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Merck’s HCV Regimen ‘C-Worthy’ in Early Test; Competitive Waters Ahead

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By Jennifer Boggs
Managing Editor

With Gilead Sciences Inc. barely a month away from a possible history-making FDA approval of an all-oral regimen for hepatitis C virus (HCV), the American Association for the Study of Liver Diseases (AASLD) meeting in Washington put the spotlight on other HCV contenders over the weekend, with much of the buzz focused on a protease inhibitor/NS5A inhibitor combination from Merck & Co. Inc.

Interim results from Merck’s Phase II study, dubbed C-Worthy, showed that all-oral regimens containing MK-5172 and MK-8742, with or without ribavirin (RBV), produced sustained virologic responses (SVRs) at week 12 ranging from 96 percent to 100 percent. The Whitehouse Station, N.J.-based pharma also has completed enrollment in a 400-patient Phase IIb trial testing MK-5172/MK-8742, with and without RBV, with data from that study expected at the European Association for the Study of the Liver meeting in April.

The regimen already earned breakthrough designation and, should it progress into pivotal testing without a hitch, could reach the market in 2017.

Following a meeting with Merck’s HCV experts over the weekend, ISI Group analyst Mark Schoenebaum wrote in a research report that Merck may be roughly 18 months behind Gilead “in the race to develop an all-oral regimen” for genotype 1 HCV.

Patients enrolled in C-Worthy to date were treatment-naïve, with diagnoses of either genotype 1a or genotype 1b disease. Of the 22 patients randomized into the MK-5172 100 mg/MK-8742 20 mg/RBV arm, 76 percent had genotype 1 disease, 100 percent of 21 evaluable patients at week 12 had SVR. The second arm enrolled 24 patients (70 percent genotype 1) to receive MK-5172 100 mg/MK-8741 50 mg/RBV, and data showed SVR of 96 percent. Of the 12 patients enrolled in the third arm, testing MK-5172 100 mg MK-8742 50 mg without RBV, all had genotype 1b disease and 100 percent of 11 evaluable patients at week 12 showed SVR.

Leerink Swann analysts said the AASLD news positions Merck “as the lead contender among the second wave” of interferon-free regimens, following Gilead’s nucleotide drug sofosbuvir and ABT-450, a direct-acting antiviral combination from Abbvie Inc. and Enanta Pharmaceuticals Inc. ABT-450 is in Phase III testing in genotype 1 HCV patients.

The results, however, might be too early stage to assess competitive threats, noted Wells Fargo analyst Brian Abrahams. “We believe it will be critical to see whether such high SVRs hold up when the regimen is stretched – such as cirrhotics, prior null responders, GT-1as without RBV and over eight weeks in naives – all of which will be necessary for [Merck] to gain meaningful share long term.”

For Merck, that is the plan moving forward. As reported in its AASLD presentation, the company has expanded C-Worthy to include about 400 additional patients, namely those with difficult-to-cure HCV genotype 1 disease. The trial is now also testing an eight-week regimen with RBV in treatment-naïve noncirrhotic patients; a 12-week regimen without RBV in treatment-naïve noncirrhotic patients; 12-week regimens, with or without RBV in patients co-infected with HIV; 12-week or 18-week regimens, with or without ribavirin, in patients with cirrhosis; and 12-week or 18-week regimens, with or without RBV, in null responders, defined as patients who had failed to respond to prior peginterferon and RBV therapy.

Niches in HCV?

The all-oral HCV treatment race is one that launched very quickly – so quickly that it barely gave first-generation protease inhibitors, which are approved for use with RBV and interferon, more than a few years of solid revenues. Vertex Pharmaceuticals Inc. already reported falling sales of Incivek (telaprevir) and reported a work force reduction in its third-quarter earnings call. (See BioWorld Today, Oct. 31, 2013.)

And Foster City, Calif.-based Gilead is easily in the lead. Sofosbuvir got a unanimous vote in favor from the FDA’s advisory committee last month and is expected to get a nod from the agency by the Dec. 8 PDUFA date. Among data Gilead presented at AASLD were results from the Phase III VALENCE study showing an 85 percent SVR12 in treatment-naïve and treatment-experienced patients with genotype 3 disease, as well as Phase III data showing a 76 percent SVR12 in genotype 1 patients co-infected with HIV.

In its pending new drug application, Gilead is seeking approval for use in genotype 2 and 3 hepatitis C virus HCV patients and for treatment-naïve genotype 1 and 4 patients.

Breaking out HCV subpopulations could prove crucial for Merck and other firms hoping to compete with sofosbuvir. ISI’s Schoenebaum noted that Merck “views the future hepatitis C market as complex and one in which (like in HIV) no one drug or regimen is able to fully capture the market.” Each drug regimen, instead, “will have its strengths/weaknesses, reimbursement/payor issues.”

In fact, more than one analyst noted that Merck’s MK-5172/MK-8742 combo will pose more of a threat to other protease inhibitor-based regimens such ABT-450. Abbvie and Enanta presented data at AASLD from the Phase III PEARL-1 study showing rates of SVR12 of 95 percent in HCV genotype 1b treatment-naïve patients and 90 percent in prior null responders.

Bristol-Myers Squibb Co. also has a late-stage protease inhibitor-based regimen, edaclatasvir/asunaprevir, for which it recently submitted a new drug application in Japan, based on Phase III data showing that the interferon-free and RBV-free regimen produced SVR24 of 84.7 percent in Japanese patients with chronic HCV genotype 1b.

Deutsche Bank analyst Robyn Karnauskas said she expects Merck to focus its regimen in Japan and emerging markets, though “we remain unclear of their strategy in a very rapidly evolving market in which [Gilead] will soon emerge with a likely approval.”

Attempts to find niche opportunities in specific populations such as genotypes 1a and 1b also might not work in the real-world setting. “In our checks, we don’t think payers and docs may see a difference in these data,” Karnauskas wrote in a research note, referring to genotype 1a and 1b data for both Merck’s regimen and Gilead’s sofosbuvir.

‘Cornerstone’ in HCV Treatment

Overall, the pharma’s AASLD presentation marked two positives. For one, Merck’s data provided another example of protease inhibitors as the “cornerstone” agents in HCV treatment, noted Leerink’s Howard Liang.

The advent of so-called “nucs” in the HCV space – Gilead’s sofosbuvir, for example, is a nucleotide analogue – has drawn attention away from protease inhibitors, due to better efficacy. Though nucs have had their share of bad news, too. Safety concerns caused BMS to halt development of BMS-986094 after a patient death last year, while the FDA had public clinical holds or partial holds on drugs from Idenix Pharmaceuticals Inc. and Vertex. (See BioWorld Today, Aug. 3, 2012, Aug. 17, 2012, and Aug. 27, 2012.)

But protease inhibitor-based regimens could also have their place in HCV, Liang wrote in a research note, pointing specifically to the activity of MK-5172 against resistant mutations, particularly R155K, a mutation that has resulted in reduced susceptibility to protease inhibitors. “It appears that activity against R155K may be the key,” he said.

Second, Merck’s data offer a much-needed positive headline for the big pharma, which has suffered a string of embarrassing late-stage failures, prompting executives to launch a massive restructuring program last month to revamp its R&D unit. Merck disclosed that it was eliminating another 8,500 positions, in addition to the previously reported reduction of 7,500 jobs, all aimed at cutting operating expenses by about $2.5 billion by the end of 2015. (See BioWorld Today, Oct. 2, 2013.)