Citations

Abstract Apilimod dimesylate is a first-in-class phosphoinositide kinase, FYVE-type zinc finger-containing (PIKfyve) inhibitor with a favourable clinical safety profile and has demonstrated activity in preclinical C9orf72 and TDP-43 amyotrophic lateral sclerosis (ALS) models. In this ALS clinical trial, the safety, tolerability, CNS penetrance and modulation of pharmacodynamic target engagement biomarkers were evaluated. This phase 2a, randomized, double-blind, placebo-controlled, biomarker-end-point clinical trial was conducted in four US centres (ClinicalTrials.gov NCT05163886). Participants with C9orf72 repeat expansions were randomly assigned (2:1) to receive twice-daily oral treatment with 125 mg apilimod dimesylate capsules or matching placebo for 12 weeks, followed by a 12-week open-label extension. Safety was measured as the occurrence of treatment-emergent or serious adverse events attributable to the study drug and tolerability at trial completion or treatment over 12 weeks. Changes from baseline in plasma and CSF and concentrations of apilimod dimesylate and its active metabolites and of pharmacodynamic biomarkers of PIKfyve inhibition [soluble glycoprotein nonmetastatic melanoma protein B (sGPNMB) upregulation] and disease-specific CNS target engagement [poly(GP)] were measured. Between 16 December 2021 and 7 July 2022, 15 eligible participants were enrolled. There were no drug-related serious adverse events reported in the trial. Fourteen (93%) participants completed the double-blind period with 99% dose compliance [n = 9 (90%) apilimod dimesylate; n = 5 (100%) placebo]. At Week 12, apilimod dimesylate was measurable in CSF at 1.63 ng/ml [standard deviation (SD): 0.937]. At Week 12, apilimod dimesylate increased plasma sGPNMB by >2.5-fold (P < 0.001), indicating PIKfyve inhibition, and lowered CSF poly(GP) protein levels by 73% (P < 0.001), indicating CNS tissue-level proof of mechanism. Apilimod dimesylate met prespecified key safety and biomarker end-points in this phase 2a trial and demonstrated CNS penetrance and pharmacodynamic target engagement. Apilimod dimesylate was observed to result in the greatest reduction in CSF poly(GP) levels observed to date in C9orf72 clinical trials.

Increasing rates of burnout—with accompanying stress and lack of engagement—among faculty, residents, students, and practicing physicians have caused alarm in academic medicine. Central to the debate among academic medicine’s stakeholders are oft-competing issues of social accountability; cost containment; effectiveness of academic medicine’s institutions; faculty recruitment, retention, and satisfaction; increasing expectations for faculty; and mission-based productivity. The authors propose that understanding and fostering what contributes to faculty and institutional vitality is central to preventing burnout during times of change. They first look at faculty vitality and how it is threatened by burnout, to provide a framework for a greater understanding of faculty well-being. Then they draw on higher education literature to determine how vitality is defined in academic settings and what factors affect faculty vitality within the context of academic medicine. Next, they propose a model to explain and examine faculty vitality in academic medicine, followed by a discussion of the need for a greater understanding of faculty vitality. Finally, the authors offer conclusions and propose future directions to promote faculty vitality. The authors encourage institutional decision makers and other stakeholders to focus particular attention on the evolving expectations for faculty, the risk of extensive faculty burnout, and the opportunity to reduce burnout by improving the vitality and resilience of these talented and crucial contributors. Faculty vitality, as defined by the institution, has a critical role in ensuring future institutional successes and the capacity for faculty to thrive in a complex health care economy.