Three smashing clinical successes by Gilead Sciences Inc.'s nuc drug GS-7977 for hepatitis C virus (HCV) have lit up the 2012 International Liver Congress of the European Association for the Study of the Liver, sending the company's stock up 12 percent Thursday.
Just two months ago, early results from Gilead's Phase II ELECTRON trial seemed to show GS-7977 circling the drain. Six out of eight patients with a prior null response to an interferon regimen relapsed within four weeks of completing a course of GS-7977 plus ribavirin. (See BioWorld Today, Feb. 21, 2012.)
However, the trial made a thrilling turnaround, handing in a result of 88 percent of genotype 1 patients showing undetectable HCV RNA at four weeks post-treatment. GS-7977 also performed well in combination with pegylated interferon and ribavirin in Foster City, Calif.-based Gilead's Phase II ATOMIC trial, with 90 percent of treatment-naive genotype 1 patients achieving a 12-week sustained virologic response (SVR) after completing therapy.
Perhaps most significant, though, are results reported by Bristol-Myers Squibb Co. showing that an all-oral combination consisting of its investigational NS5A inhibitor daclatasvir and GS-7977 achieved a stunning 100 percent sustained virologic response at four weeks after treatment.
Gilead's vice president of public affairs, Amy Flood, told BioWorld Today that the difference between the early results for ELECTRON, reported in February, and the current results is in the patient population. Those earlier results were from a cohort of null responders.
"The cohort announced today was a group of genotype 1 treatment-naïve patients," she said. "We are encouraged by the results and look forward to advancing further studies of GS-7977."
In the randomized, open-label trial, patients with genotype 1, 2 or 3 HCV received eight or 12 weeks of treatment with GS-7977 400 mg once-daily with or without ribavirin (RBV) and/or pegylated interferon (PEG-IFN). The primary endpoints of the trial were safety and tolerability. Populations within the study group included treatment-naive, noncirrhotic patients and null responders, or patients who had failed prior interferon-based therapies.
BMO Capital Markets analyst Jim Birchenough called the ELECTRON results "impressive," noting, "The 88 percent SVR4 rate for GS-7977 plus ribavirin is above Street expectations and confirms our view that GS-7977 will likely be a backbone of choice in future treatment of HCV."
Gilead also reported interim results from QUANTUM, a Phase II, randomized, double-blind, placebo-controlled study of GS-7977 for chronic HCV infection. Patients in the trial were randomized to GS-7977 400 mg once-daily plus ribavirin for 12 or 24 weeks. The study group included cirrhotic and noncirrhotic, treatment-naïve patients with genotype 1, 2 or 3 HCV. Results for the cohort that received and completed 12 weeks of therapy showed that at four weeks after treatment, 10 out of 17 patients (59 percent) remained HCV RNA undetectable, and seven patients (41 percent) had relapsed.
An additional seven patients who had achieved SVR4, have reached the eight week mark and remain HCV RNA undetectable.
A third set of study results from the randomized, open-label Phase II (ATOMIC) trial of GS-7977 plus pegylated interferon and ribavirin also showed strong results. In a group of treatment-naive patients with genotype 1 chronic HCV, after a 12-week course of treatment with GS-7977/Peg-IFN/RBV, 47 out of 52 (90 percent) of patients achieved a 12-week SVR.
The Interferon-Free Regimen Leader
The cascade of positive results for GS-7977 drives home the point that the drug is a strong contender in a very crowded field. It also puts Gilead at the front of the pack to develop the coveted all-oral, interferon-free HCV treatment regimen.
The daclatasvir/GS-7977 dream combo has a lot going for it. The 100 percent SVR4 compares well with Abbott's 93 percent to 95 percent for ABT-450/ABT-333 (Co-Pilot), and 91 percent for Abbott's ABT-450/ABT-072 (Pilot).
Jefferies & Co. analyst Tom Tarrant noted that the trials are small enough that there's no meaningful difference between 91 percent, 95 percent and 100 percent. "The difference between this 100 percent cure rate and the 93-95 percent seen in Co-Pilot is merely down to one patient in each arm discontinuing treatment it is not due to failed efficacy. Not until the larger Phase III studies readout will we truly be able to determine the relative differences."
The Abbott combo has an important advantage in that it has already met the SVR12 benchmark required for regulatory approval. Roche AG reported that its interferon-free regimen danoprevir/mericitabine yielded SVR12 of 26 percent and 71 percent in genotype 1a and genotype 1b patients, respectively, putting it far behind BMS/Gilead and Abbott. Novartis AG put its antiviral DEB025 on clinical hold following reports of pancreatitis.
Achillion Pharmaceuticals Inc., which did not release any new data at EASL, nonetheless took some punishment in terms of lost stock value. Achilllion's pipeline includes NS3 protease inhibitor ACH-1625, NS5A inhibitor ACH-2928, and a number of other compounds in development. Achillion stock (NASDAQ:ACHN) lost $1.20, or 12.6 percent, on Gilead's big day, closing at $8.30.
Wells Fargo analyst Brian Abrahams saw that as an opportunity. "Today's data does not change our view that ACHN's agents will likely find a place in future all-oral paradigm and enable the company to capture some meaningful revenues in this major market. We would be buyers on today's weakness," Abrahams wrote.
Pharmasset Buy Vindicated
The success of GS-7977 also vindicated Gilead's $11.2 billion purchase of Pharmasset Inc. six months ago. At the time, some analysts questioned the huge investment. Leerink Swann's Joshua Schimmer wrote, "While we understand the strategic rationale, the price tag is lofty for a pre-commercial asset and not aligned with what we would like to see from GILD in terms of capital allocation." (See BioWorld Today, Nov. 22, 2012.)
A poll in November 2011 by ISI Group analyst Mark Schoenebaum showed analysts split down the middle on whether the deal would create (49 percent) or destroy (51 percent) value for Gilead.
In spite of the obvious strength of the daclatasvir/GS-7977 combination, there is some doubt as to whether it will progress into Phase III studies. BMS spokeswoman Sonia Choi confirmed rumors that Gilead had turned down an opportunity to partner with BMS for a Phase III trial.
"Bristol-Myers Squibb was interested in a Phase III collaboration with Gilead for this combination, given the potential benefit for patients; however, Gilead was not interested," Choi told BioWorld Today.
Gilead would neither confirm nor deny that assertion. "We don't and haven't in the past discussed possible business deals or collaborations publicly, so we can't comment further," Flood told BioWorld Today. "What we have said is that there are a number of new datasets at EASL and we need to evaluate and understand all of them. We're going to do that, and look at the best option or options for proceeding as quickly as possible to advance the best all-oral regimen."
At the time it acquired Pharmasset, Gilead announced its intention to develop an in-house combo regimen, using components from the combined Gilead/Pharmasset pipeline. "We have all the ingredients in hand now, so to speak, to explore whatever we need," Gilead Chief Scientific Officer Norbert W. Bishofberger said. Such a combo would pair GS-7977 (formerly PSI-7977) with PSI-938, another protease inhibitor, and/or an NS5A inhibitor.
Gilead execs were very pleased with the results for GS-7977, noting that it had the potential to be the cornerstone of an all-oral combination regimen in chronic HCV infection. The company has begun a Phase III program for genotype 2 and 3 patients.
"We are looking at many options to proceed as quickly and efficiently as possible toward our goal of developing a safe, effective, simple all-oral therapy that will eliminate the need for interferon and/or shorten duration of therapy. We will be continuing our ongoing discussions with FDA regarding the best and most efficient path forward," said Flood.
Gilead stock (NASDAQ:GILD) gained $5.64 to close at $52.25 on Thursday.
In other EASL news:
Abbott, of Abbott Park, Ill., and Enanta Pharmaceuticals Inc., of Watertown, Mass., reported data from CO-PILOT, an interferon-free, Phase II study of Abbott's direct-acting antivirals in hepatitis C (HCV), indicating more than 90 percent of patients new to HCV treatment achieved sustained viral response through 12 weeks (SVR12). In the three-arm CO-PILOT study, different doses of ABT-450/r, plus ABT-333 and ribavirin administered for 12 weeks, showed SVR12 post-treatment in 95 percent and 93 percent of treatment-naive genotype 1 patients, with no post-treatment relapses. Response was independent of HCV subtype, host IL28B genotype or dose of ABT-450/r. In addition, SVR12 was achieved in 47 percent of patients who were previous non-responders to past HCV treatment. Separately, the companies reported data from the PILOT study, Abbott's initial interferon-free study of its direct-acting antiviral agents for the treatment of hepatitis HCV, showing that 91 percent of genotype 1 infected, treatment-naive patients taking ABT-450/r and ABT-072 combined with ribavirin administered for 12 weeks achieved SVR24, and 82 percent achieved SVR36. This is among the first 12-week, interferon-free HCV regimens with 36-week post-treatment data in genotype 1 patients. Abbott is developing ABT-450, discovered as part of a potential $307 million HCV alliance with Enanta, for use in combination with its non-nucleoside polymerase inhibitors, ABT-333 and ABT-072, and NS5A inhibitor ABT-267. (See BioWorld Today, Dec. 13, 2006.)
Boehringer Ingelheim Pharmaceuticals Inc., of Ridgefield, Conn., reported data from a descriptive subanalysis of patients with compensated liver cirrhosis showing that up to 43 percent of genotype-1a (GT1a) and up to 71 percent of GT1b hepatitis C virus (HCV) patients achieved sustained viral response. The descriptive subanalysis from SOUND-C2, an open-label Phase IIb study evaluating interferon-free treatment with the company's investigational direct-acting antiviral compounds BI 201335 and BI 207127 plus ribavirin, includes 362 HCV GT1a and 1b patients with compensated liver cirrhosis, regardless of IL-28B allele status. No patients treated with BI 207127 twice-daily experienced relapse after treatment completion. Seven patients discontinued treatment early due to adverse events, including rash, photosensitivity and jaundice caused by isolated hyperbilirubinemia not associated with liver dysfunction.
Danish researchers reported data suggesting childhood obesity is positively linked with developing hepatocellular carcinoma (HCC), the most common form of liver cancer, in adulthood. The Danish study monitored birth weight and body mass index at school age of 165,540 men and 160,883 women born between 1930 and 1989. The authors calculated and compared the risk of developing HCC from the 252 participants who had developed HCC at follow-up. At age 7, the risk of developing HCC increased by 1.12 per unit of increase in BMI; however, at age 13 this risk increased to 1.25. Therefore, as units of BMI increased into adulthood, so did the risk of developing HCC. The findings were consistent across both sexes and all ages. Results did not change when participants with comorbidities such as alcoholism, hepatitis B and C infection and other liver diseases were removed from the study, indicating childhood obesity was the major factor in the development of HCC. The study was funded and carried out as part of the Fatty Liver Inhibition of Progression consortia, supported by the European Commission through the Seventh Framework Programme for Research and Development.
Merck and Co. Inc., of Whitehouse Station, N.J., reported results from a Phase III open-label trial of two anemia management strategies for patients in treatment with Victrelis (boceprevir) and Pegintron (peginterferon alfa-2b) and ribavirin for hepatitis C virus. The objective was the effect on sustained virologic response (SVR). The two strategies were ribavirin dose reduction and addition of erythropoietin. The SVR rate was 71 percent for both groups, and the rate of relapse was 10 percent for both groups.
Santaris Pharma A/S, of Hoersholm, Denmark, presented final data from a randomized, double-blind, placebo-controlled, ascending multiple-dose Phase IIa trial showing that miR-122 antagonist miravirsen, given as a four-week monotherapy treatment in treatment-naïve patients with chronic hepatitis C virus (HCV) genotype 1 infection, provided robust dose-dependent antiviral activity, with a mean reduction of two to three logs from baseline in HCV RNA (log10 IU/mL) that was sustained well beyond the end of therapy. For four of nine patients treated at the highest dose (7 mg/kg) of miravirsen, HCV RNA was undetectable with five weekly doses of monotherapy, with no evidence of viral resistance. Study results demonstrated miravirsen was safe and well tolerated, with adverse events generally infrequent, mild and similar between treatment groups. No dose-limiting toxicities or discontinuations due to adverse events occurred. Santaris has a potential $614 million deal with Pfizer Inc. to extend their collaboration to develop and commercialize as many as 10 new RNA targets using Santaris' locked nucleic acid platform. (See BioWorld Today, Jan. 5, 2011, and Jan. 13, 2009.)
Vertex Pharmaceuticals Inc., of Cambridge, Mass., reported that a retrospective subanalysis of its Phase II (PROVE 2) trial showed 12 out of 12 (100 percent) patients with the IL28B CC hepatitis C virus (HCV) genotype who were new to treatment achieved a viral cure after 12 weeks of treatment with Incivek (telaprevir), pegylated interferon and ribavirin. The data supported an ongoing Phase IIIb trial evaluating treatment duration of 12 weeks in people with that genotype. The company also said that it will open enrollment for a Phase IIb study of an all-oral, interferon-free, 12-week regimen for people with genotype 1a and 1b HCV.