There is little doubt that the treatment of hepatitis C is heading for a seismic shift. With the first protease inhibitors already making a huge splash – Vertex’s Incivek sold a staggering $420m in its first full quarter on the market – Pharmasset announcing the start of phase III trials of the first all-oral treatment regimen and The Liver Meeting in San Francisco this weekend promising a slew of data on experimental agents, progress is readily apparent.
Behind the protease inhibitors other drug classes are yielding candidates viewed as future contenders for a combination approach to vanquishing the hepatitis C virus, without the need for interferon. One of the least explored is the cyclophilin inhibitors although Novartis has a candidate, alisporivir, in phase III. Considered a valuable addition to the armoury due to a high barrier to resistance, Biotica announced a new class of cyclophilin inhibitor earlier this week that it believes is more potent; partners are being sought to help progress a lead candidate through the clinic.
Named the sangamides by Biotica, the company has generated candidates using its polyketide platform technology. The British drug researcher has also used the technology to make analogues of rapamycin and erythromycin for therapeutic applications – none of which have publicly made it into the clinic although partnerships with GlaxoSmithKline and Wyeth, subsequently terminated by Pfizer, have been forged.
While Novartis’ alisporovir is a derivative of cyclosporine the sangamides are derived from sanglifehrin, also a known cyclophilin inhibitor. Proteins found in the host and recruited by the hepatitis C virus at a number of stages of its life cycle – including replication and cell entry – cyclophilins have emerged as a prime target for direct acting anti-viral agents.
Novartis is leading the way in this class. Two phase III trials are under way testing alisporivir in combination with interferon and ribavirin although results are unlikely to emerge until 2013. Mid-stage data is due to be presented at the Liver conference over the weekend in hepatitis C genotypes 2 and 3 – one advantage of the cyclophilin inhibitors is activity across all genotypes, because they are host rather than virus targeted.
The only other clinical stage cyclophilin is Scynexis’ phase II candidate, SCY-635; little has been revealed by the private company this year on the compound.
Ideal for combination
Biotica is convinced that the cyclophilin inhibitors will have an important role to play in the future of hepatitis C.
“The holy grail of HVC treatment will be a combination of drugs that work by different mechanisms of action, including drugs that rapidly kill the virus and drugs which prevent emergence of resistant forms,” says Edward Hodgkin, Biotica’s chief executive. “The cyclophillin inhibitors appear to have the highest barrier to resistance and therefore we believe they will be a key component of that successful combination.”
The company also believes that its lead sangamide, BC556, holds greater potential than alisporivir. Binding to the same active site but in a slightly different way, the drug appears to be more potent and selective.
“Another advantage is that we have a very clean drug-drug interaction profile,” says Barrie Wilkinson, Biotica’s head of research.
“One of the issues with alisporivir has been hyperbilirubinemia so you are limited by the dose, which limits the effectiveness of the compound. It also reacts with other drug transporters, so by virtue of that it limits potentially the range of compounds you can combine that molecule with.
“We’ve recognised that this is a key differentiator for us – a better drug-drug interaction profile that makes us ideal for combination.”
Shout to be heard
Biotica believes it is 12 months from the clinic with BC556 and wants to take the drug as far as it can on its own. Partners will be sought to take the compound into combination trials, a strategy that has been successfully pursued by Pharmasset with its class-leading polymerase inhibitors (Pharmasset's soaring valuation prompts pressure to deliver, July 6, 2011).
However clinical development will require cash and Mr Hodgkin says he hopes to strike a deal in the next 12 to 18 months that will bring funds into the company – he believes projects most attractive to partners will be BC556 and the sangamides or the rapamycin analogue programme, which has yielded pre-clinical candidates showing promise in multiple sclerosis and lupus.
Given that hepatitis C is about as hot as it gets at the moment, BC556 should have no trouble piquing interest.
“We have relationships with quite a few companies who are interested in this programme,” Mr Hodgkin says.
However, with the field attracting huge amounts of research dollars at the moment and new agents entering the clinic at a rate of knots, Biotica will need to generate some convincing data to be heard.