Technology
13-M is Serca Pharmaceutical’s novel drug candidate in clinical development for treatment of acute myocardial infarction (MI). The clinical aim is to provide a medical treatment to patients with acute myocardial infarction who are subject/eligible for percutaneous coronary intervention (PCI; stenting) procedure – either immediate after hospitalization (patients with MI that show ST elevation upon EKG examination (STEMI patients)) or PCI within 24 – 48 hours after initial hospitalization (non-STEMI patients).
13-M is a small molecule with a unique mechanism of action (MoA) that distinguishes it from existing drug candidates targeting ischemic reperfusion injury. This MoA has been identified exclusively in heart tissue.
Specifically, 13-M modulates the Sarcoplasmic Reticulum Ca2+-ATPase 2 (SERCA2) pump resulting in reduced cardiomyocyte activity in response to adrenergic stimulation (Figure 1).
As a first-in-class agent, 13-M minimizes the expansion of infarcted areas by selectively inhibiting adrenergic pacing of cardiac contractility directly within myocardial cells. The MoA makes 13-M well suited for limiting the myocardial infarction size in patients being treated by PCI. PCI is associated with adrenergic stress and ischemic reperfusion injury (IRI) when the myocardium is re-perfused.
Figure 1: Illustration of Mode of Action of 13-M on SERCA2 in cardiac myocyte. Reabsorption of Ca2+ in diastole is mediated by SERCA2 and other membrane proteins; PKA, AKAP18, PLB.
A: Heart cell in resting condition in which PLB is coupled to SERCA2.
B: Adrenergic stimulation leads to increase in cAMP phosphorylation, PLB is released from SERCA2, Ca2+ is reabsorbed into Sarcoplasmic Reticulum, contractility is increased with increased energy consumption.
C: Disruption of AKAP18-PLB complex due to the effect of 13-M prevents PLB dissociation and the SERCA2 activation result in decreased contractility and energy consumption.
Robust efficacy signals of 13-M in non-clinical models
13-M disrupt the binding of AKAP18∂/PLB to the same extent in rat, pig and human protein complex (figure 2) indicating 13-M can reduce energy consumption also in the human cardiomyocyte.
Figure 2: AlphaScreen signal in rat, pig and human AKAP
13-M showed a clear reduction in the infarct size in an acute ischemic–reperfusion model in pig Myocardial infarction was induced by ligation of LAD of 60 min followed by reperfusion of 2 hours. 13-M was administered IV starting prior to and during reperfusion period. Infarct size was measured by histology examination. Cardiac function was assessed by echocardiography. 13-M showed a clear reduction in the infarct size in this acute ischemic–reperfusion model in pig, and reduced the infarct size up to 36% relative to control (figure 3). In addition, 13-M significantly increase cardiac function by restoring fractional shortening and ejection fraction to” healthy” values and caused an increase of stroke volume post infarction compared to control (figure 4).
Figure 3: Infarcted-Area (%) as % of Area-at-risk (%) in an acute ischemic–reperfusion model in pig after administration of 13-M. Infarct size was measured by histology examination (Area-at risk; Evans blue and Infarcted-Area; TCC staining).
Figure 4: Cardiac function in an acute ischemic–reperfusion model in pig. Cardiac function after administration of 13-M was assessed by echocardiography.
13-M is in Early Clinical Development stage
13-M is in early clinical development stage, Phase 1. The lead candidate 13-M has shown compelling results in reducing infarct size and restoring normal heart function post MI in large animals. A Clinical Trial Application Phase 1 is submitted (India). The regulatory pathway is well-understood and de-risked development is achieved through Partnership with Cadila Pharmaceuticals.