Industry Trend Analysis - Increasing Pressure On Developing Antimalarial Treatment Against Drug-Resistant Plasmodium - APR 2017

BMI View: Drug- resistant malaria is becoming more common and there is increased interest in possible solutions from pharma ceutical companies. The greater the range of action against multiple strains of malaria plasmodium will lead to a greater success rate for the new ly developed drug s . However, pricing strategy will be crucial to the uptake of new antimalarial treatment s .

Although malaria is one of the more prevalent tropical diseases, commercial interest has historically been lacking in the pharmaceutical industry. However, resistance has become a significant threat to current antimalarials becoming redundant, which has led to an increased interest in the discovery and development of novel antimicrobials to control the disease.

Malaria is a significant unmet burden on the world, with the World Health Organization (WHO) estimating roughly 212mn malaria cases and an estimated 429,000 deaths in 2015. Sub-Saharan Africa was home to 90% of malaria cases and 92% of the total deaths in 2015. It has been reported that deaths related to malaria have decreased by 29% amongst all age groups since 2010, however parasites resistant to artemisinin are becoming increasing common; this has been detected in five separate countries in South-East Asia: Cambodia, Laos, Myanmar, Thailand and Vietnam. The standard-of-care treatment (artemisinin-based combination therapy [ACT]) still remains effective, as long as the partner drug in combination is locally effective.

Malaria Still A High Threat
Malaria DALYs (mn)
Source: BMI Disease Database

Solutions To Drug-Resistant Plasmodium

With the increased interest in developing potential solutions to antimicrobial resistance, there has been increased funding into possible alternatives to the common ACT. The highest priority for researchers is to develop a single exposure radical cure and prophylaxis (SERCaP), a single dose drug that would cure patients after one exposure and provide substantial post-treatment protection from relapse as well as block transmission to mosquitoes.

One of the most developed is Novartis' KAF156, a novel antimalarial candidate from a class of compounds called imidazolopiperazines. This drug would be the first antimalarial approved with a wholly novel mechanism of action in many years and has potential to be used as a crucial defence against drug-resistant forms of the disease. The WHO guidance recommends that antimalarials be co-formulated to reduce resistance development and KAF156 would provide a significant improvement to performance of co-formulations if validated.

A Phase II, open-label, two-part study was completed in August 2013 and was designed to assess KAF156 in adult patients with acute uncomplicated P lasmodium vivax (11 patients) or P lasmodium falciparium (10 patients) malaria. Multiple-dose (400mg once daily for three days) cohorts assessing parasite clearance rates were followed by a single-dose cohort in P. falciparum malaria assessing 28 day cure rates. Researchers saw that KAF156 resolves signs and symptoms of illness and cleared parasitaemia rapidly in both P. vivax and P. falciparum malaria patients, including infections with artemisinin-resistant parasites. The ability to target artemisinin-resistant parasites is by far the most promising result of the research. Although the majority of malaria cases do not see significant resistance to existing antimalarial therapies, drug resistance remains a pressing threat and some areas experience endemic resistance. Resistance to typical antimalarial therapies is increasing as use expands across the globe and while co-formulations can slow the progress of resistance, novel solutions will always be needed.

Taking a step further, Eisai entered into a joint research agreement for the development of new antimalarial medicines in November 2015 with the Liverpool School of Tropical Medicine and the University of Liverpool. Under this agreement, the three parties will conduct preclinical development of a new antimalarial candidate compound, E209. Research so far has shown that E209 is rapidly acting and shows efficacy against all types of malaria parasites, which means that it could be effective in patients for whom artemisinin-based malaria treatments are ineffective due to resistance. If successful, a drug active against all strains of malaria could have great success against the resistance plasmodium.

Global Portfolio Of Antimalarial Medicines
Stage Of Development Drug Company Mode Of Action
*indicated when it is a Medicines for Malaria Venture. GSK: GlaxoSmithKline, UCT: University of Cape Town, UW: University of Washington, GNF: Genomics Institute of the Novartis Research Foundation, LSTM: Liverpool School of Tropical Medicine, UHKST: The Hong Kong University of Science and Technology , ITM: Institute of Tropical Medicine, MRC: Medical Research Council, DNDi: Drugs for Neglected Diseases Initiative. Source: Medicines for Malaria Venture, updated December 31 2016.
Preclinical GSK030* GSK PfATP4 inhibitor
DSM421* Takeda Plasmodium dihydroorotate dehydrogenase (DHODH) inhibitor
AN13762* Anacor Pharmaceuticals Unknown
UCT943* UCT PfPA4K inhibitor
NPC1161B University of Mississippi Unknown
MK4815 Merck & Co Unknown
DDD498* Merck KGaA P. falciparum EF2 inhibitor (novel mechanism)
PA92* Drexel/UW/GNF PfATP4 inhibitor
MMV253* Zydus Cadila Mutants identified in vascular ATP-synthase sub-unit D
JPC3210 Jacobus Unknown
GSK607 GSK Unknown
Human Volunteers P218* Biotec Thailand P . falciparum dihydrofolate reductase (DHFR) inhibitor
SJ733* St Jude/Eisai PfATP4 inhibitor
ACT-451840 Actelion Dual activity against asexual and sexual stages of P. falciparum and P. vivax
CDRI9778 Ipca Laboratories Targets the erythrocytic stage of development. No progress report in the last two years
N-tert butyl Isoquine LSTM/Liverpool/GSK Avoids the formation of quinone imine. No progress report in the last two years
Patient Exploratory Artefenomel/Ferroquine* Sanofi Inhibition of heme detoxification and inhibits OZ439 (trioxolane)
KAF156/Lumefantrine* Novartis Decreased susceptibility associated with mutations in three P. falciparum genes; CARL, UDP-galactose and acetyl-CoA transporters
Cipargamin* Novartis PfATP4 inhibitor
DSM265* Takeda Plasmodium dihydroorotate dehydrogenase (DHODH) inhibitor
Fosmidomycin Piperaquine Jomaa Pharma Acts through inhibition of isoprenoid biosynthesis
Methylene Blue-amodiaquine Heidelberg Acts in the asexual blood stages. No progress in the last two years
SAR97276 Sanofi Acts in the asexual blood stages. No progress in the last two years
Artemisone UHKST Acts in the asexual blood stages. No progress in the last two years
AQ13 Immtech Pharmaceuticals Acts in the asexual blood stages. No progress in the last two years
Sevuparin Dilaforette Pre-referral treatment against severe malaria
MMV048* UCT PfPI4K inhibitor
Patient Confirmatory Tafenoquine* GSK Single-dose treatment for relapsing P. vivax malaria
Dihydroartemisinin piperaquine Sigma-Tau/Pierre Fabre ACT against P. falciparum in paedatrics
Co-trimoxazole ITM Antwerp Unknown
Artemisinin naphthoquine Kunming Pharma ACT against P. falciparum
Artemether sub-lingual spray MRC/Suda Pre-referral treatment against severe malaria
Regulatory Review Rectal artesunate* Cipla Pre-referral emergency intervention for severe P. falciparum malaria in children <6 years and >6 hours from a treatment centre
Arterolane/piperaquine* Sun Pharma ACT against P. falciparum
Post Approval Coartem (Artemether lumefanthrine)* First Approved: Novartis; Generics by Ajanta, Cipla, Ipca, Strides, Macleods, Mylan ACT against P. falciparum
Coartem Dispersible (Artemether-lumefantrine Dispersible)* First Approved: Novartis; Generic by Ajanta ACT against P. falciparum
Artesun (Artesunate for Injection)* Guilin Treatment of severe malaria caused by P. falciparum, followed by oral medication
Euaratesim (Dihydroartemisinin piperaquine)* Sigma-Tau/Pierre Fabre ACT against P. falciparum
Pyramax (Pyronaridine artesunate)* Shin Poong ACT against P. falciparum or P. vivax
Pyramax (Pyronaridine artesunate granules )* Shin Poong ACT against P. falciparum or P. vivax in children and infants
ASAQ Windrowq (Artesunate amodiaquine)* Fixed approved fixed-dose combination: Sanofi/DNDi; Generics by Ajanta, Cipla, Guilin, Ipca and Strides ACT against P. falciparum in adults, children and infants
ASMQ (Artesunate mefloquine)* Cipla ACT against P. falciparum in adults, children and infants
SPAQ-CO (Sulfadoxine pyrimethamine+amodiaquine)* Guilin Seasonal malaria chemoprevention for children from 3 to 59 months in eligible region

Pricing Strategy Is Key For Success

With the increased commercial possibilities, pharmaceutical companies have to choose an appropriate market access strategy. We have highlighted ( see ' Malaria Will Continue To Attract Multinational Expansion Throughout Africa ' , April 8 2016) some strategies pharmaceutical companies have adopted when entering the African market. These include Novartis lowering the price of its antimalarial products Riamet (artemether/lumefantrine) and Coartem (artemether/lumefantrine) by 20% to improve affordability in malaria-endemic regions of Africa. In addition, GlaxoSmithKline has committed to a not-for-profit price for its malaria vaccine Mosquirix (RTS,S) so that, if approved, the price would cover the cost of manufacturing the vaccine together with a small return of around 5% that will be reinvested in R&D for second-generation malaria vaccines. This will be a crucial strategy to adopt for the novel antimalarial treatments to succeed.