Avila Aims to Trump Vertex With Drug that Hits Hepatitis C Virus and Won’t Let Go

Avila Aims to Trump Vertex With Drug that Hits Hepatitis C Virus and Won’t Let Go

Luke Timmerman 2/26/10 http://www.xconomy.com

Avila Therapeutics can’t be accused of thinking too small. This Waltham, MA-based startup is on a quest to show it has the scientific chops to build a better drug than one of Boston’s anchor biotech companies—Vertex Pharmaceuticals.

So this is shaping up to be a big year for Avila (AH-vill-uh), as it plans to start clinical trials of a drug for hepatitis C, and another with potential for certain cancers and autoimmune diseases. The company raised $30 million last July, recruited an experienced biotech dealmaker as CEO, and has laid out some ambitious goals to put its money and people to work.

For those new to the Avila story, it’s built on chemistry. The company is developing conventional small-molecule oral pills with a special feature. The Avila drugs form covalent bonds with their targets on cells. These bonds are supposed to completely, and irreversibly, shut down the biological activity of the intended protein target they hit on cells. That’s different from conventional therapies that connect with their targets via ionic or van der Waal bonds, which puts them in a state of “dynamic equilibrium” in which they are bouncing on and off the target, says CEO Katrine Bosley.

Why does that matter? By completely shutting down the target, Avila thinks it has found a way to improve upon the trailblazing work of Vertex in hepatitis C, and it might be able to nail other targets pharma companies have long pursued, but couldn’t effectively block.

“It’s getting the attention of pharma companies. Pharma companies are always looking for new innovation from beyond what they do within their four walls, and covalent drugs haven’t been much explored in the industry,” Bosley says. “As we develop a data set that says we can develop very specific covalent drugs, it’s intrigued a lot of people. Scientists are scientists. If you can get a new result that can’t be achieved another way, they want to talk about that.”
Katrine Bosley

Katrine Bosley

I pressed Bosley for a bit more explanation of how its lead drug is differentiated from Vertex’s telaprevir. That drug, a protease inhibitor, has helped Vertex create an $8 billion stock market valuation, largely because clinical trials have shown it can basically double the traditional cure rates for patients with hepatitis C, while shortening the usual year-long treatment regimen by half. Analysts predict Vertex could exceed $2 billion in U.S. sales alone after a couple years on the market, and the worldwide potential is vast with an estimated 170 million people infected.

Bosley didn’t want to sound dismissive of what Vertex has done. “Obviously everybody is excited about Vertex’s telaprevir, it’s a great drug, they’ve done a beautiful job advancing the molecule and developing the clinical paradigm in treating hepatitis C,” Bosley says.

But Bosley clearly sees room for improvement, and Avila thinks it has found a way. One of the challenges with viruses is that they mutate, essentially switching

around an amino acid or two, which is a sort of a survival mechanism to escape from the pressure of a drug that’s trying to kill it, Bosley says. There are four or five slightly mutated versions of the hepatitis C protease, and the Vertex drug and others like it have varying degrees of potency when they encounter the mutants, she says.

The advantage of a covalent drug, which forms a permanent linkage with the target, is that it doesn’t allow the virus to escape via mutation, Bosley says. Plus, with hepatitis C, there are different genotypes of the virus to begin with. Vertex’s telaprevir is most effective against genotype 1, while Avila’s treatment is thought to be effective against all genotypes, she says.

“Telaprevir is a great drug, but if you want to improve upon it, you want to go across genotypes and across mutant forms. That’s the profile you want,” Bosley says.

So Avila went to work on making a covalent drug, AVL-181, to do that and more. It ought to completely shut down all the mutant forms of the hepatitis C virus, all genotypes, and, importantly, come in a convenient once-daily pill. Vertex has tested three-times daily dosing and twice-daily dosing of telaprevir in clinical trials, in its search for the best balance of safety, effectiveness, and convenience.

Avila didn’t generate nearly the same attention as clinical trial data from Vertex, but the startup had some data to support these remarks from animal experiments that was presented in November at the American Association for the Study of Liver Disease meeting in Boston. That was where the findings perked up the interest of partners, Bosley says.

The next program Avila has on the docket is a covalent binder against a target called Bruton’s tyrosine kinase (Btk). This target has been studied for years, but which has been an especially hard target for medicinal chemists to hit in the pharmaceutical industry. It’s thought to be valuable because it’s involved in activating immune system B-cells, which can flip into overdrive, harming healthy tissues, and leading to certain lymphomas or autoimmune diseases like rheumatoid arthritis and multiple sclerosis, Bosley says.

The role of B-cell proliferation in those cancers and autoimmune diseases has been proven over the years by rituximab (Rituxan), the hit antibody drug from Roche and Biogen that depletes excess B-cells.

Avila presented a poster at the American Association for Cancer Research meeting last spring, in which it suggested it had developed a potent covalent-binding drug against this notorious hard target. It’s a conventional small-molecule that can be taken orally once a day. The research is still at an early stage, not yet in the clinic, but this also turned some heads.

“A lot of people find you from the scientific data you put out there. People are quite intrigued on a couple fronts. People have known about the Btk target for a long time. They like the target, and a lot of people have worked on it and not achieved the profile they’d like. So when they see a poster, they say ‘Oh, you have a potent and specific Btk inhibitor? Let’s talk.’”

Talk is great, but clinical data and partnership deals speak volumes in biotech. Bosley has experience doing deals, as a former vice president of business development at Biogen, and a vice-president of Adnexus Therapeutics before that company was bought by Bristol-Myers Squibb. If Bosley and the Avila team can deliver on some of this early promise, it will be one of the young biotech startups to watch in Boston this year.

Luke Timmerman is the National Biotechnology Editor for Xconomy