RESUMEN
Apilimod dimesylate is a first-in-class phosphoinositide kinase, FYVE-type zinc finger containing (PIKfyve) inhibitor with favourable clinical safety profile and has demonstrated activity in preclinical C9orf72 and TDP-43 amyotrophic lateral sclerosis models. In this amyotrophic lateral sclerosis 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-endpoint clinical trial was conducted in four USA centres (ClinicalTrials.gov NCT05163886). Participants with C9orf72 repeat expansion were randomly assigned (2:1) to receive twice-daily oral treatment of 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 adverse or serious adverse events attributable to study drug, and tolerability as trial completion on treatment over 12 weeks. Changes from baseline in plasma and CSF and concentrations of apilimod 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]). Between Dec 16, 2021, and Jul 7, 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 (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 endpoints in this Phase 2a trial and demonstrated CNS penetrance and pharmacodynamic target engagement. Apilimod dimesylate was observed to have the greatest reduction in CSF poly(GP) levels observed to date in C9orf72 clinical trials.
RESUMEN
BACKGROUND: Inadequate fall in the intraoperative parathyroid hormone (PTH) level after removing enlarged parathyroid gland(s) typically signifies additional hyperfunctioning gland(s), prompting further neck dissection, but it may also be a false negative result. We analyzed intraoperative management of patients with an inadequate fall on PTH after excision of enlarged parathyroid gland(s). METHODS: Analysis involved a prospective database of 189 patients undergoing 193 procedures for primary hyperparathyroidism. The PTH level was determined before neck incision and 10-15 min after excision of enlarged parathyroid gland(s). A PTH decrease > 50% and into normal range was used as the criterion of successful parathyroidectomy. RESULTS: In 48 of 193 operations, initial postexcision PTH level did not fall appropriately. That inadequate fall in PTH level was a false negative result in 16 patients (33%) and cure was achieved without additional neck exploration in all but one patient, who had additional (negative) neck exploration after excision of a parathyroid adenoma. In all patients with false negative postexcision PTH assay, operative findings concurred with preoperative imaging tests. CONCLUSIONS: Inadequate fall in intraoperative PTH may be false negative, particularly after removal of an adenoma found in the location determined by preoperative imaging. Repeat PTH may confirm the initial assay as false negative, obviating the need for additional neck dissection. Importantly, if repeat PTH does not fall appropriately, additional neck exploration needs to be performed.
