HCV Relapses Short Circuit Gilead's ELECTRON Study
By Catherine Shaffer
Disappointing results from Gilead Sciences Inc.'s Phase II ELECTRON study of nucleotide analogue polymerase inhibitor GS-7977 showed that 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.
With analysts still picking apart the big biotech's recent acquisition of GS-7977 through its $11 billion buyout of Pharmasset Inc., the news sent Gilead stock's (NASDAQ: GILD) plummeting $7.81, or 14 percent, to close Friday at $46.82. (See BioWorld Today, Nov. 22, 2011.)
Gilead hasn't lost confidence in GS-7977, however, and is looking forward to gathering more data on the drug, either in the context of a longer treatment, or in combination with other drugs. ELECTRON results suggest that additional direct-acting antivirals may be necessary to treat those null responders, though they tend to deflate hopes in the "nucs" as panacea in HCV.
In a conference call Friday morning, Gilead's chief scientific officer, Norbert W. Bischofberger, said, "My own personal opinion would simply be that GS-7977/ribavirin for 12 weeks is not enough virological suppression that you could clear the virus in 12 weeks."
Earlier this month, Gilead disclosed earlier data from ELECTRON showing that 100 percent of patients in two cohorts – treatment-naïve and null responders – achieved rapid viral response at four weeks. (See BioWorld Today, Feb. 6, 2012.)
"Maybe we were a little more enthusiastic than we should have been," said John F. Milligan, Gilead's chief operating officer. The company speculated that the later relapses may have resulted from virus present below detection limits.
Milligan called null responders the "most difficult" group. "Null responders have always been different," Milligan said. "Historically, they've always responded less."
Gilead execs said they believe that extended treatment with GS-7977, or a combination of GS-7977 and another agent such as NS5A inhibitor GS-5885, could get them "over the hump" in terms of sustained virologic response in null interferon responders.
Each quarter of 2012, the GS-7977 picture will get a little clearer.
First data from the QUANTUM study are due at the end of the first quarter. That study is evaluating GS-7977 plus ribavirin for 12 weeks in genotype 1 naive patients. In the second quarter, Gilead will report data from the genotype 1 naive arm including 25 patients. The third quarter will bring data on GS-7977 and ribavirin for 24 weeks.
Gilead also is enrolling for a pivotal study, FISSION, in treatment-naive patients with genotype 2 or 3 HCV, and those data should be available early in 2013.
With the discouraging results from null responders in ELECTRON, Gilead is looking forward to positive results from a Phase II study of GS-7977 in combination with GS-5855 that it is preparing to launch. If remaining results for ELECTRON are positive, and if things go well for FISSION and QUANTUM, Gilead is maintaining that GS-7977/ribavirin could still be approved in 2014.
In spite of the stock slide, analysts are not too worried about the null responder results. "Although these results are disappointing, wrote Oppenheimer & Co.'s Bret Holley, "we expect '7977+RBV to be substantially more effective in the more prevalent treatment-naive [genotype] 1 population and expect QUANTUM/ELECTRON results in this population in 1Q12/2Q12, respectively." He added, "We view today's weaknesses to be a substantial overreaction."
Piper Jaffray's Ian Somaiya maintained an "overweight" rating on Gilead's stock. "We believe the feature of the HCV pipeline will be the combination of GS7977+GS5885 (NS5A inhibitor), which should address the relapses seen in the ELECTRON trial."
Wells Fargo analyst Brian Abrahams was more cautious in his assessment. "Although this initial data was in a very difficult to treat 'null' population, we believe the results could indicate '7977 alone +RBV will not be sufficient in any [genotype 1] group. The setback could push timelines for capturing this broad population back modestly (reducing their first-mover advantage a bit), adds some risk if GILD needs to rely on another agent in combination to get over the line in [genotype 1 patients], and is likely to add to the perception that GILD may have overpaid" for Pharmasset.
Abrahams noted, however, that the "backup plan" of combining GS-7977/ribavirin with GS-5885 was "very viable."
Gilead's HCV pipeline is broad. In addition to GS-7977 and GS-5885, Gilead also has protease inhibitors GS-9541 , GS-9190, and GS-9256 in Phase II trials. TLR-7 agonist GS-9620, non-nucleoside polymerase inhibitor GS-9669 and nucleoside reverse transcriptase inhibitor GS-7340 are in Phase I trials.
The firm is depending on its HCV franchise to offset threats of generic competition to its HIV business. Its four-drug, single-tablet HIV regimen called Quad is under review in the U.S. and Europe. Quad is composed of Truvada (emtricitabine/tenofovir disoproxil fumarate), elvitegravir and cobicistat.
It won approval of Complera – a combination of Truvada with Tibotec Pharmaceuticals Inc.'s rilpivirine – in August 2011 . Gilead also is developing drugs in cardiovascular, respiratory and oncology indications, including Phase III-stage aztreonam for inhalation solution for brochiectasis and GS-1101, a P13K delta inhibitor in Phase III testing in chronic lymphocytic leukemia.
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