Catalyst Pharmaceuticals (United States)

BackgroundLambert-Eaton myasthenic syndrome (LEMS) is an autoimmune neurologic condition causing progressive muscle weakness that can occur as a paraneoplastic disorder, most commonly in patients with small cell lung cancer (SCLC). In limited prospective and retrospective studies, LEMS incidence in SCLC populations ranges 3-6%. Because LEMS may present a diagnostic challenge, we determined the prevalence of LEMS in a large, real-world, U.S.-based SCLC cohort.Materials and methodsWe conducted a retrospective analysis of administrative data from Symphony Health’s PatientSource®, which represents over 300 million U.S. patients. In the primary analysis, we identified claims for LEMS (available starting in 2014) among patients with lung cancer claims between 2017 and 2022 who received etoposide and platinum-based chemotherapy (a validated approach to SCLC case identification).ResultsAmong 867,170 patients with lung cancer claims, 46,995 (5.4%) received platinum-etoposide-based therapy (putative SCLC cohort), of whom 77 (0.16%) had LEMS claims. In a subset of 8,513 patients with ≥12 months of claims preceding and following lung cancer diagnosis, 16 (0.19%) had LEMS claims. LEMS cases were more frequently diagnosed by neurologists (30%) than by oncologists (13%).ConclusionsIn a large real-world cohort of patients with lung cancer, LEMS is diagnosed far less frequently than would be expected and rarely by oncologists. Because LEMS may convey substantial morbidity and specific LEMS treatments are available, further efforts to understand and address this discrepancy are warranted.

BackgroundSpinal muscular atrophy (SMA) is an autosomal recessive disease where a deficient amount of SMN protein leads to progressive lower motor neuron degeneration. SMN-enhancing therapies are now available. Yet, fatigue and signs of impaired neuromuscular junction (NMJ) transmission could contribute to SMA phenotype. Amifampridine prolongs presynaptic NMJ terminal depolarization, enhancing neuromuscular transmission.MethodsSMA-001 was a phase 2, 1:1 randomized, double-blind, placebo-controlled crossover study. Ambulatory (walking unaided at least 30 m) SMA Type 3 patients, untreated with SMN-enhancing medications, entered a run-in phase where amifampridine was titrated up to an optimized stable dose. Patients achieving at least three points improvement in Hammersmith Functional Motor Score Expanded (HFMSE) were randomized to amifampridine or placebo, alternatively, in the 28-day double-blind crossover phase. Safety was evaluated by adverse events (AE) collection. Primary efficacy measure was the HFMSE change from randomization. Secondary outcomes included timed tests and quality of life assessment. Descriptive analyses and a mixed effects linear model were used for statistics.ResultsFrom 14 January 2019, 13 patients, mean age 34.5 years (range 18–53), with 5/13 (38.5%) females, were included. No serious AE were reported. Transient paresthesia (33.3%) was the only amifampridine-related AE. Six patients for each treatment sequence were randomized. Amifampridine treatment led to a statistically significant improvement in HFMSE (mean difference 0.792; 95% CI from 0.22 to 1.37; p = 0.0083), compared to placebo, but not in secondary outcomes.DiscussionSMA-001 study provided Class II evidence that amifampridine was safe and effective in treating ambulatory SMA type 3 patients. Clinical Trial Registration: NCT03781479; EUDRACT 2017-004,600-22.Supplementary InformationThe online version contains supplementary material available at 10.1007/s00415-022-11231-7.

BackgroundRisdiplam has been approved for Compassionate Use (CUP) since 2019, for SMA type 1 and type 2 who could not receive the approved treatment for the disease. It’s an orally administered drug targeting SMN2 gene. More than 200 patients have had access to this program in Italy, up to June 2021.AimsTo describe the clinical and demographic features of patients included in CUP amongst the iSMAc’ Italian centers.MethodsThis is a retrospective study including demographic, neuromotor, respiratory and nutritional data, shifts, adverse events and dropouts.Results44 out of 576 Italian iSMAc patients (7.6%) are on risdiplam (8 SMA1, 36 SMA2). Age ranges: 0-10 yrs (n = 1, SMA2); 11-17 yrs (n = 13, 4 SMA1, 9 SMA2); 18-25 yrs (n = 15, 3 SMA1, 12 SMA2); 18-25 yrs (n = 15.3 SMA1, 12 SMA2) and older than 25 yrs (n=14 SMA2). The majority (73%) are non-sitters. Concerning respiratory status, 6 patients are in invasive-ventilation, 26 use NIV and 8 patients do not require respiratory support. Regarding the nutritional status, 11 have a PEG and 12 have dysphagia. About 20% of patients switched from nusinersen for difficulties in intrathecal administration. 3 dropped-out respectively for side-effects, subjective inefficacy, shift to gene therapy.ConclusionsConsidering the criteria to access risdiplam so far, all but one are older than 11 yrs, have severe motor, nutritional and respiratory conditions and are naive due to inaccessibility to nusinersen for technical difficulties. After open clinical use, further follow-up data will provide information on additional reasons and number of patients accessing risdiplam.

Metabolite-specific, scalar spin-spin coupling constant (J)-editing 1H MRS methods have become gold-standard for measuring brain γ-amino butyric acid (GABA) levels in human brain. Localized, two-dimensional (2D) 1H MRS technology offers an attractive alternative as it significantly alleviates the problem of severe metabolite signal overlap associated with standard 1D MRS and retains spectroscopic information for all MRS-detectable species. However, for metabolites found at low concentration, a direct, in vivo, comprehensive methods comparison is challenging and has not been reported to date. Here, we document an assessment of comparability between 2D 1H MRS and J-editing methods for measuring GABA in human brain. This clinical study is unique in that it involved chronic administration a GABA-amino transferase (AT) inhibitor (CPP-115), which induces substantial increases in brain GABA concentration, with normalization after washout. We report a qualitative and quantitative comparison between these two measurement techniques. In general, GABA concentration changes detected using J-editing were closely mirrored by the 2D 1H MRS time courses. The data presented are particularly encouraging considering recent 2D 1H MRS methodological advances are continuing to improve temporal resolution and spatial coverage for achieving whole-brain, multi-metabolite mapping.