13M - Novel treatment of acute myocardial infarction

During 2021 the Project work has been focused on a)developing a clinical formulation suitable for intravenous injection and b) developing robust animal models to study in vivo dose response efficacy signals of lead formulation candidates. Further, optimization of the manufacturing process of the API (13-M) has been done and the regulatory (ICH) stability study of the 13-M is ongoing. To date, 8 months stability data are available and indicate good stability. 13-M Formulation work: To provide a formulation for systemic injection with 13-M is challenging considering this compound?s low solubility in solutions/buffers. Various compositions and different salt forms to increase the solubility have been screened, but no appropriate solutions were found to be sufficiently stable over time and clinically user friendly. Therefore, focus was shifted to work with the free base of the compound in oily emulsion. More than 100 lab scale batches have been prepared and analyzed by our partner without reaching optimal formulation. However, additional external expert in emulsion formulation is being consulted and further pre-formulation work is ongoing to identify the optimal compatibility of the ingredients and define the ideal manufacturing process. Further, an in vitro release model to assess the release kinetics of 13-M out of the formulation (to check it is not trapped in the formulation) has been developed and will be applied as part the formulation screening. Preclinical safety and pharmacology: Pharmacokinetics and single dose toxicity studies in rats and mice were initiated with the lead formulation candidate, but later put on hold until final formulation has been selected. The pharmacology/Proof of Principle studies were initiated early this year at Oslo University Hospital (OUH). A model in pigs, based on the principles used in the earlier studies from University of Oslo (UoO) in rats was developed. The model is set up to monitor the effect of 13-M to inhibit the adrenergic effect on heart contractility upon isoprenaline stimulation (?ISO model?). Two formulations were studied, but conclusive data could not be achieved, and it was concluded to continue pharmacology work in rats. A CRO in Hungary, well known for its competence within cardiology and preclinical models, were selected. The ?ISO model? in rats was set up as per the protocol used in Oslo previously and pilot studies done in rats with 2 formulations. Data showed an adrenergic overstimulation, and the results were therefore inconclusive. This will be further explored in in vivo and in vitro studies at OUH starting in December this year. A program to screen for possible backup/second generation compounds is ongoing in collaboration with OUH and a commercial research partner. In August the planned private fundraising was completed with 11 M NOK raised.

Serca Pharmaceuticals was founded in late 2018 to develop and commercialize a new drug candidate intended for treatment of the large number of patients diagnosed with acute myocardial infarction (MI). Extensive research by Kjetil Tasken and collaborators (UiO) identified a small molecule, called 13M. 13M selectively modulates a intracellular signal pathway in the heart, called serca2. Serca2 controls the adrenergic stimulated contractile force. In rat models treatment with 13M protected the heart, resulting in a clinical meaningful reduction in infarction size and improved heart function after MI. Thereby, 13M has the potential to protect the heart from further damage frequently observed as a result of the reperfusion of the heart during percutaneous intervention (PCI) in treatment of acute MI. These Proof of Concept data form the basis for further preclinical and clinical development of 13M. In early 2019 Serca Pharmaceuticals entered into a collaboration agreement with Cadila Pharmaceuticals in India to develop 13M with the goal to achieve Clinical Proof of Concept by completion of clinical Phase 2. Serca and Cadila have started the preclinical work with the intent to secure preclinical data on 13M required to start clinical Phase 1. Development of a suitable clinical drug formulation of 13M is a key part of the Project. R&D activities in this Project also include performing preclinical safety/toxicology studies necessary to document the safety margin of 13M. Further, the pharmacologic mechanism and efficacy potential, short and long term, of 13M in large animals will be documented. A successful outcome of the project will be to achieve Phase 1 ready status of 13M. This is a significant milestone and the foundation for further development of this novel treatment which potentially can benefit a substantial number of patients suffering from acute MI by reducing the risk of post-infarction heart failure.