GSK692 - a novel compound steadfast in the face of resistance

Dr Paul Willis, Director of Drug Discovery, MMV, and Dr Laura Sanz, Tres Cantos Medicine Development Campus, GlaxoSmithKline

GSK692 is an antimalarial compound with a novel mode of action which enables it to kill the malaria parasite quickly. Its overall properties indicate it could form part of a single- dose cure and it has a low propensity to generate resistance in laboratory studies as well as activity against current drug-resistant strains – key attributes for a next-generation antimalarial. In recognition of this, the GSK692 project team has won MMV’s 2015 Project of the Year award and MMV’s External Scientific Advisory Committee (ESAC) has approved the compound as a clinical candidate for further research. 

GlaxoSmithKline (GSK) and MMV have worked in a productive and open collaboration on malaria drug discovery for several years. GSK’s facility at Tres Cantos in Spain houses one of MMV’s centres of excellence for screening and testing new compounds in biological assays, transmission-blocking models and parasite-killing studies. It is expected that further clinical candidates will emerge from the MMV/GSK collaboration in the future – following in the footsteps of GSK692.

Dr Paul Willis and Dr Laura Sanz talk about the award, the compound and the collaboration.

1. What is special about GSK692?

LS: GSK692 is special because it combines a number of desirable properties for an antimalarial. It targets blood-stage activity of the Plasmodium falciparum and Plasmodium vivax parasites. It provides a rapid response when tested in vivo in laboratory models of malaria. Importantly, this is complemented by a rapid in vitro response. The molecule also displays an extremely low propensity to select for resistance in vitro, hence, we predict a low rate of selection for resistance in the field. Its fast mode of action could make it a suitable replacement for artemisinin, the current gold standard treatment. Also, GSK692 is not structurally related to artemisinin and has a unique mode of action, which is of paramount importance when developing effective, novel combination treatments for a disease that has a history of developing drug resistance.

2. How was the compound discovered? 

LS: The molecule was identified in collaboration with MMV through a programme which screened the entire GSK corporate compound collection against malaria at Tres Cantos in Spain in 2010. This programme led to the identification of what we call the ChEMBL TCAMS (Tres Cantos Antimalarial Set). The results were published in Nature1 in 2010 and made publicly available to the global drug discovery community.

The next step was to triage the active compounds, using innovative tools such as assays, to determine speed of killing and transmission-blocking potential as well as GSK’s rigorous quality criteria. Ferrer, a pharmaceutical company based in Barcelona, then joined the team working with GSKand MMV to further improve the series until 2013 when they stopped their malaria research activities. The joint programme focused on improving the molecules’ developability properties, like solubility and physicochemical properties. GSK692 emerged as the best molecule.

3. What are the next steps for the project?

PW: As GSK692 has now been approved as a clinical candidate by the ESAC, the next step is to prepare a larger quantity of the compound for regulatory studies, which will determine whether it is safe to progress to clinical trials. The plan would then be to start a phase I clinical trial looking at tolerability and pharmacokinetics in human volunteers and studies in the controlled human malaria infection model (page 18) to explore efficacy.

4. What value has MMV added to the project as a partner?

LS: MMV provides overall guidance based on its extensive experience in the discovery and development of antimalarial molecules. Specifically, MMV has been fundamental in the final profiling of the molecule’s activity against the various stages of the parasite’s lifecycle by providing access to critical biological assays through its established network of collaborators.

MMV’s Project Director Paul Willis and other MMV staff members act as consultants. Their support and guidance has helped us overcome the challenges that arose during the project’s progress. The consistent level of open communication in this partnership has significantly contributed to the success of the project and the molecule’s selection as a potential new medicine.

5. Why does the collaboration between MMV and GSK work so well? What does GSK bring to malaria drug discovery?

PW: There has been an excellent collaborative atmosphere – both sides respect and value each other’s contributions. It means we can discuss the science in an open and transparent manner. In addition to the drug discovery projects, GSK houses one of our screening centers of excellence at Tres Cantos. They run several key biological assays for malaria, providing data on efficacy, transmission-blocking potential and the rate of killing of the malaria parasite for all projects in the MMV drug discovery portfolio. Their broad malaria expertise and drug discovery knowledge makes for a really powerful, promising and beneficial collaboration. To illustrate this, GSK also had another candidate – GSK030 – approved last year and there are several promising new projects in the portfolio which we hope will deliver exciting new drug candidates in the future.

1 Gamo FJ et al. “Thousands of chemical starting points for antimalarial lead identification.” Nature. 20;465(7296):305-10 (2010).