Swiss TPH

Development of a novel, orally applicable drug for treatment of first stage sleeping sickness (Pafuramidine maleate-DB289)

Only a very limited number of drugs is available for treatment of human African sleeping sickness and none of them is applicable by the oral route. The international Consortium for Parasitic Drug Development (CPDD) led by the University of North Carolina, Chapel Hill, USA, is receiving funding by the Bill & Melinda Gates Foundation (BMGF) to discover and bring selected molecules to registration.

DB289 (pafuramidine maleate), an orally active pro-drug with considerable trypanocidal activity and low toxicity was chosen for further development in the year 2000. The compound underwent extensive preclinical, Phase I (healthy volunteers) and Phase II testing (proof of concept in patients). In 2001 the Pharmaceutical Medicine Unit (PMU) was subcontracted by the US Company Immtech Pharmaceuticals Inc. to plan and conduct the clinical trials needed for registration of DB289 for first stage sleeping sickness with the US Food and Drug Administration (FDA). Subsequently the PMU contributed to several Phase II and one Phase III trials through scientific advice, site selection, improvement and management, trial coordination, logistics and monitoring.

The Phase II trials were mostly carried out in the Democratic Republic of Congo, but also in Angola. They provided very promising results in terms of drug safety, but a prolongation of the treatment duration from five to ten days became necessary to increase the efficacy. The protocol for a pivotal Phase III trial was developed in close collaboration with the US FDA. Patients were recruited in four centers in the DRC and one center each in Angola and South Sudan between August 2005 and March 2007 and followed up for two years after treatment. 273 patients including pregnant and lactating women as well as adolescents were randomized in an open-label design to treatment with DB289  100 mg BID oral for 10 days or the comparator drug pentamidine 4 mg/kg IM for 7 days.

In October 2007 a Phase I study was initiated in South Africa in parallel with the ongoing Phase III follow up. The study was requested by the US FDA to acquire additional safety data for the registration of DB289 for sleeping sickness and Pneumocystis carinii. Eighty healthy volunteers received DB289 100 mg BID for 14 days.

In February 2008 the DB289 development program was discontinued when liver toxicity and later renal insufficiency were observed in a number of participants in the additional Phase I trial. The cause for those unforeseen adverse drug reactions is unclear and is being investigated. The Phase III sleeping sickness trial data was unblinded at that time and reviewed by study Sponsors and advisors. Liver toxicity was significantly lower in the DB289 group than in the pentamidine group. However, re-examination of the data revealed three subjects which had developed glomerulonephritis/nephropathy post DB289 treatment, of which two events may retrospectively be considered possibly related to DB289. No patient in the pentamidine group was reported to have renal disease.

The DSMB recommended to amend the examination of patients with ongoing active follow up with a biochemistry panel. This safety follow-up was implemented by the PMU in April 2008 and has not revealed any major abnormal findings so far.