Introduction and Background of the Project

Introduction

With continued financial support from GHIT the project team have developed a novel series of compounds with a very compelling parasitological and ADME profile resulting in identification of MMV172, which meets the MMV Late Lead criteria. The compound is fast-killing, exhibits high antimalarial potency across all the stages of the parasite lifecycle, including P. vivax hypnozoites (TCP-1, 3, 4 and 5 potential), has a high barrier to generation of resistance, exhibits good physicochemical and pharmacokinetic properties, shows high efficacy in mouse models of malaria and has a low predicted human oral dose both for treatment and chemoprevention indications. The series achieves its antimalarial activity via a novel mode of action – selective inhibition of an enzyme critical to the survival of the malaria parasite.

Project objective

The key project aim is to complete the IND-enabling preclinical development studies on MMV172 targeting monthly single oral dose chemoprevention. The project will also continue to determine the efficacy of MMV172 in the primate model of relapsing P. vivax malaria to develop understanding of the anti-hypnozoite PK/PD relationship required to determine if MMV172 also meets the dose criterion for SERCAP (Single Encounter Radical Cure and Prophylaxis) or, if necessary, to guide selection of alternative compounds from the series that may be better suited. The second aim of the project is to deliver one or more differentiated Late Lead(s) against a second target product profile; either an oral treatment for relapsing P.vivax malaria or a long-acting injectable for chemoprevention, depending on the outcome of profiling studies and the eventual indication for MMV172. Those compounds would be potential back-up if MMV172 is not meeting TPP (Target Product Profile) criteria.  

Project design

A multi-disciplinary project team has been assembled, utilizing the inputs and diverse skills and experiences of experts in medicinal chemistry, biology, parasitology, pharmacokinetics, toxicology, formulation and scale-up chemistry. MMV will also draw on the knowhow of its global network of scientific experts to support the activities and review the progress of the project.

Starting with the confirmed Late Lead MMV172, the necessary candidate profiling and preclinical development studies will be performed to confirm the compound meets the desired candidate profile and has the necessary data package required to obtain authorization from regulatory authorities to progress into first in human study.

Additional parasitology, efficacy, ADME and PK studies will be performed on other compounds to determine their potential to address attrition of MMV172 and/or to meet differentiated target product profiles, and to collect the necessary data package required to confirm them as new Late Lead(s).

How can your partnership (project) address global health challenges?

Malaria caused approximately 597,000 deaths in 2023, mostly in children under five years of age. Malaria is caused by a parasite from the genus Plasmodium. In humans, five species of Plasmodium are known to cause the disease. Of particular relevance are P. falciparum, which is the most lethal and accounts for 93% of cases in sub-Saharan Africa and P. vivax which is prevalent in Southeast Asia and the Americas and causes post-treatment disease relapse due to a latent liver form of the parasite (the hypnozoite). Current antimalarial control is highly dependent on artemisinin combination therapies (ACTs), and it is concerning that decreased parasite sensitivity has emerged to all currently-used ACTs, leading to significant failure rates in parts of Southeast Asia and increasingly also in Africa, where partner drug resistance is evident. If resistance becomes widespread in Africa (where most deaths occur), a major health crisis is feared. In response to this impending crisis and with the ultimate aim of eradicating the disease, new drugs with novel modes of action which overcome known resistance associated with existing therapeutics are needed. Development of compounds which can block transmission and be used for chemoprevention, in addition to acute treatment, and treatment of relapsing malaria are especially valuable to drive eradication. Additionally, new drugs which can be used safely in all trimesters of pregnancy are highly desirable.

This project, due to the ability of the series to kill P. vivax blood and liver stages, as well as P. falciparum blood, liver and sexual stages, with high potency, has the potential to deliver a clinical candidate for P. falciparum or P. vivax malaria (including mixed infections) with the additional upside of being able to block transmission. This profile would have a major impact on the path to malaria elimination.

What sort of innovation are you bringing in your project?

The series is chemically novel, has a new mode of action and a unique parasitological profile with the potential to deliver candidates which meet multiple target product profiles. Whilst further development of MMV172 is targeting oral monthly chemoprevention there are related compounds with the appropriate physicochemical properties which, subject to further evaluation, could be developed as long-acting injectables that provide three or more months of protection from malaria.

Notably, the series also has the potential to generate data which validates the first molecular mechanism that kills P. vivax hypnozoites and can therefore be used for treatment of relapsing P. vivax malaria with the additional benefit of not requiring pre-treatment testing of patients for G6PD deficiency, a requirement and limitation of current therapies.

Role and Responsibility of Each Partner

The Tanabe Pharma (Tanabe Pharma Corporation), UGA (University of Georgia) and MMV (Medicines for Malaria Venture) teams will be jointly responsible for the conduct of the project, including design, implementation and interpretation of the studies required to achieve the project objectives. Tanabe Pharma will apply their expertise in drug discovery and preclinical development. MMV will apply their malaria expertise to ensure the project deliverables meet the required profile for the intended clinical impact. The UGA team will apply their expertise of hypnozoite parasitology to guide evaluation of compounds in in-vitro and in-vivo P. vivax malaria models. Many activities will also be conducted at trusted contract research organizations and via partners in the MMV network. The scientific leadership will be jointly held by representatives of all the collaboration partner organizations.