Gilead Sciences and Bristol-Myers Squibb may be taking a commanding lead in achieving the first all-oral interferon free treatment in hepatitis C, but other contenders believe they can get back on even footing. Idenix Pharmaceuticas is one of the last remaining small-cap companies in the game, and its executive team believes phase II combination trials hoped to begin later this year could put it on the same schedule as its big pharma competitors (Hep C competitors need to make most of window of opportunity, April 24, 2012).
The Massachusetts group wants a non-exclusive partnership to test lead candidate IDX-184 with a protease inhibitor and ribavirin, a mid-stage study that if successful could enable a partnership for pivotal trials next year, Douglas Mayers, chief medical officer, tells EP Vantage in an interview at the EASL liver disease conference. “If we really like the protease inhibitor, we could go into an end of phase II meeting mid-next year and actually be in pivotal trials in the second half of 2013,” Dr Mayers says. “This means we’re on a competitive timeline with Abbott and Gilead and BMS. This gets you there (on the market) in 2015.”
With all-oral combinations expected to launch around then, it will be vital to have a marketed product in the US and the five biggest European markets, he adds: “You’re either in the game with your phase II regimen in the next 12-18 months or you’re going to get there too late.”
With an ambitious schedule like that, it raises a question of why IDX-184 has not been out-licensed or the whole group bought by a bigger company, as happened with Gilead’s acquisition of Pharmasset and BMS’ swoop on Inhibitex to obtain leading candidates in the nucleotide inhibitor class that includes IDX-184 (Bristol-Myers Squibb lays claim to new hep C stake with Inhibitex buyout, January, 9, 2012).
Novartis currently holds a 31% stake in Idenix as a result of a 2003 deal to market hepatitis B drug Tyzeka and the company's remaining pipeline. However, the Swiss group has waived its rights to IDX-184.
Potency is a question that hangs over IDX-184; as analysts from Morgan Stanley suggested in an April 4 note disappointing results for Roche’s mericitabine could be a poor sign for IDX-184. The two drugs have shown similar viral suppression during treatment, an early sign of a hep C drug’s effectiveness. IDX-184’s achieved undetectable virus loads in 73% of patients in its highest-dose 100mg arm once daily treatment after four weeks, slightly greater than mericitabine’s 1,000mg highest dose.
However, in follow-up, mericitabine failed to sustain viral suppression, with half or more of patients having the virus return in the six months following treatment even when used in combination with interferon and ribavirin. The data have been viewed as very disappointing among industry observers, who are now downplaying a significant role for the agent.
There is also the matter of the partial clinical hold placed on the IDX-184 development programme, resulting from elevated liver function tests from a combination safety trial with the now-shelved IDX320, which has been blamed for the safety issue (FDA actions more bitter than sweet for Idenix, February 10, 2011). De-risking IDX-184 in a larger phase II programme would probably go a long way toward improving confidence in the compound’s safety.
Thus, post-treatment viral suppression data for IDX-184 in combination with interferon and ribavirin later this year will obviously be an important moment for the Massachusetts group.
Investors appear to have been cognizant of the risk this year. After reaching a six year high of $14.42 in January on hopes of an acquisition following the Pharmasset and Inhibitex buyouts, Idenix shares fell back to $7.39 on April 13 before rising again as EASL approached. Shares stood at $8.61 in early trading today, down slightly for the session.
Significant numbers of investors are also expecting failure: 15% of free-floating shares have been sold “short,” indicating that many are betting on share price falls.
Defending the drug, Dr Mayers emphasises IDX-184’s effects across all six genotypes of the disease. Genotype 1 is by far the most common in the US and in the major European markets, and has also proved the most difficult to treat with the current regimen of interferon and ribavirin. However, other strains have a high prevalence in other countries, such as genotype 3 in the UK, Russia, Brazil and India.
So far the newer of the direct acting antivirals, Incivek and Victrelis, have only been licensed in genotype 1. Thus there is a portion of patients who will be waiting for the next generation of direct acting antiviral to launch before seeking treatment. Mr Mayers believes this will offer Idenix and a combination of IDX-184 with phase I NS5A inhibitor, IDX-719, a significant opportunity.
“You’re going to see a number of companies get 85-plus percent response rates in genotype 1. That’s going to be the new barrier,” Dr Mayers says. “Then the issue is not going to be potency anymore. It’s going to be around tolerability, safety, drug-drug interactions, pill burden and cost.
“We have the potential, with a 100mg once a day with ‘184 and 100mg once a day of ‘719, to have a fixed dose combination pill - one pill, once a day, pan-genotypic. That would make it a very compelling combination.”
Idenix hopes to move that combination forward in the fourth quarter in a dose ranging phase II study with ribavirin.
As for the IDX-184 plus protease inhibitor combination, the current plan is to secure a non-exclusive partnership to test the regimen, with an out-licensing deal necessary to move into phase III trials.
The company had $118m cash at the end of the year, an amount it estimates will be sufficient to carry it through to the end of 2012 if a partnership fails to materialise and it is forced to purchase a protease inhibitor. There are currently no plans to raise more funds, Idenix's head of communications, Teri Dahlman, confirmed.
Expectations in new hep C drugs are now sky high after Gilead's data from EASL. It will be a big ask for any drug to match '7977, and Idenix's entries have much to prove.