Merck & Co. Inc. nearly stole the show at the European Association for the Study of the Liver (EASL) meeting in London with results from an ongoing phase II trial testing its all-oral combo drug for hepatitis C virus (HCV), but other firms kept the program lively, as Gilead Sciences Inc. held onto rock-star status. Mostly.

The C-worthy study by Merck features a pill that combines the NS3/4A protease inhibitor MK-5172 with MK-8742, an HCV NS5A replication complex inhibitor to treat patients with genotype 1 infection. Sustained viral responses (SVRs) with 12-week dosing in genotype 1 treatment-naïve patients reached 94 percent to 98 percent, said Whitehouse Station, N.J.-based Merck, even without ribavirin in the mix. The SVR dipped to 83 percent at the eight-week treatment mark, but onlookers were cautiously impressed with Merck's chances against HCV competitor Gilead. About 75 percent of HCV patients in the U.S. are genotype 1.

"Most analysts (me included) have assumed Gilead will capture perhaps 60 percent to75 percent [of the genotype 1 HCV market] share at peak," wrote ISI Group analyst Mark Schoenebaum in an email alert to investors. "The open question, however, has been which company grabs the other 25 percent to 40 percent of the market? I would propose to you that perhaps Merck is now the leading contender for this position."

Wells Fargo analyst Brian Abrahams sounded less sanguine about Merck's odds, though not quite bilious. He wrote in a research report that Merck's regimen "may be over-hyped as a potential competitive threat – given intrinsic potency limitations of a nucleotide-free PI/NS5A regimen, the narrower therapeutic window of Merck's protease inhibitor, and breakthroughs that have already been observed." All, in Abrahams' view, will "make it difficult for Merck's regimen to look as competitive" with Gilead across the broadest range of patients and treatment durations.

"We believe this data supports our view that Merck is less important as a future competitive threat to Gilead, and that [Wall Street] may be overestimating the likelihood of this becoming an interchangeable three or four-handed all-oral HCV market in the next three years," Abrahams wrote.

Foster City, Calif.-based Gilead provided data from a pair of phase II studies evaluating all-oral regimens containing its approved nucleotide analogue polymerase inhibitor Sovaldi (sofosbuvir). The first, called ELECTRON2, is an ongoing, open-label experiment trying a once-daily fixed-dose combination of 400 mg of Sovaldi with the NS5A inhibitor ledipasvir 90 mg, with and without ribavirin twice-daily (1,000 or 1,200 mg/day) in HCV. In February, Gilead filed for FDA approval of the combo as a once-daily, fixed-dose therapy.

In ELECTRON2, 100 percent (n = 26/26) of treatment-naïve genotype 3 patients who got 12 weeks of the combo plus ribavirin and 64 percent (n = 16/25) of the same patients without ribavirin achieved SVR 12 weeks after treatment was done (SVR12, considered a cure). Among genotype 1-infected patients who had failed prior treatment with Sovaldi plus ribavirin, all 19 hit the SVR12 goal after 12 weeks of the combo plus ribavirin.

What's more, 65 percent (n = 13/20) of genotype 1-infected patients with decompensated or Child-Turcotte-Pugh class B cirrhosis given 12 weeks of the combo without ribavirin reached SVR12. Gilead said the combo was well tolerated with and without ribavirin, even among patients with advanced liver disease.

A second Gilead study, called GS-US-342-0102 (Oral #111), is an ongoing randomized phase II trial in which treatment-naïve, non-cirrhotic patients with genotypes 1-6 HCV took a 12-week course of Sovaldi plus the pan-genotypic NS5A inhibitor GS-5816. Patients were given Sovaldi 400 mg and either GS-5816 25 mg (n = 77) or GS-5816 100 mg (n = 77). The upshot was that 94.8 percent (n = 73/77) of patients who got the 25-mg dose of GS-5816 and 96.1 percent (n = 74/77) of patients receiving the 100-mg dose achieved SVR12.

GILEAD 'STILL #1'

Merck's success "adds to the long-term concern that Gilead is seeing more competition in the next two years and adds to possible pricing pressure and flattish or declining Sovaldi revenues," in the view of RBC Capital Markets analyst Michael Yee. He cited another contender: Abbvie Inc., of Chicago, partnered with Enanta Pharmaceuticals Inc., of Watertown, Mass., on a three-way combo that adds the protease inhibitor ABT-450 (ritonavir) and the NS5A inhibitor ABT-267 to the non-nucleoside polymerase inhibitor ABT-333 in a phase III trial known as SAPPHIRE II. (See BioWorld Today, Dec. 10, 2013.)

The triple drug plus ribavirin given over a 12-week course won SVR12 in 96.3 percent of previously treated genotype 1 patients, Abbvie said at EASL. Enrolling 394 genotype 1s who hadn't responded to pegylated interferon and ribavirin, SAPPHIRE II took patients if they had relapsed, had a partial response or had a null response – that last category making up 49 percent of subjects. The study gave a 12-week course of interferon-free treatment, with patients randomized 3:1 to get the oral combo or placebo. Seven patients experienced a viral breakthrough between the second and eighth weeks after treatment finished, and all but one had been null responders to earlier drugs.

Also heard from at EASL was New York-based Bristol-Myers Squibb Co. (BMS), which earlier this week submitted the new drug application for daclatasvir (DCV), an NS5A replication complex inhibitor, and asunaprevir (ASV), an NS3 protease inhibitor, to treat genotype 1b patients. BMS offered data from the global phase III HALLMARK-Dual study, showing that DCV plus ASV given in a 24-week regimen gained SVR12 among treatment-naïve patients (90 percent), peg-interferon/ribavirin non-responders (82 percent), and those who were peg-interferon/ribavirin ineligible or intolerant (82 percent), including cirrhotic and non-cirrhotic patients (84 percent and 85 percent, respectively). The regimen was generally well tolerated, BMS said.

Weighing all of the available evidence, ISI's Schoenebaum may have quelled jitters among Gilead investors when he pointed out that the firm's regimen ". . . can be used (eventually) in all genotypes and is likely eight weeks. Merck's can be used only in genotype 1 (we are awaiting genotype 2 and 3 data) and appears to need to be dosed for 12 weeks. Thus, barring massive price differences, Merck will not threaten Gilead for the #1 position."

Gilead's dominion is safe, agreed Credit Suisse analyst Ravi Mehrotra. "We see a greater impact on Abbvie than Gilead from Merck's continued emergence," he wrote in a research report from the meeting, "but continue to view Abbvie as a key player in the market who could boost its competitive position with disclosures from its next generation program later this year. By far, we continue to see Gilead as the market leader in this space, with data from its next generation regimen suggesting a continued leadership position."

Merck's phase III program is moving along briskly and the drug "could be in market by late 2015/early 2016, slightly ahead of our previous mid-2016 assumption," Mehrotra wrote. "On the heels of this data release combined with a more aggressive registrational schedule and breakthrough therapy designation from the FDA, we see Merck as a serious competitor in the HCV market."

The news about HCV candidates came just as the World Health Organization released its first-ever guidelines regarding the disease, listing nine recommendations that include screening and limited alcohol intake.

Gilead had more antiviral-related news. In a new petition to the FDA, the company is asking that the agency reconsider its decision to extend to five years (from three) the marketing exclusivity for fixed-dose combinations that include a new chemical entity with previously approved components – but that the extension would not apply retroactively, which left Gilead's HIV therapy Stribild without the advantage. Approved in 2012, Stribild combines two new active moieties, elvitegravir and cobicistat, and two previously approved components, emtricitabine and tenofovir disoproxil fumarate. (See BioWorld Today, Aug. 27, 2013, and Feb. 25, 2014.)

In the new petition, the law firm of Hogan Lovells wrote on behalf of Gilead that the company "does not believe that FDA has adequately considered the relevant information," and that "sound public policy grounds [exist for] supporting reconsideration," including Gilead's good faith in coming up with the drug. "Not only did Gilead develop a product that met the federal government's goal of developing a 'single pill regimen' for the treatment of HIV, but Gilead also advanced a significant structural change to the development of medically important fixed-combination products," according to the petition.

The biotech sector was down generally Thursday, although RBC's Yee speculated that Merck's data put special pressure on Gilead. "Investor sentiment on Gilead continues to shift from bullish to very mixed with long-term debate and uncertainty," he wrote in a mid-afternoon research report, as investors continued to debate the meaning of what's been unveiled so far at the EASL meeting.

Gilead's shares (NASDAQ:GILD) closed at $65.48, down $5.17, Merck (NYSE:MRK) ended the day at $55.85, down $1.25, and BMS (NYSE:BMY) finished at $49.29, down $1.28.