Vertex Pharmaceuticals (Canada)

Etripamil is a calcium channel blocker currently in Phase 3 trials for the treatment of paroxysmal supraventricular tachycardia (PSVT). Systemic and local toxicity following once-weekly intranasal administration of etripamil was evaluated in cynomolgus macaques to support clinical development. Groups of animals (N = 8, 4 males and 4 females) were administered etripamil into the left nostril weekly at dose levels of 0 (vehicle), 1.9, 3.8, or 5.7 mg/kg/dose for 26 doses. Persistence, reversibility, and progression of findings were examined following a 28-day recovery period. Clinical signs were transient and were related to the intranasal administration (e.g., nasal discharge, sneezing, etc.) of etripamil. There were no macroscopic or systemic microscopic findings at any dose. Etripamil-related adaptive and reactive local changes affecting the nasal cavity, larynx, and nasopharynx were observed at ≥1.9 mg/kg/dose. Minimal to severe dose-dependent nasal epithelial damage was observed, mainly affecting respiratory and transitional epithelium. Following the 28-day recovery period, microscopic changes were confined to the left nasal cavity and nasopharynx. These changes were significantly lower in incidence and severity, with noticeable reversal of the adaptive and reactive changes, indicating partial to complete recovery of the epithelial lining. Based on the lack of systemic toxicity and the minimal and transient nasal changes, the systemic, no observable adverse effect level (NOAEL) of etripamil in monkeys was the high dose, 5.7 mg/kg/dose. The NOAEL for local toxicity was 1.9 mg/kg/dose. Collectively, these data support further study of etripamil in human trials as a potential treatment for PSVT.

Abstract Chronic kidney disease affects ~10% of people worldwide and there are no disease modifying therapeutics that address the underlying cause of any form of kidney disease. Genome wide association studies have identified the G1 and G2 variants in the apolipoprotein L1 (APOL1) gene as major contributors to a subtype of proteinuric kidney disease now referred to as APOL1‑mediated kidney disease (AMKD). We hypothesized that inhibition of APOL1 could have therapeutic potential for this genetically-defined form of kidney disease. Here we describe the development of preclinical assays and the discovery of highly potent and specific APOL1 inhibitors with drug-like properties. We provide evidence that APOL1 channel activity drives podocyte injury and that inhibition of this activity stops APOL1-mediated cell death and kidney damage in a transgenic mouse model. These preclinical data, combined with recent clinical data, support the potential of APOL1 channel inhibition for the treatment of AMKD.

The regulation of the informational flow from the mitochondria to the nucleus (mitonuclear communication) is not fully characterized in the heart. We have determined that mitochondrial ribosomal protein S5 (MRPS5/uS5m) can regulate cardiac function and key pathways to coordinate this process during cardiac stress. We demonstrate that loss of Mrps5 in the developing heart leads to cardiac defects and embryonic lethality while postnatal loss induces cardiac hypertrophy and heart failure. The structure and function of mitochondria is disrupted in Mrps5 mutant cardiomyocytes, impairing mitochondrial protein translation and OXPHOS. We identify Klf15 as a Mrps5 downstream target and demonstrate that exogenous Klf15 is able to rescue the overt defects and re-balance the cardiac metabolome. We further show that Mrps5 represses Klf15 expression through c-myc, together with the metabolite L-phenylalanine. This critical role for Mrps5 in cardiac metabolism and mitonuclear communication highlights its potential as a target for heart failure therapies.

Abstract Background: The coronavirus disease 19 (COVID-19) pandemic threatens to overwhelm the capacity of a vulnerable healthcare system in the occupied Palestinian territory (oPt). Sufficient training of healthcare workers (HCWs) in managing COVID-19 and the provision of personal protective equipment (PPE) are essential in allowing oPt to mount a credible response to the crisis.Methods: A cross-sectional study was conducted using a validated online questionnaire between March 30, 2020 and April 12, 2020. Primary outcomes were availability of PPE and HCWs preparedness in oPt for COVID-19 pandemic. Secondary outcome was regional and hospital differences in oPt in terms of availability of PPE and HCWs preparedness.Results: Of 138 respondents, only 38 HCWs (27.5%) always had access to facemasks and 15 (10.9%) for isolation gowns. Most HCWs did not find eye protection (n=128, 92.8%), N95 respirators (n=132, 95.7%), and face shields (n=127, 92%) always available. Compared to HCWs in West Bank, those in the Gaza Strip were significantly less likely to have access to alcohol sanitizers (p=0.03) and gloves (p <0.001). On average, governmental hospitals were significantly less likely to have all appropriate PPE than non-governmental institutions (p = 0.001). Only 16 (11.6%) surveyed felt confident in dealing with a potential COVID-19 case, 57 (41.3%) having received any COVID-19-related training, and 57 (41.3%) not having a local hospital protocol.Conclusion: HCWs in oPt are underprepared and severely lacking adequate PPE provision. The lack of PPE provision will exacerbate spread of COVID-19 and deepen the crisis, whilst putting HCWs at risk.

Benzimidazole 1 is the lead compound resulting from an antibacterial program targeting dual inhibitors of bacterial DNA gyrase and topoisomerase IV. With the goal of improving key drug-like properties, namely, the solubility and the formulability of 1, an effort to identify prodrugs was undertaken. This has led to the discovery of a phosphate ester prodrug 2. This prodrug is rapidly cleaved to the parent drug molecule upon both oral and intravenous administration. The prodrug achieved equivalent exposure of 1 compared to dosing the parent in multiple species. The prodrug 2 has improved aqueous solubility, simplifying both intravenous and oral formulation.