AbbVie (formerly Abbott), a research-based biopharmaceutical company, has been providing pro bono drug discovery resources and expertise to MMV since 2011. The focus of the collaboration has been to help advance compounds from the laboratory to clinical studies in humans, specifically two exciting compounds with the potential to become single-dose cures, DSM265 and MMV390048. Dr Kennan Marsh, the interface between MMV and AbbVie, talks about the collaboration, compounds and the motivation to get involved.
1. How did the collaboration between AbbVie and MMV first come about and why did you decide to get involved?
In 2010, we created a new model of corporate citizenship, one aspect of which is to offer scientific expertise to not-for-profit pharmaceutical companies like MMV. In 2011, MMV approached us for formulation advice on the preclinical candidate DSM265. The team was in need of preclinical formulations, with improved dissolution and absorption (bioavailability) for toxicity studies.
We offered to liaise with Contract Research Organizations specializing in different formulation technologies and conduct several pharmacokinetic (PK)1 studies of the resulting formulations. These kinds of studies help determine which formulation will be able to provide the highest, most reproducible exposure in toxicity studies. For us, it’s relatively simple to add an occasional PK study to the schedule and the insights we gain can be valuable in the design of further formulations for Phase 1 clinical studies.
I personally really enjoy working with “formulation-challenged compounds”, so I volunteered to help. At the first meeting, I casually asked if it would help if we were to conduct some preclinical PK studies with some of the proposed formulations – we were instantly integrated into the team.
2. What is most exciting about DSM265 and MMV390048 as antimalarial compounds?
In searching for a single-dose cure for malaria, MMV has set a very high bar for the PK profile of any potential compounds. The preclinical data we have suggests that both DSM265 and MMV390048 are compounds with the potential to reach that bar. They both have good oral bioavailability, low clearance2 and a sufficient half-life3. These factors combined mean they have the potential to remain in the body long enough to be efficacious. In other words, they have beautiful PK!
3. What was your main role in the project?
My role has been to coordinate AbbVie’s nonclinical contributions of the characterization of DSM265 and MMV390048. The contributions of our team include characterizing the metabolites4 circulating in the preclinical models, PK studies, formulation evaluation and pathology peer review. I have also designed and conducted a series of PK studies with both compounds to define the formulation variables contributing to oral absorption.
4. What have been the main challenges the project team has encountered and how have they been overcome?
DSM265 is a lipophilic compound, with low aqueous solubility, which means it is not well absorbed by the body, making it challenging to achieve an efficacious concentration. We worked to develop an appropriate formulation for preclinical toxicology studies to overcome this and thereby provide sufficient exposure. We also needed to define, evaluate and manufacture a formulation for Phase 1 trials in humans. In the end, we were able to develop a formulation to provide comparable exposures at a ten-fold lower dose than used in the initial pharmacokinetic studies.
5. What do you find most rewarding about working on these projects with MMV?
It is refreshing and rewarding to work with a team so dedicated to a project. Seeing how the compounds have progressed with the efforts from such a small yet diverse group of people is wonderful.
6. How do you see the partnership with MMV and AbbVie progressing in the future?
We would like to continue to offer our expertise, whether it be with regard to PK studies, formulation exploration or other as yet unidentified areas to help MMV efficiently progress compounds through preclinical studies and into the clinic.
1. Pharmacokinetics: the study of what the body does to the drug, determining where and when the drug will have its effect, for how long and at what level of intensity.
2. Clearance: is the measure of how quickly a drug is excreted from the body.
3. Half-life: a measure of the duration of action of a drug in the body. It is the period of time required for the concentration to be reduced by half.
4. Drug metabolite: a degradation product of a drug once it has been processed by the body.