TAGline/Volume 5 Issue 6

Contents:

1. Jubilation, and Skepticism, Greet Announcement of First Phase III Trial of an AIDS Vaccine
2. Crypto Treatment Hopes Dashed as Sloppy, Divisive Unimed Fails to Provide Clean Data -- or Proof of Efficacy
3. The Elusive C. parvum (Table)

This June, the FDA gave the go-ahead to VaxGen, Inc., a subsidiary of Genentech, the biotechnology firm, to conduct the first phase III efficacy trial of a vaccine to prevent HIV infection. The story made the front page of almost every major newspaper in the country. The International AIDS Vaccine Initiative (IAVI)’s president Seth Berkeley heralded the trial’s approval as “a watershed event in the AIDS crisis.” The trial’s go-ahead is a victory for VaxGen virologist Donald Francis who has been pushing for wide-scale testing of this product for several years. TAG’s Gregg Gonsalves reports.

Media hoopla notwithstanding, not everyone is quite as excited about VaxGen's initiative as Drs. Berkeley and Francis. Leading HIV researchers including John Moore of the Aaron Diamond AIDS Research Center, Arthur Ammann of the American Foundation for AIDS Research and Nobel laureate David Baltimore of the California Institute of Technology and chair of the NIH's AIDS Vaccine Research Committee placed little or no hope in VaxGen's product in statements made to the press. Indeed, the NIH decided back in 1994 not to pursue phase III studies of a similar VaxGen product based on unpromising preliminary data on the vaccine (see TAGline, vol. 1, no. 5). Over fifty AIDS researchers wrote a letter to Science magazine in May of this year reaffirming the NIH's decision and criticizing further testing of the class of vaccines which include VaxGen's product.

There is a clear split in the AIDS research community over the FDA's decision. Many clinical vaccine researchers support the phase III study of AIDSVax, VaxGen's product. Meanwhile, many basic researchers working on vaccines support the NIH's 1994 decision not to go-ahead with phase III testing of Genentech/VaxGen's product and don't think the new generation of AIDSVax merits further testing.

VaxGen and their supporters argue that since the vaccines are safe and the earlier generation of AIDSVax induced antibody responses to the immunizing strain of HIV we should go ahead and test the efficacy of these products. They also contend that the only way to finally know if these products have any efficacy at all is to put them to the test to see if they can prevent HIV transmission in humans. If AIDSVax is only partially effective, we will have made great strides in preventing HIV infection. If AIDSVax turns out to be a dud, VaxGen and their supporters contend that we will be able to draw upon the results of the study to construct better vaccines in the future.

The AIDSVax skeptics see the upcoming trials as a waste of time and money. They point to the fact that none of the subunit envelope vaccines including the earlier generation of AIDSVax has been able to generate strong and broadly reactive neutralizing antibody responses to primary isolates of HIV and are even worse at inducing strong and relevant CD8+ cytotoxic T-lymphocyte (CTL) responses. They also point to studies of trial participants who have been infected with HIV despite vaccination with these products (see Steve Wolinsky's analysis of vaccine 'failures' in the 2/98 Journal of Virology). Those infected with HIV had no difference in their immune responses to the virus than did vaccine recipients that remained uninfected. Viral loads in the infected and immunized individuals were also no different than in unvaccinated HIV+ subjects.

From looking at the data, the AIDS skeptics are probably right. While we still don't know what the correlates of protection against HIV are, it seems at least reasonable that an effective vaccine will generate strong and broadly cross-reactive neutralizing antibodies and/or CTLs to primary isolates of virus. Ten years ago, we didn't have great surrogate markers for antiretroviral drug efficacy, but it at least seemed reasonable then to base phase III go-ahead decisions on whether or not a drug could modestly boost CD4+ T-cell numbers. If a drug didn't raise CD4+ cells back then, it generally didn't make its way further along in the pipeline. If a vaccine can't induce antibody or CTL responses that reflect our latest understanding of HIV pathogenesis, what is the real scientific basis for going ahead with a large-scale trial?

Just announced results from sophisticated X-ray crystallography of HIV's glycoprotein spikes, due out in the weekly journals Nature and Science, cast still further doubt on the envelope-based vaccine approach. "The much-hyped antibodies produced by this vaccine," Aaron Diamond's John Moore writes in the Nature commentary, "play into the virus's hands because they attack its defenses head on." Dana-Farber's Joseph Sodroski, an author on one of the papers, is more brutal still: "One doesn't need the crystal structure [of the virus' envelope] to put a nail in that [gp120] coffin. The virus has evolved so as to evade immune responses and to make gp120 a not very effective provoker of antibody responses." But Genentech's crusading Francis (now the president of VaxGen) remains undeterred, "It works in a chimp, it's safe in humans, and it produces a better immune response in humans than in chimps," Dr. Francis argues. "To sit back and wait for more lab tests would, I think, be unconscionable."

We can at least be grateful that no public funds are being used for VaxGen's trial. A trial of this size would eat up a major portion of the NIH's vaccine budget and take precious resources away from more important research. There are still lingering concerns about study participants in VaxGen's trial. Any participating trial sites should make sure that participants in the study are told of the scientific skepticism about AIDSVax. With little chance of trial enrollees being protected by the vaccine, a truly informed consent would include discussions of the scientific debate surrounding this product. Many of the domestic trial sites will be at institutions that have already been preparing for phase III studies of a vaccine through programs supported by the NIH. These sites have developed strong relationships with communities at high risk of HIV infection. We can only hope that if VaxGen's trial bombs, the important relationships between these research sites and the community won't be negatively affected.

A truly effective vaccine is our only hope of stemming the tide of this epidemic in the U.S. and abroad. It is truly tragic that we don't have a vaccine candidate right now that is more promising than AIDSVax. The real headline for the newspapers is that after almost two decades of this epidemic there isn't more commercial interest in developing a vaccine and that the NIH has only recently decided to make AIDS vaccine development a priority.

The real challenge for those involved in AIDS vaccine development right now is to build on our current knowledge about HIV and the immune response to manufacture new immunogens that may have a better chance of protecting people against HIV infection. If industry is not going to pick up the slack, the NIH and private research organizations like IAVI and AmFAR have to jump start this effort by developing and producing new candidate vaccines that can quickly be pushed into phase I studies in humans. While the NIH has been increasing its investment in AIDS vaccine development, it's time for the agency to streamline its vaccine efforts. In addition to ramping up its capacity to develop and produce new candidate vaccines, the agency should better coordinate the evaluation of new immunogens in non-human primates. Right now, monkeys studies of new vaccines are small and employ different routes and viral strains to challenge vaccinated animals. Assays of the immune response to vaccine candidates are similarly varied. The NIH to its credit has established the AIDS Vaccine Research Committee that has begun to guide the NIH's efforts in vaccine research and has brought some needed focus to the program.

A little over a year ago, President Clinton, in a speech at Morgan State University, committed the nation to the goal of developing an AIDS vaccine within the next ten years. The achievement of this goal will not be easy, but it is not impossible. The VaxGen trial is no great leap forward; it's a great distraction from the difficult tasks ahead.

On May 6th, the FDA’s Antiviral Drugs Advisory Committee met to consider an application for approval of Unimed Pharmaceuticals’ cryptosporidiosis treatment, nitazoxanide (NTZ), for the treatment of cryptosporidial diarrhea in PWAs. TAG’s Laura Morrison was there and prepared this report.

Despite more than ten years of clinical trials on dozens of agents for cryptosporidiosis, there is still no FDA-approved therapy and no standard of care for its treatment. In fact, prior to NTZ, not a single New Drug Application (NDA) had been filed for the treatment of cryptosporidiosis. Efforts to find useful therapies have been impeded by the absence of an in vitro model and the lack of a universally accepted animal model with which to screen potential agents. Potential treatments at present (see table below) include spiramycin, diclazuril, letrazuril, octreotide (Sandostatin), azithromycin, hyperimmune bovine colostrum, hyperimmune egg yolks (IGX-CP) and paromomycin (humatin). But nothing is reliably effective, and even the best response rates are notoriously low. Rifabutin and clarithromycin may have a prophylactic effect against C. parvum, but more research is needed. Because of this longstanding void and the devastating, debilitating nature of cryptosporidiosis, Unimed's NTZ application generated an unusual amount of excitement among treatment activists.

Unimed's application itself was unusual in that it was based solely on open-label, compassionate-use data. While Unimed did support a study of NTZ vs. placebo (ACTG 336), that study had to be terminated due to abysmal accrual (only 9 patients over a year's time). The FDA, recognizing the difficulties of enrolling such a study in the era of protease inhibitor combination therapy, encouraged Unimed to submit its NDA based on data collected from its open-label studies. The FDA proposed using data from the placebo arms of ACTG 192 (paromomycin) and Pfizer study 143 (azithromycin) as historic controls.

Unfortunately, even within the FDA's rather loose requirements, Unimed came up far short. Unimed presented data on 226 people with AIDS in three open-label studies. UMD-95-004 was a phase I/Il dose escalation study (500-2,000 mg/day) in 28 PWAs with microbiologically confirmed cryptosporidial diarrhea. Approximately 32% of the patients achieved a complete response (clinical resolution of diarrhea to 1-3 bowel movements per day), and 18% had a partial response (at least a 50% reduction in the average number of daily bowel movements but still >4 bowel movements per day or change in stool consistency to >75% formed at the end of the study). UMD-95-009A and UMD-95-009B were open-label, multicenter studies of 139 and 57 PWAs, respectively, with diarrhea "attributed to" cryptosporidiosis who were refractory to other experimental cryptosporidiosis therapies. Although Unimed documented that approximately 50% of patients achieved a clinical response in terms of reduced watery and total stools, both studies were fraught with problems that limited the credibility of their findings, including:

• Only 39 patients from 009A and none from 009B met Unimed's definition of "per protocol," i.e., they were on a 1,000 mg NTZ/day regimen, had microbiologically confirmed presence of C. parvum in their stool at baseline, had >4 liquid stools/day at baseline and at least 1 post-baseline visit with stool frequency data.

• For most patients there was no information about relevant concomitant medications (i.e., antidiarrheals), and there was no analysis of outcome based on whether patients were on a protease inhibitor.

• Unimed performed its analysis using a "Last Non-missing Observation Carried Forward" (LOCF) method, thus true, full-course outcomes were not known for many patients.

Regrettably, it became apparent during the FDA's presentation at the hearing that Unimed's data were even weaker and sloppier than we suspected. The FDA reviewer revealed that 34% of patients in the three trials had been lost to follow up. When asked what had happened to those patients, none of Unimed's representatives could answer. (We later found out that the vast majority of these lost-to-follow-ups had died.)

The FDA reviewer said that if we assumed the worst case -- that those lost to follow up were failures -- clinical benefit would drop to just 31%. Even in a best-case scenario, the FDA calculated a clinical benefit in only 43% of patients.

When an FDA statistician compared 91 patients from the NTZ studies to the 14 patients in the placebo arm of ACTG 192 (and separately to the 41 patients in the placebo arm of Pfizer study 143), no statistically significant difference was observed using numerous criteria. (It should be noted that the small numbers of patients in each placebo arm made achieving statistical significance a particularly high hurdle. Nonetheless, this torpedoed Unimed's chances.)

Perhaps the most damning part of the hearing came when the Advisory Committee members asked their questions. Unimed was grossly unprepared and was not even able to handle a challenge from panel member Cynthia Sears (a gastroenterologist from Johns Hopkins) on the percentage of cryptosporidiosis patients whose symptoms spontaneously remit. The panel members, sensing a weak applicant, went for the kill.

By the time the panel broke for lunch there was little doubt what the outcome would be. They voted 9-1 against approval, with TAG's Michael Marco, the community representative on the advisory committee, casting the lone "yes" vote in deference to the community consensus. The clear message after the FDA hearing was that Unimed would need to do another study, one that could be small but tightly monitored and rigorously assessed. The biggest fear of treatment activists was that Unimed would abandon NTZ for cryptosporidiosis entirely. In fact, the position Unimed struck following its defeat at the FDA was even worse.

In a May 14th conference call Unimed Vice President Dr. Robert Dudley told treatment activists from around the country that Unimed was seeking a "conditional approval" from the FDA that would allow the company to market the NTZ pending completion of a confirmatory study. Barring that, the company would discontinue its cryptosporidiosis research and end its expanded access program as well. Furthermore, Unimed would not grant rights to any other company willing to pursue the NTZ indication. Dudley pleaded poverty saying Unimed had already invested too much in NTZ at the expense of other agents. Then he said the company didn't have the supply of NTZ available to continue expanded access -- this despite the fact that the company is planning to begin studies of NTZ for treatment of H. pylori. Dudley's ultimatum smacked of blackmail. Either the community mounted a gargantuan effort that would somehow sway the FDA to grant conditional [sic] approval (based on nothing) or we would lose access to a promising therapy (short of getting it through buyers clubs which import the drug from Mexico for those with the financial resources to purchase it). TAG sent word to the community that we flatly refused to play into Unimed's hands (or speak to their Ken doll, ex-AIDS activist PR agent) by senselessly pleading with the FDA to conditionally [sic] approve a drug with no efficacy data. Unimed didn't even realize that there is no such thing as "conditional approval" -- it's called "accelerated approval" and it comes with strict FDA regulations.

After considering Unimed's position, many in the community finally decided they were unwilling to make excuses for the company's sloppy data and plead with the FDA. Linda Grinberg and Martin Delaney (of Project Inform) drafted a community consensus statement calling on Unimed to immediately amend its application to seek instead a cost-recovery Treatment IND (investigational new drug) and urging the FDA to immediately begin work with Unimed to design an appropriate follow-up study capable of confirming the drug's efficacy. By June 1, signators to the statement included TAG, Project Inform, FAIR and the San Francisco AIDS Foundation. While the FDA has indicated willingness to offer a cost-recovery Treatment IND, Unimed is apparently unwilling to pursue that option at this time. As TAGline goes to press, treatment activists continue to develop a strategy which might convince an incompetent, mean-spirited little company to do the right thing.