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Partial Clinical Hold Shakes Vertex, Most Trials Continue

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By Catherine Shaffer
Staff Writer

The FDA imposed a partial clinical hold on an ongoing Phase II study of Vertex Pharmaceuticals Inc.'s hepatitis C virus candidate, VX-135, due to observations of elevated liver enzymes in patients receiving a 400-mg dose of the drug in the trial.

The hold will stop evaluation of the 200-mg dose, but assessment of the 100-mg dose of VX-135 in combination with ribavirin will continue as planned.

Vertex stock (NASDAQ:VRTX) lost $6.91, or 7.9 percent, to close at $80.71 on Friday.

"We will be providing requested data to the FDA on an ongoing basis over the coming months," Zachry A. Barber, director of corporate communications for Vertex told BioWorld Today.

The data include clinical, preclinical and pharmacokinetic data from ongoing studies. "We have already provided preliminary safety data to the FDA from the U.S. and European studies, and we plan to complete submission of the requested data in the fourth quarter."

Vertex's other ongoing and planned studies of VX-135 include a U.S.-based, 12-week Phase II study of 100-mg VX-135 in combination with ribavirin; a European, 12-week, Phase II study of 100-mg and 200-mg VX-135 with ribavirin; a collaborative Phase II study with Bristol Myers Squibb Co. of VX-135 with daclatasvir; and a combination study of VX-135 and simeprevir in genotype 1 hepatitis C.

Vertex, of Cambridge, Mass., and Glaxosmithkline plc, of London, recently terminated a collaborative Phase II study of VX-135 and GSK-2336805 to prioritize other projects, although preclinical and early stage clinical data supported continued development of the combo.

Vertex's strategy in hepatitis C is to develop an all-oral treatment with a high cure rate for a multiple hepatitis C genotypes. "With multiple studies under way with VX-135, including the U.S. and European studies with ribavirin and the recently initiated study with daclatasvir in New Zealand, our hepatitis C strategy is unchanged, and we look forward to generating data from these studies over the coming months," Barber said.

VX-135 is designed to target the NS5B polymerase of hepatitis C virus. Vertex's in vitro studies showed antiviral activity against all genotypes of HCV. The compound was acquired through a licensing agreement with Alios Biopharma Inc. in June 2011. (See BioWorld Today, June 14, 2011.)

Vertex paid Alios $60 million up front, and promised research and development milestone payments of up to $715 million, and another $750 million in sales milestones, plus tiered royalties on product sales.

Preliminary efficacy data for VX-135 have been promising. In two small European study cohorts, rapid virologic response (RVR) rates were 70 percent and 80 percent, for the 100-mg and 200-mg doses, and after 12 weeks all patients were undetectable with no breakthroughs.

That result falls short of competing investigational combo treatment by Gilead Sciences Inc., sofosbuvir plus ribavirin, which had a striking 100 percent RVR rate in treatment-naive and null patients in Gilead's ELECTRON study. Wells Fargo's Brian Abrahams cautioned, "The limitations of comparing across studies with different geographies and with small numbers make it difficult to conclude that '135 is less potent than sofosbuvir at the 100 mg and 200 mg doses."

Abrahams had some concerns about the hold on VX-135, and its restriction on exploring the 200 mg dose. "We believe the narrower therapeutic window adds some developmental risk. . . . Still, the drug looks to be reasonably potent at lower doses and could produce competitive SVRs in a go-forward cocktail, and despite the setback, we think scarcity value and blockbuster potential remain."

All About Cystic Fibrosis

RBC Capital Markets analyst Michael Yee saw opportunity in the stock drop related to the news about the FDA's hold. "We'd be buyers on weakness as the HCV program is only upside and the real long-term value is still 'all about cystic fibrosis.'"

Vertex tallied net product revenues of $62 million from its recently launched cystic fibrosis drug Kalydeco (ivacaftor) in the first quarter of 2013. Following the February 2012 launch of the drug, its rapid uptake in a majority of eligible patients in the U.S. contributed to the solid revenue.

Abrahams also highlighted a development in the cystic fibrosis program, the expansion of a Phase II trial of VX-661 to include heterozygotes and to explore Kalydeco/VX-661 dose-ranging. "It is a positive surprise to us that VRTX is already starting to explore other ways to approach heterozygous patients – who may comprise 15 percent+ of the CF population – in parallel with their regulatory discussions on next steps for '661, and believe additional details on their strategy . . . could solidify enthusiasm over their approach to capturing the broadest CF opportunity."