HCV Forecast: Merck, AbbVie Next-Gen Data Not Overtaking Gilead

The hepatitis C competition has thinned out in recent years, but several companies are still pursuing Gilead Sciences Inc., including AbbVie Inc., Merck & Co. Inc., Bristol-Myers Squibb Co. and Johnson & Johnson. The main battle now is for short-duration, pan-genotypic regimens, but coming out of the American Association for the Study of Liver Diseases conference, the general assessment is that Gilead is stabilizing its position at the front of the pack.

Analyst reviews of Phase II data of next-generation combination therapies in development at AbbVie and Merck were uniformly positive, but Gilead already has a next-generation two-drug combo under review at FDA and is in Phase III with a three-drug combo that analysts see as maintaining Gilead's dominance in the HCV space (Also see "Gilead Details Its HCV Dominance As AbbVie Seeks Meaningful Market Position" - Pink Sheet, 3 Aug, 2015.).

Competitors to Gilead have sought niches within the HCV-infected population and shorter durations of therapy than Gilead can offer, but despite reams of impressive data, nothing has given Merck, AbbVie or any other company a defined edge in the current or future competition.

After speaking with HCV key opinion leaders at AASLD, held Nov. 13-17 in San Francisco, UBS Investment Research analyst Matthew Roden headlined his Nov. 17 note "Gilead HCV positioning stronger coming out of AASLD," adding that competitors failed to "mount a major threat."

"Gilead's [Phase III] ASTRAL dataset was a shock-and-awe campaign with very high SVRs across all six genotypes, including decompensated cirrhotics," the analyst wrote. "This sets a much-higher bar for next-gen regimens, which at some point may need to show non-inferiority to gain FDA approvals (as seen in HIV)."

Decompensated cirrhotics represent a crucial subset of HCV patients as they are the toughest subpopulation to cure. [This may be yet another HCV subpopulation in which Gilead is working toward a competitive advantage, see related story: (Also see "Decompensated Cirrhosis May Be Another HCV Edge For Gilead; Bristol, J&J Still In Contention" - Pink Sheet, 23 Nov, 2015.).]

Jefferies Equity Research analyst Brian Abrahams agreed that Gilead's top spot looks secure coming out of the meeting. Data presented by Merck showed "no clear duration, dosing, efficacy or safety advantages versus Gilead's products," he wrote in a Nov. 16 note.

At the conference, Gilead presented data from a series of Phase III trials testing the combo of its nucleoside polymerase inhibitor Sovaldi (sofosbuvir) and next-generation NS5A inhibitor velpatasvir (GS-5816), which was filed for approval at FDA on Oct. 28 as a possible successor to Harvoni (sofosbuvir/ledipasvir), currently the dominant product in HCV therapy (Also see "Gilead Addresses HCV Vulnerability With Strong Genotype 3 Data" - Pink Sheet, 18 Nov, 2015.). Ledipasvir is Gilead's first-generation NS5A inhibitor, but does not offer pan-genotypic activity.

Especially noteworthy were data in the tough-to-treat genotype 3 subpopulation – in its ASTRAL-3 study, Gilead tested 12 weeks of sofosbuvir/velpatasvir against the current standard-of-care with Sovaldi and ribavirin for 24 weeks (Also see "New Phase III Data May Give Gilead A Leg Up In Genotype 3 HCV Patients" - Pink Sheet, 21 Sep, 2015.). The next-gen regimen posted a 95% sustained virologic response rate 12 weeks after the conclusion of therapy (SVR12), compared to 80% for the control regimen. In cirrhotic genotype 3 patients, sofosbuvir/velpatasvir cured 89% compared to 58% in the control arm.

Not only is genotype 3 the toughest of the six genotypes to cure, but it is the second-largest after genotype 1, representing an estimated 30% of global HCV-infected population, roughly 54.3 million people. Gaining a majority share of this subpopulation remains a top priority for Merck's, AbbVie's and Bristol's HCV development programs.

Concerns Rise About Protease Inhibitor Safety

Roden suggested that Gilead's two-drug regimens may have an additional advantage, as they don't include a protease inhibitor. Clinicians are beginning to worry about protease inhibitor-based HCV therapy, due to incrementally more liver toxicity findings as well as susceptibility to resistance-associated mutations (RAVs) at baseline, he said.

"Hence, we think Gilead's nuc-based regimens are comparatively more attractive and thus see upside to our Gilead market-share assumption," Roden wrote.

AbbVie's Viekira Pak and Technivie both include the PI paritaprevir, while J&J has reached market with the PI Olysio (simeprevir), which is often used in combination therapy with Sovaldi (Also see "U.S. HCV Competition Increases As Bristol, AbbVie Get Same-Day Approvals" - Pink Sheet, 24 Jul, 2015.). Merck has a Jan. 28 user fee date for its once-daily, two-drug fixed-dose combo of PI grazoprevir and NS5A inhibitor elbasvir, and has moved a next-generation three-drug combo of grazoprevir with the pan-genotypic NS5A inhibitor MK-8408 and "nuc" MK-3682 into Phase III (Also see "Merck's HCV Strategy Might Be: Get To Market, Then Improve Incrementally" - Pink Sheet, 16 Nov, 2015.).

Despite this potential advantage, Gilead is not ceding the protease inhibitor-based therapy space to competitors – it has a combination in Phase II of sofosbuvir, velpatasvir and its next-generation PI candidate GS-9857.

"Although Gilead's strategy for the … triple [combo] isn't fully set, we surmise they will position 12-week sofosbuvir/velpatasvir as the basic regimen to treat all patients up front in an effort to broaden the prescribers and ease treatment of large numbers of patients," Roden said. "The triple may then be used by specialists as a salvage regimen, potentially addressing hundreds of thousands of patients over time."

The main benefit of the three-drug combo for Gilead may be a chance to offer an eight-week duration of therapy for some patients, but shortening of therapy below 12 weeks is becoming less of a priority, he added, especially as next-generation C-CREST data presented by Merck at AASLD put into question how viable its own efforts to develop an eight-week regimen remain. Going forward, Merck continues to investigate eight-week therapy, but no longer appears to be pursuing six-week regimens.

Shorter Than 12-Week Therapy May Be Unlikely

Roden suggested that Merck probably will have to use 12 weeks of therapy to produce SVR rates across genotypes that will be competitive with Gilead's therapeutic options. AbbVie is testing its pan-genotypic, next-generation duo of protease inhibitor ABT-493 and NS5A inhibitor ABT-530 in 12-week regimens, and has produced strong data, but in easier-to-treat patients, the analyst said.

In a Nov. 16 note, Leerink Partners analyst Seamus Fernandez said Merck's eight-week SVR data with its three-drug combo "appears less compelling" than that being produced by Gilead's three-drug regimen in the crucial genotype 3 patient group. Still, he predicted Merck might succeed in producing an eight-week regimen that is competitive with Gilead, but that price and access then will be the "major determinant of success."

Near-term, Fernandez paints a brighter picture for Merck in terms of possibly usurping AbbVie from its distant second-place positioning in HCV. The grazoprevir/elbasvir fixed-dose combo "will likely become preferred over Viekira Pak upon its approval," he said in a Nov. 18 AASLD overview note.

Merck's initial SVR rates with eight weeks of treatment in genotypes 1, 2 and 3 "appear to support broad activity … in treatment-naïve, non-cirrhotics, but we await further data in more difficult-to-treat patients," Fernandez added. Similarly, he said AbbVie's ABT-493/ABT-530 combo demonstrated impressive cure rates over 12 weeks of therapy in non-cirrhotic genotype 1, 2 and 3 patients, holding out the potential for an eight-week regimen for genotype 1 patients.

"However, without a nuc in the combo, we remain cautious about its prospects for shortened durations in harder-to-treat patients," the analyst said.

AbbVie VP-Infectious Disease Development Barry Bernstein said in an interview that his company continues to believe it does not need to add a nuc to its pipeline or test the '493/'530 combo with another company's HCV drug or drug candidate.

"The results we are seeing in our Phase II studies look very promising," he said, "and we think that the profile will be highly competitive with other regimens that will be introduced in a similar timeframe and that the addition of other agents is unlikely to result in significant benefit."

Merck VP-Infectious Disease Eliav Barr, meanwhile, said the soon-to-be new kid on the block is focusing on a tough-to-treat population that largely has been ignored or overlooked in HCV studies to date: HCV-infected people who inject drugs. This group is thought to be responsible for about 80% of the transmission of HCV, yet often gets excluded from studies due to stigmatization or an expectation that such participants won't comply with the trial regimen, he explained.

Merck has yielded a 91% SVR12 rate looking at this population in the Phase II C-CREST CO-STAR study, and the cure rate is 95.5% if patients who get re-infected are excluded from the results, Barr said. Twenty-one percent in this study are cirrhotic and 7% are co-infected with HIV.