Important note: Information in this article was accurate in May 2000. The state of the art may have changed since the publication date.
American Foundation for AIDS Research, May 2000
Dave Gilden
Gilead is threatening to retreat from providing compassionate access to its new HIV drug, the nucleotide analog tenofovir. Meanwhile, expanded access is barely on the radar screen for Trimeris and Roche, who are codeveloping the fusion inhibitor T-20. This bleak picture came out of two recent meetings between company officials and community members.
For the present, people who have multidrug-resistant HIV will be able to obtain only one new drug through expanded access. That drug is Abbott Laboratories' experimental protease inhibitor lopinavir (ABT-378).
Lopinavir may be comparatively potent and tolerable, but HIV is able to develop resistance to it. Although it can form the core of an effective salvage regimen, lopinavir will not suppress HIV all by itself. Without effective supporting drugs, there is a high likelihood that patients on lopinavir will find that their HIV develops lopinavir resistance and rebounds. They will then lose the ability to use lopinavir successfully in the future.
Those who already have experienced failure with several different regimens will have multidrug-resistant HIV. They will have great difficulty constructing an effective lopinavir combination with any of the approved drugs.
One possible lopinavir helpmate is tenofovir. Gilead Sciences, which is developing this new nucleotide analog, has just assembled the 48-week data from its 186-person phase two trial. In that study, volunteers received either tenofovir or placebo in addition to continuing their prior regimen for at least four weeks. After that, they could alter their concurrent medications. The 186 enrollees had to have detectable viral loads (from 400 to 100,000 copies/mL), so the trial was essentially a treatment intensification experiment.
The mean baseline viral load was 5,000 copies/mL. The trial cohort had an average treatment history of 4.5 years, and 97% of them had HIV with resistance mutations to nucleoside or nucleotide analogs. Nonetheless, viral loads dropped an average 0.8 logs (84%) in the first two weeks on the highest dose (300 mg once a day). Mean viral load tended upward slightly and then downward again, ending the 48 weeks at 0.7 logs (80%) below baseline.
More than a third of the trial participants had modified their background therapies by week 24. Gilead is now analyzing the contribution that switching these other drugs made to the observed antiviral effect. Still, it is clear from the data that tenofovir is useful as part of combination regimens for rescuing patients with drug-resistant, refractory HIV.
Gilead is just completing recruitment for a 600-person Phase III intensification trial. It is also going ahead with a 600-person Phase III international trial in treatment-naïve patients. It did have a 300-person limited compassionate use program in place, but that program is now filled. (The compassionate use program was generally open only to highly treatment-experienced persons who had both a CD4 count less than 50 and a viral load greater than 10,000.)
In a letter dated May 13, 1999, Howard Jaffe, at that time head of Gilead drug development, said that Gilead planned to follow in Abbott's footsteps. He told the Coalition for Salvage Therapy, an activist group, that the company was "anticipating initiating a broad PMPA [tenofovir] expanded access program during the summer of 2000." This plan is now defunct, and tenofovir may not be available outside clinical trials for the foreseeable future. Such was the message that the Gilead scientists who head the tenofovir development program, James Rooney and Norbert Bischofberger, relayed to community members at a meeting on May 8.
The reason for this indefinite postponement, Rooney and Bischofberger said, lay in a meeting held with FDA officials back in October, 1999. The FDA told Gilead that it would have to submit 48-week safety data from a large trial comparing tenofovir head-to-head against another drug. Those data were necessary for tenofovir to receive any marketing approval, whether accelerated or traditional.
Gilead says that the FDA requirements will push approval back about two years, into 2003. It will have to wait for completion of its Phase III treatment-naïve study, which has just begun enrollment. This trial tests tenofovir against d4T - both combined with 3TC and efavirenz in a protease inhibitor-sparing combination. Gilead is reluctant to devote "resources" (personnel or money) to an expanded access program that will last more than a year or grow beyond a few thousand persons. Of course, the experience from a large expanded access program could be very useful in determining tenofovir's overall safety.
The October FDA meeting took place with the pending rejection of Gilead's adefovir already a strong likelihood. Adefovir, which is structurally related to tenofovir, causes kidney malfunction in many of the people taking it for longer than six months. For the past two years, Gilead has known that monkeys, dogs and rats ingesting very high doses of tenofovir for long periods were exhibiting decreases in bone density. The monkeys started developing spontaneous bone fractures after a year on tenofovir. This bone loss might be related to kidney toxicity.
Gilead has done nothing to change tenofovir's development program since the FDA meeting last fall. Instead, it has relied on its 48-week Phase II human data to persuade the FDA to change its mind. A meeting on the subject probably will take place in September, when the Phase II analysis will be finished. Rooney and Bischofberger argued that tenofovir looks very clean in humans. And indeed it does, from the data they showed - except for certain nagging doubts.
There were almost no abnormalities in creatinine clearance (a measure of the kidney's filtering capacity) after 48 weeks. Blood markers for bone loss, including calcium and phosphate levels, also were essentially unchanged during this period. A substudy of 51 trial participants did find a "minor" 1% to 2% decrease in bone density in the two highest dose arms (150 mg/day and 300 mg/day). Members of the placebo arm showed no loss until after they were switched to open label 300 mg tenofovir at 24 weeks. Those in the lowest dose arm (75 mg/day) on average had no loss at 48 weeks.
No statistical analysis of these data was done, so the significance of the results is hard to determine. Ordinarily, adults over age 35 lose 0.5% to 1% of their bone density per year. (The average age in the Phase II study was 42.)
The FDA may not find these results very compelling since they lack a comparison arm and cover only 51 people. These results leave open the question of what will happen after 72, 96 or more weeks. Delayed side effects might then appear, as they did in adefovir after six months.
Another worry is the two reports at last winter's Conference on Retroviruses. They associated protease inhibitors with bone density loss. These reports raise the specter that tenofovir and the protease inhibitors will have mutually reinforcing toxicities - toxicities that will become all the more profound when combined with the effects of age.
There is a further problem: Virtually no data are available concerning women taking tenofovir. Only about 9% of the Phase II trial participants were female. Attendees at the community meeting fretted about the unknown gender differences in bone loss, especially as they concern postmenopausal women. In response, Rooney and Bischofberger could only repeat the general Gilead goal of having the same proportion of women in its trials as are infected with HIV.
The issue, though, goes far beyond equal access to clinical trials. There must be enough women in the trials to build up statistically significant data on potential gender differences.
Gilead's hopes for inducing the FDA to loosen up sound uncomfortably like its strategy with adefovir. In that case, it tried to argue about the interpretation of unpleasant results rather than trying to supply new and more convincing positive results. Gilead again seems to hope that the community will pressure the FDA on its behalf without offering to put any extra effort into meeting community concerns.
Gilead is refusing to commit any resources to tenofovir expanded access after having the best financial results in its history. Compared to last year, total revenue was up 18% in the first quarter of 2000, when it reached $45.2 million. Net losses were down by two-thirds last quarter, and the company still has almost $300 million in liquid assets. In addition, adefovir is by no means dead. Low-dose adefovir for hepatitis B is in Phase III trials. Its hepatitis B sales could be enormous.
Gilead's income comes mainly from AmBisome (liposomal amphotericin for fungal infections) and DaunoXome (liposomal daunorubicin for malignancies). Gilead obtained these products, both of which have applications in AIDS, when it acquired NeXstar last year. A new major source of revenue is Gilead's flu drug Tamiflu. Marketed by Roche, Tamiflu came on the market just as the most recent flu season was getting under way.
Tenofovir is not in short supply. Gilead says it will have bulk quantities of tenofovir starting in November. There is nothing holding up an expanded access program, and if tenofovir approval is far off, then there is all the more need for one.
Meeting attendees demanded a conference call with Gilead president John Martin and an official response to their pleas to at least continue enrollment in the current compassionate use protocol. Rooney and Bischofberger, who maintained a noncommittal attitude throughout the meeting, acquiesced to requests that the company provide a formal reply within a week.
As of May 24, no official statement on the issue has been forthcoming. Different factions within the company are still arguing the question. Ben Cheng and Marty Delaney had a telephone conversation with Gilead president John Martin on May 10 and said that they had received a sympathetic response. Ben Cheng said, in an e-mail on the subject, that he and Delaney "felt confident that there would be an enlargement of the expanded access program although it is not clear when that will take place."
The only public reaction to the May 8 meeting so far has come from the European AIDS Treatment Group (EATG). On May 16, that activist coalition asked the European Medicines Evaluation Agency to "speed up access to tenofovir."
The statement asked regulators "to approve the drug for salvage therapy based on more limited data [than the FDA is currently requiring], and as quickly as possible," the EATG statement continued.
So, at least one community group has yielded to the pressures stemming from Gilead's present attitude: Either community treatment advocates have to help Gilead speed up tenofovir approval, or no one who cannot enroll in the trials will receive the drug for years, no matter what their need. The advocates are finding themselves in a very difficult position. Gilead's lack of cooperation with the community should be irrelevant to the approval process. The company's recalcitrance is neither a reason to delay tenofovir's FDA approval unnecessarily, nor is it a reason to force the FDA into precipitous action.
T-20 is a likely third drug for a salvage therapy combination. It has the advantage that it attacks a completely novel target - the gp41 glycoprotein on HIV's envelope. The harpoon-like action of gp41 pulls HIV and a cell into contact, allowing their membranes to fuse and HIV to enter the cell.
T-20's activity is not perturbed by patients' prior history with current HIV drugs. Its structure is also novel. Since it is a peptide - a short string of 36 amino acids - it does not affect the liver, kidneys, mitochondria or other organs sensitive to current drugs. There are no metabolic interactions with current drugs, either. Blood levels of any of the present drugs do not alter those of T-20, and vice versa. Finally, HIV resistant to any of the antiretrovirals on the market is still completely sensitive to T-20.
One of T-20's biggest problems is that it cannot enter the body through the digestive system. The gut would break down T-20 into its component amino acids. The favored mode of administration is to inject T-20 under the skin, but this causes swelling and inflammation at the injection site.
Another major problem is the cost and difficulty of synthesizing bulk quantities of peptides. A shortage of T-20 forced a postponement of clinical trials last year. When the drug comes on the market, its expected price will be far higher than those of the protease inhibitors.
At a March 3 community meeting, Trimeris announced that it had solved the production bottleneck and had also developed a new, more concentrated formulation. That formulation should cause less soreness. It allows administering 100 mg in a single injection. The preferred T-20 dose appears to be 100 mg twice a day, but that dose was difficult to achieve with the present version of T-20. Patients had to give themselves four of the irritating injections -two injections twice daily - to achieve this dose.
Enrollment progressed very slowly for a 68-person Phase II study that is testing different doses of the old T-20 formulation in combination with abacavir, amprenavir, ritonavir and efavirenz. Trial participants had to be protease inhibitor-experienced but NNRTI-naïve. Their baseline viral loads had t be between 400 and 100,000 copies/mL. These restrictions, especially the viral load upper limit, considerably reduced the population eligible for this trial.
T-20 is now moving into Phase III trials. The latest (May) version of the Phase III T20-301 trial calls for recruiting 525 volunteers with past or present experience with all three classes of antiretroviral medications (nucleoside analogs, NNRTIs and protease inhibitors). Volunteers also must have viral loads over 5,000. They will be prescribed a new combination regimen optimized by the use of drug-resistance testing. The trial will then randomize them to add either T-20 or nothing to their optimized regimen for 48 weeks. Trial participants will be allowed to switch to a second optimized regimen plus open label T-20 in the case of treatment failure. Another T-20 salvage therapy trial of this nature and size will soon commence in Europe.
Women's participation in past T-20 trials has been low, and Trimeris has yet to devise a specific plan to increase that participation. For the Phase III trials, Roche and Trimeris are "looking at sites that have a high proportion of female patients and that have programs that encourage women to volunteer," Roche scientist Mickey Salgo, who heads the Roche end of the collaboration, told the meeting. Once again, the main issue is not equal access to the trials, but establishing a large enough data set to document safety and dose response in women.
The Phase III trials' optimized background therapy may include drugs obtained through expanded access programs, but persons outside the T-20 trials will not be able to obtain T-20 in this manner for some time. Production of T-20 remains a stumbling block. Trimeris argues that it needs to ensure a three- to six-month reserve of T-20 for its trials before embarking on an expanded access program. Building up an adequate stock for the trials means that an expanded access program cannot begin until the spring of 2001. This is at most a year before T-20's anticipated approval date.
One potential controversy is an unprecedented eligibility criterion for entering the expanded access program. At the March 3 meeting, Mickey Salgo floated the idea of requiring applicants to supply resistance assay results to prove that their HIV is refractory to approved drugs.
This is more than just an extra hurdle. Resistance assays are very expensive, and not everyone has third-party health coverage that will pay for them. Also, these assays will not reveal residual resistance to drugs an individual has not taken recently. Surviving HIV subpopulations that retain resistance to past antiviral agents may represent only a small fraction of the total HIV in someone's body. They will be undetectable by resistance assays but could rapidly reappear if an individual restarts past drugs.
About 2,400 people have now received lopinavir through the expanded access mechanism. The program's eligibility criteria were greatly loosened last February, when Abbott eliminated the CD4 count and viral load limits. Since then, the only requirement is an inability to construct a tolerable, effective anti-HIV regimen with currently approved medications. A pediatric program similar to the adult one is awaiting an FDA go-ahead. It should start in mid-June.
Abbott's first lab testing of lopinavir occurred in 1995. Lopinavir has moved ahead quickly since then, and activists have had to rush to keep up. They managed to pressure Abbott into instituting a restrictive, small compassionate use program in September, 1999 and then a much broader expanded access program last winter. With FDA approval of lopinavir expected early next year, this broad program will last for only about a year.
The community should beware: Abbott's patient-doctor expanded access information number, 888/711-7193, has never updated its information about the eligibility criteria for expanded access. As of mid-May, it was still telling callers that lopinavir is available only to those who have failed at least two protease inhibitors and have CD4 counts under 200 and viral loads over 10,000. Abbott, with FDA approval, removed these criteria on January 25.
Tenofovir has safety questions, T-20 has production and formulation difficulties and lopinavir is rushing toward approval. These are three very different situations, yet expanded access for each agent will probably last only for the same period of time - the 12 months preceding approval. This pattern appears to have more to do with companies' desire to limit their investment risk than with any of these drugs' individual situations. But since the expanded access programs are foreshortened and do not overlap, doctors and patients have to cobble together salvage therapies that are unlikely to be fully effective. While the companies play it safe, people with drug-resistant HIV end up risking their health and their future treatment options.
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