Last December, Unimed Pharmaceuticals submitted a New Drug Application (NDA) for NTZ (brand name: Cryptaz). This was the first time a drug for treating cryptosporidiosis was brought to the FDA. Although NTZ is an antiparasitic, Unimed did not request that the FDA approve NTZ for treating the infection itself. The data from Unimed supported approval only as an agent to reduce cryptosporidiosis-associated diarrhea. Even this restricted basis was too much for the FDA's Antiviral Drugs Advisory Committee, which advised against approving NTZ after a May 6 meeting to review Unimed's application.

Cryptosporidiosis is an AIDS-defining condition, caused by the relatively common, highly infectious protozoan parasite Cryptosporidium parvum. The primary clinical manifestation, chronic diarrhea, can be debilitating with as many as 15 to 20 liquid bowel movements per day. This infection is diagnosed in 10% to 20% of persons with AIDS who have diarrhea. The availability of HAART (highly active antiretroviral therapy) has led to a major reduction in the incidence of cryptosporidiosis -- as high as 80% in some surveys -- but has not eliminated it entirely. Still, the sharp decline in incidence has made it difficult to recruit suitable volunteers of anticryptosporidial clinical trials, to say nothing of curtailing the financial incentives for developing such drugs.

Clinical Trials

Early accounts of NTZ's surprising efficacy in small studies in Mali and Mexico fueled community excitement about the drug. Unfortunately, follow-up trial data have been meager. Reports from Mexico, where NTZ is approved, claimed that it reduced symptoms and cleared the parasite in most of 30 participants treated in a small trial. Those who failed on daily doses of 500 mg and 1,000 mg per day responded when the dose was increased to 4,000 mg (see Treatment Issues, Nov. 1996).

Unimed's application for FDA approval was based on a limited data set from three open-label studies involving about 200 participants between 1995 and 1998: UMD-95-004; UMD-95-009A; and UMD-95-009B. These studies were not designed to demonstrate efficacy. The NIH-sponsored trial, ACTG 336, testing NTZ against placebo, was supposed to have been used for licensure, but due to poor accrual (only 11 of the required 60 participants enrolled in one year), the study was closed in April. And therein lies the crux of the problem.

Protocol 004 enrolled 30 persons with AIDS in a phase I/II pilot study of the drug using doses ranging from 500 to 2,000 mg per day. Participants had a baseline median CD4 count of 25.3 and chronic cryptosporidial diarrhea, defined as greater than four stools per day. All participants were on a stable antiretroviral regimen and had no other intestinal parasites.

Twenty-eight of these participants finished at least two weeks of NTZ therapy. Complete response was defined as clinical resolution of diarrhea, with remaining bowel movements limited to one to three per day. Partial response was defined as at least a 50% reduction in the average number of stools per day (but still greater than four) or a change in stool consistency so that more than 75% of the defecations were formed stools. By these criteria, 50% of participants experienced a clinical response -- 32.1% had a complete response and 17.9% a partial one. In addition, 30% exhibited either complete or substantial elimination of C. parvum oocysts (parasite eggs) in their stools, a heretofore unobserved feat.

There was a trend toward greater response associated with a longer duration of therapy (eight weeks compared to four weeks) and with higher doses of NTZ (greater than 500 mg/day). Rosemary Soave, M.D., of Cornell Medical Center in NY, one of the study investigators, commented that there is a time lag between clinical improvement of diarrhea, which usually takes two weeks, and signs of parasite suppression (such as loss of stool oocysts), which can take an additional two to four weeks.

Protocol 009A enrolled 139 participants with a baseline median CD4 count of 21.4 and chronic cryptosporidial diarrhea that was refractory to other cryptosporidiosis therapies. Concurrent microsporidiosis was allowed. Participants were required to be on stable antiretroviral therapies, but protease inhibitors were not widely used among study subjects. Participants received 1,000 mg of NTZ per day for at least four weeks.

By week eight there was a statistically significant reduction in stool frequency from baseline in 124 participants. However, only 39 participants met all the protocol requirements, including a positive stool exam for C. parvum within two months of baseline. This subgroup was referred to as "per protocol." Complete response was defined as a 50% to 100% reduction in average daily liquid stool count and partial response was defined as a 30% to 49% reduction in liquid stools. In the "per protocol" group, 53.8% of the participants had a complete response at week eight, and 12.8% had a partial response. Eighteen of the 39 participants in this group could be assessed for change in number of oocysts: 8 (44%) showed improvement.

NTZ was usually discontinued upon resolution of symptoms. In most participants who experienced a recurrence of cryptosporidial diarrhea, whether because the parasite had not been eradicated or through reinfection, NTZ was effective when readministered.

The third protocol, 009B, randomized 41 participants to receive 1,000 mg or 2,000 mg of NTZ for at least eight weeks. Inclusion criteria and definition of response were identical to 009A. Median baseline CD4 count was 17.5. In 35 participants at week eight, there was a significant decrease in liquid and total stools per day at both doses, and there was a trend towards better response at 2,000 mg per day. Dr. Soave would prefer to use the 2,000 mg daily dose. She stated, "If there is any fear that 2,000 mg might be too high a dose, then I would start at 1,000 mg and go up to 2,000 mg if there is a poor response. But I would like to give 2,000 mg a shot before saying that NTZ doesn't work."

There was no evidence of significant drug-induced toxicity in any of the protocols. Nonetheless, Unimed recommends that anyone treated with NTZ be regularly checked for liver abnormalities.

Weak Data Doom the Drug

The quality of the data presented by Unimed was mediocre and there was a large amount of missing data, which is why the Advisory Committee did not recommend approval. Data from the 009 protocols were not broken down by viral load or CD4 count. Further, there was no adjustment for the use of HAART. Therefore, it is not clear how cryptosporidiosis would progress in populations similar to those in the open-label studies receiving the same antiretroviral therapies but placebo NTZ.

The lack of enrollment in placebo-controlled ACTG 336 forced Unimed to compare the NTZ results with placebo cohorts in previous cryptosporidiosis trials (ACTG 192 and Pfizer Study 143, which respectively tested two unsuccessful drugs, paromomycin [Humatin] and azithromycin [Zithromax]). Such "historical" controls from other trials are always weak because the groups being compared may not be similar enough. In this case, antiretroviral therapies in particular have changed over time.

According to an FDA reanalysis of the data, no statistically significant difference was found in the response rate between the NTZ group and the control group in six different categories. Robert Dudley, Ph.D., of Unimed argued that the Advisory Committee looked very narrowly at a single analysis of the data, focusing only on 14 participants who completed the entire three-week protocol in the ACTG 192 placebo group. Dr. Dudley claimed that when participants from both the ACTG and Pfizer placebo groups were included in the analysis, the difference in response rates approached statistical significance (43% in the NTZ group versus 21-23% in the placebo group).

What Now?

Open-label study data, such as those presented by Unimed, are not generally central to a drug's approval. But in this case they were the only data available. Nineteen community organizations signed a consensus letter supporting Unimed's application, stating that NTZ's clinical benefit outweighs the modest safety risks especially considering the lack of other FDA-approved treatments for cryptosporidiosis. In light of the Advisory Committee recommendation, Unimed requested conditional FDA approval for its drug with a commitment to conduct post-marketing studies. While some community groups support Unimed's proposal, others argue that the company presented shoddy data and must conduct better controlled trials to prove drug efficacy before approval is granted.

Unfortunately, the introduction of HAART means that Unimed probably has missed the window of opportunity to get the type of data on NTZ and cryptosporidiosis that the FDA typically requires. Since people with CD4 counts over 180 are usually able to clear the parasite from their intestines unaided by other therapies, HIV suppression, when possible, looks like the best treatment. As with other opportunistic infections such as CMV, new cryptosporidiosis trials will struggle to find eligible participants.

The overriding issue is how to develop and test opportunistic drugs in the era of HAART. The FDA has traditionally considered large-scale placebo-controlled trials the gold standard for approval. Such trials are no longer feasible for drugs like NTZ that treat conditions found in very small patient populations where only limited data sets can be generated. Dr. Soave expressed her concern, "We know that placebo-controlled trials are the standard, but if you can't do them, does that mean that you should just give up? Do you say the data is absolutely useless because it's not the way we like to have data and never make the drug available?"

It is unlikely at this point that the FDA will go against the Advisory Committee recommendation and approve NTZ without new data. Reportedly, the agency is proposing that Unimed establish a new premarketing highly regulated, rigorously assessed trial (not necessarily placebo controlled) that need run for as few as two weeks with no more than 50 participants. Such a trial could be conducted in a foreign country with a continued high incidence of cryptosporidiosis.

But Unimed intends to cut its losses. If the current application is rejected, Unimed says that it will drop the drug for the treatment of cryptosporidial diarrhea, although it plans to eventually pursue NTZ for treatment of other indications with larger target patient populations. Such a move potentially creates severe hardship for people who contract cryptosporidiosis. Outside of Unimed, the only U.S. access to NTZ is through the PWA Health Group in New York, which brings it in from Mexico (for information, call 212/255-0520). The cost for a four-week course of NTZ at 1,000 mg per day is about $150. Larger doses and a longer course of treatment will drive the cost up higher. If the FDA rejects the application, Unimed also will stop admitting new patients to trial 009B, its compassionate use protocol, but will continue to supply the drug free of charge to current participants. Physicians can still request NTZ after obtaining emergency IND (investigational new drug) approval from the FDA by calling Medical Affairs at Unimed at 800/864-6330. Drug supplies will expire in about 18 months.