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Published in the Bulletin of Experimental Treatments for AIDS December 1996 issue, by the San Francisco AIDS Foundation. |
AIDS Treatment Advocacy Issuesby Ron Baker, PhD When Will Glaxo Wellcome Make 1592 Available Through Expanded Access?Although they may not know it yet, for many people with AIDS the most important drug in the AIDS research pipeline is not a new protease inhibitor. Rather, it's Glaxo Wellcome's 1592 (also known as 1592-U89), a nucleoside analog drug like its chemical cousin AZT. The drug's importance stems from the fact that many people with AIDS have already exhausted the benefits of the available nucleoside analog drugs (AZT, ddC, ddI, d4T and 3TC). These individuals are waiting desperately for a new nucleoside analog to use in combination with protease inhibitors. Without access to 1592 -- the only nucleoside analog in the research pipeline that appears safe and potent -- these individuals will have little chance of finding an effective drug regimen. Early Data on 15921592 has not yet entered Phase III efficacy trials, but such studies will begin recruiting soon. The available data on the drug from Phase I and II studies are promising. The drug shows in vitro synergy with the nucleoside analogs AZT, ddI, ddC and 3TC, and with the protease inhibitors saquinavir and 141-W94 (Glaxo Wellcome). No in vitro cross-resistance with AZT has yet been observed, and AZT-resistant HIV remains sensitive to 1592. HIV that is resistant to ddI, ddC and 3TC appears only slightly cross-resistant to 1592. Perhaps most importantly, significant amounts of 1592 cross the blood-brain barrier (13% in rats, 26% in monkeys), which suggests that the drug may be especially important in the prevention and treatment of HIV-related dementia. In its oral formulation, 1592 exhibits an excellent bioavailability level of approximately 70%. After 8 weeks of combination therapy with AZT (600 mg/day), 1592 (at doses ranging from 200 - 400 mg/day) reduced HIV RNA levels by 1.90-2.70 logs from baseline levels (99% reduction) among 29 study participants with less than 12 weeks of previous AZT treatment. Median CD4 count increases among the 3 dosage groups were 79-127 cells/mm3. Reported adverse events associated with 1592 are mild, and include nausea, headache, asthenia (weakness), insomnia and abdominal pain. Nausea was the most common adverse side effect at the 400 mg twice-daily dose. These data on 1592, while promising, represent experience in only a small number of HIV positive volunteers. Why are many treatment activists and people with AIDS so anxious to use 1592 before more data become available? The answer is simple and compelling: thousands of people with AIDS have already exhausted the benefits of 2- and 3-drug combination regimens that include a protease inhibitor plus one or more of the available nucleoside analogs. While there are 3 commercially available protease inhibitors to choose from (and one on expanded access), these individuals have already developed resistance to the available nucleoside analogs. In order to build an effective combination treatment regimen, they must have access to at least one nucleoside analog drug to which they are not already resistant. Otherwise, the regimen is doomed to failure. It has become clear that, despite their potency against HIV, protease inhibitors quickly lose their effectiveness when combined with previously used nucleoside analog drugs. 1592 is the only option available to individuals who have failed or are intolerant to all other approved therapies. In addition, as outlined above, 1592 is vitally important to those individuals who need at least one new, previously unused nucleoside analog in order to construct a viable combination regimen. For all these reasons, patient advocacy groups, including the San Francisco AIDS Foundation (SFAF), are calling on Glaxo Wellcome to quickly establish an expanded access program for 1592 and to seek accelerated approval for the drug as soon as possible. Through expanded access, drug companies provide experimental drugs free to patients through their physicians. The primary objective of such a program for 1592 is to provide the drug to those patients in the greatest need of a new anti-HIV therapeutic option. In discussions with representatives of the AIDS community, Glaxo Wellcome has acknowledged that certain individuals have a compelling need to receive experimental therapies through expanded access programs. But the company argues that expanded access for 1592 is inappropriate now for the following reasons: (1) more safety data on 1592 are required (the drug has been tested in fewer than 200 people so far); (2) an expanded access program will decrease patient enrollment in the pivotal upcoming Phase III trials; and (3) drug supply of 1592 is inadequate for an expanded access program. Although safety is a legitimate concern, and more data are undeniably needed, SFAF believes that one of the primary functions of an expanded access program is to collect safety information on drugs prior to their approval. With this in mind, Glaxo Wellcome's first objection is unwarranted. Concerning the possibility that expanded access enrollment might delay or derail patient accrual into Phase III studies, SFAF sees no historical basis for this argument. No recent expanded access program has dramatically impacted Phase III trial enrollment. In fact, Glaxo Wellcome itself operated a 3TC expanded access program for 30,000-plus people without interfering with that drug's Phase III trial enrollment. Finally, in response to the inadequate drug supply argument, SFAF believes that this problem can be overcome if there is the will to do so. SFAF believes that Glaxo Wellcome, arguably the preeminent developer of drugs for the treatment of HIV and its complications, and a company that has exhibited exceptional support for the AIDS community, now has an opportunity to reaffirm its leadership among the world's pharmaceutical manufacturers by rapidly establishing an expanded access program for 1592. For Glaxo Wellcome to provide expanded access to a new, much-needed drug for people without other treatment options is in the best interests of both the company and the AIDS community. To ignore such an obvious need would surely breed ill-will and cast a shadow on Glaxo Wellcome's relations with the AIDS community. Such a decision by the company risks bringing us back to that bleak period when there existed a deep chasm of mistrust between people with HIV/AIDS and the manufacturer of AZT. Let's not go there again. Organizations wishing to sign a consensus statement urging FDA and Glaxo Wellcome to establish an expanded access program for 1592 as soon as possible should contact Linda Grinberg of Project Inform at 310-471-6565. Chiron and Roche Agree to Nationwide Patient Assistance Programs for Viral Load TestingFollowing several months of discussion with AIDS community advocates, Chiron Corporation and Roche Molecular Systems have agreed to establish nationwide patient assistance programs to provide free HIV viral load testing to patients without adequate insurance. Chiron produces the branched DNA (bDNA) viral load test, also known as the Quantiplex HIV RNA assay. Roche manufactures the reverse transcriptase polymerase chain reaction (RT-PCR) test, also known as the Amplicor HIV-1 Monitor assay. HIV viral load testing is now the de facto standard of care for HIV disease, and it is unacceptable to the AIDS community that access to this technology be determined by financial status. Over a hundred community organizations have called on the test manufacturers to operate patient assistance programs until the government provides funding for HIV viral load testing for those who need it. After activists harshly criticized its Amplicor Access program (which resulted in a backlog of about 25,000 unprocessed blood samples), Roche Molecular Systems instituted a follow-up program to eliminate the backlog. The company also has offered affected patients the opportunity to send in new blood specimens for testing (see News Briefs). In addition, Roche has created a national patient assistance program to provide up to 50,000 PCR tests to qualified individuals. The major requirement for acceptance into the Roche program is lack of insurance or inability to pay for the test. Interested individuals should call Roche Molecular Systems toll-free at 1-888-TEST-PCR beginning January 2, 1997. Chiron Corporation also has agreed to provide free HIV RNA testing for indigent individuals, but its patient assistance program will be implemented in stages, and initially only in certain geographic locations. San Francisco is the first of 10 major cities to participate in the Chiron program. The SF Department of Public Health will offer free bDNA tests to SF residents at Ward 86 of San Francisco General Hospital and at neighborhood public health clinics. To participate in the program, individuals must call Ward 86 or a clinic site to make an appointment. For the locations and telephone numbers of participating SF clinics, call the SFAF Hotline toll-free at 1-888-HIV-LOAD, beginning January 2, 1997. Other cities expected to offer free bDNA testing in the near future are Los Angeles, Boston, Chicago, Philadelphia and New York. In addition, sites in Atlanta, Houston, Dallas and Miami are expected to participate in the Chiron program sometime in 1997. For updates on Chiron test sites nationwide, call the SFAF Hotline at 1-888-HIV-LOAD, beginning January 2, 1997. Currently, Chiron has no specific timeline for offering free testing to people who live outside the metropolitan areas mentioned above, although the company has made a verbal commitment to do so in the coming months. For these individuals, the Roche program may be the best available option, because it has no geographic restrictions. 1997 Treatment Advocacy Efforts by SFAFIn 1997, the overarching goals of SFAF's treatment advocacy efforts are to slow HIV disease progression, increase survival and improve the quality of life for people living with HIV infection and AIDS. To achieve these goals, SFAF's major advocacy objectives are (1) to lobby FDA and drug manufacturers to assure accelerated approval of at least 4-6 new AIDS drugs by the end of 1997; (2) to lobby drug manufacturers to establish expanded access programs to make promising experimental drugs available, prior to FDA approval, to people without other treatment options; (3) to negotiate with HIV viral load test manufacturers for the establishment of patient assistance programs to provide broad patient access to these tests; (4) to lobby researchers, clinicians, and professional and government groups to create a new, higher standard of care for HIV disease; (5) to help assure that as many HIV positive individuals and caregivers as possible have knowledge of and access to an improved standard of care for HIV disease; and (6) to promote the adoption and integration of this new standard of care by Kaiser Permanente and other managed care organizations. FDA Approval of Chiron's HIV Viral Load TestChiron Corporation submitted its application to FDA for approval of the branched DNA (bDNA) test, its first-generation HIV RNA assay, in February 1996. Not only has FDA not approved this assay, the agency has not even set a date for hearings on the approval. FDA approved the Roche RT-PCR viral load test in June 1996. SFAF is concerned about FDA's excessive delay in considering approval for Chiron's first-generation bDNA test. It is the second-generation Chiron test, with a lower detection limit of 500 copies/mL, which is of greater use to clinicians and patients in the management of HIV infection. Few physicians knowledgeable about AIDS are recommending the first generation bDNA tests to their patients. Unable to detect HIV viral load levels below 10,000 copies/mL, Chiron's first generation bDNA test is something of a white elephant. Still, until it receives FDA approval, the more useful, second-generation assay remains in limbo. SFAF calls on FDA to approve the Chiron first generation HIV viral load test as soon as possible. People with HIV/AIDS not only require access to the Chiron HIV RNA test, they also require reimbursement for the test, which will remain problematic until FDA approves the assay. Access to Promising New DrugsSFAF is actively promoting the swift development by industry and fast-track approval by FDA of several important new drugs for the treatment of HIV infection. These efforts generally involve action taken in collaboration with other AIDS advocacy groups, but sometimes SFAF acts alone or as part of a minority coalition when such action is considered to be in the best interests of people with HIV/AIDS. A primary objective in 1997 is to secure as soon as possible expanded access for 1592, the promising anti-HIV drug from Glaxo Wellcome (see above). SFAF also supports broadening patient participation in the expanded access program for nelfinavir (Viracept), the new protease inhibitor drug from Agouron Pharmaceuticals. The nelfinavir program's entry criteria are far too restrictive, requiring that individuals have fewer than 50 CD4 cells/mm3 and have failed all 3 commercially available protease inhibitors. This means that, in order to receive the Agouron drug, a patient must be at high risk for imminent death! In a recent communication with Agouron, the company informed SFAF that about 30 people per day enter the nelfinavir expanded access program and, further, that actions have been taken to increase drug production and to admit more patients into the program. The company is now conducting Phase III trials of nelfinavir, and expects to file for accelerated approval of the drug in the spring of 1997. SFAF will continue to lobby Agouron to liberalize entry requirements for the nelfinavir expanded access program so that people with higher CD4 cell counts who are without protease inhibitor treatment options can receive the drug. The FDA Antiviral Advisory Committee met in November to consider accelerated approval for delavirdine, the anti-HIV drug from Pharmacia and Upjohn. At the public hearing, SFAF testified in favor of immediate accelerated approval for the drug. Unfortunately, among the community groups present, only SFAF, ACT UP/Golden Gate and the National AIDS Treatment Advocacy Project spoke in favor of accelerated approval for delavirdine. Following the public testimony, the FDA Antiviral Advisory Committee voted 4 in favor and 4 against recommending accelerated approval, setting the stage for a final decision at a later date by Antivirals Division Director David Feigal, MD, and outgoing FDA Commissioner David Kessler, MD. SFAF feels strongly that delavirdine should immediately receive accelerated approval from FDA. People with AIDS have far too few anti-HIV drug options. Many people have exhausted the benefits of all the existing approved antiretrovirals, and it is inappropriate to deny them the right to access delavirdine. The drug qualifies for conditional approval under the accelerated approval guidelines, and should not be held to a higher standard than other drugs. While not a blockbuster AIDS drug, delavirdine has shown significant anti-HIV activity when used in combination with 2 or more nucleoside analogs. The drug also has an excellent safety profile, with the most severe adverse event being a transient skin rash. In addition, delavirdine shows synergistic anti-HIV activity in combination with 3TC, and has the unique ability to increase HIV susceptibility to AZT and to reduce HIV resistance to AZT. Because delavirdine increases concentrations of indinavir, it could help to reduce significantly the cost of combination regimens using both compounds. Delavirdine also increases saquinavir levels by 5-fold (in contrast, nevirapine decreases saquinavir levels by about 25%!). The combination of delavirdine/saquinavir could be an effective regimen. Finally, delavirdine's resistance patterns could make it uniquely useful in multiple drug combinations. For these reasons, SFAF will continue to lobby FDA to make delavirdine available under accelerated approval regulations. SFAF is closely monitoring the development status of other anti-HIV drugs. SFAF is anxious for Agouron to file for accelerated approval of its protease inhibitor nelfinavir as early as possible, preferably no later than April 1997. 141-W94 (also called VX-478), the protease inhibitor from Glaxo Wellcome, has captured our attention for 2 reasons: (1) 141 crosses the blood-brain barrier; and (2) 141 is not cross-resistant to any commercially available protease inhibitor. SFAF will lobby Glaxo Wellcome to make 141 available in 1997 through expanded access to people failing or intolerant to other protease inhibitors. SFAF is also keenly interested in 2 other protease inhibitors in early human testing: DMP-450 from Avid Pharmaceuticals and PNU-140690 from Pharmacia and Upjohn. In addition, Abbott Laboratories is expected to start human studies of its second-generation protease inhibitor in 1997. Other new anti-HIV drugs in development include AD-439 and AD-519 (Tanox Biosystems), adefovir dipivoxil (Gilead Sciences), Aztec controlled-release AZT, CI-1012 (Warner Lambert), cytomegalovirus immune globulin (MedImmune), DMP-266 (Du Pont Merck), topical cidofovir (Gilead Sciences), GEM 91 (Hybridon), HBY-097 (Hoechst Marion Russel), KNI-272 (Japan Energy), n-docosanol (LIDAK Pharmaceuticals), lobucavir (Bristol-Myers Squibb), probucol (Vyrex), protovir for CMV retinitis (Protein Design Labs), RBC-CD4 (Sheffield Medical), tucaresol (Glaxo Wellcome) and zintevir (Aronex Pharmaceuticals). SFAF also is following the development of vaccines for HIV, gene therapies, immunomodulators, and drugs for HIV wasting, HIV-related dementia, AIDS-related diarrhea and HIV-related neuropathy. We are in contact with the manufacturers of these medications to discuss issues relating to protocol design, expanded access programs, drug supply and approval timelines. Ronald Baker is Editor-in-Chief of BETA and Director of Treatment Education and Advocacy at the San Francisco AIDS Foundation. Page last updated 20 December 1996 |
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