On July 30th, Triangle Pharmaceuticals announced the early plans to unblind a pivotal study investigating the effect of FTC (Coviracil) in the treatment of HIV disease. As an investigator for the study, the news came to us with much surprise, since the trial was expected to continue in its original blinded design for another six months.
Triangle Pharmaceuticals is a small biotech company formed by David Barry in 1995. Dr. Barry was the former President of Wellcome Research Laboratories, who along with other of the company's senior management and scientists formed Triangle Pharmaceuticals. These former senior executives at Wellcome played pivotal roles in the development of drugs such as Zovirax (acyclovir) for the treatment of herpes infections, and in the discovery and development of Retrovir (zidovudine, AZT) for the treatment of HIV infection and AIDS. To put things in its historical perspective, the two drugs revolutionized antiviral therapy and established Wellcome's preeminent billion dollar anti-viral business, which eventually became Burroughs Wellcome, subsequent to acquisition by Glaxo, and today is GlaxoSmithKline. The clinical and regulatory pathways for Retrovir's approval have become models for the development of new products to treat life-threatening diseases.
Triangle Pharmaceuticals, based in Durham, North Carolina, began developing a number of HIV antiviral compounds. In a very short time they were involved in a candidate non-nucleoside, several candidate nucleosides and even a prospective protease inhibitor. During the entire flurry, and in 1999, Triangle entered into a collaborative relationship with Abbott Laboratories to co-market several Triangle and Abbott drug candidates and to gain access to Abbott's manufacturing capacity and international sales and marketing capabilities. As part of this collaboration, Abbott also made a significant and needed investment in Triangle.
However, Triangle has gone through hard times. Their candidate non-nuke (MKC-442 or Coactinon) did not perform well in drug trials and was terminated. Also trials with FTC (Coviracil) had to undergo various hurdles. One snag was related to the original design of the study itself (FTC-301), which had to undergo changes months after the study had already begun. More than two years ago, it originally involved abacavir (Ziagen) as part of the study arms. Concern was voiced by the U.S. Food and Drug Administration (FDA) regarding the possible difficulties in differentiating a skin rash or drug reaction of abacavir to one due to efavirenz (Sustiva). Eventually the study was modified in its original approach, but also had to endure further difficulties in enrolling treatment naïve patients. (Fortunately however, the study did complete enrollment and has since been going smoothly.) Also, recently, Dr. Barry, the founder and CEO of Triangle, suddenly died.
Now, related to the recent positive news of this study, Triangle reacquired the rights to its drug candidate FTC (as well as their other drug candidates) from Abbott Laboratories.
On July 26, in a conference call to us and the other investigator sites involved in the phase III study FTC-301, the surprising news was issued. The Data Safety Monitoring Board (an independent committee of experts that review and oversee studies for safety and efficacy throughout the length of a trial), after reviewing the interim data, found a significant difference in safety and effect favoring the FTC treated patients. Because of these differences the DSMB recommended that the study be unblinded and that all patients be offered FTC. The FTC arm showed statistically superior benefits in suppressing HIV over the d4T (Zerit) arm. Study drug-related adverse events also favored FTC as being safer.
Adverse event data showed that in most cases where patients dropped out of the study due to "study medication" side effects, it was a d4T-related problem or complication. Previously reported, side effects that have been observed by physicians associated with d4T treatment include lipodystrophy, facial atrophy and elevated lipids and peripheral neuropathy. One easily recalls the recently presented tenofovir trial, also of naïve patients, presented during the late-breaker session at the International AIDS Conference in Barcelona in July comparing tenofovir and d4T. In this trial (Study 903) patients on the d4T arm also had significant increases in cholesterol and triglycerides. Also, lipodystrophy was more prominent in the patients taking d4T.
FTC-301 was designed as a double-blinded randomized trial of FTC + ddI (Videx) + efavirenz vs. d4T + ddI + efavirenz in antiretroviral naïve patients (those taking their first antiviral regimen). Having passed the 96 week mark, we had just previously submitted protocol amendments to continue the study for 144 weeks when the company switched gears in announcing the aforementioned changes. The study will remain open for all patients to obtain open-label drug until FDA approval. Since the company plans to submit a new drug application (NDA) with the FDA during the third quarter of this year, we expect FTC's approval sometime in the early part of 2003.
FTC (Coviracil) is a very potent nucleoside reverse transcriptase inhibitor (NRTI). In addition to its activity against HIV, the drug showed activity against hepatitis B. Also, preliminary studies demonstrated FTC to be more potent than 3TC (Epivir) in that it was associated with a 2 log drop in HIV-RNA (viral load). It is also dosed once daily. However, in comparison to 3TC, patients who have developed resistance to 3TC are not likely to derive further benefit from FTC. Also, in preparation to FTC's expected launch and in response to market driven motivations to develop once-daily HIV regimens, 3TC also has been studied and found to be effective at once daily dosing. (See "FDA Approves Once-Daily Epivir" in News Briefs this issue.)
Daniel S. Berger, MD is Medical Director for Northstar Healthcare, Clinical Assistant Professor of Medicine at the University of Illinois at Chicago and editor of AIDSInfosource (www.aidsinfosource.com). He also serves as medical consultant and columnist for Positively Aware. Dr. Berger can be reached at DSBergerMD@aol.com or (773) 296-2400.