Bristol-Myers Squibb (BMS), a large entity within the pharmaceutical industry, has from the beginning of the AIDS epidemic been involved in HIV drug development, research, education and community support. One of the first antiretroviral drugs to reach the market was ddI (Videx) in 1989. Several years later they brought us d4T (Zerit). However, as HIV drug development progressed so did many dynamics within the industry. During the past year, another drug company, DuPont, manufacturer of the non-nuke drug efavirenz (Sustiva), was acquired by BMS.
DuPont Pharmaceuticals successfully brought Sustiva to market in record time, and with a rich drug pipeline of HIV drugs sought to develop the next generation of non-nukes. DuPont originally began clinical trials with one of their experimental non-nucleoside reverse transcriptase inhibitors, DPC-083, as an option for those patients failing other currently available non-nukes. Moreover, since 083 has activity against virus that is resistant to nevirapine (Viramune) and Sustiva, it would be vitally important to patients in the future.
However, right from the outset there were snags; changes and decisions occurred at various levels of DuPont and within the scientific staff. The variety of difficulties included attempting to begin trials with their second-generation non-nuke at a differently proposed dosage; this then was followed with various hurdles with the actual conducting and dynamics of the trial, and then finally to the BMS acquisition.
DuPont scientists were the originators of the protocol design implemented at five sites within the U.S. As principle investigator at one of these sites, NorthStar Healthcare, I and our dedicated staff provided a great deal of effort towards conducting this study. Initially, the FDA had problems with the intended dosing -- they required the original proposed dosing to be decreased due to safety issues. The protocol consequently had to be re-written. Naturally, one wonders whether the decreased dose may have been less efficacious (although this was studied in Europe), and could a third dose have the potential for demonstrating better results? Also, a tight set of inclusion criteria and rigid protocol design made it quite difficult to enroll patients.
During the course of the trial, DuPont executives decided to put their pharmaceutical division up for sale. When word leaked, most of their senior clinical trial people left the company for other opportunities within the industry. A second or "transition staff," upon taking over the reins, did not seem to us as committed to the study. Eventually the well endowed and experienced BMS, with a new set of goals and priorities, looked at the project from their own perspective.
Bristol-Myers Squibb recently decided to halt trials with 083. On May 14th, I received a memo from Dr. Nancy Ruiz, BMS Director of Infectious Diseases Clinical Development and Evaluation, stating that the phase 2 study, DPC083-203 had indeed been terminated. Reasons that were cited included recruitment, logistical issues and cumbersome implementation. Also the heterogeneity of patient population and their management made results of the study "difficult to interpret." The discontinuation of the study was not related to any adverse events encountered during the study, but because the study objectives could not be met. These explanations were discussed in a follow-up telephone conversation with Dr. Ruiz. New study designs may be discussed, but probably the other experimental non-nukes of DuPont will be considered for future clinical trials.
Harriett Wittert, R.N. senior coordinator at NorthStar Healthcare and the research coordinator of the 083 protocol stated, "... to these pharmaceutical companies, 083 may be a small fish in a large fish tank, but to our patients and the community a second generation non-nuke could have vital implications." Clearly, as regimens continue to fail AIDS patients and drug resistance increases, there is a greater need for more treatment options, which should include the development of second generation of non-nukes.
Bristol-Myers Squibb has developed a new protease inhibitor that is about to be added to the U.S. market, making it number seven of the protease inhibitors being currently prescribed. Atazanavir (marketed under the name Zrivada) will be the first new protease inhibitor (PI) to hit the market since Kaletra became available almost two years ago.
Of the several protease inhibitors that are presently available for patients by prescription, most have similar complications associated with their use. Well known to most individuals taking these drugs are the body habitus changes that can potentially occur, increased levels of cholesterol and/or triglycerides are often seen and there are many pills to swallow per dose. Other problems associated with PIs include abdominal bloating, nausea and diarrhea. Unfortunately there are not many drugs in development near approval now and more often than not the "new" drugs are not milestone improvements over present available therapies. Often pharmaceutical companies try to tout their agent as being superior and various marketing ploys are always being attempted. Sometimes it is not until the wide and general use of a drug that the final assessments of its "treatment niche" are understood.
However, uniquely and very importantly, atazanavir's profile demonstrates it is less likely to cause lipid abnormalities. There has been concern that eventually those patients who have untreated elevations in lipids, due to protease inhibitors, will develop premature onset of cardiovascular disease. These lipid elevations are often associated with body habitus changes or lipodystrophy. Thus the big question is, will atazanavir have less associated fat redistribution complications?
Another unique property of this PI drug, that many patients can look forward to, is a low pill burden and its once daily dosing. There has been a movement to attempt construction of once daily regimens. This movement has recently gained momentum with the advent of Viread (tenofovir), Gilead Sciences' recently approved nucleotide reverse transcriptase inhibitor that is taken once a day. There are also other once-a-day drugs currently available.
In terms of resistance, various laboratory studies have demonstrated atazanavir to have similar resistance mutations as other available protease inhibitors. A study with patients who were previously treated with protease inhibitors was done; those individuals were placed on their second-line treatment. They were administered either 400 or 600 mg of atazanavir in combination with 1200 mg saquinavir (Fortovase) once daily and were compared with a third patient group on a ritonavir (Norvir)/saquinavir regimen. Of the two atazanavir patient arms, 53% and 40%, respectively, reached undetectability (less than 400 copies) vs. 38% on the ritonavir/saquinavir arm. Also, patients on the atazanavir arms did not have elevations in cholesterol or triglycerides vs. the patients on ritonavir/saquinavir, who had significant elevations.
BMS has also recently opened an early access program for this new drug to treat HIV disease for patients with greater need. In summary, the eligibility criteria for gaining access to this program includes CD4 count less than 300 cells/mm3. Also, patients must have a lack of response to HAART with HIV RNA (viral load) being greater than 5,000 copies, due to failure with other available antivirals, and are required to be unable to construct an effective alternative treatment regimen. Various toxicities or intolerance to other agents and/or significant hyperlipidemia (high cholesterol or triglycerides) are also listed as separate inclusion criteria for an inability to construct an effective regimen in this program. The toll-free phone number for the atazanavir study hotline is (877) 726-7327 (8 A.M.-5 P.M. CST).
Daniel S. Berger, M.D. is Medical Director for NorthStar Healthcare; Clinical Assistant Professor of Medicine at the University of Illinois at Chicago and editor of AIDS Infosource (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.