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Home , Eflornithine, Meglumine antimoniate, Melarsoprol, Pentavalent antimonial

The Need for New Agents

Professor PL Chiodini Global Impact of Infectious Diseases in Disability Adjusted Life Years (WHO,2001)

• Band 1: DALYs >70 million Acute Respiratory (96.7) Diarrhoeal Diseases (72.1) HIV/AIDS (89.8) • Band 2: DALYs 20-69 million Malaria (45.0) Tuberculosis (33.3) Measles (29.8) Global Impact of Infectious Diseases in Disability Adjusted Life Years (WHO,2001)

• Band 3: DALYs 10-19 million Sexually-transmitted infections (19.7) Pertussis (10.9) Tetanus (12.0) Global Impact of Infectious Diseases in Disability Adjusted Life Years (WHO,2001)

• Band 4: DALYs <10 million Lymphatic filariasis and onchocerciasis(6.0) Meningitis (9.8) GI nematode infestations (2.7) Hepatitis (2.8) (2.0) Schistosomiasis (1.9) Trachoma (1.2) WHO/Industry Drug Development Working Group, July 2001 •“For many infectious diseases, such as HIV/AIDS and sexually transmitted diseases, there is currently a substantial level of R&D activity underway. By contrast, major diseases which present scientifically tractable targets but have had insufficient product R&D are malaria and tuberculosis.” WHO/Industry Drug Development Working Group, July 2001 Second tier requiring additional drug R&D •African • •Leishmaniasis •Lymphatic filariasis •Onchocerciasis •Schistosomiasis Weerasuriya (2002) WHO SE Asia Region In the 25 years to 2002: •1393 New Chemical Entities granted Market Authorisations •Only 16 were Drugs for Neglected Diseases •All were in the WHO Model Essential Drug List •Longer mean time for Clinical Development 8.8 vs 5.4 years The Disappearing Arsenal of Antiparasitic Drugs (White, 2000) In the decade to 2000: •Quinacrine for •Niclosamide for tapeworm •Diethylcarbamazine for lymphatic filariasis

Were all withdrawn from the United States market Antiparasitic Agents

•New and resurgent parasitoses Cryptosporidiosis Cyclosporiasis Microsporidiosis •Have aggravated the problem Why and Where Do We Need New Antiparasitic Agents? •Where current drugs are failing Eg Malaria •Where current drugs are toxic Eg Trypanosomiasis •Where there is no effective drug Eg Against some microsporidia •Where there is only one drug available Eg Cryptosporidiosis What Kind of Antiparasitic Drugs Do We Need? •Orally active •Single dose •Combination therapies •Wide spectrum of activity? •Deliverable, ie very cheap

The global burden of malaria

•One fifth of world population at risk •Up to 500 million clinical cases a year •1 to 2 million deaths per year •>90% of deaths in Africa •Slows economic growth in Africa by up to 1.3% per year Roll Back Malaria

October 1998 WHO World Bank UNICEF UNDP Aim to halve global malarial burden by 2010 Antimalarials

Name Date introduced Pyrimethamine Late 1940s, early 1950s Proguanil Late 1940s, early 1950s Chloroquine 1950 Mefloquine 1980s Halofantrine 1980s Atovaquone/Proguanil Late 1990s Antimalarial Drug Resistance

Chloroquine resistance •Late 1950s in SE Asia and South America 1980s in Africa •Now virtually useless for P.falciparum Up to 64% Rx failure in East Africa •Some resistance in P.vivax In SE Asia and Oceania Antimalarial Drug Resistance

•Sulfadoxine-pyrimethamine (SP) Widespread in East Asia & South America 45% Rx failure in East Africa and rising Impact of Antimalarial Drug Resistance •Senegal community-based study •Onset of Chloroquine resistance increased childhood malaria death risk 2 to 11 fold (Trape et al 1988) •East & southern Africa, doubling of proportion of child malaria deaths following establishment of CQ then SP resistance (Korenromp et al 2003) Antimalarial Strategy Combination therapy to conserve drugs Malariologists learned this lesson late! •Atovaquone/Proguanil (Malarone®) •Chlorproguanil/Dapsone (LapDap) •LapDap/Artesunate •Other artemisinin combinations: Artesunate/Amodiaquine Artesunate/Mefloquine New Antimalarials

•Second generation endoperoxides Semi-synthetic derivatives of artemisinin Fully synthetic endoperoxides Clinical studies due to begin New Antimalarials

•Blockage of the choline transporters of the parasite, affecting membrane synthesis •G25, a choline analogue, binds competitively to the choline carrier •Effective against P.falciparum in monkeys •Absorbed via the oral route Other targets for antimalarials

•Haemoglobin degradation Aspartic proteinases: Plasmepsins 1 and 2 Cysteine proteinase: Facipain •Surface proteases Protease which undertakes secondary processing of P.falciparum MSP-1

Leishmaniasis

•350 million at risk •12 million infected •1.5 to 2 million new cases annually but only 0.6 million reported •0.5 million new visceral cases annually Rx of

• compounds antimoniate •Parenteral only •Myalgia, anorexia, Q-T prolongation •Up to 65% primary unresponsiveness in Bihar, India (Guerin et al, 2002) Rx of Visceral Leishmaniasis

• (micellar suspension) •Intravenous only •Serious toxicity: Rigors Anaemia Renal function Rx of Visceral Leishmaniasis •Lipid-associated Amphotericin B Liposomal Amphotericin B (phospholipid-containing liposomes) Amphotericin B colloidal dispersion (lipid discs containing cholesterol sulphate) Amphotericin B lipid complex (complexed with phospholipids) •Intravenous only •Very expensive Visceral Leishmaniasis Future Needs (Guerin et al, 2002) •Further development of Oral administration But a potential teratogen •Registration of •Evaluation of short course Rx with lipid-associated Amphotericin B •Prioritization of drug combination Rx

African Trypanosomiasis

•60 million people exposed •Estimated 300,000 infected •Angola •Democratic Republic of Congo •Sudan •Central African Republic Rx of

•East African rhodesiense Rx: Early - Late - •West African Trypanosoma brucei gambiense Rx: Early - Late - or Melarsoprol Drugs for Human African Trypanosomiasis

Drug Year of introduction Suramin 1922 Pentamidine 1937 Melarsoprol 1949 Eflornithine 1990 African Trypanosomiasis

•Late-stage (CNS) disease Arsenical compounds in use before 1920 Melarsoprol (less toxic) in 1949 Derivative of trivalent melarsen oxide and dimercaprol (BAL) in Problems with Melarsoprol (1)

Side-effects •Fever, abdominal pain, dermatitis, arthralgia •Polyneuropathy in 10% •Reactive arsenical encephalopathy Develops in about 6% of cases Case fatality rate about 60% Problems with Melarsoprol (2)

•Treatment failure usually 5 to 10% •Now up to 30% failure rate in parts of Central Africa Melarsoprol Refractory cases

•Eflornithine •Combinations: Melarsoprol / Eflornithine Melarsoprol / low dose Eflornithine

•Registered 1990 •Expensive, with limited market •Continued manufacture assured by its use for removal of unwanted facial hair •Eflornithine hydrochloride cream •US$42 to pharmacist for 30g tube •Donation programme MSF/ WHO/ Aventis Human African Trypanosomiasis The Need for New Drugs •Non-toxic and active orally •Combination therapy •Greatest need in late-stage (CNS) disease •DB 289, an orally active diamidine FDA Fast Track Designation April 2004 •Megazol, a 5-nitro-imidazole Active in animal models, but mutagenic South American Trypanosomiasis Chagas’Disease •Trypanosoma cruzi •Mexico, Central & South America •Acute •Indeterminate •Chronic Cardiomyopathy Mega-syndromes South American Trypanosomiasis Chagas’Disease

•Nifurtimox • •Both have significant side-effects •New agents active in the indeterminate phase are needed

Schistosomiasis

•500 to 600 million at risk •200 million infected •120 million symptomatic •20 million severely affected Treatment of Schistosomiasis

•Schistosoma mansoni Praziquantel Oxamniquine Not available in the UK •Schistosoma haematobium Praziquantel Metrifonate Not available in the UK •Schistosoma japonicum Praziquantel Praziquantel (PZQ)

•Registered in 1980 •Widespread use in control programmes •Lower cure rates reported in high transmission areas, but PZQ does not kill immature schistosomes •Individual cases of treatment failure reported Treatment of Schistosomiasis

•No new agent under development •Options under evaluation: 1 Higher doses of praziquantel 2 Combination therapy: Praziquantel with Artemether –unwise Praziquantel with Oxamniquine Cryptosporidiosis •Self-limiting with normal immune response •Immune reconstitution, Eg with HAART •Some benefit from: Paromomycin Azithromycin • now licensed in the US for use in immunocompetent children <12y old Nitazoxanide and Cryptosporidium

•A nitrothiazolyl-salicylamide derivative •Significant improvement in adults and children with mild cryptosporidiosis •Clinical and parasitological improvement and improved survival in malnourished children with chronic cryptosporidiosis in Zambia Nitazoxanide and Cryptosporidium

•Early work showed poor results in patients with advanced HIV infection, but was effective in patients with higher CD4 counts •Studies to clarify its role in Rx of patients with very low CD4 counts Nitazoxanide and other parasites

•Effective in giardiasis •Suggested efficacy in cyclosporiasis, isosporiasis, and amoebiasis •Effective against Ascaris, Trichuris, and Hymenolepis Conclusions

•Although there is hope, parasitic diseases remain the poor relations when it comes to support for drug development •This will change only if substantially more funding is provided, eg from partnerships including WHO TDR, Industry, Governments, Benefactors etc.