14th Stakeholders Meeting

Transcription

1 14th Stakeholders Meeting Steady progress towards malaria elimination: Interventions for today and tomorrow Denpasar, Bali October 2017 David Hughes, Novartis 12th October 2017 Defeating Malaria Together

2 Conflict of Interest, Legal & Regulatory Context I am a full-time employee of Novartis Pharma AG This presentation is intended for non-promotional scientific purposes only. This presentation contains data about Novartis and non-novartis agents which are based on publicly available information at the time of presentation. This presentation contains information on agents currently under investigation and/or planned for future development studies that have not been approved by Regulatory Authorities. 2

3 Novartis R&D Programs for Tropical Medicines Collaboratively targeting conditions with high unmet medical need Drug Discovery Novartis Institute for Tropical Diseases, Singapore -> Emeryville, CA Drug Development Anti-Infectives Development Unit, Basel and East Hanover Malaria Dengue Fever Human African Trypanosomiasis Chagas Disease Leishmaniosis Cryptosporidiosis KAF156 KAE609 Lumefantrine SDF* Clofazimine (DR-TB) *solid dispersible formulation 3 Restricted

4 Current Development Programs in Malaria Targeting various stages of the parasite life cycle Two drug candidates (KAE609 and KAF156) in phase II development KAE609 (spiroindolone) KAF156 (imidazolopiperazine) Diagana, Drug Discov Today (2015) 4 4 Restricted

5 KAF156 positive Proof of Concept Study Distinct and novel mechanism with potential for disease prevention Imidazolopiperazine, a new class of antimalarial and the 2 nd new antimalarial to achieve PoC in the last 20 years PoC study: 400 mg of KAF156 daily for 3 days (39 patients) can treat uncomplicated P. vivax and P. falciparum malaria in adults (PCT med * 48 hours) A single dose of 800mg resulted in a 28-day cure rate of 67% Ongoing human challenge study to explore potential in malaria prevention 5 Restricted Source: NEJM 375;12 ; September 22, 2016 * PCT med = Median Parasite Clearance Time

6 KAF156X2201 Part 1: Clearance of P. vivax and P. falciparum (400 mg daily for 3 days) 1. Median parasite clearance time (PCT) for P. vivax = 24 hours for 10 patients 2. Median PCT for P. falciparum = 45 hours for 10 patients 6 Restricted

7 KAF156X2201 Part 2: Safety and PK data summary (single 800 mg dose) 1. Safety The most frequent adverse events were sinus bradycardia, thrombocytopenia, hypokalemia, anemia, vomiting, decreased appetite and ALT elevations These events can be seen in malaria, with the exception of sinus bradycardia More adverse events seen with a single 800 mg dose than with 400 mg for 3 days, but the follow-up period was longer 2. Pharmacokinetics The exposure after a single 800 mg dose was comparable to the Day 3 exposure following 400 mg daily for 3 days 13 of 21 patients maintained total plasma concentrations >2-times the P. falciparum IC 99 (58 ng/ml) for 6 days 3. Efficacy 5 of the 7 patients with a recrudescence could not maintain such concentrations Median parasite clearance time (PCT) for P. falciparum was 49 hours The 28-day cure rate was 66.7%, comparable to multiple doses of artemisinin monotherapy 7 Restricted

8 KAF156 Comparison of P. vivax parasite clearance time (PCT) to other agents 1. Time until parasites no longer detectable in the peripheral blood smear Highly dependent on baseline parasite load and how often blood smears obtained More active agents have lower values 2. Estimated PCT for KAF156 against P. vivax compares favorably to other agents Antimalarial agents Number of patients Mean (SD) PCT in hours Pyrimethamine-sulfadoxine (44) Quinine (23) Primaquine (34) Halofantrine (24) Mefloquine (22) Chloroquine (18) Chloroquine-primaquine (22) Artemether (11) Artesunate (13) KAF (7.5) KAE (7.6) Pukrittayakamee et al 2000; SD = standard deviation. 8 Restricted

9 Lumefantrine - SDF PK Summary 480 mg single oral dose, under fasting Semi-log view LUM-SDF Variant 1 Conventional tablet LUM-SDF Variant 2 Restricted 9

10 Phase IIb Study KAF156/LUM SDF Study design allows to select dose and duration for phase III development Run-In Patients 12 years 35 kg KAF mg + Lum-SDF 960mg (single dose, n=12) Part A Part B* Patients 12 years 35 kg Patients 2-12 years >10 kg KAF mg + Lum-SDF 960mg QD for 1 day KAF mg + Lum-SDF 960mg QD for 1 day KAF mg + Lum-SDF 960mg QD for 2 day KAF156 + Lum-SDF selected 1-2 day regimen KAF mg + Lum-SDF 960mg QD for 3 day PK/PD Modelling KAF156 + Lum-SDF selected 3-day regimen KAF mg + Lum-SDF 480mg QD for 3 day Coartem n~25 KAF mg + Lum-SDF 480mg QD for 3 day Primary Endpoint: PCR corrected cure rate at Day 29 n~25 Coartem * Protocol reflects the potential for an additional cohort (total of up to 512 patients. Budget amendment required if additional cohort needed. 10 Restricted

11 No one should die of malaria today 11 Restricted