Pipeline

Using a structure-assisted drug design approach, we incorporated key elements of the known prototypical capsid modulators into a new chemical series and refined the potency, oral bioavailability and safety of the compounds via iterative rounds of medicinal chemistry.  SMP-9945 (formerly VNRX-9945) exhibited potent (i.e., single digit nanomolar), pan-genotypic antiviral activity against HBV both in vitro and in animal models of HBV infection. Combination and cross-resistance studies supported regimens that include both SMP-9945 and a nucleoside analog reverse transcription inhibitor. SMP-9945 exhibited high oral bioavailability and repeated doses for up to 28-days were well tolerated across multiple animal species in preclinical testing. Based on its preclinical profile, SMP-9945 was advanced into human testing and successfully completed single ascending dose studies in health volunteers. Sustained plasma concentrations consistent with potent in vivo antiviral activity were observed following a single oral dose of SMP-9945. Moreover, SMP-9945 was found to be generally safe and well tolerated in human testing. Next steps include completing the multiple ascending dose study in healthy volunteers with the goal of advancing SMP-9945 into phase 1b proof-of-concept testing in chronically infected HBV individuals.

We are also focused on discovery, optimization and development of novel small molecule inhibitors of the Penicillin Binding Proteins in other clinically relevant Gram-negative bacteria focused on agents active against carbapenem-resistant Enterobacterales (CRE) and carbapenem-resistant Pseudomonas aeruginosa (CRPA). Enterobacterales and P. aeruginosa rank among the “Priority 1: Critical” antibiotic resistant pathogens on the World Health Organization’s list of bacteria for which new antibiotics are urgently needed. Multidrug resistant pathogens pose a particular threat in hospital intensive care units and nursing homes, as well as among patients whose care requires devices such as ventilators and catheters. These bacteria have become resistant to a large number of antibiotics, including carbapenems and third generation cephalosporins.

The potential for intentional or unintentional release of variola virus, the causative agent of smallpox, remains a significant bio-security threat. The rapid spread of monkeypox clade IIb virus from endemic countries during the 2022 outbreak and a second outbreak of a more transmissible and pathogenic form of monkeypox virus (clade I) demonstrates the impact of inadequately protecting vulnerable populations with effective vaccines and therapeutics. There are currently only two approved antiviral therapeutics for the treatment of smallpox disease, and neither are approved for monkeypox virus infections. Without continued drug discovery efforts, the potential for drug resistance and significant off-target toxicities leaves the public poorly prepared to face bioterrorism and re-emerging threats from orthopoxviruses. To that end, the Spring Mill Pharma discovery team identified a lead series of potent and orthopox-selective direct-acting antiviral inhibitors of ectromelia virus (ECTV, a mousepox virus) exhibiting a novel mode of action (distinct from brincidofovir and tecovirimat) from a phenotypic high throughput screen utilizing a proprietary small-molecule library of nearly 300,000 compounds. Further optimization is underway to optimize physicochemical properties and oral exposure to advance a first-in-class orthopox virus small molecule inhibitor with a unique mechanism of action, high genetic barrier to resistance (by contrast to tecovirimat) for public health and procurement into the national stockpile for biodefense purposes.