HBV candidate falters in phase II; Gilead Sciences to seek other options?
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By Jennifer Boggs
Managing Editor
Investors watching for signs of M&A activity from Gilead Sciences Inc. could be eyeing the big biotech even more closely after top-line phase II data revealed a missed primary endpoint for hepatitis B virus (HBV) contender GS-4774, prompting speculation that the Foster City, Calif.-based firm could tap other players to shore up its early but promising HBV pipeline.
Meanwhile, it's not the end of the road for GS-4774, though partner Globeimmune Inc.'s stock (NASDAQ:GBIM) took a hit Wednesday – falling $4.23, or 51.3 percent, to close at $4.01 – on data showing that the therapeutic vaccine failed to produce a reduction in hepatitis B surface antigen (HBsAg) at week 24 in patients with chronic HBV on long-term viral suppression with oral antiviral (OAV) therapy. The company, however, pointed to biological activity seen with longer treatment duration.
At 48 weeks, patients given the highest dose of GS-4774 plus ongoing oral antiviral therapy (OAV) had a mean -0.17 log10 reduction of HBsAg vs. -0.04 log10 reduction in the OAV group. While not statistically significant, Globeimmune said the results suggest "initial biologic activity at the highest dose tested."
Notably, three patients in the highest dose cohort had HBsAg reductions between -0.94 log10 and -3.89 log10 at week 48; however, there were no differences in HBsAg reductions between either of the two lowest-dose groups vs. the control arm.
The trial – 0101 – enrolled 178 patients randomized to one of three doses – 2YU, 10YU or 40YU, with one YU equal to 10 million yeast cells – in combination with OAV vs. OAV alone. The product was found to be generally safe and well tolerated.
Globeimmune will be working with Gilead to further characterize the T-cell response to GS-4774, while awaiting results from a second phase II study in treatment-naïve HBV patients. The Louisville, Colo.-based biotech declined further comment, but Deutsche Bank analyst Robyn Karnauskas said in a research note that the company was looking "more at immunological parameters" such as robust antibody, S antigen or T-cell responses, in the phase II study.
Developed from Globeimmune's Tarmogen platform, GS-4774 is a yeast-based vaccine designed to express recombinant antigens targeted for an HBV-specific immune response. It is designed to generate a T-cell immune response against cells containing HBV antigens, thereby increasing the cure rate in HBV.
The question is whether that response will be strong enough.
For his part, RBC Capital Markets analyst Michael Yee has remained skeptical. In a research note during last year's American Association for the Study of the Liver meeting in Boston, he suggested "more is needed besides an immune stimulation to cure HBV."
Following the phase II data reveal, Yee reiterated that the "slight evidence of a dose response and better effect over [a] longer period of time" is "not impressive enough." He added that he remains doubtful the second phase II in treatment-naïve patients will yield sufficiently positive data.
That means, in Yee's view, Gilead will need more options, and "down the road we predict [Gilead] will have to do more deals in this space." He suggested, in particular, that the firm was likely tracking early players Tekmira Pharmaceuticals Corp. and Assembly Biosciences Inc.
Burnaby, British Columbia-based Tekmira, which merged its HBV portfolio through a deal early this year with Oncore Biopharma Inc. – a firm founded by former execs at Pharmasset Inc., a company snagged by Gilead for the hepatitis C virus (HCV) candidate that would become Sovaldi (sofosbuvir) – recently began phase I testing of two TKM-HBV candidates. Described as multicomponent RNAi therapeutics, they are designed to target three sites on the HBV genome simultaneously and differ only in their liposomal nanoparticle formulation. (See BioWorld Today, Jan. 13, 215.)
Results from healthy volunteers are expected to determine which formulation will advance into a multidosing regimen in chronically infected patients, set to start testing in the second half of this year. Coming up behind TKM-HBV are candidates from Oncore's pipeline, specifically a second-generation cyclophilin inhibitor targeting viral replication, also set to start phase I studies in the latter half of 2015.
Shares of Tekmira (NASDAQ:TKMR) closed Wednesday at $13.85, up 30 cents. The firm has a market cap of about $751 million.
Work at Assembly is even earlier stage, with the San Francisco-based firm not planning to move into clinical trials until 2016 with its first-generation lead core protein allosteric modulators, or CpAMs. In preclinical testing, CpAMS appeared to be able to selectively reduce the production of viral antigens and reduce viral load, which could allow for both monotherapy and combination therapy approaches, the company has said.
Assembly, which was founded in 2014 with the merger of publicly held Ventrus Biosciences Inc., recently padded its balance sheet with a $75 million public offering. The firm's shares (NASDAQ:ASMB) gained 65 cents to close Wednesday at $15.92. Its market cap is estimated at about $272 million. (See BioWorld Today, March 20, 2015.)
SIGNIFICANT MARKET OPPORTUNITY
A chronic infectious disease that also is the leading cause of chronic liver disease and liver transplants, HBV is estimated to affect nearly 350 million people worldwide, according to the World Health Organization. That's about 6 percent of the global population. Currently, the standard antiviral regimen for HBV is interferon alpha, a nucleoside or nucleotide analogue or various combinations, but the disease has proved a tough one to treat, perhaps even more so than HCV.
Among other potential competitors in the space include privately held Novira Therapeutics Inc., which is in phase I trials with NVR 3-778, an HBV capsid assembly inhibitor. Later-stage candidates are ARC-520, an RNAi candidate from Arrowhead Research Corp. that is in a phase IIb multiple-dose trial, and Abivax SAS, which recently launched a pivotal phase IIb/III trial of therapeutic vaccine ABX203, targeted specifically to e-antigen-negative active HBV patients. (See BioWorld Today, Feb. 27, 2015.)
Gilead, which inked the Globeimmune deal in 2011, has been actively building up its HBV franchise in much the same manner as it did in HIV and, more recently, HCV. Its product pipeline already includes Viread (tenofovir disoproxil fumarate), a drug approved for HBV since 2008, and the firm is in phase III testing with tenofovir alafenamide, or TAF, a nucleotide reverse transcriptase inhibitor. (See BioWorld Today, Oct. 26, 2011.)
On its own, it also has GS-9620, an interferon alpha ligand and Toll-like receptor 7 agonist, in phase II testing against HBV. Data are expected later this year. In that trial, Deutsche Bank's Karnauskas noted, Gilead believes that it does "not need to see a complete S antigen conversion, but would like to see a signal that clearly indicates a reduction of S antigen to move into [phase III]," though she acknowledged that the "key unknown is how much of a reduction in S antigen is required to drive a functional cure."
Overall, Karnauskas predicted that HBV could be a $15 billion opportunity for Gilead, which also boasts an early stage screening program to identify oral, small molecules targeting covalently closed circular DNA, or cccDNA, whose presence in the nucleus of infected cells is believed to be the primary mechanism of chronic HBV disease.
Shares of Gilead (NASDAQ:GILD) closed Wednesday at $112.46, up $2.69. 作者: newchinabok 时间: 2015-5-31 10:13
