Background on Malaria and Combination Anti-Malarial Drug Therapy

FDA Workshop: Clinical Trial Design Considerations for Malaria Drug Development 30 June 2016

Prof. Arjen M. Dondorp Mahidol Oxford Tropical Medicine Research Unit The 5 human Plasmodium species

P. falciparum P. vivax Anopheles

P. knowlesi

P. malariae P. ovale H. sapiens M. fascicularis/ nemestrina Life-cycle of Plasmodium

White et al; Lancet 2014 Artemisinins: the best drugs for reducing malaria mortality

Log-rank p=0.0002 SEAQUAMAT Asia 4 countries N=1,461 Δ=35% (202 children)

AQUAMAT

Artesunate Africa 9 countries Δ=23% N=5,425 Quinine (all children)

Dondorp et al. Lancet 2010; SEAQUAMAT investigators group. Lancet 2005 Broader stage specificity explains superiority of artemisins

rapid action, broad stage specificity, safe, easy administration

White; Science 2009 Differences in potency

TOTAL PARASITES Artesunate best drug to treat severe malaria 1012

Fastest for the artemisinins 1010

Detection limit 108

106

104 104 103 102 10 Reduction/ 48h-cycle 102 MQ, PQP, 0 Artesunate Malarone Doxycycline

0 1 2 3 4 WEEKS = artemisinin resistance

Courtesy NJ White Courtesy NJ White NJ Courtesy

Plasma concentration (%) 100% 0%

0

A

pharmacokinetics in Differences

Q

Time Time afterstart treatment (weeks)

1

P

2

C

3

M

4

Artemisinin resistance: a prelude to ACT failure 1. W-Cambodia

2007-2008 2012-2013 2012-2014

Slow clearance DHA-piperquine efficacy DHA-piperquine 42-day failures

Source CNM Cambodia/ WHO Map by Richard Maude

Dondorp et al. Amaratunga et al. N Eng J Med 2009 Lancet Infect Dis 2016 The molecular marker for artemisinin resistance: Kelch 13

K13 mutations in the “propeller region” strongly associates with the slow clearing phenotype

multiple SNPs in the propeller region, but: only 1 mutation per clone seems permitted

Ariey et al. Nature 2013 Regional distribution of Kelch13 ∆ propeller 2015

Menard et al. N Engl J Med 2016 jumping versus popping

Neighbour –joining tree of samples carrying K13 SNPs

Median Joining Haplotype Network K580Y mutant found in Myanmar did not spread from Cambodia of K13 Mutations and SNPs within Linkage Disequilibrium -it arose independently in Myanmar of the K13 Propeller Protein

Shannon Takala-Harrison et al Miotto et al. Nature Gen 2015 J Infect Dis 2014

Artemisinin resistance: selects for partner drug resistance 2. Thai-Myanmar border

2010 2010

2001-2013 1995-2011

Aung Pyae Phyo et al. Carrara et al. Lancet 2012 PLoS Med 2013 Resistance to artemisinins or partner vs ACT failure

*Burkina Faso, Rwanda ** Rwanda, Zambia, DRC Artemisinin resistance → treatment failure

after artesunate-mefloquine, also with little MQ resistance

SMRU Aung Pyae Phyo et al. Thai-Myanmar border ACC 2016 Antimalarial drug resistance ⇒ ↑ transmission

Resistance

More drug used Delayed response

More clinical cases Recrudescent infections

Larger reservoir Increased gametocyte carriage Mefloquine : x4.0 Fansidar : x4.1 Increased transmission Chloroquine : x2.9 – x12

Drakely et al. 2004; Price et al. 1996; Bousema et al 2003 Barnes & White 2005 The doom scenario: for artemisinins/ ACTs?

Spread of resistance: chloroquine & pyrimethamine

1980 1980 1960 1959 1957 1970 1997 1982 1978

Dondorp et al Adapted from Chris Plowe Nat Rev Microbiol. 2010 Options with failing ACTs using existing drugs

1st. Triple therapies (TACT): DHA-PQP-MQ; AM-LUM-AQ: TRAC II

2nd. Arterolane-piperaquine: TRAC II

3rd. 5-day regimen of DHA-PQP or AM-LUM Needs trialing & reassurance of safety concerns (QTc-prolongation); new problem: PQP resistance.

4th. Drug rotation of DHA-PQP and MAS3, guided by prevalence of PfMDR1 copy-number

5th. Sequential use of two different ACTs (e.g. DHA-PQP and MAS3)

6th. Artesunate-pyronaridine efficacy<90%; cross resistance with PQP??

TACT: DHA-piperaquine + mefloquine

No interaction Possible counter-acting Reasonably matching re QTc time resistance mechanisms PK-profiles

Price et al. Lancet 2004 TACT: Artemether-lumefantrine + amodiaquine

Artemether-Lumefantrine Treatment Artesunate-amodiaquine failure Counter-acting resistance mechanisms

PfMDR1 N86Y Reasonably matching PK-profiles

PfMDR1 D1246Y

Venkatesan et al. Am J Trop Med Hyg 2014 Conclusions: Combination therapy

• Fast acting drug (artemisinin) confers survival advantage • Partner drug with longer half life permits construction of 3 day regimen • Combination increases genetic barrier to resistance

• Significantly increases complexity in terms of drug development

Conclusions II: resistance • Artemisinin resistance now with us: -Expanding in SE Asia; not yet in Africa -Contributes to treatment failure -Selects for partner drug resistance -Might increase transmissibility

• Partner drug resistance: -Increasing problem in SE Asia (Greater Mekong Subregion)

• Few options left in GMS: -Triple combination therapies

• New antimalarials urgently needed! -Choice of partner drug no longer trivial…

Global Portfolio of Antimalarials Research Translational Product development Access Lead Human Patient Patient Regulatory Preclinical Post approval optimization volunteers exploratory confirmatory review Artemether- DHODH 1 project P218 MMV048 OZ439/FQ Tafenoquine Rectal Artesunate * UTSW/UW/Monash UCT/TIA GSK Cipla/Strides/WHO-TDR lumefantrine Novartis (Biotec) Sanofi Dispersible 1 Novartis Open Source Drug 2 projects DDD498 ACT-451840 KAE609 Dihydroartemisinin - Arterolane/ Artesunate GSK Actelion Discovery Merck Serono Novartis piperaquine Piperaquine for injection Univ. Sydney (Dundee) Paediatric Sun Pharmac* * Guilin 2

Sigma-Tau Heterocycles Orthologue Leads PA92 CDRI 9778 KAF156 Dihydroartemisinin- UCT Sanofi (Drexel/UW/GNF) Ipca Co-trimoxazole Novartis piperaquine ITM Antwerp Sigma-Tau 3 Diversity Oriented Tetraoxanes N-tert butyl Isoquine MMV253 Pyronaridine- Synthesis LSTM/Liverpool LSTM/Liverpool/GSK DSM265 Artemisinin (AstraZeneca) artesunate Broad/Eisai UTSW/UW/ Naphthoquine * * Shin Poong 4 Monash KPC dUTPase Whole cell GSK030 SJ733 Inhibitors St Jude/Rutgers/USF Fosmidomycin Artemether sub- Pyronaridine- GSK St Jude/Eisai Medivir Piperaquine lingual spray artesunate Paediatric

Jomaa Pharma/GmbH Photo Pharma Ltd Shin Poong Imidazolidine Heterocycles DSM421 diones Celgene (UTSW/UW/ Methylene WRAIR Artesunate- Monash) Blue/AQ amodiaquine * Heidelberg Pf NDH2 Pf NMT Sanofi/ DNDi 5 Imperial College Imperial College AN762 SAR97276 London London Anacor Artesunate- Sanofi mefloquine * Pantothenamides Cipla/DNDi TropIQ/RUMC/ NPC1161B Pansynt Mississippi Artemisone UHKST SPAQ Guilin JPC2997 6 Jacobus AQ13 Immtech

MK4815 Merck Sevuparin Dilaforette Thank you