EASL 2013 – In the shadow of Gilead, hep C progress continues

After the breakneck pace of hepatitis C drug development in the past two years, the sector seems to be catching its breath as it awaits some of the biggest news of all: whether there can be a feasible drug regimen free of both interferon and ribavirin. Still, companies continue to generate data that will support regulatory submission of new drug cocktails that will include one or both of the mainstays of antiviral treatment.

The meeting of the European Association for the Study of the Liver is the usual early-year opportunity to detail the findings of hepatitis C trials, and this year's is no exception. It also gives some insight into the business development options of companies trailing behind acknowledged clinical leader Gilead Sciences, such as Bristol-Myers Squibb signing a new non-exclusive deal to test daclatasvir in combination with an antiviral developed by Merck & Co.

Combining to win

This week, Bristol-Myers announced it has agreed to test a combination of its NS5A inhibitor with Merck & Co’s protease inhibitor MK-5172, with Merck taking the lead role in the phase II trial of the once-daily regimen. This announcement comes just a couple of weeks after Bristol-Myers entered into a non-exclusive pact to test daclatasvir with Vertex Pharmaceuticals’ nucleotide NS5B inhibitor VX-135, also known as ALS-2200.

In addition, both the Bristol-Myers compound and the Vertex agent are being trialled with the protease inhibitor simeprevir (TMC-435), developed by Johnson & Johnson and Medivir, giving a clear picture of the level of collaboration underway as the chasers try to respond to the possibility that Gilead’s sofosbuvir will mop up the market.

Bristol-Myers famously was on the losing side of a non-exclusive collaboration with Gilead on daclatasvir and sofosbuvir, also known as GS-7977 – it is likely that the need for the California group to extract as much of the value out of the NS5A it acquired with the $11.2bn buyout of Pharmasset, not clinical concerns, drove Gilead to take a solo path (EASL – Gilead-BMS score all-oral hep C win but will pairing last?, April 19, 2012).

In any case, Bristol-Myers immediately acknowledged the need for further collaboration – even though it has similar assets to Merck, J&J and Vertex in the form of protease inhibitor asunaprevir and NS5B candidate BMS-791325 (EP Vantage interview – BMS collaborating to win in hepatitis C, April 20, 2012).

The suspension of its work on nucleoside NS5B inhibitor BMS-986094, which it bought for $2.5bn, has no doubt only hastened its desire to enter such collaborations (Bristol-Myers setback another blow to hep C field, August 24, 2012). Based on its continued activity, Bristol-Myers will probably figure in the future hep C landscape, but there are still some other significant players, as data published at EASL reveals.

Elbowing in

AbbVie could be a force to be reckoned with if a late-breaking paper at EASL on one of its combinations is anything to go by. The paper contains data from a phase IIb trial concerning viral response 24 weeks after the end of treatment with its interferon and ribavirin-free three-drug combination. In patients never treated before, 90% had undetectable virus loads, and in patients who had failed previous treatment, 95% had undetectable virus loads.

The regimen included the protease inhibitor ABT-450 boosted with the HIV protease inhibitor ritonavir, plus the NS5A inhibitor ABT-267 and NS5B inhibitor ABT-333. All four drugs are AbbVie's, so the company does not find itself in the same position as Bristol-Myers – especially as a phase III trial of the same combination could read out later this year and a regulatory submission could come in mid-2014, on a similar timeframe as Gilead’s long-awaited sofosbuvir-lepidasvir combination.

J&J and Medivir’s simeprevir has been a leading second-generation protease inhibitor following Vertex’s Incivek and Merck’s Victrelis, and the EASL late-breakers included phase III data from a trial with interferon and ribavirin. The trial found 81% of patients had no detectable virus 12 weeks after the end of treatment with simeprevir, and 91% were able to end their continuing treatment with interferon and ribavirin at 24 weeks rather than continuing to 48 weeks as usual.

This “interferon-sparing” approach could be sufficient to earn regulatory approval – eliminating nearly six months of treatment on interferon should reduce the burden of interferon’s flu-like side-effects – but would probably be insufficient to compete commercially against an all-oral interferon-free regimen. It could also potentially win converts in cash-strapped countries given that all-oral combinations would likely be priced at a premium.

Boehringer Ingelheim followed a similar approach in releasing data on faldaprevir, which showed a similar viral cure rate to simeprevir – 80% 12 weeks after the end of treatment with the higher dose – 240mg – combined with interferon and ribavirin.

Bristol-Myers released data from both daclatasvir in combination with interferon and ribavirin in the less studied genotypes 2 and 3; viral cure rates ranging from 69% to 88% were achieved depending on treatment regimen and genotype.

Unlike ths scene at recent hepatology conferences, Gilead proved itself to be the least dramatic company working in hep C, given that it had already released a flurry of data on various combinations of sofosbuvir treatment (Regulators await Gilead's hep C candidate, February 21, 2013). Expectations are sky-high for the compound with ribavirin or interferon, or as the single pill combination with lepidasvir; that single-pill combination is the last piece of the puzzle, and the data is some months away.

The manoeuvring has not ended yet. A swarm of companies are betting that the market is big enough to sustain more than just Gilead’s candidates, but they will have to be increasingly creative in their strategies.

To contact the writer of this story email Jonathan Gardner in London at [email protected] or follow @JonEPVantage on Twitter.

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