Confident that its daclatasvir will prove the best-in-class NS5A replication complex inhibitor for hepatitis C, Bristol-Myers Squibb Co. on April 22 signed its second non-exclusive partnership this month to test the compound in tandem with another company’s HCV candidate. The agreement to test Phase III daclatasvir in a Phase II combination trial with Merck & Co. Inc.’s MK-5172 follows on a similar arrangement signed with Vertex Pharmaceuticals Inc. April 5 to test the NS5A inhibitor with nucleotide analog VX-135.

Along with Phase III protease inhibitor asunaprevir, daclatasvir has been central to Bristol’s HCV strategy since a headline-making clinical failure last year. In August, Bristol shut down a trial investigating nucleoside polymerase inhibitor (or “nuc”) BMS-986094, acquired the year before in a $2.5 billion buyout of Inhibitex Inc., due to cardiotoxicity that resulted in one trial patient’s death and eight hospitalizations Also see "Bristol Halts HCV Trial Of Inhibitex Nuc Due To Possible Cardiac Toxicity" - Pink Sheet, 2 August, 2012.. Development of the compound was shelved shortly thereafter, making an already scarce class of HCV nucs even thinner.

In the aftermath, FDA placed two nucs in development at Idenix Pharmaceuticals Inc. on clinical hold due to concerns about a class-wide safety effect, sending Idenix back to the drawing board – it currently is trying to bring new, preclinical nucs into development. As a result, Gilead Sciences Inc. and Vertex have the only two nucs – thought to be a potential backbone of the next wave of HCV drugs due to pan-genotypic activity, strong potency and resistance to mutant strains of the virus – in clinical development. As of April 5, Bristol is testing daclatasvir with both of those nucs, as well as Merck’s next-generation protease inhibitor and another PI owned by a Johnson & Johnson affiliate.

The Gilead (GS-7977) and Vertex nucs have avoided a clinical hold because of a different chemical structure than the Bristol and Idenix nucs.

Since last August, Bristol has been one of several companies, along with AbbVie Inc. and Achillion Pharmaceuticals Inc., seeking to demonstrate that a next-wave, all-oral combination of direct-acting antivirals for hepatitis C does not need to include a nuc. The J&J and now Merck tie-ups are part of that effort, but Bristol is also is hedging its bets by testing daclatasvir with the two nucs now in clinical development.

NS5A Gene Function Not Fully Understood

In an interview, Bristol’s Doug Manion, senior VP of development, neuroscience, virology and Japan, noted that NS5A inhibition is a compelling pathway for treating HCV, in part because the exact function of the NS5A gene product in HCV is not fully understood.

“It’s very complicated,” he said. “It does a large number of things and the virus can’t survive without it, we know that for sure. We were the first company to actually ‘crack the nut’ in terms of how to drug it. Daclatasvir was the first NS5A inhibitor to get into the clinic, the first to get into Phase II, the first to get into Phase III, and it’ll be the first to be filed anywhere in the world.”

Bristol plans to file the combination of daclatasvir and asunaprevir for Japanese approval later this year, specifically to treat genotype 1b of the virus, the version most prevalent in Japan ([A#00120213015]). The pharma is presenting new data on the two-drug combination in genotypes 1a and 1b at the European Association for the Study of the Liver meeting later this week in Amsterdam, Manion added.

“We think daclatasvir is a pretty special drug, it’s been given to over 4,100 patients for varying durations and it’s proven itself to have a very good safety profile,” he said. “In fact, there have been no signature adverse events seen with it yet. Our approach with it is we think it belongs in the drinking water when it comes to a foundational component of [all-oral] regimens moving forward.”

That two-drug combo was the first to demonstrate the theory that HCV could be cured solely with oral therapies, and without interferon, an injectable that requires a long treatment period and presents an undesirable side-effect profile ([A#14120119002]).

Few details were disclosed about the partnership with Merck, which like most in the HCV space to study combinations of two firms’ drugs is non-exclusive. Merck will run the Phase II trial in genotype 1 patients to study the combo’s safety and efficacy. Previously, Merck completed a Phase I study to check the combo’s safety.

The deal includes no financial considerations; Merck will fund the trial, with Bristol only contributing the volume of study drug needed, Manion said. The arrangement is open-ended, like the other combo trial collaborations Bristol has entered – if the two companies want to move on to Phase III work with the combo being studied, they need to work out a new agreement.

Merck also is investigating MK-5172 internally with its own NS5A inhibitor, MK-8742 Also see "Merck Makes Hepatitis C A Priority" - Pink Sheet, 11 November, 2011.. Likewise, in addition to its external collaborations, Bristol is studying daclatasvir and asunaprevir in a proprietary three-drug combo with BMS-791325, a non-nucleoside polymerase inhibitor. Compared with nucs, so-called “non-nucs” so far have proven be a less-potent class of drug in HCV. They also are genotype-specific, whereas nucs are pan-genotypic.

MK-5172 May Be Pan-Genotypic

Merck launched the first protease inhibitor approved in the U.S. for HCV, Victrelis (boceprevir), but that drug quickly and consistently lost market share to Vertex’s Incivek (telaprevir), which boasted higher cure rates in clinical trials. In an e-mail, Merck said ‘5172 would offer advantages over boceprevir.

“MK-5172 is a potent NS3/4 protease inhibitor currently in Phase II studies, being evaluated for effective, convenient, differentiated regimens that can be used in a broad population of patients,” explained Eliav Barr VP, infectious disease, project leadership and management, Merck Research Labs. “In non-clinical studies, it has been shown to maintain potency against HCV genotype I mutants that cause resistance to boceprevir. Unlike boceprevir, MK-5172 has not yet been evaluated in large Phase III studies.”

Like the Merck arrangement, Vertex will run the program pairing daclatasvir with VX-135, a Phase II uridine nucleotide analog. It will include two Phase II studies, first a trial investigating the combo in treatment-naïve genotype I patients to begin this quarter. Then, pending data from the first study, Vertex later in 2013 will begin a subsequent trial in treatment-naïve patients infected with genotypes 1, 2 or 3 of the virus, including patients with cirrhosis of the liver.

The first trial will enroll 20 patients, while the second will be much larger, with up to 250 patients, Vertex said in a statement. Both studies will measure the combination’s sustained virologic response (SVR) rates at four weeks and 12 weeks of treatment.

Previously, Bristol arranged to study daclatasvir in tandem with GS-7977, then owned by Pharmasset Inc. and called PSI7977 [See Deal]. Months later, it signed with J&J to study the NS5A inhibitor with TMC435, a protease inhibitor [See Deal].

Collaboration With Merck’s Protease Inhibitor The Fourth HCV Tie-Up For Bristol’s Daclatasvir

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