Drugs for treatment and chemoprevention of malaria. Tim Wells, Chief Scientific Officer, MMV

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1 Drugs for treatment and chemoprevention of malaria Tim Wells, Chief Scientific Officer, MMV

2 SETTING THE GOALS FINDING THE MOLECULES MEASURING SUCCESS WINNING COMBINATIONS

Ideal Product has several activities Clears blood stages rapidly Long acting Blocks transmission Kills dormant forms Active against all current and emerging resistance Safe

3 Ideal Product has several activities Clears blood stages rapidly Long acting Blocks transmission Kills dormant forms Active against all current and emerging resistance Safe enough to give to all Alonso P et al., A research agenda for malaria eradication: drugs PLoS Med 8(1): e Target Candidate Profiles: Burrows JN et al., Malaria J. 12:187 (2013)

4 Malaria Drug Resistance 2009 Thailand t 1/2 = 4h Cambodia t1/2 = 6h Artemisinin resistance in the Mekong: slower rate of killing parasites Puts pressure on partner drugs: multidrug resistance 4 Noedl H, et al., (2008) N Engl J Med. 359: ; Dondorp AM et al., (2009) N Engl J Med. 361: Ariey F, et al Nature :50-5. Straimer J,et al Science :428-31

Need to show activity in artemisinin resistant malaria One Dose High compliance Low cost of goods Split Dose Back-up therapy where

5 Districts where ACTs still effective Districts where ACTs have failed Focus on simplifying treatment or fighting resistance? One Dose High compliance Directly observed therapy Low cost of goods? Need to show activity in artemisinin resistant malaria One Dose High compliance Low cost of goods Split Dose Back-up therapy where ACTs fail Some compliance benefit vs. ACTs? Cost of goods benefit vs. ACTs Split Dose Limited interest to replace ACTs where they are still active No compliance benefit vs. ACTs? Cost of goods benefit vs. ACTs

6 1 Balancing Efficacy and Safety Drug concentration Increasing the drug dose increases the chance of side effects Safety threshold Ideally the compound needs to be active (above the minimum threshold) for 28 days or more Minimum inhibitory concentration Time 6

2008 Lead generation 3 projects Novartis Research Lead optimization DHFR BIOTEC/Monash/ LSHTM Translational Product development Access Preclinical OZ439 Monash/UNMC/STI Human volunteers Isoquine GSK

Tübingen Patient confirmatory Regulatory review Pyronaridine- Artesunate Shin Poong Post approval Artemetherlumefantrine Dispersible Novartis 1 2 projects GSK 4 projects GSK MK4815 (Merck)

7 2008 Lead generation 3 projects Novartis Research Lead optimization DHFR BIOTEC/Monash/ LSHTM Translational Product development Access Preclinical OZ439 Monash/UNMC/STI Human volunteers Isoquine GSK Patient exploratory IV Artesunate Univ. Tübingen Patient confirmatory Regulatory review Pyronaridine- Artesunate Shin Poong Post approval Artemetherlumefantrine Dispersible Novartis 1 2 projects GSK 4 projects GSK MK4815 (Merck) Tafenoquine GSK Artemisone UHKST DHA-Piperaquine Sigma-Tau 5 projects Broad/Genzyme DHODH UTSW/UW/Monash 2 compounds GSK Pyridones Immucillins Albert Einstein Aminoindoles Broad/Genzyme (+)-Meflonquine Treague Heterocyclic Hit to Lead TDR/Pharmacopeia Ozaonides Monash/UNMC/STI 2 compounds Novartis Quinolones USF 2 projects Novartis 3 projects Natural products 4 projects Other screenings

Lead generation Miniportfolio Novartis Miniportfolio GSK Miniportfolio Sanofi Heterocycles Univ.

GSK Orthologue Leads Sanofi Tetraoxanes LSTM/Univ. Liverpool DHODH UTSW/UW/Monash Heterocycles UCT Open Source Drug Discovery Univ.

(BIOTEC Thailand) DDD498 Merck Serono (Dundee) PA92 (Drexel/UW/GNF) MMV253 (AstraZeneca) GSK030 GSK DSM421 (UTSW/UW/ Monash) GSK692 GSK AN13762 Anacor Human volunteers MMV048 UCT SJ733 St Jude/Eisai

8 Lead generation Miniportfolio Novartis Miniportfolio GSK Miniportfolio Sanofi Heterocycles Univ. Campinas Heterocycles Daiichi-Sankyo Heterocycles Takeda Heterocycles Eisai Screening Merck Serono Pathogen Box MMV Other projects 24 projects Research Lead optimization 1 project Novartis 2 projects GSK Orthologue Leads Sanofi Tetraoxanes LSTM/Univ. Liverpool DHODH UTSW/UW/Monash Heterocycles UCT Open Source Drug Discovery Univ. Sydney Heterocycles Celgene Whole cell St Jude/Rutgers/USF Diversity oriented Synthesis Broad/Eisai Pantothenamides TropIQ/RUMC/ Pansynt Translational Product development Access Preclinical P218 (BIOTEC Thailand) DDD498 Merck Serono (Dundee) PA92 (Drexel/UW/GNF) MMV253 (AstraZeneca) GSK030 GSK DSM421 (UTSW/UW/ Monash) GSK692 GSK AN13762 Anacor Human volunteers MMV048 UCT SJ733 St Jude/Eisai 2016 Patient exploratory OZ439/FQ Sanofi KAE609 Novartis KAF156 Novartis DSM265 UTSW/UW/ Monash Patient confirmatory Tafenoquine GSK Dihydroartemisinin piperaquine Paediatric 3 Sigma-Tau Regulatory review Rectal Artesunate * Cipla/Strides/WHO-TDR Post approval Artemetherlumefantrine Dispersible Novartis Artesunate for injection Guilin Dihydroartemisininpiperaquine Sigma-Tau 3 Pyronaridineartesunate Shin Poong/ Univ. of Iowa Pyronaridineartesunate Paediatric Shin Poong/ 4 Univ. of Iowa Artesunateamodiaquine Sanofi/ DNDi Artesunatemefloquine Cipla/DNDi /Farmanguinhos 4 Sulfadoxine - pyrimethamine + amodiaquine 6 Guilin 16 new candidates March 2016

9 SETTING THE GOALS FINDING THE MOLECULES MEASURING SUCCESS WINNING COMBINATIONS

Less potent on embryos and on granulocytes Active vs artesunate resistance

10 1 Building on an existing template OZ03 OZ277/ RBx11160 OZ439 Reduce logp Improve solubility Decrease interaction with ferrous iron (single electron) Less potent on embryos and on granulocytes Active vs artesunate resistance Vennerstrom JL, et al. Nature 2004;430(7002):900 4 Charman SA, et al. PNAS 2011;108(11):4400 5

11 2 Molecular Design: DHODH DSM1 EC 50 3D7 79 nm No oral efficacy DSM191 EC 50 3D7 220 nm ED 90 Pf SCID 57 mg/kg DSM265 EC 50 3D7 8 nm ED 90 Pf SCID 8.1 mg/kg Phase IIa completed December 2015 Coteron JM, et al. J Med Chem 2011;54(15):

12 3 Optimising phenotypic hits

13 New targets from parasite screening Chemotype and related series Multiple diverse series Imidazolopiperazine CARL New Biological Target ATP4 Na channel Molecules KAE609, SJ733, GSK030, PA92 KAF156 Triazolopyrimidine DHODH DSM265 (DSM421) Aminopyridine PI4K MMV048 (UCT943) Quinoline eef2 DDD498 Triaminopyrimidine V-type H+ ATPase AZ412 Target Identification Consortium: 50 compounds from Malaria Box new targets Collection of irresistable scaffolds

14 New Chemotypes by calculation Sequence alignments Homology models/docking Validating models to drive compound design Prioritization of new chemistry 14

15 SETTING THE GOALS FINDING THE MOLECULES MEASURING SUCCESS WINNING COMBINATIONS

16 parasites /ml parasites /ml Standard Phase II data Response in patients for first 36h P. falciparum P. vivax 20,000 18,000 18,000 16,000 14,000 12,000 10,000 8,000 6,000 4, mg 400 mg 800 mg 1,200 mg 16,000 14,000 12,000 10,000 8,000 6,000 4, mg 400 mg 800 mg 1,200 mg 2,000 2, Time /h Time /h 16 log 10 PRR(48h) P. falciparum log 10 PRR(48h) P. vivax

17 Total number of parasites Measuring the MIC clinically _ 10 9 _ 10 7 _ 10 5 _ 10 3 _ microscopic limit PCR limit 10 1 _ days [Concentration] > MIC 17 P t = t P 0. G D 0. C t H /(C t H + IC 50 H. dt [Concentration] > MIC [Concentration] > MIC

18 Early data in CHMI models saves time and money Australian Volunteers ( mg) Thai Patients (100 mg) 1 month per cohort, 1 centre All year round 6 months, 4 centres, seasonal 18

19 Parasites/mL Human volunteer challenge early readout that the drug works S1056 MQ1 S1057 Redo S1058 S1059 S1060 S1064 S1065 S1068 Redo Average DSM S1070 MQ2 150 mg DSM265 predicts Human Effective Dose as 400 mg Day 19

20 SETTING THE GOALS FINDING THE MOLECULES MEASURING SUCCESS WINNING COMBINATIONS

21 Development for combination medicine New Chemical Entity Candidate selection Transition to human Discovery Discovery and Candidate Profiling in vitro and in vivo activity DMPK Solid state characterization Salt/Form screen Candidate Profiling Preclinical Single agent Preclinical GLP Tox DMPK Pre-formulation studies Phase I Phase IIa End of Phase IIa Phase I (h.v.) and Phase IIa (adult pts) Single agent - Safety - PK - Parasite clearance and time to recrudescence (up to Day 28) Combination - Safety - Drug-Drug interactions - PK/PD modeling DDI Phase I Phase IIb Phase IIb (adult and pediatric pts) Safety, tolerability Dose finding Contribution of each agent to the efficacy of the combination (FDA rule) Efficacy (ACPR Day 28 and 42) Initiate Phase III Phase III Combination (with Pharma Partner) Phase III (adult and pediatric pts) Safety, tolerabiliyt SRA filing Confirm efficacy of fixed dose combination (ACPR Day 28, 42 and 63) Preclinical formulation Phase I and Phase IIa formulation Phase IIb loose combination or dose scalable formulation Phase III FDC market formulation 21

Differentiated partner protects against resistance trusted friend or beautiful stranger?

22 Next steps: find the right partner Find the right partner WHO guidance: differentiated partner to protect against resistance: trusted friend or beautiful stranger? Can you afford to wait for the next best thing? Differentiated partner protects against resistance trusted friend or beautiful stranger? can you afford to wait for the next best thing? 22

23 Partner selection Matrix Factor High Score (5) Low Score (1) TPP - SERCap TCP1, 2 and 3 Insufficient TCP1 & 2 Safety Different organ tox & manageable Same organ tox + SAEs Dev Stage Both drugs approved Both preclinical stage PK- time > MPC Complete overlap > MPC for > 2wk Very short acting + very long acting Total Dose (mg) <150mg >1200mg BCS -Formulation No challenges Two drugs with bad formulation Prophylaxis-Liver Stage Both drugs 3-4wks > MPC Neither has >1 wk prophylaxis Resistance None to either drug Widespread to 1 or 2 drugs Food Effect No food effect for both Both food effect + severe safety issue DDI between partners No predicted DDI Clinically concerning DDI DDI with other conc-med No predicted DDI Clinically concerning DDI MOAs Complementary Identical MOA + resistance mutation IP Flexibility Two drugs from same group Owner unwilling to partner Wes van Voorhis, MD PhD, Stephan Challon MD PhD 23

Partner selection matrix 40 35 30 25 20 15 10 5 0

24 Partner selection matrix Mefloq Pyronaridine PQP KAE609 FQ DSM265 KAF156 MMV048 24

25 Newer Newest Two new combination phase II studies are ongoing

26 Options for clinical development Single dose cohort safe and >95% efficacy Phase IIb One day three days Adults and children Dose range to satisfy FDA combination rule Three day cohort safe and >95% efficacy Single Dose Phase III program Confirm safety Multiple dose Phase III program Confirm safety Drug interaction studies with third partner (at risk) Launch single dose cure 2021 Launch multiple dose cure 2021 Phase III with three drug combination

27 Eliminating the last parasite Are medicines safe and well tolerated enough to use in subjects with Repeated infection asymptomatic infection undiagnosed early pregnancies? in HIV patients (comedication, immunosuppresed)? malnutrition?

28 SETTING THE GOALS FINDING THE MOLECULES MEASURING SUCCESS WINNING COMBINATIONS

29 A glass half full? How we are doing Blood stage killers: fast and long acting Chemoprevention: liver schizonticides Transmission blocking: safely sparing primaquine 6/10 5/10 4/10 Relapse Prevention 8/10

30 A glass half full? How we are doing Blood stage killers: fast and long acting: safe and well tolerated for asymptomatics? Chemoprevention: liver schizonticides: once per month once per season Transmission blocking: safely sparing primaquine Relapse Prevention in G6PDindividuals 3/10 2.5/10 4/10 0/10

31 If you want to go fast, go alone If you want to go far, go together

32 Our partnerships are our greatest strength 32

33 Drugs for treatment and chemoprevention of malaria Tim Wells, Chief Scientific Officer, MMV

34 Products with impact

35 Molecule Lumefantrine 4 x 480 mg 2000 mg over 3 days 90.0% 96.0% Artemether 4 x 80 mg 45.5% Ferroquine 3 x 200 mg 79.4%* KAF156 1 x 800 mg 67% DSM265 1 x 400 mg 89% * PCR corrected

THE ROLE OF THE MMV-SIGMA TAU PARTNERSHIP IN DEVELOPING EURARTESIM AS A QUALITY ACT FOR MALARIA ENDEMIC COUNTRIES

THE ROLE OF THE MMV-SIGMA TAU PARTNERSHIP IN DEVELOPING EURARTESIM AS A QUALITY ACT FOR MALARIA ENDEMIC COUNTRIES GEORGE JAGOE MMV (Medicines for Malaria Venture), Geneva, Switzerland The MMV Imperative