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in Six Months By Dave Gilden 
Tenofovir, Gilead Sciences' candidate reverse transcriptase
inhibitor, could be approved in about six months. In an
unexpected move, the company announced May 1 that it had
filed a New Drug Application with the FDA. After approval,
tenofovir could be prescribed for any adult with HIV,
according to the company's proposed labeling. Gilead will
soon proceed with similar marketing applications in Europe.
Tenofovir, or PMPA, stops the infection of new cells by halting the gene-building activity of HIV's reverse transcriptase enzyme. The drug is similar to nucleoside analogs such as ddI but requires less intracellular processing to reach its active state. Tenofovir is distinguished by its long intracellular half-life, which allows once-a-day dosing. It also has a somewhat different resistance profile than the standard nucleoside analogs, so it may be active against many HIV isolates that have mutated to resist the approved nucleoside analogs. In trials so far, resistance to tenofovir has been slow to develop -- although it has been found. Tenofovir's safety profile is considerably improved over adefovir, a closely related compound developed by Gilead. Adefovir was rejected by the FDA because of severe kidney toxicities coupled with modest efficacy. Gilead's new drug may be helpful in a salvage regimen, but it does not represent any dramatic breakthrough. In a 189- person phase II treatment-intensification trial,(1) tenofovir was added to volunteers' previous regimens at doses of 0 mg (placebo), 75 mg, 150 mg or 300 mg per day. The trial participants had a mean 4.6 years prior anti-HIV therapy and a mean baseline viral load of 5,000. At study entry, 94% of the enrollees also had HIV with mutations conferring resistance to various nucleoside analogs, principally AZT and 3TC. HIV in more than half of the participants also had resistance to protease inhibitors. The trial participants on 300 mg/day - the preferred dose - recorded viral load reductions averaging about 0.6 log (75%) through both weeks 24 and 48. The presence or absence of AZT or 3TC resistance was not associated with a major difference in the response. The modest, stable viral load reduction was not accompanied by any appreciable change in CD4 count, either.
Expanded Access: Gilead Drops CD4, Viral Load Exclusions Since last February, an expanded-access program has been open to people whose advanced disease state and treatment history mandate immediate use of new drugs to suppress their HIV (see AIDS TREATMENT NEWS #360, February 23, 2001). Gilead always intended that this program would be very small. It at first restricted entry to persons with viral loads over 10,000 and CD4 counts under 100 - plus documented treatment failure with at least two protease inhibitors or one PI and one non-nucleoside reverse transcriptase inhibitor (NNRTI). (Those with a CD4 count between 100 and 200 could also apply if they had had an AIDS-defining opportunistic infection within the last 90 days.) Expanded-access enrollment has been even slower than anticipated. Public dissatisfaction over the paltry enrollment figures led Gilead to abandon its viral load and CD4 count entry criteria. As to speeding up the enrollment process, Debbie Fletcher of Gilead said in an interview, "About 20% of the doctors have submitted incomplete registration materials and had their applications returned. The paper work can go back and forth and back and forth. Our field representatives will follow up with the physicians who don't finish filling out the forms." One HIV specialist summed up his frustrating experience with Gilead: "Paperwork did go back and forth. It took them weeks to turn it around and tell you they needed something more. Then you would send that, and they would come up with something else." The Coalition for Salvage Therapy has asked the company for a full and regular accounting of the program's enrollment. In a strongly worded letter, this national activist network said that applicants to the program "are not only patients with few or no remaining options for treatment, but also patients whose disease has been allowed to progress to the point where 'waiting for things to get sorted out' with the program is simply not an option." The Coalition had long pressured Gilead for a much broader expanded-access distribution before finally settling for the present restricted effort. For the expanded-access program, Gilead advises doctors to prescribe at least one new anti-HIV agent in addition to tenofovir. Tenofovir naturally substitutes for other nucleoside analogs, not for protease inhibitors or NNRTIs. Some treatment activists have argued that Gilead should abandon the requirement that enrollees have past failure with PIs or NNRTIs. The program should be open to anyone lacking new nucleoside analogs to create a viable treatment combination. This is the way tenofovir expanded access works in France, where the drug is recommended for patients with nucleoside analog intolerance or with nucleoside analog-resistant HIV, as demonstrated by resistance assays. In the United Kingdom, tenofovir is available to any patient who, in the judgment of his or her doctor, could not otherwise construct an effective anti-HIV regimen. Regulations in both countries preclude strict entry criteria, including CD4 count or viral load limits. When tenofovir is approved, the issues around expanded access will be largely academic. At least the program is growing. Enrollment has picked up dramatically in the U.S., where about 150 people are now signed up. Also, Gilead has asked Germany, Italy and Spain for permission to extend the program beyond the U.S., UK and France. Further information can be obtained from Gilead at 1-800-Gilead-5 in the US and 33-1-44-90-34-46 in Europe. References 1. Miller MD et al. Baseline and Final Phenotypic Analysis of HIV-1 from Patients Adding Tenofovir Disoproxil Fumarate (TDF) Therapy to Background ART. 8th Conference on Retroviruses and Opportunistic Infections. February 4-8, 2001. Poster 441. AIDS Treatment News Published twice monthly Subscription and Editorial Office: 1233 Locust St., 5th floor Philadelphia, PA 19107 800/TREAT-1-2 toll-free email: aidsnews@critpath.org useful links: http://www.aidsnews.org/ Editor and Publisher: John S. James Associate Editor: Tadd T. Tobias Statement of Purpose: AIDS Treatment News reports on experimental and standard treatments, especially those available now. We interview physicians, scientists, other health professionals, and persons with AIDS or HIV; we also collect information from meetings and conferences, medical journals, and computer databases. Long-term survivors have usually tried many different treatments, and found combinations that work for them. AIDS Treatment News does not recommend particular therapies, but seeks to increase the options available. AIDS Treatment News is published 24 times per year, on the first and third Friday of every month, and print copies are sent by first class mail. Email is available (see below). Back issues are available at http://www.aidsnews.org/ To subscribe, you can call 800-TREAT-1-2 or 415-255-0588: |
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