Murphy, C.K., Dixit, B., Oleson, F.B., Dolle, R.E., Farquhar, R. and McCormick, B.A. (2023) Development of ADS051, an oral, gut-restricted, small molecule neutrophil modulator for the treatment of neutrophil-mediated inflammatory diseases. FEBS Open Bio 13, 1434–1446. https://doi.org/10.1002/2211-5463.13668
Uncontrolled neutrophil activity can lead to inflammation and tissue damage in acute and chronic diseases. Approved small molecules targeting neutrophils display efficacy and safety limitations. ADS051 is an orally administered, gut-restricted, novel small molecule modulator of neutrophil trafficking and activity via blockade of multidrug resistance protein 2- and formyl peptide receptor 1-mediated mechanisms. Our results support clinical development of ADS051 for treating neutrophil-mediated diseases.
How/when/where did the initial hypothesis arrive?
A small team from Adiso Therapeutics took a trip to University of Massachusetts Chan Medical School (Worcester, MA, USA) and Dr Beth McCormick’s lab, with an interest in her academic research and the potential translatability of her findings in neutrophil biology to the inflammation associated with ulcerative colitis. After spending a few days with her, we decided to move her lab’s findings toward the clinic. Ulcerative colitis patients still lack safe and effective therapies and hit a 30% efficacy ceiling, leaving 70% of patients without opportunities for relief.
How did it fit with the current understanding or questions in your field?
The detrimental role of neutrophils is widely accepted in the field of ulcerative colitis, but no therapeutic has aimed at targeting those neutrophils in the manner that we have. Neutrophils are measured in the clinical setting via the biomarkers fecal calprotectin and myeloperoxidase. They are a very important player in inflammation and tissue damage – two of the hallmarks of disease.
Who else was involved in the work of this paper and how did you collaborate?
This work was a beautiful example of the magic of academic and industry collaborations, bringing together the best minds and labs to advance ideas in therapeutics: UMass Chan Medical School researchers, medicinal chemists, drug developers, and contract research organizations, among others.
What aspect of the project did you most enjoy?
The best part about this project is the many brains working on it. We have a fantastic team of experienced drug developers along with a stable of great partners in clinical, manufacturing, pre-clinical and thought leadership to help to advance this novel therapeutic approach to patients as quickly and efficiently as possible.
Did you get a chance to discuss your work in a seminar or conference?
We have had quite a number of opportunities to share our novel approach at scientific, medical and industry conferences over the years, in addition to sharing with potential pharma partners.
How did you celebrate acceptance of the paper?
Champagne! We are always so excited to achieve these significant milestones in a drug development process that can take 10 to 15 years to get a therapy to market. Anytime we get the opportunity to share our science, its novelty and, most importantly, its potential benefit to patients, we have reason to celebrate!
The Adiso team is planning the next phase of development in patients suffering from ulcerative colitis. This paper represents the foundational work that supported that important mission.
The authors of this FEBS Network post are employees of Adiso Therapeutics.
Top image of post: A modified cyclosporine scaffold was covalently attached to a 2000 molecular weight polyethylene glycol (PEG) via a short linker. The scaffold provided inhibition of MRP2- and FPR1- mediated neutrophil migration and activation while the PEG ensured gastrointestinal restriction after oral dosing.