Reviewer 2: NIFURTIMOX+EFLORNITHINE(N+E)

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1 Reviewer 2: NIFURTIMOX+EFLORNITHINE(N+E) 1. The multicenter clinical trial of N+E combination therapy for second-stage sleeping sickness presented on behalf of G. Priotto and the NECT Study Team offers a better option than Eflornithine alone. In the comparative trial between the two arms, Eflornithine is given at 400mg/kg/day QIDX 14 days and the N+E combination of Nifurtimox at 15 mg/kg/day for 10 days and Eflornithine at 400mg/kg/day BID X 7 days. Thus the reduced dose of Eflornithine (reduced by half per day and for half the duration)can explain that while primary efficacy in one-sided non-inferiority test already show difference in cure rate in favor of N+E and the secondary efficacy indicators are also in favor of N+E, the major adverse events particularly fever, infection and neutropenia aside from selected clinical events (hypertension,diarrhea) are much lower with N+E. The presence of more seizure events with N+E has to be explained. Additional Related Materials reviewed: 2. Nifurtimox plus Eflornithine for Late-Stage Sleeping Sickness in Uganda: A Case Series (F Checchi et al, Plo Negl Trop Dis 1(2):e64. doi: /journal.pntd ) A prospective case series of 31 late-stage trypanosoma brucei gambiense sleeping sickness (Human African Trypanosomiasis, HAT) reports efficacy and safety outcomes in patients treated with a combination of nifurtimox and eflornithine in Yumbe,northwest Ugandain , following on a previously reported terminated trial in nearby Omugo, where 17 patients received the combination under the same conditions. Eligible sequential late-stage patients received 400mg/kg/day eflornithine for 7 days plus 15mg/kg/day nifurtimox (20 mg/kg for children <15 years old) for 10 days. Efficacy (primary outcome)was monitored for 24 months post-discharge. Efficacy ranged from 90.3% to 100%; 5patients had major adverse events (neutropenia common, 9/31 patients) The Conclusions/Significance reads: Combined with the previous group of 17 trial patients, this case series yields a group of 48 patients treated with N+E among whom no deaths judged to be treatment- or HAT-related, no treatment terminations and no relapses have been noted,a very favourable outcome in the context oflate-stage disease. N+E could be the most promising combination regimen available for sleeping sickness, and deserves further evaluation. 3. Nifurtimox-Eflornithine Combination Therapy for Second-Stage Trypanosoma brucei gambiense Sleeping Sickness: A Randomized Clinical Trial in Congo (G Priotto et al, Clinical Infectious Diseases 2007;45: ) Efficacy and safety compared N+E combination (Nifurtimox 15mg/kg/day given orally every 8 hours for 10 days plus Eflornithine 400mg/kg intravenously every 12 hours for 7 days) with Eflornithine alone given 400 mg/kg per day intravenously every 6 hrs for 14 days, for treatment of second-stage disease in a randomized, open-label, active-control Phase III clinical trial. Patients were observed for 18 months. The study's outcomes were cure and adverse event attributable to treatment. A total of 103 patients were enrolled.cure rates were similar for both groups (E 94.1% vs N+E 96.2%). Severe reactions were less with the N+E group, 9.6% versus E 25.5%.There were no deaths in the N+E group versus 1 in E. The conclusion was that the N+E combination was promising and if corroborated by ongoing findings from other study sites, it will be a major advance over current therapies. 4. Three drug combinations for late-stage trypanosoma brucei gambiense Sleeping Sickness: A Randomized Clinical Trial in Uganda. G Priotto et al 2006, PloS Clin Trials 1(8): e39. doi: /journal.pctr

2 This was a randomized open-label, active control, parallel clinical trialcompring three arms. Three drug combinations were randomily assigned to patients: melarsoprol-nifurtimox or M+N, melarsoproleflornithine or M+E, and nifurtimox-eflornithine or N+E. Dosages were uniform: Intravenous melarsoprol 1.8 mg/kg/day, daily for 10 days; IV eflornithine 400 mg/kg/day, every 6 hrs for 7 days; oral nifurtimox 15mg/kg /day(adults) or 20 mg/kg/day (children <15 years) given every 8 hrs for 10 days. Patients were followed up for 24 months. Outcomes were cure rates and adverse events attributable to treatment. Result: Randomization performed in 54 patients before enrollment was suspended due to unacceptable toxicity in one of the three arms. Cure rates obtained with ITT analysis were M+N 44.4%, M+E 78.9%, and N+E 94.1%. Significantly higher with N+E (p=0.003) and M+E (p=0.045). Adverse events were less frequent and less severe with N+E, resulting in fewer treatment interruptions and no fatalities. N+E is a promising combination but no conclusion can be drawn from this interrupted study. (See larger current studies above)

3 Title, Author, Journal (year, volpp) Nifurtimox Eflornithine Combination Therapy for Second Stage T. b. gambiense Sleeping Sickness: A Randomized Clinical Trial in Congo (Priotto et. al.) Clinical Infectious Diseases, December 2007, Vol. 45, pp Three Drug Combinations for Late Stage Trypanosoma brucei gambiense Sleeping Sickness: A Randomized Clinical Trial in Uganda (Priotto et. al.) PLOS Clinical Trials, December 2006, pp. 1-8 Nifurtimox plus Eflornithine for Late Stage Sleeping Sickness in Uganda Objectives of the study To evaluate the efficacy of the nifurtimox + eflornithine combination therapy To compare the efficacy and safety of 3 drug combinations for the treatment of late stage human African trypanosomiasis cause by Trypanosoma brucei gambiense To report the efficacy and safety outcomes from a Design Randomized, open-label, active-control, phase III clinical trial comparing 2 arms Randomized, open-label, active control, parallel clinical trial comparing 3 arms Case series Participants Interventions Outcome parameters/en dpoints Inclusion criteria: confirmed 2 nd stage T.b.gambiense infection Exclusion criteria: -Age<15 years old -pregnancy -history of stage 2 HAT treated during the preceding 36 months -severe comorbidities -hemoglobin < 5g/dL -inability to complete 18 months of follow up for other reasons Stage 2 patients diagnosed in Northern Uganda Inclusion criteria: confirmed 2 nd stage T.b.gambiense infection Exclusion criteria: -BW<10kg -pregnancy -history of stage 2 HAT treated during the preceding 24 months -unlikelihood of completing the 2 year follow up Late stage patients with a confirmed diagnosis of T.b. gambiense infection Eflornithine alone versus eflornithine + nifurtimox. Patients were observed for 18 months. 3 drug combinations: Melarsoprol + nifurtimox (M+N), melarsoprol + eflornithine (M+E), nifurtimox + eflornithine (N+E). Melarsoprol and eflornithine were given IV while nifurtimox was given orally. Dosages were uniform. Patients were followed up for 24 months. Patients received 400 mg/kg/day eflornithine for 7 days plus 15 Cure rates and adverse events attributable to treatment Cure rates and adverse events attributable to treatment Cure rates and efficacy were monitored for 24 months post Results 103 patients with second stage disease were enrolled. Cure rates for eflornithine: 94.1%, for E+N 96.2%. Severe reactions: Eflornithine: 25.5% E+N: 9.6% There was one death in the E arm and no death in the E+N. 54 patients were randomized. Enrollment was suspended because of unacceptable toxicity in one of the three arms. Cure rates obtained with ITT analysis were M+N 44.4%, M+E 78.9%, N+E 94.1%, and were significantly higher with N+E (p=0.003) and M+E (p=0.045) than with M+N. Adverse events were less frequent and severe with N+E, resulting in fewer treatment interruptions and no fatalities. 4 died who were taking M+N and one who was taking M+E. Efficacy ranged from 90.3% to 100.0% according to analysis approach. All 31 patients were discharged Conclusi,on/ Recommendations N+E appears to be a promising first line therapy for second stage sleeping sickness. N+E appears to be a promising first line therapy that may improve treatment sleeping sickness. However, larger studies need to be done to evaluate the drug combination. Combined with the previous group of 17 trial patients, this case series yielded 48

4 Title, Author, Journal (year, volpp) Checchi et. al. PLOS Neglected Tropical Diseases, 2007, Vol 1, Issue 2, pp. 1-6 The blood brain barrier significantly limits eflornithine entry into T. brucei brucei infected mouse brain (Sanderson et. al.) Journal of Neurochemistry, 2008, Vol. 107, pp Melarsoprol free drug Objectives of the study prospective case series of 31 late stage T.b. gambiense sleeping sickness treated with a combination of eflornithine and nifurtimox in Uganda To explore the pharmacokinetic characteristics of eflornithine transport across the healthy blood-cns interfaces both alone and with other antitrymanosomal drugs To investigate the potential removal of eflornithine by the BBB efflux transporter To explore eflornithine drug delivery and blood-cns barrier integrity at set time points in mice affected with T.b. brucei and to correlate the parasite existence within the CNS Design Participants Interventions Outcome parameters/en dpoints Experimental with animal model Editorial Inclusion criteria: -non pregnant -BW>10kg -late stage T.b. gambiense HAT -no history of HAT treatment in the prior 24 months -follow up can be insured Murine model of sleeping sickness mg/kg/day nifurtimox for 10 days. Patients were monitored for 24 months post-discharge. Eflornithine and Eflornithine + other drug combinations to investigate transporters discharge; clinical and laboratory adverse events were monitored during treatment. Effect of drug on barrier integrity Effect of parasite on barrier integrity/permea blility Effect of drugs on transporters Results alive, but 2 died post discharge of non-hat and non-treatment causes, one was lost to follow-up. Five patients had major adverse events during treatment and neutropenia was common. Eflornithine crosses the blood-cns interface by diffusionand eflornithine entry into the CNS can be enhanced with suramin. This explains the observed synergy of eflornithine and suramin combinations in CNS efficacy models and is first to demonstrate that combination therapy can prove efficacious due to enhanced delivery of the drug to the CNS. The parasites reach the CNS early in the course of infection, irreversible bloodbrain and blood-csf barrier breakdown is unnecessary for parasites to reach the CNS. Parasites that cross the BBB in vivo remain viable, and widespread BBB dysfunction occurs during the terminal stage of the disease. Conclusi,on/ Recommendations patients treated with N+E, among whom a very favorable outcome after treatment was found. N+E could be the most promising treatment regimen for sleeping sickness and deserves further evaluation. Eflornithine crossed the healthy blood- CNS interfaces poorly, but this could be improved by coadministering suramin, but not nifrutimox, penatmidine or melarsoprol.

5 Title, Author, Journal (year, volpp) combinations for Second Stage Gambian Sickness: The Way to Go (Chappuis, Francois) Clinical Infectious Diseases, December 2007, Vol. 45, pp Innate lack of susceptibility of Ugandan Trypanosoma brucei rhodesiense to DL-alphadifluoromethylornithine (DFMO) (Iten, M. et. al.) Trop Med Parasitol, 1995, Vol. 46, No. 3, pp High-dose nifurtimox for arseno-resistant Trypanosoma brucei gambiense sleeping sickness: an open trial Objectives of the study To characterized Trypanosoma brucei rhodesiense isolates from South East Uganda for susceptibility to the drugs suramin, nifurtimox, melarsoprol and DL-alphadifluoromethyl ornithine (DFMO) To determine the effectivity of high dose nifurtimox for arsena-resistant Design Participants Interventions Outcome parameters/en dpoints commentary Open Trial Thirty patients with arsenoresistant Trypanosoma brucei gambiense Two different assays were used to determine the drug susceptibility of the field isolates: the [3H]hypoxanthi ne incorporation assay (24 hours) and the long term viability assay (10 days) Patients were treated with high-dose nifurtimox (30 mg/kg/d) for Results All trypanosome stocks were susceptible to suramin and nifurtimox. Differences in the susceptibility to melarsoprol were observed in the [3H]hypoxanthine incorporation assay, but could not be confirmed in the long term viability assay. All T. b. rhodesiense stocks were found in vitro to have innate tolerance to DFMO, under conditions where T. b. gambiense stocks from West Africa were susceptible to the drug. Ugandan T. b. rhodesiense stocks did respond to micrograms/ml after 10 days of drug exposure, but the DFMO level reached in cerebrospinal fluid during treatment is only /- 7.8 micrograms/ml The cerebrospinal fluid (CSF) white blood cell (WBC) count decreased in all patients except one (mean CSF WBC count Conclusi,on/ Recommendations DFMO is not an appropriate alternative or backup drug for treatment of Rhodesian sleeping sickness in Uganda. High-dose nifurtimox seems more effective than the previously used regimen (15

6 Title, Author, Journal (year, volpp) in central Zaire (Pepin, J. et al.) Trans R Soc Trop Med Hyg, 1992, Vol. 86, No. 3, pp Advances in sleeping sickness therapy (Van Nieuwenhove, S.) Ann Soc Belg Med Trop, 1992, Vol. 72, Suppl 1, pp Objectives of the study T. b. gambiense To review the efficacy and adverse effects of nifurtimox and DFMO in the treatment of sleeping sickness Design Participants Interventions Outcome parameters/en dpoints Results sleeping sickness 30 days. before nifurtimox: 117/mm3; after nifurtimox: 25/mm3), and trypanosomes disappeared from the CSF of all 9 patients in whom parasites had been demonstrated before nifurtimox. Among 25 patients seen at least once after treatment, 9 (36%) have relapsed so far. High-dose nifurtimox was significantly toxic: one patient died during treatment and 8 others developed adverse neurological effects. Both new substances constitute effective novel therapeutic agents for gambiense sleeping sickness, including melarsoprol-refractory disease. DFMO is not very active in rhodesiense sleeping sickness and experience with nifurtimox in this form of trypanosomiasis is too limited to draw valid conclusions. The toxicity of nifurtimox and DFMO is not negligible. Conclusi,on/ Recommendations mg/kg/d for 60 d), but at the expense of significant toxicity. The current availability of several effective late-stage drugs (melarsoprol, nifurtimox and DFMO), that show synergistic activity in experimental models, should allow the establishment of optimum combination treatment regimens.

7 Bouteille, B., O. Oukem, et al. (2003). "Treatment perspectives for human African trypanosomiasis." Fundam Clin Pharmacol 17(2): Human African trypanosomiasis (HAT), or sleeping sickness, is currently on the rise. HAT develops in two stages, the first involving the hemolymphatic system, and the second, the neurological system. Left untreated, HAT is invariably fatal. There have been no therapeutic advances in more than 40 years. Stage 1 can be treated with pentamidine and suramin, but stage 2 can only be treated with melarsoprol, a toxic arsenic derivative that has a 2-12% incidence of fatal side-effects (encephalopathy). Eflornithine has never achieved widespread use because it is difficult to administer under field conditions. Nifurtimox has been used successfully in the treatment of American trypanosomiasis, or Chagas disease, but only in small studies or as a compassionate use treatment. There is little research and development for new drugs in this area: only one prodrug is in the clinical development phase, a pentamidine analog that offers hope for the replacement of injectable pentamidine with an orally administered drug. Current efforts appear to be focused on reevaluating older drugs. A course of treatment with melarsoprol for 10 days at 2.2 mg/kg/day is now in the multicenter evaluation phase. Orally administered eflornithine is also slated for reevaluation. In addition, studies of drug combinations are recommended to determine possible combined or synergistic effects and find ways to reduce toxicity. Burchmore, R. J., P. O. Ogbunude, et al. (2002). "Chemotherapy of human African trypanosomiasis." Curr Pharm Des 8(4): Human African trypanosomiasis or sleeping sickness is resurgent [1,2]. The disease is caused by subspecies of the parasitic haemoflagellate, Trypanosoma brucei. Infection starts with the bite of an infected tsetse fly (Glossina spp.). Parasites move from the site of infection to the draining lymphatic vessels and blood stream. The parasites proliferate within the bloodstream and later invade other tissues including the central nervous system. Once they have established themselves within the CNS, a progressive breakdown of neurological function accompanies the disease. Coma precedes death during this late phase. Two forms of the disease are recognised, one caused by Trypanosoma brucei rhodesiense, endemic in Eastern and Southern Africa, in which parasites rapidly invade the CNS causing death within weeks if untreated. T. b. gambiense, originally described in West Africa, but also widespread in Central Africa, proliferates more slowly and can take several years before establishing a CNSinvolved infection. Many countries are in the midst of epidemics caused by gambiensetype parasites. Four drugs have been licensed to treat the disease [3]; two of them, pentamidine and suramin, are used prior to CNS involvement. The arsenic-based drug, melarsoprol is used once parasites are established in the CNS. The fourth, eflornithine, is effective against late stage disease caused by T. b. gambiense, but is ineffective against T. b. rhodesiense. Another drug, nifurtimox is licensed for South American trypanosomiasis but also been used in trials against melarsoprol-refractory late sage disease. This review focuses on what is known about modes of action of current drugs and discusses targets for future drug development. Croft, S. L. (2008). "Kinetoplastida: new therapeutic strategies." Parasite 15(3): New formulations and therapeutic switching of the established drugs, amphotericin B and paromomycin, together with the discovery of miltefosine, have significantly improved the opportunities for treatment of visceral leishmaniasis (VL) chemotherapy. However, for human African trypanosomiasis (HAT), Chagas disease and cutaneous

8 leishmaniases there has been limited progress. For HAT, a novel diamidine, parfuramidine, is in phase III clinical trial for early-stage disease, but for the treatment of late-stage disease there are no new drugs and combinations of eflornithine with melarsoprol or nifurtimox have been the focus of clinical studies. For Chagas disease, different classes of compounds that have validated biochemical targets, sterol biosynthesis methylases and cysteine proteases, are in various stages of development. The genome sequences that are now available for the pathogens that cause the leishmaniases and trypanosomiases, and new methods for rapid validation of targets, are part of the solution to discover new drugs. The integration of medicinal chemistry, pharmacokinetics, project planning and interaction with the pharma/biotech sector are essential if progress is to be made. Although there are financial constraints, the appearance of new funding sources and not-for-profit product development partnerships offers hope for drug development. Harder, A., G. Greif, et al. (2001). "Chemotherapeutic approaches to protozoa: kinetoplastida- -current level of knowledge and outlook." Parasitol Res 87(9): The possibilities for treating haemoflagellate infections (African trypanosomiasis) are very limited (Table 1; Mehlhorn and Schrevel 1995; Croft 1997; Hunter 1997; Wang 1997; Trouiller and Olliaro 1998). All the available drugs have severe side-effects in humans and animals. Vaccination is not really an option, in view of the wide antigen variability. At present, there are several drug combinations in clinical trials: suramin/eflornithine, suramin/metronidazole, suramin/pentamidine, melarsoprol/pentamidine, melarsoprol/nifurtimox and nifurtimox/eflornithine. Some of these combinations were successful in treating resistant Trypanosoma brucei rhodesiense and/or T. b. gambiense infections (Keiser et al. 2001). In leishmaniasis, the tendency is still to resort to the old antimony compounds, with their severe side effects. At present, miltefosine is in clinical phase and is the first oral drug against visceral leishmaniasis (Jha et al. 1999). Two drugs are currently used against Chagas' disease, although these do not cure chronic effects. There is no prospect of novel drugs in this indication either (Pecoul et al. 1999; Morel 2000). Kennedy, P. G. (2008). "The continuing problem of human African trypanosomiasis (sleeping sickness)." Ann Neurol 64(2): Human African trypanosomiasis, also known as sleeping sickness, is a neglected disease, and it continues to pose a major threat to 60 million people in 36 countries in sub-saharan Africa. Transmitted by the bite of the tsetse fly, the disease is caused by protozoan parasites of the genus Trypanosoma and comes in two types: East African human African trypanosomiasis caused by Trypanosoma brucei rhodesiense and the West African form caused by Trypanosoma brucei gambiense. There is an early or hemolymphatic stage and a late or encephalitic stage, when the parasites cross the blood-brain barrier to invade the central nervous system. Two critical current issues are disease staging and drug therapy, especially for late-stage disease. Lumbar puncture to analyze cerebrospinal fluid will remain the only method of disease staging until reliable noninvasive methods are developed, but there is no widespread consensus as to what exactly defines biologically central nervous system disease or what specific cerebrospinal fluid findings should justify drug therapy for late-stage involvement. All four main drugs used for human African trypanosomiasis are toxic, and melarsoprol, the only drug that is effective for both types of central nervous system disease, is so

9 toxic that it kills 5% of patients who receive it. Eflornithine, alone or combined with nifurtimox, is being used increasingly as first-line therapy for gambiense disease. There is a pressing need for an effective, safe oral drug for both stages of the disease, but this will require a significant increase in investment for new drug discovery from Western governments and the pharmaceutical industry. Legros, D., G. Ollivier, et al. (2002). "Treatment of human African trypanosomiasis--present situation and needs for research and development." Lancet Infect Dis 2(7): Human African trypanosomiasis re-emerged in the 1980s. However, little progress has been made in the treatment of this disease over the past decades. The first-line treatment for second-stage cases is melarsoprol, a toxic drug in use since High therapeutic failure rates have been reported recently in several foci. The alternative, eflornithine, is better tolerated but difficult to administer. A third drug, nifurtimox, is a cheap, orally administered drug not yet fully validated for use in human African trypanosomiasis. No new drugs for second-stage cases are expected in the near future. Because of resistance to and limited number of current treatments, there may soon be no effective drugs available to treat trypanosomiasis patients, especially second-stage cases. Additional research and development efforts must be made for the development of new compounds, including: testing combinations of current trypanocidal drugs, completing the clinical development of nifurtimox and registering it for trypanosomiasis, completing the clinical development of an oral form of eflornithine, pursuing the development of DB 289 and its derivatives, and advancing the pre-clinical development of megazol, eventually engaging firmly in its clinical development. Partners from the public and private sector are already engaged in joint initiatives to maintain the production of current drugs. This network should go further and be responsible for assigning selected teams to urgently needed research projects with funds provided by industry and governments. At the same time, on a long term basis, ambitious research programmes for new compounds must be supported to ensure the sustainable development of new drugs. Pepin, J. and F. Milord (1994). "The treatment of human African trypanosomiasis." Adv Parasitol 33: Van Voorhis, W. C. (1990). "Therapy and prophylaxis of systemic protozoan infections." Drugs 40(2): This article summarises current therapy and prophylaxis for Pneumocystis carinii, Toxoplasma gondii, Leishmania species, African trypanosomes (Trypanosoma brucei gambiense and T. b. rhodesiense), and American trypanosome (Trypanosoma cruzi) infections. Each agent and the disease it causes is briefly reviewed, and current data on the structure, mode of action, indications for treatment, dosage, administration, duration of therapy, efficacy, toxicity, and necessary monitoring during therapy are discussed for each drug. Drugs considered include cotrimoxazole (trimethoprim + sulfamethoxazole), pentamidine, dapsone (diaphenylsulfone), trimetrexate, eflornithine (DFMO), and primaquine/clindamycin and pyrimethamine/sulphonamide combinations for Pneumocystis pneumonia; pyrimethamine/sulfadiazine, spiramycin, and clindamycin for toxoplasmosis; pentavalent antimonials ('Pentostam' and 'Glucantime'), pentamidine, amphotericin B, allopurinol, ketoconazole, and itraconazole for leishmaniasis; suramin, pentamidine, melarsoprol, tryparsamide, Mel W, berenil, and eflornithine (DFMO) for African trypanosomiasis; and nifurtimox, benznidazole and

10 gentian violet for American trypanosomiasis.