Using biology to help guide the search for new molecules

2018
Dr Didier Leroy, Senior Director, Drug Discovery, MMV and Dr Alain Pellet, Pharmaceutical Chemistry Team Leader, Sanofi

The discovery team led by Dr Alain Pellet at Sanofi and Dr Didier Leroy at MMV receives MMV’s 2017 Project of the Year award for the identification and development of SAR441121 (shortened to SAR121). The team applied a smart approach to screening guided by biology, which led to the accelerated discovery of this promising molecule.

SAR121, the first antimalarial candidate molecule to be delivered by the team, kills the malaria parasite very quickly, and so may also rapidly reduce malaria symptoms. It has been very difficult to generate parasites that are resistant to SAR121 in the laboratory, which, if replicated in a real-world setting, means the molecule could be one of our strongest weapons in combatting parasite resistance.

The current focus of the team is to show that the molecule is sufficiently well tolerated to be tested in humans. The goal will then be to test it initially in human volunteer infection studies (VIS) in 2018. In addition, the team is working to identify the best partner molecule for a combination therapy.

Dr Alain Pellet, Pharmaceutical Chemistry Team Leader, Sanofi and Dr Didier Leroy, Senior Director, Drug Discovery, MMV talk about the partnership and the exciting features of the antimalarial compound SAR121.

1. How does it feel to be a part of the team selected to receive the MMV Project of the Year 2017?

Alain: We feel honoured to receive this recognition, which extends beyond the immediate team. This project was also recognized by Sanofi as one of the best R&D projects of 2017. I personally feel very proud, as combatting malaria was a motivation for me when I joined the pharmaceutical industry.

Didier: This molecule is the result of a long-standing collaboration between Sanofi and MMV. I am extremely pleased to have contributed to its discovery, and now to see the molecule being moved forward to trials in humans. I’m delighted to have achieved this in partnership with Sanofi.

2. What is exciting about SAR121 as a future antimalarial?

Alain: Based on the data we have from cell biology and mouse models, SAR121 is expected to be well tolerated, both fast and long acting, and promises to be part of a simpler therapy, perhaps a single dose. It has also been shown to have a very low potential to induce resistance in the field.

Didier: In the early stages of drug discovery, we put ourselves in the shoes of the physicians treating patients and ask what characteristics they would like to see: for example, a fast-acting drug.

At the peak of malaria infection, there can easily be more than a trillion parasites in the body, and these can kill the patient by blocking the capillaries in the brain, the lungs or simply killing the red blood cells, leading to anaemia. The faster the parasites are killed, the sooner the patient will recover.

The ideal antimalarial also needs to resist the human metabolism so it can be present in the bloodstream for more than a week. It also needs to be potent and easily administered – large tablets are extremely difficult for young children to swallow. SAR121 remains at a concentration that can kill the parasite in the blood for a week or more, from a single dose of 100 mg, and this could be sufficient to be curative.

Another potential advantage is that our attempts to raise resistance to SAR121, by challenging parasites with suboptimal doses over a 2-year period, was almost "mission impossible". The resistance that eventually appeared was extremely limited. This suggests SAR121 should be highly unlikely to induce resistance in the field. Together, these factors make SAR121 exceptional in the current landscape of drug candidates.

3. What process was followed to discover this promising compound?

Didier: Sanofi took a different approach from everyone else, which they called ‘orthology’-based screening. Usually we start by screening a large library of up to one million molecules against the parasite; this is like looking for a needle in a haystack. Sanofi instead picked out compounds from their in-house collection that were from families already known to hit targets from other therapeutic areas (and therefore potentially more likely to be active against malaria).

A total of 66 common targets were identified between Plasmodium parasites and human diseases. For each target, a variety of different compounds were picked, some potent against the human target, and others that were similar, but less potent. This gave a library of around 1,000 compounds, which were then tested on the parasite. Usual screening procedures give a ‘hit rate’ for activity of less than 0.1%. Following this orthology-based screening process, the hit rate was 15%.

Using medicinal chemistry, these hits were modified to make new compounds. The best performing compounds were more specific for the parasite and less specific for human cells, giving a lower likelihood of side effects. Molecules were then optimized to increase their half-life1 in vivo and to make sure the final candidate was as potent as possible.

4. How has the MMV and Sanofi partnership helped the drug discovery efforts?

Dider: Having the right team is important. Over the last 5 years we have also been fortunate to have Sir Simon Campbell working with us as a mentor. He brings over 50 years’ experience in drug development. The team had exceptional motivation and commitment, were hard working, and understood and appreciated each other. This is important, since in the 9-year journey there were always difficult lessons to be learned along the way. One of our best insights came from an unknown compound that the team decided to identify: attention to detail and a willingness to explore the unknown, and to persevere, are critical in drug discovery.

Alain: Throughout the project there was super team spirit and enthusiasm, and the team benefited greatly from MMV’s and Sanofi’s wide network of experts.


 

1. Half-life: the period of time required for the concentration or amount of drug in the body to be reduced by one-half