Wall Street was unforgiving Tuesday, one day after Vertex Pharmaceuticals Inc. and partner Aventis SA voluntarily stopped a Phase IIb trial of a rheumatoid arthritis candidate on news that a related animal toxicology study turned up liver abnormalities.
Vertex's stock (NASDAQ:VRTX) fell $4.65 Tuesday, or 36.8 percent, to close at $8.
Pralnacasan, the candidate in question, is an oral interleukin-1 beta converting enzyme (ICE) inhibitor being studied in rheumatoid arthritis (RA), osteoarthritis and potentially in psoriasis.
In a conference call after the markets closed on Monday, Vertex officials said clinical investigators observed minimal to moderate fibrosis in circumscribed regions of the liver in animals who received daily doses of pralnacasan that were well in excess of the highest dose used in humans as required for study by the FDA or other regulatory agencies. The animals were dosed over a nine-month period.
"We don't believe these findings indicate a risk to patients or the pralnacasan doses we are contemplating for human use," said John Alam, senior vice president of drug evaluation and approval at Cambridge, Mass.-based Vertex. "However, we don't know why these animals demonstrated these findings, and we don't know if it is reversible. As a result, Aventis and Vertex are pausing to fully evaluate these findings and will evaluate results of a 12-month toxicology study that is in progress before making specific decisions about how to move forward in Phase II and Phase III clinical development."
Alam believes it will take at least 12 months to investigate the problem.
A research note released by Phil Nadeau, an analyst with SG Cowen Securities Corp., in New York, characterized the discontinued trial as "a sizable negative for Vertex because it puts at significant risk the most visible, and heretofore most promising, member of Vertex's pipeline."
In July 2003, Vertex and Aventis, of Strasbourg, France, announced initiation of the Phase IIb randomized, placebo-controlled, double-blind, multicenter study to evaluate the safety and efficacy of pralnacasan in RA patients. Individuals participating were allowed to continue background methotrexate therapy, the industry standard for treatment of RA, which also can induce liver toxicity, Vertex said.
The Phase IIb was designed to evaluate 340 patients for 12 weeks. Thus far, 330 patients had been randomized and about 50 had completed treatment. On completing the 12-week portion of the trial, patients were allowed to roll over into the extended study.
No one in the study has been dosed beyond four-and-a-half months, Maurice Gately, senior distinguished scientist and global project team leader at Aventis Pharmaceuticals Inc., of Bridgewater, N.J., told BioWorld Today.
The nine-month animal study was supposed to support the possibility that after six months of treatment, patients could continue to receive the drug, Gately said.
Both Gately and Alam agreed that toxicity findings at high doses are not uncommon.
"All compounds will have toxicity if you dose high enough and long enough," Gately said.
Such studies are supposed to elicit information about potential toxicity in order to define a safety margin for an investigational agent and so that a therapeutic window for safe dosing in humans can be established.
The FDA is allowing the partners to continue with two short-term ongoing Phase I trials based on the belief that longer-term regimens in animals did not imply safety concerns in the significantly shorter Phase I trials.
Also, Vertex said it selected a candidate from its portfolio - merimepodib (VX-497), an oral treatment for hepatitis C virus - for advanced clinical development. Selection of merimepodib fulfills a corporate objection for 2003, the company said. Six-month results from a Phase II study demonstrated that relative to placebo treatment, merimepodib treatment produced a statistically significant, dose-dependent increase in the percentage of treatment-refractory patients with HCV genotype-1 who achieved undetectable levels of HCV-RNA.
Planning is now under way to enable a pivotal study with merimepodib in 2004.
Meanwhile, in late October, Vertex and partner GlaxoSmithKline plc, of London, won FDA approval for Lexiva (fosamprenavir calcium), a protease inhibitor indicated in combination with other antiretroviral agents for the treatment of HIV infection. GSK is scheduled to launch Lexiva in the U.S. this week. Approval in Europe is expected next year. (See BioWorld Today, Oct. 22, 2003.)
Vertex released its third-quarter financial report Monday afternoon, saying as of Sept. 30, it had approximately $596 million in cash, cash equivalents and available-for-sale securities. The company has $315 million in convertible debt due September 2007.
For the third quarter, the company's net loss, including a charge of $42.4 million associated with lease restructuring, was $86.4 million, or $1.12 per basic and diluted share, compared to a net loss of $33.5 million, or 44 cents per basic and diluted share in the quarter ended Sept. 30, 2002.
Total revenues for the three months ended Sept. 30, 2003, were $18.4 million, compared to $34.3 million in 2002.