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.
