Dr. Cyrus Bacchi writes his account of a discovery of a cure for African trypanosomias for our kfwh website. Dr. Bacchi works at Haskins Laboratories in New York City.
Cyrus J. Bacchi, Ph.D.
41 Park Row, New York, NY 10038
March 21, 2006
In 1974, my laboratory at Pace University began studying an enzyme (GPDH) which is critical to the cell respiration of African trypanosomes. The enzyme needed the metal magnesium for full activity, but the magnesium could be replaced by the polyamines spermidine or spermine. Polyamines are small molecules which are required by all cells for division and growth. Polyamines have many functions in cells including interacting with DNA, RNA to stabilize it, and stimulating processes like protein and nucleic acid synthesis.
The fact that the magnesium was replaced by polyamines in activation of the GPDH was interesting and I was encouraged to pursue polyamine metabolism in trypanosomes by my Ph.D. mentor, the late Dr. Seymour H. Hutner.
Since intracellular polyamines are turned over very rapidly, their depletion results in blockage of cell division. Once this was recognized, polyamines quickly became targets for drug development, especially in cancer cells. One of the key enzymes of polyamine synthesis is ornithine decarboxylase (ODC) which is very carefully regulated in human cells.
I began investigating polyamine metabolism, synthesis and function in African trypanosomes, and was introduced to this area of research and aided in the initial studies by Dr. Seymour Cohen, a member of the National Academy of Sciences, who had done pioneering work in the field. Dr. Cohen urged me to attend the Gordon Conferences on Polyamines, which were held biannually starting in 1975. Gordon Conferences are specialized meetings which bring together scientists from various research disciplines in informal settings, allowing free exchange of ideas. I started attending these conferences in 1977, and in August 1979 I met Dr. Peter McCann, a research scientist with the then Richardson-Merrell Pharmaceutical Company. The company had developed a potent inhibitor of ODC, the initial enzyme of polyamine synthesis. Difluoromethylornithine (DFMO) was being studied as an anticancer agent and was available in only limited supply. During a lunch time conversation at the Conference, I asked Peter for some DFMO for my African trypanosome studies, and he responded by offering me 25 g a significant amount at that time.
Once we received the DFMO, my colleague at Pace, Dr. Henry Nathan and I began a series of in vivo experiments using Trypanosoma brucei, a veterinary parasite of cattle, as a model for human disease. After infecting mice with trypanosomes, we waited 24 h and then began treating with 2% DFMO in the drinking water. Treatment was for 3 days. To our amazement, the treated mice were cured. We repeated the experiment three times before, in November 1979, I called Peter to give him the news.
This work the initial finding that DFMO cured mice of a model sleeping sickness infection was published in the March 1980 issue of Science by myself, Peter McCann, Henry Nathan, Seymour Hutner, and Albert Sjoerdsma, head of the now Merrell-Dow Pharmaceutical Research Institute.
Since human toxicology studies had been done with DFMO as part of ongoing clinical trials in cancer, initial trials of DFMO against sleeping sickness in Africa rapidly ensued. These studies were begun by Dr. Simon von Nieuwenhove in Sudan in 1981 under the auspices of the World Health Organization and Merrell-Dow. The drug (now known as Eflornithine) was initially dissolved in fruit juice and given orally at 400 mg per kg, 4 times per day for 2 to 3 weeks. Despite problems with diarrhea, temporary hearing and hair loss, and non-compliance due to the difficult dose regimen, DFMO cured about 80% of patients, including late stage cases. Shortly after von Nieuwenhove’s clinical work was in full operation, a Dutch physician, Dr. Henry Taelman, cured a woman who had immigrated to Europe from Africa using an intravenous DFMO treatment regimen. The woman was deeply comatose and he named DFMO, “the resurrection drug” for its curative activity in late-stage sleeping sickness. From these initial clinical trials, more organized studies began which resulted in the development of an i.v. treatment regimen – 400 mg per kg – 4 times per day for two weeks.
My greatest personal career high point came during the 1985 International Congress of Protozoologists where, at the Kenyatta Center in Nairobi, I met Simon von Nieuwenhove after both of us had given papers on DFMO and sleeping sickness. We spoke for a long time about the scientific basis for DFMO activity vs. trypanosomes and the clinical activity that was being demonstrated.
During the 1990’s, because of the difficulty of giving DFMO 4 times per day by the i.v. route and the expense of approximately $700 per patient, combined with the reluctance of Marion Merrell-Dow (Hoechst Marion-Rousseau) to produce DFMO for non-profit purpose, its clinical availability and use became restricted. At last count approximately 4000 patients had been treated with DFMO, with an overall cure rate of > 90%.
In 2000, Bristol-Meyers-Squibb began marketing a product called Vaniqa, a prescription depilatory cream. The active agent in the cream was 18% wt / vol. DFMO. The latter was supplied by Aventis, which was the ultimate corporate sequel to Merrell-Dow. Thus DFMO was being made available for cosmetic use but not for saving lives. In February 2000, the story of Dr. Michaleen Richer, medical coordinator of the Nairobi-based International Medical Corps appeared on CBS TV’s “60 minutes”. The story documented her work in Simon von Nieuwenhove’s former clinic in the Sudan, and the overall lack of drugs for use against sleeping sickness. In a short time, Aventis responded to this negative publicity by arranging to supply W.H.O. with 60,000 doses of DFMO per year for 5 years, while donating $25 million to W.H.O. for sleeping sickness research. Since Aventis had taken over the remnants of May & Baker and Rhone-Poulenc, they also agreed to continue the supply of standard trypanocides pentamidine (May & Baker), and melarsoprol (Rhone-Poulenc). The supply of both of these agents was in danger of being eliminated by the corporate mergers.
W.H.O. is starting new clinical trials in the Congo. It is going back to oral administration because it is needed in rural settings and the i.v. form of DFMO administration can only be given in a hospital setting. Only ~ 10% Trypanosoma gambiense-infected patients receive the i.v. formulation. W.H.O. is therefore attempting a new trial giving DFMO orally to determine the maximum tolerated dose and to see whether it can be effective in > 80% of treated patients. If the criteria are met, then WHO would file for registration (presumably as a new clinical regimen). If this fails, W.H.O. will consider combination studies, probably with Nifurtimox, another experimental antitrypanosomal agent. Eflornithine will be dissolved in water and taken as a drink. Fulcrum. a CRO (Contract Research Organization) is helping W.H.O. in working out an approach to the French Regulatory authorities for oral DFMO. A Phase II study would then be done in the Congo. W.H.O. has assembled a product development team for this work and a parallel one would be set up for Nifurtimox. Aventis has continued to supply DFMO and will transfer technology to a company in India and another in Taiwan. The issues still remain as to overall costs of producing pure DFMO. The major problem with oral DFMO was an osmotic diarrhea, which made for significant non-compliance and reduced overall efficacy below that of i.v. DFMO (85% vs. 99%, respectively). W.H.O. remains uncertain of the supply of DFMO after 2006, since Aventis may also be taken over by merge with another company (Sanofi or Novartis).