GMHC Treatment Issues; Volume 4 no. 2 April 6, 1990
Kevin Armington

In the American study, 387 patients with AIDS or ARC were randomized to placebo or 10 mg/kg Imuthiol a week. Patients were evaluated after an average treatment period of 18.5 weeks. Those who responded best were people with AIDS, who had fewer that 200 T4 cells (15). The most significant finding was a difference in numbers of opportunistic infections (OIs): 25 OIs occurred in patients on placebo as opposed to 10 in those on drug. (In a recently completed study [ACTG #019], a similar finding persuaded FDA to approve AZT for patients with T4 cell counts under 500.) In addition, patients on drug had a reduction in thrush, oral hairy leukoplakia (white ridges or lesions on the side of the tongue) and certain clinical symptoms (fever, fatigue, night sweats). A slight rise in T4 cell counts was seen in those on drug after 24 weeks of treatment. Aside from a metallic taste and gastrointestinal upset, no toxicity was seen.

Results from a German study of Imuthiol were published in the March 24, 1990 Lancet (16). This group's findings were similar to earlier data in terms of toxicity and efficacy. Sixty patients with ARC were randomized to oral Imuthiol, intravenous Imuthiol or placebo. After 24 weeks of treatment, six patients on placebo versus none on drug progressed to AIDS. Although T4 cell counts did not rise significantly in patients on drug, Imuthiol appears to stabilize T4 levels, according to these researchers. This study also noted that Imuthiol has activity against a number of microbes that are commonly seen in HIV- infected individuals.

Why did the FDA Say No?

According to representatives of Institut Merieux, the FDA raised objections about the limited survival data. In addition, there was some concern about the methaline chloride content of the coating on the capsule, which preserves the drug from digestion in the stomach. Finally, the FDA argued that the availability of AZT in this country makes access to Imuthiol unnecessary.

Officials at the FDA disputed that the Treatment-IND was rejected on such rigid grounds. In general, regulators who reviewed the data are not convinced that Imuthiol slows progression of HIV illness or that there is "significant" evidence of efficacy. The most common infection reported in the placebo group was PCP, and the data were re-examined after Merieux specified who received prophylaxis, which was optional in the study. Treatment Issues was unable to obtain these data. Excluding PCP, however, ten OIs were reported in those on placebo, while only three OIs were seen in those on drug. Officials at the FDA asserted, however, there was some disagreement about these numbers. It appears that the availability of AZT did have an impact on the FDA's decision to deny the Treatment-IND, which is difficult to understand from a scientific point of view. AZT is approved as an antiviral treatment; Imuthiol appears to work through immunomodulatory mechanisms. The two drugs appear to be perfectly safe when used together and could be effective complementary therapy.

The FDA's unfortunate decision is yet another example of an overly cautious regulatory process which errs on the side of blocking access to potential treatments. If Imuthiol is compared to ddI, it is especially baffling that the Treatment-IND was denied. Seven years of clinical experience have demonstrated Imuthiol's safety, and more than one placebo-controlled trial have provided evidence of efficacy. Treatment-INDs were envisioned to allow very ill patients with no other treatment options early access to promising drugs. In this case, it seems that the standard the FDA is using is equivalent to the standard for full approval and licensing of a new drug.

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