Center, Taipei, Taiwan, 6ID/Vaccines Clinical Research, Merck Research Laboratories, West Point, PA, USA, 7Biostatistics, Merck Research Laboratories, West Point, PA, USA *for the MK-7009 Protocol 007 Study
Copyright 2009 Merck & Co., Inc. Whitehouse Station, NJ, USA All rights reserverd
AUTHOR SUMMARY
MK-7009 showed potent antiviral effect at all doses tested.
- Viral suppression maintained after MK-7009 dosing ended, through Day 42
- Similarly high rates of RVR in all MK-7009 treatment groups:
Dose-differentiation limited by small sample size·
MK-7009 was generally well-tolerated with no serious adverse events and no adverse events leading to discontinuation.
- Incidence of vomiting appears higher in 600 mg bid dose group: Most events were short duration, of mild intensity, and no anti-emetics were required·
These results support further development of MK-7009 as an anti-HCV treatment.
INTRODUCTION
The low rate of virologic cure [40-50% sustained virologic response (SVR) of genotype 1 HCV], long treatment duration (48 weeks), and significant side effects of pegylated interferon and ribavirin therapy highlight the pressing medical need for advancement in anti-HCV therapy.
MK-7009 is a non-covalent competitive inhibitor of HCV NS3/4A protease, with demonstrated safety and efficacy when administered as monotherapy for 8 days.
We now present the primary analysis from an ongoing Phase IIa study of MK-7009 for 28 · days in combination with pegylated-interferon and ribavirin (peg-IFN/RBV).
METHODS
Study Design
A randomized, placebo-controlled, double-blind study of MK-7009 in treatment-naive patients with chronic genotype 1 HCV infection.
MK-7009 was administered for 28 days with peg-IFN/RBV in 1 of 5 regimens: placebo, 300 mg bid, 600 bid, 600 mg qd, or 800 mg qd.
All patients continued peg-IFN/RBV for an additional 44 weeks.
The primary endpoint was the percent of subjects with viral suppression to below the lower limit of detection at day 28 (rapid viral response or RVR).
HCV RNA was measured by Roche Cobas Taqman which has a lower limit of detection (LLOD) of 10 IU/mL and a lower limit of quantification (LLOQ) of 25 IU/mL.
Primary hypotheses
RVR rates for at least 1 MK-7009-treated group superior to placebo.
Acceptable safety and tolerability of MK-7009 compared with placebo.
Patient Population
Key Inclusion Criteria:
- Chronic, compensated genotype 1 HCV infection
- HCV RNA ≥400,000 IU/mL at screening
- Treatment-naive
Key Exclusion Criteria:
- Non-HCV-related chronic hepatitis
- HIV co-infection
- Evidence of cirrhosis on liver biopsy or approved non-invasive imaging
- Any other condition contraindicated for treatment with peg-IFN/RBV
Data Analysis
Safety analysis based on the All-patients-as-treated population
Reasons for exclusion from Per-protocol (PP) population:
- Taking a restricted concomitant medicine
- Missing more than the allowed number of doses for MK-7009/ placebo, peg-IFN, or RBV
Statistical Definition of Superiority for RVR rates:
(Lower bound of 95% CI of [MK-7009 group RVR - placebo group --RVR]) >0
Protocol-defined Virologic Failure:
- Relapse: a >1 log increase from nadir at two consecutive --measurements, or HCV RNA >100 IU/mL on 2 measurements after LLOD
- Nonresponder: ≤2 log decrease through Day 28--
Because the study is ongoing, some data points are subject to change by the time the final study report is submitted
Viral Resistance: Population Sequencing of NS3/4A gene
- DNA Amplicons obtained at baseline and the indicated failure time points were purified and subjected to DNA-sequence analysis.
- For technical reasons, population sequence analysis could only be performed on patient samples with >1000 IU/mL HCV RNA.
Results
Patient Population
95 patients with no prior treatment for HCV infection were randomized to 1 of 5 groups [placebo and 4 dose groups of MK-7009 (Table 1)].
One patient withdrew consent after screening and did not receive any study therapy after randomization. This patient was excluded from all analyses.
Efficacy (Table 2)
RVR rates in MK-7009-containing arms ranged from 69% to 82% vs. 6% of the control (per-protocol population).
MK-709 RVR rates were similar for the full analysis set population (range, 71 to 83%).
All of the MK-7009 dose groups were superior to control (p<0.0001), satisfying the primary efficacy hypothesis.
Efficacy
Percent of Subjects LLOD and LLOQ (Figure 3):
Greater than 80% of subjects treated with MK-7009 (all doses) had viral suppression to below LLOD on Day 28.
Viral suppression continued after MK-7009 was stopped, with 77 to 94% of subjects below LLOD on Day 42.
100% of subjects in the 600 mg bid MK-7009 dose group were below LLOQ from Day 21 through 42.
Efficacy
Protocol-defined Virologic Failures (Figure 3)
- Through day 42, patients in 600 mg qd and 600 mg bid groups who met criteria failure (Methods) did not have sufficient level of HCV RNA to perform resistance analysis (<1000 IU/mL). As a result, no resistance mutations were detected.
- Virologic failure was observed in 300 mg bid and 800 mg qd groups, with detection of HCV mutations known to confer resistance to MK-7009.
- Current studies are focused on understanding the evolution of resistance via longitudinal analysis of patient samples throughout the MK-7009 dosing period.
- In addition, amplicons will be subjected to clonal analysis to identify possible linkage between the observed mutants (i.e., R155K and D168V).
Safety
NNo serious adverse events and no discontinuations due to an adverse event were observed during the first 42 days.
TThe most common adverse events reported were headache, nausea, fatigue, and influenza-like illness, which were reported at similar rates across all treatment groups, including placebo (Table 3).
TThe incidence of nausea and vomiting appeared to be higher in the MK-7009 treatment groups compared to placebo (Table 3).
NNo increase in rash adverse events over placebo were observed.
No clinically significant changes in ECGs were observed.
Summary of reported adverse experiences of vomiting (600 mg bid MK-7009)
DDay of onset: 1, 4, 5, 10, 16, 18, 20, 21.
DDuration: from 1d to 23d
44 out of 8 subjects had vomiting of 1 day or less in duration.
IIn 1 subject, vomiting routinely coincided with MK-7009 administration (Day 5 to --28)
VVomiting did not require anti-emetic treatment and did not lead to discontinuation, or dose reduction of MK-7009.
Laboratory trends over the treatment period showed:
DDecreasing and/or stable liver transaminase levels
Mean decreases in hemoglobin and absolute neutrophil count for MK-7009 groups similar to placebo
EASL April 23-26 2009 Copenhagen Denmark
Reported by Jules Levin
Michael P. Manns,1 Edward Gane,2 Maribel Rodriguez-Torres,3 Albrecht Stoehr,4 Chau-Ting Yeh,5 Richard T. Wiedmann,6 Peggy M. Hwang,7 Erin Quirk,6 Jeffrey Silber,6 and Andrew W. Lee6 1Medical School of Hannover, Hannover, Germany, 2Auckland Clinical Studies, Auckland, New Zealand, 3Fundacion de Investigacion de Diego, San Juan, and Ponce School of Medicine, Ponce, Puerto Rico, 4ifi-institute for interdisciplinary medicine, Hamburg, Germany,5Liver Research Unit, Chang Gung Medical Center, Taipei, Taiwan, 6ID/Vaccines Clinical Research, Merck Research Laboratories, West Point, PA, USA, 7Biostatistics, Merck Research Laboratories, West Point, PA, USA *for the MK-7009 Protocol 007 Study
Copyright 2009 Merck & Co., Inc. Whitehouse Station, NJ, USA All rights reserverd
AUTHOR SUMMARY
MK-7009 showed potent antiviral effect at all doses tested.
- Viral suppression maintained after MK-7009 dosing ended, through Day 42
- Similarly high rates of RVR in all MK-7009 treatment groups:
Dose-differentiation limited by small sample size·
MK-7009 was generally well-tolerated with no serious adverse events and no adverse events leading to discontinuation.
- Incidence of vomiting appears higher in 600 mg bid dose group: Most events were short duration, of mild intensity, and no anti-emetics were required·
These results support further development of MK-7009 as an anti-HCV treatment.
INTRODUCTION
The low rate of virologic cure [40-50% sustained virologic response (SVR) of genotype 1 HCV], long treatment duration (48 weeks), and significant side effects of pegylated interferon and ribavirin therapy highlight the pressing medical need for advancement in anti-HCV therapy.
MK-7009 is a non-covalent competitive inhibitor of HCV NS3/4A protease, with demonstrated safety and efficacy when administered as monotherapy for 8 days.
We now present the primary analysis from an ongoing Phase IIa study of MK-7009 for 28 · days in combination with pegylated-interferon and ribavirin (peg-IFN/RBV).
METHODS
Study Design
A randomized, placebo-controlled, double-blind study of MK-7009 in treatment-naive patients with chronic genotype 1 HCV infection.
MK-7009 was administered for 28 days with peg-IFN/RBV in 1 of 5 regimens: placebo, 300 mg bid, 600 bid, 600 mg qd, or 800 mg qd.
All patients continued peg-IFN/RBV for an additional 44 weeks.
The primary endpoint was the percent of subjects with viral suppression to below the lower limit of detection at day 28 (rapid viral response or RVR).
HCV RNA was measured by Roche Cobas Taqman which has a lower limit of detection (LLOD) of 10 IU/mL and a lower limit of quantification (LLOQ) of 25 IU/mL.
Primary hypotheses
RVR rates for at least 1 MK-7009-treated group superior to placebo.
Acceptable safety and tolerability of MK-7009 compared with placebo.
Patient Population
Key Inclusion Criteria:
- Chronic, compensated genotype 1 HCV infection
- HCV RNA ≥400,000 IU/mL at screening
- Treatment-naive
Key Exclusion Criteria:
- Non-HCV-related chronic hepatitis
- HIV co-infection
- Evidence of cirrhosis on liver biopsy or approved non-invasive imaging
- Any other condition contraindicated for treatment with peg-IFN/RBV
Data Analysis
Safety analysis based on the All-patients-as-treated population
Reasons for exclusion from Per-protocol (PP) population:
- Taking a restricted concomitant medicine
- Missing more than the allowed number of doses for MK-7009/ placebo, peg-IFN, or RBV
Statistical Definition of Superiority for RVR rates:
(Lower bound of 95% CI of [MK-7009 group RVR - placebo group --RVR]) >0
Protocol-defined Virologic Failure:
- Relapse: a >1 log increase from nadir at two consecutive --measurements, or HCV RNA >100 IU/mL on 2 measurements after LLOD
- Nonresponder: ≤2 log decrease through Day 28--
Because the study is ongoing, some data points are subject to change by the time the final study report is submitted
Viral Resistance: Population Sequencing of NS3/4A gene
- DNA Amplicons obtained at baseline and the indicated failure time points were purified and subjected to DNA-sequence analysis.
- For technical reasons, population sequence analysis could only be performed on patient samples with >1000 IU/mL HCV RNA.
Results
Patient Population
95 patients with no prior treatment for HCV infection were randomized to 1 of 5 groups [placebo and 4 dose groups of MK-7009 (Table 1)].
One patient withdrew consent after screening and did not receive any study therapy after randomization. This patient was excluded from all analyses.
Efficacy (Table 2)
RVR rates in MK-7009-containing arms ranged from 69% to 82% vs. 6% of the control (per-protocol population).
MK-709 RVR rates were similar for the full analysis set population (range, 71 to 83%).
All of the MK-7009 dose groups were superior to control (p<0.0001), satisfying the primary efficacy hypothesis.
Efficacy
Percent of Subjects LLOD and LLOQ (Figure 3):
Greater than 80% of subjects treated with MK-7009 (all doses) had viral suppression to below LLOD on Day 28.
Viral suppression continued after MK-7009 was stopped, with 77 to 94% of subjects below LLOD on Day 42.
100% of subjects in the 600 mg bid MK-7009 dose group were below LLOQ from Day 21 through 42.
Efficacy
Protocol-defined Virologic Failures (Figure 3)
- Through day 42, patients in 600 mg qd and 600 mg bid groups who met criteria failure (Methods) did not have sufficient level of HCV RNA to perform resistance analysis (<1000 IU/mL). As a result, no resistance mutations were detected.
- Virologic failure was observed in 300 mg bid and 800 mg qd groups, with detection of HCV mutations known to confer resistance to MK-7009.
- Current studies are focused on understanding the evolution of resistance via longitudinal analysis of patient samples throughout the MK-7009 dosing period.
- In addition, amplicons will be subjected to clonal analysis to identify possible linkage between the observed mutants (i.e., R155K and D168V).
Safety
NNo serious adverse events and no discontinuations due to an adverse event were observed during the first 42 days.
TThe most common adverse events reported were headache, nausea, fatigue, and influenza-like illness, which were reported at similar rates across all treatment groups, including placebo (Table 3).
TThe incidence of nausea and vomiting appeared to be higher in the MK-7009 treatment groups compared to placebo (Table 3).
NNo increase in rash adverse events over placebo were observed.
No clinically significant changes in ECGs were observed.
Summary of reported adverse experiences of vomiting (600 mg bid MK-7009)
DDay of onset: 1, 4, 5, 10, 16, 18, 20, 21.
DDuration: from 1d to 23d
44 out of 8 subjects had vomiting of 1 day or less in duration.
IIn 1 subject, vomiting routinely coincided with MK-7009 administration (Day 5 to --28)
VVomiting did not require anti-emetic treatment and did not lead to discontinuation, or dose reduction of MK-7009.
Laboratory trends over the treatment period showed:
DDecreasing and/or stable liver transaminase levels
Mean decreases in hemoglobin and absolute neutrophil count for MK-7009 groups similar to placebo
EASL Analysis, New Oral HCV Drugs What's Expected
EASL Analysis, New Oral HCV Drugs What's Expected
Reported by Jules Levin
I returned from Copenhagen on April 27 after enjoying a very exciting meeting and talking with many researchers about the development of the many promising new oral HCV drugs. There were about 25 new HCV drugs that new data was reported on at EASL in Copenhagen April 23-26 2009. The biggest story was the INFORM Study which is the first study of 2 oral HCV drugs in combination in patients, the study showed short-term efficacy/potency and safety for the combination of Roche's protease ITMN191 (R7227) and their polymerase NRTI R7128. This was the first proof of concept study for showing you can combine 2 oral HCV drugs, and the study importantly showed additive antiviral activity and safety. Of course further studies are planned to move this ahead. Of interest also was a poster on an early study of lambda interferon in patients which is a peginterferon that shows little or no interferon side effects. A major question is whether or not interferon and ribavirin can be eliminated from therapy. I have my doubts they can be and still achieve a 'cure' with time limited duration of therapy but many others are confident they can eliminate peg/RBV; many researchers and companies are planning the studies to answer this question, but if interferon is still needed at least for some patients a peginterferon like lambda without side effects would obviously be a tremendous breakthrough. Every major drug company has oral HCV drugs in development and presented data at EASL including Boerhinger who has a protease now in phase 2 & for the first time presented new data in patients on their polymerase inhibitor. Merck presented for the 2nd time on their protease this time in combination with peg/RBV with interesting and positive results, and for the first time presented new data on their polymerase. Tibotec presented 2 studies in naives and treatment-experienced patients on their once-a-day protease which looks potent. Of note, Schering presented for the first time their new protease, not boceprevir, that looks potent and will be boosted by ritonavir. Abbott has a comprehensive HCV drug program and they presented interesting preclinical data showing their protease to be potent and they had 2 posters on their 2 polymerase inhibitors. Of note there are 2 types of polymerase inhibitors, NNRTIs and NRTIs, and their are at least 2 types of NNRTIs. NNRTIs that can bind at different places may be able to be combined in a regimen and also along with a NRTI. At AASLD BMS presented their first data in patients on their NS5A inhibitor and it looked potent, and at this EASL Presidio, a biotech, presented preclinical data on their NS5A candidates. Of course as expected Vertex presented phase 2 data on telaprevir and Schering presented phase 2 data on boceprevir, and both of these proteases are now in phase 3 and expected to be ready for launch in mid 2011. Pfixer presented at EASL with a poster on their new HCV NNRTI filibuvir and it looks promising. HCV drug resistance appears to be of concern. With monotherapy drug resistance to the protease can emerge quickly, in 2 days. Combining peg/RBV with the protease can prevent resistance but if a patient develps viral failure, just like in HIV, drug resistance can emerge. In naives the results from phase 2 when using telaprevir+peg/RBV was about 65% SVR rate with 24 weeks therapy, in treatment-experienced prior nonresponders the SVR rate was 39% and this included both null and nonresponders. Also, 75% of prior relapsers and 57% of prior breakthroughs achieved SVR in phase 2 study. For boceprevir the data was 56% with 24 weeks with or without 4 week peg/RBV lead-in, and with 48 weeks 75% with 4 week lead-in and 67% without 4 week lead-in. So drug resistance is an important point to bear in mind as the proteases so far in development appear to be cross-resistant. So far there are no 2nd generation proteases that will be active against resistance like in HIV with for example darunavir. Researchers are looking for such proteases but they have not yet emerged. So be careful about acquiring drug resistance to a protease but it does appear as though other drugs will at some point in the future provide a regimen. For example, combining an NS5A inhibitor with 2 NNRTIs or an NNRTI+NRTI will be possibilities in the future. All in all, future therapy for HCV is promising for patients. After the expected launch in 2011 of telaprevir+peg/RBV and boceprevir+peg/RBV right behind that by perhaps 2 years will be Roche's 2 orals plus peg/RBV but the other companies are also developing their own multiple drug regimens and perhaps the companies will collaborate and do cross-company studies with their drugs. Vertex acquired ViroPharma's polymerase inhibitors and presented interesting data at EASL on VCH-222 which in early study showed a potent 3.7 log viral load reduction. So you can see we are headed towards regimens with 2, 3 and perhaps 4 oral HCV drugs in combination with peg/RBV and perhaps later without peg/RBV. With 2 orals plus peg/RBV I estimate 75-80% SVR rates and close to that for African-Americans and with 3 orals plus peg/RBV I estimate 85%-95% SVR rates for all including African-Americans. But to get to this point it will take some time. Briefly, regarding hepatitis B BMS reported entecavir resistance data out to 7 years and Gilead reported 2 years efficacy and resistance data on tenofovir and the data for both drugs looks good. The reports on all these presentations are linked to below and on the NATAP website. Jules Levin
Reported by Jules Levin
I returned from Copenhagen on April 27 after enjoying a very exciting meeting and talking with many researchers about the development of the many promising new oral HCV drugs. There were about 25 new HCV drugs that new data was reported on at EASL in Copenhagen April 23-26 2009. The biggest story was the INFORM Study which is the first study of 2 oral HCV drugs in combination in patients, the study showed short-term efficacy/potency and safety for the combination of Roche's protease ITMN191 (R7227) and their polymerase NRTI R7128. This was the first proof of concept study for showing you can combine 2 oral HCV drugs, and the study importantly showed additive antiviral activity and safety. Of course further studies are planned to move this ahead. Of interest also was a poster on an early study of lambda interferon in patients which is a peginterferon that shows little or no interferon side effects. A major question is whether or not interferon and ribavirin can be eliminated from therapy. I have my doubts they can be and still achieve a 'cure' with time limited duration of therapy but many others are confident they can eliminate peg/RBV; many researchers and companies are planning the studies to answer this question, but if interferon is still needed at least for some patients a peginterferon like lambda without side effects would obviously be a tremendous breakthrough. Every major drug company has oral HCV drugs in development and presented data at EASL including Boerhinger who has a protease now in phase 2 & for the first time presented new data in patients on their polymerase inhibitor. Merck presented for the 2nd time on their protease this time in combination with peg/RBV with interesting and positive results, and for the first time presented new data on their polymerase. Tibotec presented 2 studies in naives and treatment-experienced patients on their once-a-day protease which looks potent. Of note, Schering presented for the first time their new protease, not boceprevir, that looks potent and will be boosted by ritonavir. Abbott has a comprehensive HCV drug program and they presented interesting preclinical data showing their protease to be potent and they had 2 posters on their 2 polymerase inhibitors. Of note there are 2 types of polymerase inhibitors, NNRTIs and NRTIs, and their are at least 2 types of NNRTIs. NNRTIs that can bind at different places may be able to be combined in a regimen and also along with a NRTI. At AASLD BMS presented their first data in patients on their NS5A inhibitor and it looked potent, and at this EASL Presidio, a biotech, presented preclinical data on their NS5A candidates. Of course as expected Vertex presented phase 2 data on telaprevir and Schering presented phase 2 data on boceprevir, and both of these proteases are now in phase 3 and expected to be ready for launch in mid 2011. Pfixer presented at EASL with a poster on their new HCV NNRTI filibuvir and it looks promising. HCV drug resistance appears to be of concern. With monotherapy drug resistance to the protease can emerge quickly, in 2 days. Combining peg/RBV with the protease can prevent resistance but if a patient develps viral failure, just like in HIV, drug resistance can emerge. In naives the results from phase 2 when using telaprevir+peg/RBV was about 65% SVR rate with 24 weeks therapy, in treatment-experienced prior nonresponders the SVR rate was 39% and this included both null and nonresponders. Also, 75% of prior relapsers and 57% of prior breakthroughs achieved SVR in phase 2 study. For boceprevir the data was 56% with 24 weeks with or without 4 week peg/RBV lead-in, and with 48 weeks 75% with 4 week lead-in and 67% without 4 week lead-in. So drug resistance is an important point to bear in mind as the proteases so far in development appear to be cross-resistant. So far there are no 2nd generation proteases that will be active against resistance like in HIV with for example darunavir. Researchers are looking for such proteases but they have not yet emerged. So be careful about acquiring drug resistance to a protease but it does appear as though other drugs will at some point in the future provide a regimen. For example, combining an NS5A inhibitor with 2 NNRTIs or an NNRTI+NRTI will be possibilities in the future. All in all, future therapy for HCV is promising for patients. After the expected launch in 2011 of telaprevir+peg/RBV and boceprevir+peg/RBV right behind that by perhaps 2 years will be Roche's 2 orals plus peg/RBV but the other companies are also developing their own multiple drug regimens and perhaps the companies will collaborate and do cross-company studies with their drugs. Vertex acquired ViroPharma's polymerase inhibitors and presented interesting data at EASL on VCH-222 which in early study showed a potent 3.7 log viral load reduction. So you can see we are headed towards regimens with 2, 3 and perhaps 4 oral HCV drugs in combination with peg/RBV and perhaps later without peg/RBV. With 2 orals plus peg/RBV I estimate 75-80% SVR rates and close to that for African-Americans and with 3 orals plus peg/RBV I estimate 85%-95% SVR rates for all including African-Americans. But to get to this point it will take some time. Briefly, regarding hepatitis B BMS reported entecavir resistance data out to 7 years and Gilead reported 2 years efficacy and resistance data on tenofovir and the data for both drugs looks good. The reports on all these presentations are linked to below and on the NATAP website. Jules Levin
Antiviral activity and safety of TMC435
Antiviral activity and safety of TMC435 combined with peginterferon a-2a and ribavirin in patients with genotype-1 hepatitis C infection who failed previous IFN-based therapy
EASL April 23-26 2009 Copenhagen Denmark
Reported by Jules Levin
P. Marcellin,1 H. Reesink,2 T. Berg,3 M. Cramp,4 R. Flisiak,5 H. Van Vlierberghe,6 R.Verloes,7 O. Lenz,7 M. Peeters,7 V. Sekar8 and G. De Smedt7 1Hôpital Beaujon, Clichy, France; 2Amsterdam Medical Center, The Netherlands; 3Charite Campus Virchow Klinikum, Berlin, Germany; 4Derriford Hospital and Peninsula Medical School, Plymouth, UK; 5Medical University of Bialystok, Poland; 6University Hospital Ghent, Belgium; 7Tibotec BVBA, Mechelen, Belgium; 8Tibotec Inc., Yardley, PA, USA
INTRODUCTION
A substantial proportion of patients infected with hepatitis C virus (HCV) genotype 1 do not achieve a sustained virologic response (SVR) after combination therapy with pegylated interferon (PEGIFN) and ribavirin (RBV).1
Better treatment options are required for treatment-experienced patients: in a recent international, multicentre study, SVR response rates to PEGIFN and RBV were only 10% in genotype-1 prior non-responders and 27% in genotype-1 prior relapsers.2
TMC435 is a macrocyclic and selective HCV NS3/4A protease inhibitor with an in vitro EC50 value of 8 nM in a genotype-1b replicon cell line.3
In Phase I studies, TMC435 was generally safe and well tolerated, and the pharmacokinetic profile supported a once-daily (QD) dosing regimen. A median decrease of 3.9 log10 IU/mL in HCV RNA was observed after five days of monotherapy with TMC435 200 mg QD in genotype-1-infected individuals who failed previous IFN-based therapies.3-5
OPERA-1 (TMC435350-TiDP16-C201) is a double-blind, placebocontrolled, Phase IIa, proof-of-concept trial to assess the antiviral activity, safety and pharmacokinetics of once-daily regimens of TMC435 in HCV genotype-1 treatment-naïve and treatment-experienced patients.
Here we report the four-week results of OPERA-1 Cohort 4, for treatment-experienced patients receiving TMC435 in combination with PEGIFN and RBV.
METHODS
Study design
· The study design for OPERA-1 is summarised in Figure 1.
The planned Cohort 3 was cancelled prior to the initiation of treatment Patients are followed-up for 24 weeks after end of treatment to assess SVR rate PEGIFN alpha-2a, pegylated interferon alpha-2a RBV, ribavirin SVR, sustained virologic response
At the start of the double-blind treatment period of Cohort 4, patients were randomised to receive either TMC435 75 mg QD, 150 mg QD, 200 mg QD or placebo as part of a triple therapy regimen, in combination with pegylated interferon a-2a (PEGIFNa-2a) (180 µg subcutaneously, once weekly) and RBV (1000-1200 mg BID, body-weight dependent) for 28 days, followed by PEGIFNa-2a and RBV alone for a total treatment duration of 48 weeks.
Patient population
The treatment-experienced patients enrolled in this part of the study were: - prior non responders: <2 log10 IU/mL decrease from baseline in HCV RNA after 12 weeks of prior IFN-based therapy, or
- prior relapsers: confirmed detectable HCV RNA after achieving undetectable HCV RNA at the end of treatment.
Eligible patients were: aged 18-70 years with documented chronic HCV (genotype 1; diagnosis >6 months prior to screening); required to have HCV plasma RNA of >10,000 IU/mL at screening; required to have compensated liver disease.
Key exclusion criteria included: receipt of a polymerase inhibitor, protease inhibitor or dual therapy with PEGIFN and RBV during the six months prior to screening; co-infection with HIV-1 or HIV-2, hepatitis A or B, or active tuberculosis at screening.
Study assessments
Antiviral activity
The primary efficacy objective was to determine the change from baseline in HCV RNA levels at Day 28. Serum samples were obtained at baseline and on Days 1 (4 h and 10 h), 2, 3, 7, 8, 11, 14, 21 and 28, and HCV RNA levels were quantified using the Roche COBAS TaqManHCV/HPS assay v2.0.
Other efficacy endpoints were to evaluate the response to treatment (HCV RNA below the lower limit of detection, <10 IU/mL and the lower limit of quantification, <25 IU/mL) and to assess the number of viral breakthroughs (>1 log10 IU/mL increase from nadir or HCV RNA levels >100 IU/mL in patients with previous HCV RNA levels <10 IU/mL).
Safety and tolerability
Safety and tolerability were monitored continuously throughout the trial. Vital signs, electrocardiogram (ECG) recordings and clinical laboratory tests were taken on Days 1, 7, 14, 21 and 28.
Statistical analysis
A pre-planned intent-to-treat analysis was performed when all patients had either completed 28 days of treatment or had discontinued earlier. All data are presented descriptively.
RESULTS
Baseline demographics and characteristics
In total in Cohort 4, 37 treatment-experienced patients were randomised to the four treatment groups: 25 prior non-responders and 12 prior relapsers to previous IFN-based therapy for HCV. All patients completed treatment to Day 28.
Patient demographics and baseline characteristics are shown in Table 1.
Table 1. Patient demographics and baseline characteristics.
Antiviral activity
Change in plasma HCV RNA from baseline
Mean decreases in plasma HCV RNA from baseline were 4.3, 5.5 and 5.3 log10 IU/mL for the TMC435 75, 150 and 200 mg QD groups, respectively, at Day 28, compared with 1.5 log10 IU/mL in the placebo group.
Mean decreases in plasma HCV RNA over time for each treatment group are shown in Figure 2.
Week-4 virologic response
At Day 28, 4/9 (44%), 7/9 (78%) and 7/10 (70%) patients achieved plasma HCV RNA levels <25 IU/mL in the 75, 150 and 200 mg QD treatment groups, respectively, compared with no patients (0/9) in the placebo group.
The proportion of patients achieving plasma HCV RNA <10 IU/mL and <25 IU/mL for both prior non-responders and relapsers is shown in Figure 3.
Viral breakthrough
Three viral breakthroughs were observed, exclusively in patients infected with HCV genotype 1b who were prior non-responders to treatment; two in the 75 mg QD group and one in the 150 mg QD group.
At the time of the confirmed viral breakthrough, a D168V mutation in the NS3 protease domain was detected in all three patients using standard population sequencing.
Safety and tolerability
A summary of adverse events (AEs) is shown in Table 2.
Table 2. Summary of adverse events (AEs).
There were no discontinuations due to AEs, serious AEs or deaths during the study.
Alanine aminotransferase and aspartate aminotransferase levels decreased over time in all TMC435 treatment groups (Figure 4.).
Bilirubin elevations were observed in some patients receiving TMC435 (total, direct and indirect), mostly with the 200 mg dose. These elevations were generally mild and reversible in nature.
No dose trends or clinically relevant changes were noted in any other laboratory parameters, ECG parameters or vital signs.
References
1. Ghany MG et al. Diagnosis, management, and treatment of hepatitis C: An update. Hepatology 2008 2; 49:1335-1374.
2. Poynard T et al. Peginterferon alfa-2b and ribavirin: effective in patients with hepatitis C who failed interferon alfa/ribavirin therapy. The Epic Study Group. Gastroenterology 2009 Jan 22. [Epub ahead of print]
3. Lin TI et al. In vitro activity and preclinical profile of TMC435350, a potent hepatitis C virus protease inhibitor. Antimicrob Agents Chemother 2009; 53:1377-1385.
4. Reesink H et al. Presented at the 43rd EASL, Milan, Italy, April 23-27, 2008, Oral presentation.
5. Van't Klooster G et al. Presented at the 59th AASLD, San Francisco, CA, October 31-November 4, 2008, Poster 1895.
EASL April 23-26 2009 Copenhagen Denmark
Reported by Jules Levin
P. Marcellin,1 H. Reesink,2 T. Berg,3 M. Cramp,4 R. Flisiak,5 H. Van Vlierberghe,6 R.Verloes,7 O. Lenz,7 M. Peeters,7 V. Sekar8 and G. De Smedt7 1Hôpital Beaujon, Clichy, France; 2Amsterdam Medical Center, The Netherlands; 3Charite Campus Virchow Klinikum, Berlin, Germany; 4Derriford Hospital and Peninsula Medical School, Plymouth, UK; 5Medical University of Bialystok, Poland; 6University Hospital Ghent, Belgium; 7Tibotec BVBA, Mechelen, Belgium; 8Tibotec Inc., Yardley, PA, USA
INTRODUCTION
A substantial proportion of patients infected with hepatitis C virus (HCV) genotype 1 do not achieve a sustained virologic response (SVR) after combination therapy with pegylated interferon (PEGIFN) and ribavirin (RBV).1
Better treatment options are required for treatment-experienced patients: in a recent international, multicentre study, SVR response rates to PEGIFN and RBV were only 10% in genotype-1 prior non-responders and 27% in genotype-1 prior relapsers.2
TMC435 is a macrocyclic and selective HCV NS3/4A protease inhibitor with an in vitro EC50 value of 8 nM in a genotype-1b replicon cell line.3
In Phase I studies, TMC435 was generally safe and well tolerated, and the pharmacokinetic profile supported a once-daily (QD) dosing regimen. A median decrease of 3.9 log10 IU/mL in HCV RNA was observed after five days of monotherapy with TMC435 200 mg QD in genotype-1-infected individuals who failed previous IFN-based therapies.3-5
OPERA-1 (TMC435350-TiDP16-C201) is a double-blind, placebocontrolled, Phase IIa, proof-of-concept trial to assess the antiviral activity, safety and pharmacokinetics of once-daily regimens of TMC435 in HCV genotype-1 treatment-naïve and treatment-experienced patients.
Here we report the four-week results of OPERA-1 Cohort 4, for treatment-experienced patients receiving TMC435 in combination with PEGIFN and RBV.
METHODS
Study design
· The study design for OPERA-1 is summarised in Figure 1.
The planned Cohort 3 was cancelled prior to the initiation of treatment Patients are followed-up for 24 weeks after end of treatment to assess SVR rate PEGIFN alpha-2a, pegylated interferon alpha-2a RBV, ribavirin SVR, sustained virologic response
At the start of the double-blind treatment period of Cohort 4, patients were randomised to receive either TMC435 75 mg QD, 150 mg QD, 200 mg QD or placebo as part of a triple therapy regimen, in combination with pegylated interferon a-2a (PEGIFNa-2a) (180 µg subcutaneously, once weekly) and RBV (1000-1200 mg BID, body-weight dependent) for 28 days, followed by PEGIFNa-2a and RBV alone for a total treatment duration of 48 weeks.
Patient population
The treatment-experienced patients enrolled in this part of the study were: - prior non responders: <2 log10 IU/mL decrease from baseline in HCV RNA after 12 weeks of prior IFN-based therapy, or
- prior relapsers: confirmed detectable HCV RNA after achieving undetectable HCV RNA at the end of treatment.
Eligible patients were: aged 18-70 years with documented chronic HCV (genotype 1; diagnosis >6 months prior to screening); required to have HCV plasma RNA of >10,000 IU/mL at screening; required to have compensated liver disease.
Key exclusion criteria included: receipt of a polymerase inhibitor, protease inhibitor or dual therapy with PEGIFN and RBV during the six months prior to screening; co-infection with HIV-1 or HIV-2, hepatitis A or B, or active tuberculosis at screening.
Study assessments
Antiviral activity
The primary efficacy objective was to determine the change from baseline in HCV RNA levels at Day 28. Serum samples were obtained at baseline and on Days 1 (4 h and 10 h), 2, 3, 7, 8, 11, 14, 21 and 28, and HCV RNA levels were quantified using the Roche COBAS TaqManHCV/HPS assay v2.0.
Other efficacy endpoints were to evaluate the response to treatment (HCV RNA below the lower limit of detection, <10 IU/mL and the lower limit of quantification, <25 IU/mL) and to assess the number of viral breakthroughs (>1 log10 IU/mL increase from nadir or HCV RNA levels >100 IU/mL in patients with previous HCV RNA levels <10 IU/mL).
Safety and tolerability
Safety and tolerability were monitored continuously throughout the trial. Vital signs, electrocardiogram (ECG) recordings and clinical laboratory tests were taken on Days 1, 7, 14, 21 and 28.
Statistical analysis
A pre-planned intent-to-treat analysis was performed when all patients had either completed 28 days of treatment or had discontinued earlier. All data are presented descriptively.
RESULTS
Baseline demographics and characteristics
In total in Cohort 4, 37 treatment-experienced patients were randomised to the four treatment groups: 25 prior non-responders and 12 prior relapsers to previous IFN-based therapy for HCV. All patients completed treatment to Day 28.
Patient demographics and baseline characteristics are shown in Table 1.
Table 1. Patient demographics and baseline characteristics.
Antiviral activity
Change in plasma HCV RNA from baseline
Mean decreases in plasma HCV RNA from baseline were 4.3, 5.5 and 5.3 log10 IU/mL for the TMC435 75, 150 and 200 mg QD groups, respectively, at Day 28, compared with 1.5 log10 IU/mL in the placebo group.
Mean decreases in plasma HCV RNA over time for each treatment group are shown in Figure 2.
Week-4 virologic response
At Day 28, 4/9 (44%), 7/9 (78%) and 7/10 (70%) patients achieved plasma HCV RNA levels <25 IU/mL in the 75, 150 and 200 mg QD treatment groups, respectively, compared with no patients (0/9) in the placebo group.
The proportion of patients achieving plasma HCV RNA <10 IU/mL and <25 IU/mL for both prior non-responders and relapsers is shown in Figure 3.
Viral breakthrough
Three viral breakthroughs were observed, exclusively in patients infected with HCV genotype 1b who were prior non-responders to treatment; two in the 75 mg QD group and one in the 150 mg QD group.
At the time of the confirmed viral breakthrough, a D168V mutation in the NS3 protease domain was detected in all three patients using standard population sequencing.
Safety and tolerability
A summary of adverse events (AEs) is shown in Table 2.
Table 2. Summary of adverse events (AEs).
There were no discontinuations due to AEs, serious AEs or deaths during the study.
Alanine aminotransferase and aspartate aminotransferase levels decreased over time in all TMC435 treatment groups (Figure 4.).
Bilirubin elevations were observed in some patients receiving TMC435 (total, direct and indirect), mostly with the 200 mg dose. These elevations were generally mild and reversible in nature.
No dose trends or clinically relevant changes were noted in any other laboratory parameters, ECG parameters or vital signs.
References
1. Ghany MG et al. Diagnosis, management, and treatment of hepatitis C: An update. Hepatology 2008 2; 49:1335-1374.
2. Poynard T et al. Peginterferon alfa-2b and ribavirin: effective in patients with hepatitis C who failed interferon alfa/ribavirin therapy. The Epic Study Group. Gastroenterology 2009 Jan 22. [Epub ahead of print]
3. Lin TI et al. In vitro activity and preclinical profile of TMC435350, a potent hepatitis C virus protease inhibitor. Antimicrob Agents Chemother 2009; 53:1377-1385.
4. Reesink H et al. Presented at the 43rd EASL, Milan, Italy, April 23-27, 2008, Oral presentation.
5. Van't Klooster G et al. Presented at the 59th AASLD, San Francisco, CA, October 31-November 4, 2008, Poster 1895.
Hepatitis Advocacy Update for African Americans
Hepatitis Advocacy Update: Congressional Black Caucus Requests Federal Funding, for African-Americans The HCV Prevalence Rate is Double Compared To All Others in the USA; Congressmen Request Funding To on the Floor; Pres Obama Recognizes hepatitis with a Statement
Reported by Jules Levin
On World Hepatitis Day several Congressional offices and the Congressional Black Caucus expressed support for increased funding for viral hepatitis initiatives by the Federal government. Of particular note, a letter was sent by the Congressional Black Caucus led by Donna Christensen MD, representative from the Virgin Islands, and signed by 20 members of the CBC, was sent to David Obey the Chairman of the Committee on Approrpriations in the House of Representatives, requesting funding support for viral hepatitis (HCV & HBV). Congressman Mike Honda submitted a request to Congress for an increase of $40 million for HCV/HBV programs to include testing/screening, perhaps $4 million might be approved but we don't know if anything will be approved. Congressman Towns, Honda and Cassidy made statements on World Hepatitis Day in support of addressing the problem by the Federal government and the text of their comments are attached. As well, President Obama recognized the problem by issuing a statement from the White House also in support of the problem.
These are important steps forward, particularly the letter by the Congressional Black Caucus which states: "HCV is twice as prevalent among African Americans as among whites......African-Americans and Hispanic patients are less likely to be tested for HCV in the presence of known risk factors, less likely to be referred for subspecialty care and treatment, and less likely to receive antiviral treatment.....currently, the [CDC] does not have adequate resources to provide critical public health functions including education, hepatitis counseling, screening, vaccines or the surveillance that would allow states to better target their resources....Our current Federal investment is woefully inadequate."
A recent report from the Millan Group sponsored by Vertex said "HCV prevalence is over-represented in African-Americans", the relative risk of being HCV positive is 186% for African-Americans, which is about double the risk for all others in the USA.
Consequences of Hepatitis C Virus (HCV): Costs of a Baby Boomer Epidemic of Liver Disease MAY 2009 - (05/18/09)
Reported by Jules Levin
On World Hepatitis Day several Congressional offices and the Congressional Black Caucus expressed support for increased funding for viral hepatitis initiatives by the Federal government. Of particular note, a letter was sent by the Congressional Black Caucus led by Donna Christensen MD, representative from the Virgin Islands, and signed by 20 members of the CBC, was sent to David Obey the Chairman of the Committee on Approrpriations in the House of Representatives, requesting funding support for viral hepatitis (HCV & HBV). Congressman Mike Honda submitted a request to Congress for an increase of $40 million for HCV/HBV programs to include testing/screening, perhaps $4 million might be approved but we don't know if anything will be approved. Congressman Towns, Honda and Cassidy made statements on World Hepatitis Day in support of addressing the problem by the Federal government and the text of their comments are attached. As well, President Obama recognized the problem by issuing a statement from the White House also in support of the problem.
These are important steps forward, particularly the letter by the Congressional Black Caucus which states: "HCV is twice as prevalent among African Americans as among whites......African-Americans and Hispanic patients are less likely to be tested for HCV in the presence of known risk factors, less likely to be referred for subspecialty care and treatment, and less likely to receive antiviral treatment.....currently, the [CDC] does not have adequate resources to provide critical public health functions including education, hepatitis counseling, screening, vaccines or the surveillance that would allow states to better target their resources....Our current Federal investment is woefully inadequate."
A recent report from the Millan Group sponsored by Vertex said "HCV prevalence is over-represented in African-Americans", the relative risk of being HCV positive is 186% for African-Americans, which is about double the risk for all others in the USA.
Consequences of Hepatitis C Virus (HCV): Costs of a Baby Boomer Epidemic of Liver Disease MAY 2009 - (05/18/09)
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