FDA Clinical Hold as of 12/21/07 due to safety concerns

The purpose of this study is to demonstrate the non-inferiority of pafuramidine maleate (DB289)versus trimethoprim-sulfamethoxazole (TMP-SMX)for the treatment of mild to moderately severe Pneumocystis pneumonia (PCP).

The gold standard treatment for PCP is trimethoprim-sulfamethoxazole (TMP-SMX). This drug is highly effective; however, a significant number of patients are unable to complete a course of therapy due to adverse events, some of which can be life-threatening. In addition, mutations that confer resistance to sulfa-based drugs in other microorganisms are increasingly being reported in P. jiroveci. A potential role of these mutations in conferring clinical resistance to PCP and in breakthroughs to prophylaxis regimens based on sulfa drugs is being actively studied. Second and third line agents or combinations for PCP treatment are also limited in efficacy and/or by adverse events.

A new agent such as pafuramidine maleate (DB289), which has well documented activity against P. carinii in animal models, documented efficacy in a preliminary study trial in HIV-infected patients with PCP that were intolerant or resistant to TMP-SMX, was well tolerated in this trial and demonstrated a low toxicity profile in Phase 1 studies, would meet a significant medical need. Furthermore, pafuramidine maleate is active against other pathogens responsible for significant morbidity and mortality in patients with AIDS in the developing world, like different strains of Plasmodium (malaria) and Cryptosporidium parvum. The decrease in the rate of PCP in countries where patients with AIDS have access to HAART will present a significant challenge to the completion of this development program. The last published trial of PCP treatment was conducted by the ACTG in 24 U.S. sites between May 1991 and june 1993. That study needed to decrease the planned sample size to 195 due to low enrollment. This represents an important challenge for our program.

Inclusion Criteria:

• Documented or presumptive HIV infection
• Signs and symptoms of PCP present for at least 5 days
• Pneumocystis jiroveci confirmed in BAL fluid or induced sputum sample
• Suitable candidate for oral therapy
• Alveolar-arterial oxygen (A-a) gradient < or = 45 mm Hg on room air and partial pressure of oxygen (pO2) > or = 60 mm Hg
• No more than 48 hours of prior treatment in the preceding 7 days for PCP treatment at full doses; failure of Pneumocystis prophylaxis or use of medications recommended for treatment of PCP at doses less than recommended by the CDC Guidelines is acceptable.

Exclusion Criteria:

• Unwilling or unable to discontinue use of other medications with anti-PCP activity
• AIDS related cachexia (weight loss that is more than 10% of ideal body weight)
• Severe diarrhea and/or vomiting
• History of hypersensitivity or severe or life threatening toxicity to TMP-SMX, other sulfonamides or pentamidine
• Active illicit drug use
• Impending respiratory failure or need for intubation
• AST and ALT levels > 3 times the upper limit of normal
• History of pancreatitis
• Severe PCP
• Karnofsky score < or = 20
• Terminal HIV disease or life expectancy of less than 6 months
• Acute concurrent pulmonary pathological condition that would obscure the evaluation of response to therapy
• Concomitant use of amphotericin B, gangciclovir, cyclosporine, warfarin, thiazide diuretics, phenytoin, methotrexate, leucovorin
• Receipt of systemic corticosteroids (except replacement therapy) within 14 days of study entry at high doses for 3 or more consecutive days. Concomitant use of corticosteroids, other than replacement doses for adrenal insufficiency, is also excluded unless the patient meets the CDC criteria for use of corticosteroids for treatment of PCP
• Pregnant or lactating women
• The subject has been previously enrolled in the study