by author Drug Therapy in African Visceral Leishmaniasis 28th ECCMID Conference, Madrid, Spain 21 April 2018

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1 Drug Therapy in African Visceral Leishmaniasis 28th ECCMID Conference, Madrid, Spain 21 April 2018 Dr. Monique Wasunna, Director, DNDi Africa Regional Office

2 Presentation Outline Introduction leishmaniasis Global facts on leishmaniasis 3 Visceral leishmaniasis (VL) in Eastern Africa (EA) Drug Treatment for VL in EA DNDi and LEAP contribution to treatments for VL in EA 6 Challenges, future treatments and the TPP for VL treatments

3 Introduction leishmaniasis

4 Leishmaniasis 1 IN 7 PEOPLE WORLDWIDE > 616 millions for visceral leishmaniasis > 431 millions for cutaneous leishmaniasis THE PARASITE: Leishmaniasis is caused by a protozoan parasite >20 Leishmania species THE VECTOR: Transmitted to humans by the bite of infected female phlebotomine sandflies 90 sandfly species are known to transmit Leishmania parasite THE DISEASE: An estimated 900, million new cases yearly. Three main forms of the disease (visceral, cutaneous, mucocutaneous). living in leishmaniasis-endemic areas at risk of infection 1 in 7 people worldwide at risk of infection > 616 million for visceral leishmaniasis (VL) > 431 million for cutaneous leishmaniasis (CL)

5 Visceral leishmaniasis (also known as kala-azar) The parasite multiplies within macrophages throughout the reticuloendothelial system; it affects the spleen, liver, bone marrow and lymph nodes. Classical manifestations of VL include: Fever for more than 2 weeks Weight loss (cachexia; wasting) Hepatosplenomegaly Pancytopenia i.e., anaemia, leukopenia & thrombocytopenia A high total protein level and a low albumin level Lymphadenopathy may be noted, particularly in some geographic regions, such as Sudan Poor prognosis: signs of bleeding, jaundice, oedema, co-morbidities, HIV co-infection Kala-azar is fatal if untreated 20,000-30,000 deaths/year

6 Global VL burden (estimated) & reported cases Period Cases reported/year Estimated annual Americas 3,661 5,000 to 7,000 West Africa - - Eastern Africa 8,569 30,000 to 40,000 Mediterranean 875 1,500 to 2,000 Middle East & Central Asia 2,496 5,000 to 7,500 Indian Subcontinent 42, ,000 to 320,000 58, ,500 to 376, 500 SOURCE: Alvar J, et al. (2012) Leishmaniasis Worldwide and Global Estimates of its Incidence. PLoS ONE 7(5): e doi: /journal.pone

7 VL distribution in Eastern Africa 7 SOURCE: Diro E, Lynen L, Ritmeijer K, Boelaert M, Hailu A, et al. (2014) Visceral Leishmaniasis and HIV Coinfection in East Africa. PLOS Negl Trop Dis 8(6): e2869. doi: /journal.pntd E. Africa harbours highest burden of VL worldwide 30,000 to 40,000 new cases every year VL affects mainly poor communities in remote rural areas and arid regions. Majority of patients are children with the exception of North Ethiopia, where the disease affects mainly young male adults in work-related settings.

8 Drug treatments for VL in Eastern Africa

9 Existing drugs for visceral leishmaniasis Variable efficacy, serious toxicities, only one is oral & the rest are painful IV/IM Urgent need for new effective, safe, and convenient treatments painful injections cardiotoxicity hepatotoxicity pancreatitis painful injections cardiotoxicity hepatotoxicity pancreatitis rigour & chills nephrotoxicity hypokalemia anaphylaxis painful injections nephrotoxicity hepatotoxicity ototoxicity teratogenic gastrointestinal toxicity hepatotoxicity

10 First-line treatment SSG & PM - an improvement, with limitations (LEAP and DNDi) Dosage SSG (20mg/kg/day) PM (15mg/kg (11mg base)) Strengths Efficacy of 91% at 6 months Combination therapy posibility of reducing resistance to antimony Shorter length of treatment (17 days) than SSG alone (30 days) Weaknesses 17 days of 2 injections/day (34 injections) Toxicity related to SSG Lower efficacy (81% EOT) and higher mortality (9%) in > 50y and contraindicated in HIV-VL Requires hospitalization Recommended first-line treatment for VL in Eastern Africa by the WHO Expert Committee on Control of Leishmaniases

11 Second-line treatment Liposomal Amphotericin B (Ambisome) Dosage 3mg/kg for 10 days Pros Reduced toxicity has a better half-life 90% cure rate Shorter treatment period Cons Requires hospitalization, administered through IV Is very expensive (USD 280 per dose) Side effects - rigours and chills during infusion

12 Sodium Stibogluconate (SSG) monotherapy Antimonial compound Over seven decades of mainstay 30 days treatment for VL in Eastern Africa Dose 20mg/kg/day for 30 days IV/IM Dose-dependent antimonial toxicity painful injections long hospitalization high economic burden for poor families increased risk of resistance 12

13 Other available drugs Amphotericin B deoxycholate Treatment is mainly used in Asia. It was found to be highly nephrotoxic, and to minimize these side effects various colloidal and lipid formulations have been prepared. No data available from EA. Glucantime pentavalent antimonial remains a first-line treatment for VL but mainly used in the Americas. Toxicity cardiotoxicity, hepatotoxicity and pancreatitis. Painful injections. Pentamidine Not used in EA. There are reports of emergence of drug resistance in India and now it is rarely used for treating VL.

14 Pitfalls in VL treatment: the African case SSG LAB LAB Miltefosine PM SSG- LAB + SSG LAB + Milt PM + Milt LAB + Milt (20-21 mg/kg) (SD, 10 mg/kg) (2.5mg/Kg/d x 28 days) (15mg/Kg/d x 21 days) PM Asia 35-95% > 95% > 95% 90-94% 94.6% NA NA > 97% > 97% > 97% Eastern Africa 93.7% 85% (71-100%) 58% (33-100%) Table 2. Cure (effficacy) at 6 months after treatment SSG PM p Overall 107/116 (92.2%) 81/127 (63.8%) < Um el Kher, Sudan 14/17 (82.4%) 4/28 (14.3%) < Kassab, Sudan 14/15 (93.3%) 7/15 (46.7%) Kenya 15/15 (100%) 12/15 (80%) Gondar, Ethiopia 37/40 (92.5%) 30/40 (75%) Arba Minch, Ethiopia 27/29 (93.1%) 28/29 (96.6%) 1.00 p < % 63.8% (14-96%) Ranges are presented when there was a substantial inter-regional difference in efficacy SOURCE: Hailu A, Musa A, Wasunna M, Balasegaram M, Yifru S, et al. (2010). PLOS Neglected Tropical Diseases 4(10): e % 87% 77% NA NA SOURCE: Gelanew T, Kuhls K, Hurissa Z, Weldegebreal T, Hailu W, et al. (2010) PLOS Neglected Tropical Diseases 4(11): e889.

15 DNDi and LEAP contribution

16 Who we are Drugs for Neglected Diseases initiative (DNDi) is a collaborative, patients needs-driven, non-profit drug research and development (R&D) organization that is developing new treatments for neglected diseases.

17 Leishmaniasis East Africa Platform (LEAP) LEAP is a clinical research network that brings together experts from leishmaniasis-endemic Eastern African countries to facilitate clinical testing and improved access to better treatments for leishmaniasis in the region. Study sites: Gondar (Eth) Arbaminch (Eth) Abdurafi (Eth) Kassab (Sudan) Dooka (Sudan) Um el kher (Sudan) Amudat (Uganda) Kimalel (Kenya) Kacheliba (Kenya) UGANDA: Makerere Univ. Ministry of Health SUDAN: Univ. of Khartoum Federal Ministry of Health ETHIOPIA: Addis Ababa Univ. Gondar Univ. Ministry of Health KENYA: KEMRI Ministry of Health

18 Completed VL studies YEAR STUDY ENROLLED PHASE COUNTRY PROGRESS/RESULTS COMPLETED STUDIES SSG & PM 1149 Phase III Ethiopia, Kenya, Sudan, Uganda AmBisome single dose AmBisome / SSG/ Miltefosine Shorter course SSG&PM treatment. Efficacy 91.4% 124 Phase II Ethiopia, Sudan Trial terminated after the third interim analysis because of low efficacy (30%) 151 Phase II Kenya and Sudan Efficacy below 91% due to underexposure in children (led to the MF PK study) PV Study 3126 Phase IV Ethiopia, Kenya, Sudan, Uganda SSG&PM has 95% cure rate VL/HIV Study 60 Phase II Ethiopia Efficacy increased with extended treatment Miltefosine PK 30 Phase II Kenya, Uganda Final cure rate of 90% [95% CI= 73-98%]

19 LEAP 0208 trial: Ambisome combinations AmB+SSG: AmB+Milt: Miltefosine: Amb 10mg/kg SD + SSG 20mg/Kg/d IM/IV for 10d Efficacy analysis at D210, ITT AmBisome + SSG Amb 10mg/kg SD + miltefosine 2.5 mg/kg/d PO for 10d Miltefosine 2.5mg/kg/d PO for 28d AmBisome + miltefosine miltefosine N Proportion cured at day 210, (p 210 ) 47/51 (87%) 40/49 (77%) 38/51 (72%) 95% confidence interval for p None of the combinations had > 90% efficacy needed to move ahead to Phase III development. Efficacy at D210, ITT by age group AmB+Milt Miltefosine Less than 12 years 20/27 (74%) 13/22 (59%) 12 years and above 20/22 (90%) 25/29 (86%) Fisher exact test p-value (2-sided) Children had poorer clinical response as compared to adults, which could be explained by underexposure to the drug. Wasunna, M., Njenga, S., Balasegaram, M., Alexander, N., Omollo, R., Edwards, T., Musa, A. (2016). Efficacy and Safety of AmBisome in Combination with Sodium Stibogluconate or Miltefosine and Miltefosine Monotherapy for African Visceral Leishmaniasis: Phase II Randomized Trial. PLoS Negl Trop Dis, 10(9),

20 LEAP 0714: Miltefosine PK and safety in children Phase II non-comparative, open-label clinical trial to assess the PK and safety and efficacy of miltefosine allometric dose in the treatment of children with primary VL in EA Sites: Amudat, Uganda and Kacheliba, Kenya Primary VL, children 4-12 years old Adverse Events: All 30 patients showed 1 AE not related to study In total, 19 AEs related to the study drug: neutropenia (20%) and vomiting (17%) No patients had treatment discontinued Serious Adverse Events: Two SAEs were reported: anaemia and transfusion reaction, none related Efficacy: 3 failures (3/30= 10%) - 1 initial failure - 2 relapses 27 completed D210, cured Final cure rate of 90% [95% CI= 73-98%] Allometric dose was an appropriate approach to improve efficacy, keeping good safety profile.

21 Ongoing Study - MF/PM phase III clinical trial Trial design: An open label, Phase III, randomized controlled, multicentre non-inferiority trial Primary objective: To compare the efficacy of two combination regimens of PM (14 days) and MF (14 or 28 days) with the standard 17-day course of SSG-PM for the treatment of primary VL patients in EA Secondary objectives: Safety, PK, PD, compliance with oral treatment Countries: Ethiopia, Kenya, Sudan and Uganda 6 study sites Patient population: confirmed primary VL patients 4-50y old, HIV neg, signed ICF Study Arms: Arm 1. PM (20mg/Kg/d) 14 days + MF allom for 14 days Arm 2. PM (20mg/Kg/d) 14 days + MF allom for 28 days vs Arm 3. SSG (30mg/Kg/d) 17 days + PM (15mg/Kg/d) 17 days (comparator) Sample size: 192/arm, total of 576 VL patients

22 HIV-VL co-infection HIV-VL patients are a special sub-group of patients that require different management of the disease: Poor treatment outcome and higher mortality High risk of relapse, associated with low CD4 count Risk of resistance development 35 countries report HIV-VL co-infection Prevalence of HIV-VL co-infection: - India: 5.6% - Ethiopia: 15 30% - Brazil: 8.5%

23 Improvement of current treatments for HIV-VL co-infection: HIV-VL 0511 in Ethiopia A randomized, parallel arm, open-label clinical trial Primary objective: To evaluate the efficacy at day 29 of a combination regimen of AmBisome + miltefosine and AmBisome monotherapy in Ethiopian co-infected HIV- VL patients Secondary objective: To evaluate relapse-free survival at day 390 (after initial cure at day 29 or cure at day 58 after extended treatment); to assess safety of the regimens. Treatment arms: Ambisome monotherapy, total dose 40mg/kg Ambisome 30mg/Kg + Miltefosine 2.5mg/kg/day, 28 days (efficacy increased with extended treatment)

24 Efficacy assessment (at day 29 and day 58) Unbiased estimates of proportion cured Liu Method to integrate over-running Time Population Unbiased estimates of proportion cured - Liu AmBisome Day 29 ITT and PP p 29 (0.267, 0.729) Day 58 (after extended treatment) 0.55 ITT p 58 (0.32, 0.78) 0.59 PP p 58 (0.35, 0.83) AmBisome + Miltefosine (0.479, 0.817) 0.86 (0.76, 0.97) 0.91 (0.81, 1) Response to initial treatment was similar between primary/relapse cases (RR=0.80 CI )

25 Challenges, future treatments and TPP for VL treatments

26 Challenges of VL treatments in E. Africa Current treatments for VL are not optimal require injections or intravenous infusions, hospitalization or the use of antimonials VL diagnosis is difficult and invasive. Post-kala azar dermal leishmaniasis (PKDL) and asymptomatic VL patients are suspected to be disease reservoirs. HIV-VL co-infection is difficult to treat.

27 The future: development of new field-adapted combination treatments with new chemical entities (NCEs) Screening Leish H2L Booster H2L Research Screen Hit to Lead Lead Opt. Pre-clinical Phase I Phase IIa/PoC Daiichi- Sankyo LH2L DNDI-5421 DNDI-5610 Amino pyrazoles CGH VL Series 1 Leish L205 Series DNDI-6148 DNDI-0690 DNDI-5561 GSK DDD GSK DDD CpG-D35 (CL) NCEs are progressing to clinical development in Translation Q Q New L Combination If Phase I shows good safety and PK profiles, proof of concept submission in Primary VL patients (adults)

28 Development of new field-adapted combination treatments with NCEs Optimal Target Product Profile Minimum Target Product Profile Target Label VL and PKDL Primary VL Species All species L. donovani Distribution All areas Eastern Africa Target Population Immunocompetent and immunosuppressed Immunocompetent Clinical Efficacy > 95% 90% Safety and Tolerability No AEs requiring monitoring 1 monitoring visit in mid/end - point OR Baseline assessment to exclude high risk groups (dependent on the profile of the drug) and self-report if AEs Contraindications None Pregnancy/lactation Interactions No interactions between the drugs to be No interactions between the drugs to be combined for VL treatment combined for VL treatment, or for other common co-morbidities (malaria, TB, HIV) Formulation Oral / oral Oral / IM IV could be acceptable Treatment Regimen Single dose treatment or fixed combo tablet/paediatric formulation up to 7 days Bid for < 28 days po; and IM shots over 14 days Oral NCEs: 14 days Stability 3 years in zone 4 2 years in zone 4 Cost To be defined To be defined

29 THANK YOU TO ALL OUR PARTNERS IN THE REGION

30 by THANK YOU TO ALL OUR DONORS