Novel Product Formulation toModulate Alpha7 Nicotinic Receptors for Therapy in Stroke Recovery

SUMMARY Stroke remains a leading cause of death and disability. Stroke-related costs in the United States came to nearly $53 billion between 2017 and 2018. Available treatment options have been limited to early intervention with tissue plasminogen activator and endovascular thrombectomy. Management of stroke relies on initial early intervention and secondary management to reduce further brain damage and rehabilitation. There are no pharmacotherapeutic treatments for stroke recovery. Commercial opportunities for stroke have been proposed to focus on specific populations with specific treatments. Significant opportunities remain for effective treatments for stabilization of patients and their recovery post-stroke. Neuroinflammation has been proposed as a major cause for neurodegeneration post-stroke. α7 nicotinic acetylcholine receptor (nAChR) activation suppresses neuroinflammation and produces therapeutic benefits after stroke in rodent models. We introduced positive allosteric modulators (PAMs) of α7 nAChRs as a novel therapeutic approach to the treatment of acute ischemic stroke (AIS) and reported therapeutic efficacy of the prototypical PAM, PNU120596 (i.e. PNU hereafter), after AIS in a rat transient middle cerebral artery occlusion (MCAO) model of AIS with rapid reperfusion. The 7 nAChR is uniquely positioned as a target in AIS due to its potent anti-inflammatory action through the cholinergic vagal anti-inflammatory pathway. Our data demonstrate that PNU administered intravenously up to 6 hours after MCAO in rats significantly reduces infarct volume and neurological deficits. Repeated sub-chronic treatments of PNU further improve benefits suggesting that sub- chronic α7 nAChR activation is therapeutically relevant for post-stroke recovery. PNU remains the most valuable drug candidate for development yet, despite having excellent efficacy after MCAO, PNU is unsuitable for clinical applications because of poor solubility for IV use. In our previous studies, DMSO-based PNU (i.e. dPNU) was used. We developed a novel PAM formulation, exemplified by EPGN2325. In preliminary studies in rats, EPGN2325 demonstrated therapeutic efficacy comparable to dPNU. In the proposed study, our team aims to optimize the formulation suitable for intravenous (i.v.) use in both acute (72h) and recovery (2 mos) phases post-AIS. This proposal is the first step towards providing a novel α7 nAChR product to meet clinical needs. We will test optimized EPGN2325 efficacy in mice in these proposed studies using clinically-relevant functional assays for primary outcomes in stroke recovery. These studies will: 1) Develop a novel, clinically-relevant formulation of optimized EPGN2325 suitable for AIS; and 2) Determine the PK/PD profile of optimized EPGN2325 in acute and recovery (2 mos) phases post-AIS. The obtained data will determine the potential of optimized EPGN2325 for development toward IND.