Biohaven Pharmaceuticals (United States)

SummaryTrigeminal nerve injury can lead to chronic and difficult-to-treat orofacial neuropathic pain. Here, we uncover a key role for the cation channel TRPM3 in the chronic constriction injury of the infraorbital nerve (IoN-CCI) mouse model of trigeminal neuropathic pain. Wild-type (WT) mice develop spontaneous pain and mechanical allodynia for up to 6 weeks following IoN-CCI, whereas Trpm3−/− mice do not develop such symptoms. Using longitudinal RNA sequencing (RNA-seq) analysis, we obtain a detailed time course of transcriptome alterations in trigeminal ganglia during progression of the IoN-CCI model; notably, gene expression regulation is not different between WT and Trpm3−/− mice. Two structurally distinct TRPM3 antagonists, primidone and isosakuranetin, effectively reverse spontaneous pain and mechanical allodynia, whereas mavatrep, a potent TRPV1 antagonist, is without analgesic effect. These data indicate that TRPM3 is essential for ongoing pain and allodynia following trigeminal nerve injury, making it a potential target for treating trigeminally mediated neuropathic pain.

The spinocerebellar ataxia composite score (SCACOMS) comprises items from the functional Scale for the Assessment and Rating of Ataxia (f-SARA) and the Clinician Global Impression of Change (CGI-C). In the derivation of SCACOMS, weights reflecting 1-year responsiveness were assigned to each item using partial least squares (PLS) regression modeling. The current objective was to incorporate patient-feedback into the SCACOMS item weights, examine corresponding responsiveness of the composite scale, and discuss potential implications for future use. Item weights derived by PLS regression were compared to each item's relative importance as assigned by 16 patients with SCA during semi-structured interviews. SCACOMS item weights were adjusted using the following combinations: (1) 50/50 weighted combination of PLS and patient weights and (2) reducing the weight of CGI-C to 20% and averaging individual item weights obtained from each perspective. The 1-year mean to standard deviation ratios (MSDRs) for the resulting reweighted scales were compared, with larger MSDRs indicating greatest sensitivity to disease progression. The PLS-derived SCACOMS had the highest MSDR (0.99). When item weights were averaged across the two sources, the resulting MSDR was 0.91. When the weight of CGI-C was set to 20%, reflecting patient preferences for higher weights on the discrete symptoms, the MSDR was 0.79. This study took a novel approach to enhance the face validity of SCACOMS by incorporating patient feedback into the statistically optimized item weights. The result is the merging of objectively derived item weightings (reflecting optimal scale responsiveness) with patient-assigned relevance. While this update may increase the patient centricity of a composite measure, this comes at the expense of reduced sensitivity. This potential trade-off in sensitivity to detect change should be evaluated in the context of the composite measure's intended use.

a:2:{s:4:"lang";s:2:"en";s:7:"content";s:1471:"<h3>Objective</h3> This randomized, double-blind (DB) phase 3 trial evaluated rimegepant for preventive treatment of migraine in participants living in Japan. <h3>Methods</h3> Participants took rimegepant 75 mg or placebo every other day (EOD) during a 12-week DB phase, followed by rimegepant 75 mg EOD and up to once daily as needed on non-scheduled dosing days during a 40-week open-label phase. Hierarchical testing was used for efficacy endpoints to control for multiplicity. Safety assessments included adverse events and laboratory test abnormalities. DB phase data are presented. <h3>Results</h3> 484 (efficacy) and 496 (safety) treated participants were evaluable. During a 28-day pre-treatment observation period (OP), participants reported a mean±SD of 9.3±3.08 (rimegepant) and 9.0±3.14 (placebo) MMDs. The primary endpoint was met with a statistically significant difference in mean change from OP in the number of MMDs in the last 4 weeks of the DB phase for rimegepant vs placebo (difference –1.1 [95% CI –1.73, –0.38], p=0.0021). Given the first secondary endpoint was not statistically significant, formal hypothesis testing did not proceed, but results for secondary efficacy endpoints favoured rimegepant vs placebo. Rimegepant was well tolerated. <h3>Conclusions</h3> Rimegepant 75 mg EOD demonstrated efficacy superior to placebo for migraine prevention with a favourable safety profile. grant.oneil{at}pfizer.com ";}

ObjectiveTo evaluate pharmacokinetics (PK), safety, and tolerability of a weight‐adjusted dose of rimegepant orally disintegrating tablet (ODT) in children (aged ≥6 to <12 years) with a history of migraine.BackgroundRimegepant 75 mg ODT is approved for acute treatment of migraine (with or without aura) and preventive treatment of episodic migraine in adults. Studies of rimegepant in pediatric populations have not been conducted to date.MethodsIn this phase 1 open‐label study, a single dose of rimegepant ODT was administered, based on body weight, to children aged ≥6 to <12 years. Children with body weight ≥15 kg to ≤30 kg received 25 mg (group 1; n = 7), children >30 kg to ≤50 kg received 50 mg (2 × 25 mg; group 2; n = 9), and children >50 kg received 75 mg (group 3; n = 5). Blood samples were collected pre‐dose and 0.5, 1.25, 3.5, and 18 h post‐dose and then analyzed using a validated bioanalytical assay. Rimegepant PK parameters, including area under the plasma concentration–time curve (AUC) from time zero to infinity (AUCinf), AUC from time zero to 24 h after dosing, maximum plasma concentration (Cmax), and time to Cmax were estimated using a population PK approach in which pediatric PK data from this study were used to update a previous rimegepant population PK model developed with adult data. A safety follow‐up phone call was conducted 4 days after dosing.ResultsTwenty participants with ≥1 post‐dose PK sample were included in PK analyses. All 21 participants treated were analyzed for safety. A majority of the study population was White (67%) and female (57%), had a median (range) age of 9.0 (6 to 11) years, and a mean (standard deviation) body weight of 37.7 (12.3) kg. Geometric mean estimates of Cmax and AUCinf ranged from 615.9 to 811.1 ng/mL and 1987.8 to 4244.9 ng*h/mL, respectively, across weight groups. Rimegepant exposures, particularly AUCinf values, were lower in the two lower‐weight groups (groups 1 and 2) than in the higher‐weight group (group 3). Median time to Cmax was 1 to 1.5 h across weight/dose groups. Three (14%) participants (all in group 3) had ≥1 adverse event; all were mild in severity. No clinically relevant findings regarding laboratory tests, vital signs, electrocardiograms, physical examinations, local tolerability assessments, or the Sheehan‐Suicidality Tracking Scale were observed.ConclusionsA single weight‐adjusted dose of rimegepant ODT demonstrated a favorable safety profile in children aged ≥6 to <12 years with a history of migraine. Exposures in children >50 kg receiving 75 mg rimegepant were similar to observed exposures in adults receiving 75 mg. However, exposures in children >30 kg to ≤50 kg receiving 50 mg rimegepant and in children ≥15 kg to ≤30 kg receiving 25 mg rimegepant were lower than exposures in adults receiving 75 mg. These findings will be the basis for further refinement of pediatric dose in future studies.

IntroductionMeasures designed to comprehensively assess Parkinson’s disease (PD) irrespective of disease stage and treatment status may be unable to capture nuances in disease progression, particularly in early-stage PD. The objective of this paper is to develop PARkinson’s COMposite Scales (PARCOMS) with increased responsiveness to clinical decline using items of the Movement Disorder Society Unified Parkinson’s Disease Rating Scale (MDS-UPDRS) for three discrete cohorts of patients.MethodsPatients with confirmed PD from the Parkinson’s Progression Markers Initiative (PPMI) data were assigned to three cohorts based on use of dopaminergic treatment, stage of disease, and presence of motor complication. For each cohort, items from MDS-UPDRS Part I (PARCOMS-Non-Motor) and Parts II and III (PARCOMS-Motor) were selected based on responsiveness using partial least squares (PLS) regression. The responsiveness of the scales was estimated using mean-to-standard deviation ratios (MSDRs) of their change values.ResultsCompared to the original MDS-UPDRS, MSDRs for PARCOMS-Motor increased 13.1% (untreated cohort, n = 430), 78.2% (treated-without-motor-complications cohort, n = 426), and 100.6% (treated-with-motor-complications cohort, n = 538). The MSDR increases observed for PARCOMS-Non-Motor were 13.9%, 6.8%, and 20.7%, respectively. Across cohorts, turning in bed and speech items were large contributors to the PARCOMS-Motor scales. Items for cognitive impairment and urinary problems were substantial contributors to PARCOMS-Non-Motor across cohorts. There was variability in the weighting of items representing different clinical concepts across cohorts for each composite, confirming heterogeneity in disease progression across disease stages.ConclusionsPD stage-specific composite measures were developed and demonstrated greater sensitivity to change than the original MDS-UPDRS, supporting the value of weighted composites tailored for disease stage.Supplementary InformationThe online version contains supplementary material available at 10.1007/s40120-025-00771-5.

BackgroundEmerging evidence supports the diagnostic and prognostic utility of plasma biomarkers in Alzheimer’s disease (AD), particularly in early disease stages. We sought to extend these findings by evaluating the prognostic value of plasma biomarkers in a clinical trial of mild-to-moderate AD.MethodsPost-hoc analyses investigated whether baseline concentrations of plasma biomarkers (Aβ42/Aβ40, T-tau, P-tau181, NfL, and GFAP) predicted change in ADAS-Cog11, CDR-SB, and volumetric MRI among participants in T2 Protect AD, a negative 48-week, phase-2, placebo-controlled trial of troriluzole in mild-to-moderate AD. All trial participants met diagnostic criteria for probable AD. Baseline concentrations of, and 48-week changes in, plasma biomarkers were assessed for association with 48-week change in outcomes using linear regression. Combinations of baseline biomarkers that best predicted change on the ADAS-Cog11 and CDR-SB were identified using least absolute shrinkage and selection operator (LASSO) regression. Biomarker-informed sample size calculations were modeled.ResultsOf 350 trial participants, 319 had all requisite biomarker and clinical outcome data for inclusion in these analyses (mean age 71.5, SD = 8.03; 58.6% female). Higher plasma NfL at baseline predicted worsening scores on the ADAS-Cog11 (effect size (ES) = 1.42, 95%CI = [0.43, 2.41], p = 0.026) and CDR-SB (ES = 0.42, 95%CI = [0.10, 0.73], p = 0.048). LASSO regression revealed that worsening on the ADAS-Cog11 was best predicted by the combination of baseline plasma NfL, T-tau, and Aβ42/40 ratio, whereas baseline NfL alone best predicted worsening on CDR-SB. Higher baseline NfL predicted increasing ventricular volume (ES = 1.30cm3, 95%CI = [0.43, 2.17], p = 0.018) and decreasing mid-temporal cortical volume (ES = -0.47, 95%CI = [-0.74, -0.20], p = 0.003). Increasing NfL over the 48-week trial was associated with worsening on CDR-SB but not ADAS-Cog11. Modeling of biomarker-informed power calculations revealed that including high NfL as a trial entry criterion could substantially reduce requisite trial sample size.ConclusionsElevated baseline plasma NfL predicted more rapid clinical decline and MRI volume loss. Furthermore, increasing plasma NfL concentration over time was associated with worsening on the CDR-SB. Plasma NfL is an easily accessible biomarker that may enhance the design of clinical trials in mild-to-moderate AD.Trial registrationThe T2 Protect AD trial was registered as NCT03605667 on clinicaltrials.gov on 2018-07-27.

ABSTRACTThe central components of the ABA core signaling pathway are families of receptors, clade A type 2C protein phosphatases (PP2Cs), SNF1-Related Protein Kinases (SnRK2s), and diverse sets of proteins regulated by phosphorylation via these kinases, including bZIP transcription factors such as ABA-INSENSITIVE(ABI)5. The larger network of ABA signaling factors includes additional kinases and E3 ligases that modify these components to affect their activity and stability. The ABI5-Binding Proteins (AFPs) are negative regulators of ABA response. This study shows that the AFPs interact with specific family members of all components of this pathway and are substrates for SnRK2s and PP2Cs. AFPs also interact with subsets of MAP kinases (MPKs) and 14-3-3 proteins previously found to regulate activity of the ABI5-related clade of transcription factors. Residues predicted to be phosphorylated are conserved between AFPs, but are located within regions predicted to be unstructured. ABA promotes phosphorylation of AFP2, but conditions that prevent phosphorylation of AFP2 result in decreased stability, a shift in localization toward dispersed foci, and reduced effectiveness for inhibiting ABA response at germination. Thus, AFP2 appears to be an important hub in the ABA core signaling pathway.