By Mary Welch
Triangle Pharmaceuticals Inc. said the South Africa Medicine Council informed the company in a letter that a Phase III study of its anti-HIV drug, Coviracil, should be terminated, possibly due to concerns of liver toxicity.
The study, called FTC-302, of Coviracil (FTC, emtricitabine) was started in August and involved 470 patients. The trial is a comparison of Coviracil and the marketing-leading lamivudine (3TC) when used in combination with Zerit (d4T) and nevirapine.
¿At this point, because analysis of data and the trial is ongoing and is preliminary, we¿re not in a position to state specifically what the issues of the trial are, but we are comfortable that the toxicity does not appear to be related with Coviracil, and we have not seen any liver toxicity with any of the other studies,¿ said Carolyn Underwood, Triangle¿s executive vice president of commercial operations.
Underwood said two people died of liver toxicity during the trial. Three others also died of pancreatitis, central nervous system deterioriation and a reason yet undetermined.
In another Phase III study of the drug that is taking place in the U.S., liver toxicity has not been an issue. More than 450 patients are approaching 48 weeks of follow-up in that study. This American study, dubbed FTC-303, switches Coviracil for 3TC in patients with stable regimens of 3TC with Zerit (d4t) or Retrovir (zidovudine; or AZT) and a PI or non-nucleoside reverse transcriptase inhibitor (NNRTI).
Edward Tenthoff, a junior analyst with Robertson Stephens in San Francisco, agrees that Coviracil in the FTC-302 study may not be the cause of the liver toxicity.
¿We have a clear understanding that FTC is not the culprit . . . and believe it is caused by another drug in the concomitant therapy or characteristics in the underlying patient population,¿ he wrote in a research paper.
Tenthoff said the South African trouble pushes back the filing of a new drug application (NDA) for the drug, which was expected to take place in the first quarter of 2001.
Underwood said the timing of the NDA will depend on what the company can negotiate with the council. ¿If we cannot use the data from FTC-302, which we don¿t know that yet, then we would be looking at at least late 2001 because we basically would have to start another trial.¿
¿This has the potential to be a blockbuster drug, a billion dollar drug,¿ Tenthoff told BioWorld Today. ¿Now how big a deal is this news? At the very least, it pushes back the NDA to late 2001 or early 2002, which means sales of the drug are pushed back. It means that Triangle will probably have to include data from the FTC-301 trial that will start in May. The company may be able to submit on 24-week data and provide full 48-week data as it becomes available. At this point, we don¿t know if anything from the South African trial can be salvaged for use in the NDA filing.¿
Triangle also is expected to start another Phase III trial, named FTC-301, this May in the U.S., Europe and South America. This trial is designed to enroll around 300 patients and compare a regimen of Coviracil, ddi (Videx didanosine) and Sustiva (efavirenx) vs. d4T, ddi and Sustiva. The trial should take six months to enroll patients and 12 months of follow-up, Tenthoff said.
The market took the news hard, as the stock (NASDAQ:VIRS) closed at $8.75, a decrease of $4.50, or almost 34 percent.
¿The market has overacted a bit, but I don¿t blame them,¿ Tenthoff said. ¿It just bring up further management credibility issue. They¿re taking lots of shots on goal, but they¿re not getting anything through.¿
Tenthoff is still hopeful that FTC will be approved. ¿There are some who believe that FTC could go away ¿ or at least have that concern,¿ he said. ¿I am crossing my fingers on this, but I think that FTC is not lost, just delayed.¿
Coviracil, which is a nucleoside reverse transcriptase inhibitor, is one of six antiviral products being developed in a marketing deal worth up to $335 million with Abbott laboratories, of Abbott Park, Ill. (See BioWorld Today, June 4, 1999, p. 1.)