Bristol Myers Squibb Co. and Pharmasset Inc. have teamed up in a clinical partnership that marks the first cross-company collaboration to study two investigational oral drugs for the treatment of hepatitis C. The two firms announced plans to study Bristol's investigational NS5A replication complex inhibitor BMS-790052 and Pharmasset's nucleotide polymerase inhibitor in combination Jan. 10.

The deal is unusual in that drug makers generally do not collaborate on clinical trials for investigational drugs for competitive reasons, and tend instead to study combinations within their own pipelines or with at least one already marketed drug. Regulatory uncertainties and, perhaps most important, cultural resistance, also present hurdles.

But novel-novel combinations increasingly are viewed as the best way to treat certain serious diseases like cancer and hepatitis C, and in the current risk-sharing climate, they could become more common. While Bristol and Pharmasset are first in HCV, Merck and AstraZeneca have initiated a collaboration to study two cancer compounds, one in Phase 1 and one in early Phase II - the first time two Big Pharmas have collaborated in such a way Also see "In A First, Merck And AstraZeneca Team Up For Oncology Study" - Pink Sheet, 1 June, 2009.) and ('AstraZeneca And Merck: Moving Forward Cautiously,' IN VIVO, May 2010).

In hepatitis C specifically, the primary drug development focus is on combinations that could replace or reduce the use of the current standard of care, ribavirin and pegylated interferon (Roche's Pegasys or Merck's Pegintron), a regimen with a nasty side effect profile and limited efficacy. The Bristol/Pharmasset trial will explore exactly such a combination. The proof-of-concept study will evaluate the potential of the once-daily oral regimen to sustain viral response 24 weeks post treatment with and without ribavirin in treatment-naive patients chronically infected with HCV genotypes 1, 2 and 3. The companies expect to submit a protocol synopsis to FDA for input and then initiate the trial in the first half of 2011.

Bristol's decision to sign a clinical trial collaboration rather than in-licensing a polymerase inhibitor is interesting since the company recently acquired its hepatitis C partner ZymoGenetics to gain more control over the program. The company bought ZymoGenetics last year for $885 million, gaining full rights to interferon lambda, a next-generation interferon, which could have improved tolerability over existing interferons (Also see "ZymoGenetics Furthers Bristol's "Multi-Pronged" Approach To HCV, Sigal Says" - Pink Sheet, 13 September, 2010.).

In addition to interferon lambda and the NS5A inhibitor, Bristol also has a NS3 inhibitor in Phase II development.

"A clinical collaboration agreement was the right structure in this case," a Bristol spokesperson said. "It demonstrates our commitment to the goal of helping patients with HCV. We are willing to follow multiple strategies: in-house development, acquisition and now a clinical collaboration."

Options for further development or in-licensing are not part of the current arrangement, Bristol said. However, the companies will consider a future development collaboration depending on the outcome of the data. Pharmasset is still in partnering discussions with potential licensors, the company said.

First Deal Could Be The Start Of More To Come

Similar collaborations also could be coming. Bristol CEO Lamberto Andreotti hinted that collaborations like the Pharmasset arrangement would be part of the company's strategy in HCV during a presentation at the Goldman Sach's Healthcare CEO Unscripted conference Jan. 6. "We do not believe [we] need to buy companies or buy products to complement our portfolio," he said of the HCV pipeline. "You will hear over the next few months more announcements of clinical agreements with other companies that will use our products as components in a multiple [drug] therapy."

Most of the players in hepatitis C have a polymerase inhibitor in development, including Roche, Vertex Pharmaceuticals Inc. and Gilead Sciences Inc. Pharmasset's drug and a polymerase inhibitor in development by Idenix Pharmaceuticals Inc. have been considered two potential partnering candidates (Also see "Active Deal-Making Year Anticipated In HCV As New, Better Drug Combos Emerge" - Pink Sheet, 26 April, 2010.). But the Idenix candidate was put on clinical hold by FDA in September, along with a protease inhibitor IDX320 after elevated liver function tests were detected in three patients in a drug-drug interaction study exploring the two in combination.

PSI-7977 is one of Pharmasset's two lead clinical-stage assets. The other is RG7128, a cytosine nucleoside analog partnered with Roche, in Phase IIb development. The Princeton, N.J., company is focused specifically on developing oral drugs for the treatment of HCV.

The company released positive data Jan. 6 from an interim analysis of a Phase IIb study of PSI-7977 in combination with pegylated interferon and ribavirin. The data showed PSI-7977 with pegylated interferon and ribavrin resulted in rapid viral suppression, with all HCV genotype 2 or 3 patients achieving both a rapid virologic response and remaining below the limit of detection through the end of treatment at weeks 12. Genotype 2 and 3 patients are now being monitored for an additional 24 weeks to assess SVR at 12 and 24 weeks. Adverse events in the interim analysis were consistent with interferon and ribavirin treatment.

Vertex, in partnership with Johnson & Johnson, and Merck are furthest ahead in developing oral treatments with their respective protease inhibitors telaprevir and boceprevir. Both could reach the market this year, but will be used in combination with ribavirin and pegylated interferon. Vertex, also on Jan 10, gave an update on the status of telaprevir during the JP Morgan Healthcare Conference. It said it expects to launch the drug later this year, pending FDA approval (Also see "Vertex Expects Shorter Duration Of Therapy Will Give Telaprevir Long Reign Atop Market" - Pink Sheet, 10 January, 2011.).

-Jessica Merrill (j.merrill@elsevier.com)

Bristol, Pharmasset To Study Oral HCV Regimen Together

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