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EP Vantage Interview - Avila's covalent drugs looking highly attractive

Date September 25, 2009

For a young start up only in its third year of existence, Avila Therapeutics has some notable achievements under its belt. For starters, $51m of venture capital has been raised in two rounds, whilst Novartis has already bought an option over an early stage drug candidate in a deal worth up to $200m in upfront and milestone payments.

The attraction is Avila’s novel approach to designing small molecule drugs. Unlike most drug molecules which form only transitory bonds with their target, Avila’s candidates form permanent covalent bonds, completely shutting down the receptor. By silencing disease-causing proteins in this way the company believes it can create medicines with greater efficacy, tolerability and safety; certainly a winning combination. The downside is that none of the company’s candidates have yet moved into man, however, Katrine Bosley, Avila’s chief executive, tells EP Vantagethat encouraging pre-clinical work due to be presented at a hepatitis C conference next month should make interesting reading.

Serendipity

Covalently-binding small molecules that never leave their target are not new; proton pump inhibitors like omeprazole and one of the world’s biggest-selling drugs in 2008, the blood thinner Plavix, all work by this mechanism. However, these were discovered by chance rather than design and surprisingly, since then, little work has been done in the area.

“In the past, people viewed it as, 'what if you bond to something you don’t want to?'” Ms Bosley says. “But what we are looking for is one place we can target, a very specific amino acid, so we get very specific activity.”

Permanently binding to unintended receptors would certainly not be ideal. However, the specificity that Avila is seeking means their candidates should not have an effect elsewhere, by binding to other members within a similar protein family, for example.

Additionally, this highly specific mode of action means binding sites that are a constant feature of a particular protein can be targeted, carrying the potential for compounds to work against even mutated proteins. This has particularly relevance to oncology and virology, where drug resistance can be a problem.

Of course, even a covalently bonding molecule will only silence its target for the lifetime of the receptor. Once the disease cell or virus synthesise new targets, further doses will be required. However, whilst present in the body, a covalently binding drug will exert a much stronger influence, Avila believes.

Pre-clinical data

Of course, Avila still has to establish that these theories, and its drug platform, translate into viable medicines in the clinic. However, preclinical data generated so far on Avila’s two lead candidates has been encouraging.

The first silences the activity of a enzyme called NS3 protease in the hepatitis C virus, impeding its ability to replicate. The second inhibits bruton’s tyrosine kinase (btk), a protein that plays a critical role in the development and activation of B cells and could therefore have a role in cancer and immunotherapy. INDs are on track to be filed for both candidates in the second half of 2010.

Data due to be presented at the 16th International Symposium on Hepatitis C Virus and Related Viruses conference early next month will be the most advanced preclinical data released on the first candidate so far, and Ms Bosley is pretty excited about the drug’s potential.

“In ten years time HCV will be a different disease, and protease inhibitors will become the backbone of treatments,” she says. “Obviously it is early days, but we believe we have a molecule that has the potential to be the best-in-class protease inhibitor, and be that backbone.”

Stronger potency

Vertex’s telaprevir looks like being the first protease inhibitor to reach the market, and both doctors and financial analysts are predicting great things for the treatment. Consensus data from EvaluatePharma shows that analysts are forecasting sales of $3.8bn by 2014, a staggering figure considering the drug is not expected to reach the market until 2011.

“First in class is not necessarily best in class,” Ms Bosley says. “We have a completely different way of hitting the target, and a profile that can be readily combined with other treatments.”

Preclinical work comparing the Avila compound to telaprevir indicated stronger potency at lower dosages, with a longer lasting drug effect. A study looking at another promising protease inhibitor being developed by Roche and InterMune, ITMN-191, pointed to greater suppression of viral activity, when tested against a commonly seen mutated form of the virus.

Many options

With enough cash to last until the end of 2011, Avila can take both the hep C candidate and the btk inhibitor into man, hopefully next year. The future from that point has not yet been mapped out, and at this stage Ms Bosley is not ruling anything in, or out.

“We’ve mapped out a lot of scenarios. We have a lot of options and can be responsive to the data,” she says. Partnering either asset is always a possibility, as are further transactions like the Novartis deal.

If the initial clinical data is positive, it seems likely that venture capital backers will probably be happy to dig into their pockets once more, in an attempt to add even more value to the compounds. However, with a platform technology capable of generating many more covalently bonding molecules, a couple of successes will certainly pique the interest of big pharma.

“Our goal is to make covalent drugs successful. If we do that, there will be a lot of people interested,” Ms Bosley predicts.

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