Due to the new anti-HIV therapy options that have at least temporarily improved the clinical course of HIV/AIDS, trials of experimental treatments for HIV and opportunistic infections (OIs) have been unexpectedly slow to accrue participants. Even if willing to volunteer, many persons with HIV or AIDS no longer meet the entry criteria because of their newly increased CD4 counts and decreases in OIs. Slow enrollment has been especially apparent in several CMV trials and has, in some cases, led pharmaceutical companies to reassess their drug development programs.
|"Even if willing to volunteer, many persons with HIV or AIDS no longer meet the entry criteria because of their newly increased CD4 counts and decreases in OIs."|
Gilead's Broad Spectrum Antiviral: Adefovir
In an effort to speed enrollment, a large phase III trial of Gilead Sciences' nucleotide analog adefovir (the oral version of PMEA) has been adapted to allow broader entrance criteria. The drug has many attractive properties, including once-daily dosing, activity against hepatitis B and CMV, as well as HIV, and possible activity in resting cells and cell lines such as macrophages.
Results of an earlier clinical trial (GS-403) reported few resistance-inducing mutations after nine months of adefovir therapy (See Treatment Issues, January 1997). The drug reduced HIV RNA in treatment-experienced patients by a median of 32% (0.5 log) during the 12-week adefovir monotherapy phase of the trial. (It was disturbing that there was essentially no response in viral load in the five trial participants whose HIV possessed mutations conferring resistance to AZT.) Adefovir has a modest antiviral effect but it may have an important role in combination regimens tailored for certain people, especially because of its anti-CMV effects.
The large phase III adefovir study (being run by the CPCRA, protocol number 039) is a clinical endpoint (disease progression) trial that began enrolling in January 1997. The purpose of the study is: (1) to evaluate the safety and efficacy of adefovir in prolonging survival among persons with advanced HIV disease, and (2) to assess whether adefovir can prevent the development of CMV end-organ disease in persons who test positive for CMV. Participants will be randomized to either placebo or 120 mg of adefovir plus standard of care. They can be using almost any other medication, except those with anti-CMV activity. In addition, all participants will receive one 500-mg daily dose of L-carnitine. L-carnitine is involved with energy production in muscles and interacts with one of the molecules resulting from adefovir breakdown in the body. Levels of this compound can be reduced by adefovir. Participants will have kidney function monitored since adefovir has been associated with renal pr oblems as signaled by both elevated blood levels of the waste product creatinine and protein in the urine (proteinuria). Side effects also include increased liver enzymes in the blood, nausea and occasional pancreatitis.
Problems with Enrollment
The initial CPCRA protocol limited enrollment to patients with fewer than 100 CD4 cells. The first 400 participants were supposed to be part of a CMV-positive safety and virology cohort. Accrual in the CPCRA study has been slow, though, and only 220 of the first 400 were enrolled between last January and the end of August. Since the trial was designed, the pool of patients with CD4 counts below 100 has shrunk considerably due to new therapies.
According to Carol Brosgart, M.D., the study chairperson: "A lot of providers had CMV-negative patients who wanted to enroll in the trial, but the way the protocol was set up we couldn't do it until the safety and virology cohort was filled, so we decided to amend the protocol in various ways. One was to allow CMV-negative participants to enroll in the virology cohort. Then we decided to look at people whose CD4 counts were now between 100 and 200, who had previously had a nadir CD4 count less than 50." In addition to allowing more people to enter the protocol more quickly, these amendments will permit investigators to determine if restoring CD4 count through aggressive anti-HIV treatment is protective by itself against the development of CMV. The investigators obviously hope that opening up the virology cohort to CMV-negative individuals will speed enrollment of the whole trial.
All participants who come into the study will have a second-generation CMV branch DNA (bDNA) assay performed at entry. Those who are CMV-positive in the safety and virology cohort will also have the test at every visit. Investigators will be able to determine if a baseline test is predictive of development of CMV disease and how increases in CMV viral load correlate with CMV progression. Chiron, the manufacturer of the bDNA assay, is a cosponsor of the trial.
In addition to the CPCRA study in this country, another 2,000 participants are to be enrolled in an identical study in Europe and Australia (referred to as AD HOC). There also are several trials in the U.S. testing adefovir in various combination regimens in patients with little or no treatment history. Gilead completed enrollment of its pivotal trial (GS-96-408) in June of this year. Based on CD4 changes and viral load changes in this study, the company will file an FDA New Drug Application for adefovir, probably in mid-1998.
Gilead will start an expanded access program in the fall of this year for patients who cannot participate in a placebo-controlled trial. The program will be open to persons with CD4 counts less than 50, PCR-measured viral loads over 30,000 within the previous two months and failure or intolerance of combination therapy consisting of two nucleosides and one protease inhibitor. Dr. Brosgart hopes that rather than competing with her trial, the expanded access program will improve its visibility.
Slow but Steady for Glaxo's 1263W94
Glaxo Wellcome is developing another experimental drug to combat CMV, currently known as 1263W94. It has been studied in two small phase I safety trials. Doses were well-tolerated. Laboratory studies to be presented this month indicate that 1263W94 does not affect the activity of antiretrovirals. 1293W94 is a member of a new class of drugs called benzimidazole ribosides that inhibit DNA synthesis, but its precise mechanism of action against CMV remains unclear. A 65-person phase I/II study began in September 1996 at two sites in California. The study is still not completely enrolled one year later. Slow progress may, in part, be due to the fact that different dose levels are being tried. Results should be presented at the 5th Conference on Retroviruses and Opportunistic Infections in Chicago early next year. Reported side effects include a chronic bitter taste in the mouth produced by the drug. Although accrual is slow, Glaxo representative Elizabeth Swaringen stated that developm ent is moving ahead.
|"Despite much community protest, Roche has not changed its position as yet."|
Future of Roche's Ganciclovir Prodrug Still Uncertain
Meanwhile, Hoffmann-La Roche has been developing RS79070, a ganciclovir prodrug for the treatment of CMV. The prodrug is a great improvement over current formulations of oral and intravenous ganciclovir, requiring only one to two pills per day. However, this spring Roche announced that two of three planned clinical trials were being put on hold indefinitely while Roche reassessed the development of the prodrug. Roche sighted the apparent decrease in CMV disease as the reason (see Treatment Issues, April/May 1997). Despite much community protest, Roche has not changed its position as yet, although there are indications that a decision on the future of the prodrug will be made public towards the end of the year. Roche is moving ahead on enrollment of the remaining trial (WV15376), which compares intravenous ganciclovir with RS79070 as induction therapy for newly diagnosed peripheral CMV retinitis. Accrual has been slow, but several new trial sites were recently added and the entrance criteria were loosened. To date, 30 of the planned 65 participants have enrolled. Since this trial is too small to be decisive in the FDA premarketing review process, Roche hopes to work with the FDA on simplified approval requirements.
Obviously, it is crucial for drug development to go forward at a reasonable rate. It remains to be seen how the CPCRA will do with the large adefovir trial and whether Hoffmann-La Roche can come up with a working plan for prodrug approval with the FDA. Glaxo keeps plugging away with 1263W94 -- but trials that take a year or more to enroll will cause unacceptable delays in bringing new drugs to market. For information on enrolling in any of the open trials mentioned in this article, call 800/TRIALS-A.