Vion Pharmaceuticals

QuestionWhat were the long-term efficacy, safety, and pharmacokinetic profiles of monthly dosed vixarelimab in participants with prurigo nodularis?FindingsIn this randomized clinical trial including 181 participants, vixarelimab demonstrated a significant reduction from baseline in Worst Itch Numeric Rating Scale at week 16 compared with placebo at all monthly dose levels (vixarelimab at high-dose, mid-dose, and low-dose levels: -56.2%, -51.0%, and -33.0%, respectively; placebo, -14.5%). No fatal or serious drug-related treatment-emergent adverse events were reported.MeaningVixarelimab demonstrated a rapid clinical benefit that was sustained throughout the 16-week monthly dosed double-blind period and 36-week biweekly dosed open-label extension period, demonstrating a favorable benefit-risk profile. This randomized clinical trial evaluates the efficacy, safety, tolerability, and pharmacokinetics of monthly dosed vixarelimab in participants with moderate to severe prurigo nodularis. ImportancePrurigo nodularis (PN) is a chronic inflammatory skin disease characterized by severe pruritus and nodule formation, significantly affecting patients' quality of life. There is an unmet need for effective therapies to address both symptoms and disease progression.ObjectiveTo evaluate the efficacy, safety, tolerability, and pharmacokinetics of monthly dosed vixarelimab in participants with moderate to severe PN.Design, Setting, and ParticipantsThis double-blind (DB), placebo-controlled, phase 2b randomized clinical trial was conducted from December 1, 2020, to August 24, 2023, across 72 centers in the US, Canada, Europe, and Asia. The study included male and female participants aged 18 to 80 years with physician-diagnosed PN of at least 6 months' duration and moderate to severe pruritus. Data were analyzed from October 2023 to March 2024.InterventionsParticipants were randomized into 4 arms during the 16-week DB period: vixarelimab, 540 mg (high-dose group); vixarelimab, 360 mg (mid-dose group); vixarelimab, 120 mg (low-dose group); or placebo. Vixarelimab and placebo were administered subcutaneously every 4 weeks. During the 36-week open-label extension, all participants received vixarelimab, 360 mg, every 2 weeks.Main Outcomes and MeasuresKey outcomes included percentage change from baseline in the Worst Itch Numeric Rating Scale (WI-NRS) at week 16, the proportion of participants achieving at least a 4-point reduction in WI-NRS at week 16, and the proportion achieving scores of 0 or 1 in the PN Investigator Global Assessment at week 16.ResultsOf 190 randomized participants, 189 received 1 or more doses of the study drug (141 vixarelimab, 48 placebo). A total of 114 (60.3%) were female, 75 (39.7%) were male, and the mean (SD) age was 55.4 (13.8) years. There were 47 participants in the high-dose vixarelimab group, 47 in the mid-dose group, 47 in the low-dose group, and 48 in the placebo group. Vixarelimab significantly reduced mean (SE) WI-NRS scores at week 16 compared with placebo across all doses (vixarelimab at high-dose, mid-dose, and low-dose levels: -56.2% [4.84], -51.0% [4.83], and -33.0% [4.86], respectively; placebo, -14.5% [4.76]). Clinically meaningful 4-point or greater reductions in WI-NRS were achieved by 31 (66.0%), 29 (61.7%), and 14 (29.8%) in the high-dose, mid-dose, and low-dose vixarelimab groups, respectively, compared with 8 (16.7%) in the placebo group. PN Investigator Global Assessment scores of 0 or 1 were also higher in vixarelimab groups (high-dose group, 18 [38.3%]; mid-dose group, 14 [29.8%]; low-dose group, 7 [14.9%]; placebo group, 5 [10.4%]). No fatal or serious drug-related treatment-emergent adverse events were reported during the study, and no serious treatment-related treatment-emergent adverse events were observed during the DB period.Conclusions and RelevanceIn this phase 2b randomized clinical trial, vixarelimab demonstrated rapid, sustained, dose-dependent clinical benefits in patients with PN, with a favorable safety profile.Trial RegistrationClinicalTrials.gov Identifier: NCT03816891

Introduction Pathogenic variants of Plakophilin-2 (PKP2) are a significant cause of arrhythmogenic cardiomyopathy (ACM), a disorder characterized by increased risk of ventricular tachyarrhythmias, progressive heart failure, and sudden cardiac death. PKP2 variants account for up to 45% of ACM cases. Administration of AAVrh.74-PKP2a (RP-A601), a recombinant adeno-associated viral (AAV) vector in a clinically affected PKP2-ACM mouse model (typical survival ≤50 days post disease onset) after disease onset extended survival for >5 months, improved right ventricular function, decreased cardiac dilation and myocardial fibrosis, and reduced arrhythmia burden. Additional studies in rodents and non-human primates demonstrated RP-A601 safety. Hypothesis RP-A601 will be associated with acceptable safety and will ameliorate aspects of disease pathophysiology in high-risk adult patients with PKP2-ACM, based on preclinical data. Methods NCT05885412 is a multicenter, open-label, dose escalation ongoing Phase 1 trial that will evaluate the safety and tolerability of a single intravenous RP-A601 infusion in adult patients (≥18 yrs) with a PKP2-ACM and an implanted ICD. Preliminary efficacy will be evaluated by assessing change in myocardial PKP2a protein expression and clinical markers of cardiomyopathy and arrhythmia burden. Patients with severe right ventricular dysfunction, left ventricular ejection fraction ≤50% (echocardiogram or cardiac MRI) and/or NYHA Class IV are excluded. Results As of March 11, 2025, three patients with PKP2-ACM have received RP-A601 at a low dose of 8 × 1013 GC/kg (cohort 1). All patients discontinued immunomodulatory therapies at a median of 4.1 months (range: 3.3-4.8) following RP-A601 infusion. All treatment emergent adverse events (TEAEs) experienced by these patients were not serious and mild/moderate in severity. The most common non-serious TEAEs were transaminase elevations and other laboratory abnormalities, the majority of which resolved to normal range within 2 weeks following RP-A601 infusion. One patient experienced treatment-emergent serious adverse events (SAEs) of transaminase elevation, pancreatitis, sepsis and bacteremia, while receiving immunomodulatory therapy. All events fully resolved without sequalae. No arrhythmia SAEs were identified during the initial 5-11 months of post-treatment follow-up. Transient complement activation and Grade 2 thrombocytopenia were observed without evidence of thrombotic microangiopathy. Cardiac transduction and increased myocardial PKP2a protein expression were evident at 3-6 months following RP-A601 infusion via Western Blot and Immunofluorescence. Conclusions To date, RP-A601 has been well-tolerated and led to increased myocardial PKP2a protein expression in patients with this inherited ACM which predisposes to progressive cardiac failure and serious ventricular arrhythmias including sudden cardiac death.

Olutasidenib is a potent, selective, oral, small molecule inhibitor of mutant IDH1 (mIDH1) which induced durable remissions in high-risk, relapsed/refractory (R/R) mIDH1 AML patients in a phase 1/2 trial. We present a pooled analysis from multiple cohorts of the phase 1/2 trial of patients with R/R AML who received combination olutasidenib and azacitidine therapy. Adult patients with mIDH1R132 AML received 150 mg olutasidenib twice daily plus standard-of-care azacitidine (OLU + AZA) and were evaluated for response and safety. Sixty-seven patients with R/R mIDH1R132 AML received combination OLU + AZA. Median age was 66 years (range 28–82) and 54

ABSTRACT:Higher-risk myelodysplastic syndrome (HR-MDS) with RARA gene overexpression is a subset of patients (pts) with an actionable target for tamibarotene, an oral and a selective retinoic acid receptor-α (RAR-α) agonist. Tamibarotene with azacitidine (AZA) showed complete remission (CR) rates in myeloid leukemia. SELECT-MDS-1 was a phase 3 study comparing the activity of tamibarotene + AZA to placebo + AZA in these pts with newly diagnosed HR-MDS with RARA overexpression. Eligible pts had confirmed RARA overexpression, untreated MDS with higher-risk features by revised International Prognostic Scoring System (IPSS-R), and marrow blast count >5%. Pts were randomized 2:1 to receive tamibarotene + AZA or placebo + AZA, respectively. A total of 246 participants were randomized with 164 and 82 in the tamibarotene + AZA and placebo + AZA groups, respectively. Baseline characteristics included: 69.9% male; median age 75 years (range, 38-93); primary MDS, 89.8%; MDS-excess blasts-1, 48% and MDS-excess blasts-2, 52%; and IPSS-R risk category intermediate (25.5%), high (35.7%), and very high (38.9%). The study did not meet the primary end point of CR, with a P value of .2084 for the treatment effect in the tamibarotene + AZA group. The CR rates were 23.81% and 18.75% in the tamibarotene + AZA and placebo + AZA groups, respectively. The use of tamibarotene-based therapy to target RAR-α as a novel approach in pts with HR-MDS with RARA gene overexpression is not a paradigm, which can augment response rates beyond AZA monotherapy. Further explorations of alternative approaches, including those with a biomarker, to alter the natural history of this disease are warranted. This trial was registered at www.clinicaltrials.gov as #NCT04797780.

Introduction: Viloxazine extended-release (VLX-ER) is effective as monotherapy for attention-deficit/hyperactivity disorder (ADHD), and is often tried as an add-on treatment when psychostimulant therapy fails to provide an adequate treatment response. This phase 4, open-label study evaluated safety, tolerability, and efficacy of VLX-ER with optimized psychostimulants in pediatric participants with ADHD. Morning versus evening VLX-ER use was also evaluated. Methods: Children and adolescents (6-17 years) experiencing inadequate psychostimulant response (investigator-assessed ADHD Rating Scale-5 [ADHD-RS-5] score ≥24 and Clinical Global Impression-Severity of Illness [CGI-S] scores ≥3) during a 4-week screening period received flexibly-dosed VLX-ER, taken once daily in the morning (weeks 14) or evening (weeks 5-8), concomitantly with a psychostimulant. Safety (primary outcome) and efficacy were evaluated relative to baseline. Results: Fifty-six participants (26 children; 30 adolescents) enrolled, and 48 (85.7%) completed the study. Combination therapy was well tolerated, with only two participants (3.6%) withdrawing due to adverse events (AEs). The most commonly reported AEs were headache (17.9%), decreased appetite (12.5%), and upper respiratory tract infection (10.7%). Mean ± standard deviation investigator-assessed ADHD-RS-5 scores (baseline: 37.2 ± 8.4) improved progressively by -13.5 ± 9.7 points at week 4 and -18.2 ± 10.0 points at week 8 (p < 0.0001 each). Likewise, CGI-S scores (baseline: 4.4 ± 0.6) improved by -0.9 ± 0.9 at week 4 and -1.4 ± 1.1 at week 8 (p < 0.0001 each). Parent-assessed scales, including ratings of morning and evening ADHD behaviors and sleep disturbances, showed significant improvement relative to baseline regardless of morning (week 4) or evening (week 8) VLX-ER dosing. Conclusion: Combined treatment with VLX-ER and psychostimulant therapy showed acceptable safety and tolerability, with improvement in morning and evening ADHD behaviors and sleep disturbances relative to stimulant monotherapy. Timing of VLX-ER administration (morning or evening) did not appear to affect safety, drug response, or sleep improvement.