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Frexalimab is a second-generation anti-CD40L monoclonal antibody that blocks the costimulatory CD40/CD40L pathway, which is important for activation and function of adaptive and innate immunity. In the phase 2 trial (NCT04879628) in participants with relapsing MS (RMS),frexalimab was well-tolerated and showed an 89% reduction in new gadolinium-enhancing (Gd+)T1 lesions in the high-dose arm vs placebo at week 12. In the ongoing open-label extension, 96%of participants in the high-dose arm were free of Gd+ T1 lesions at week 48. FREXALT (comprising two trials, FREXALT-1 and FREXALT-2) is a double-dummy,active-controlled, event-driven (6-month composite confirmed disability worsening [cCDW] pooled across studies) trial with variable treatment duration of approximately 20‒40 months in RMS participants. Planned enrollment is 1400 participants randomly assigned 1:1 to frexalimab or teriflunomide. Key eligibility criteria include RMS diagnosis, Expanded Disability Status Scale (EDSS) ≤5.5, and ≥1 relapse within 1 year or ≥2 relapses within 2 years or ≥1 Gd+ lesion within 1year. Primary endpoint is adjudicated annualized relapse rate, and key secondary endpoint is timeto onset of 6-month cCDW (as assessed by the composite of EDSS, timed 25-foot walk and 9-hole peg tests). FREVIVA is a placebo-controlled, event-driven (6-month composite confirmed disability progression [cCDP]) trial with variable treatment duration of approximately 27‒51months in nrSPMS participants. Planned enrollment is 858 participants randomly Enrollment has started in December 2023. These phase 3 trials will assess the efficacy and safety of frexalimab in RMS andnrSPMS, which is a population with no approved therapeutic options. [ABSTRACT FROM AUTHOR]

The small sample sizes inherent in rare and pediatric disease settings offer significant challenges for clinical trial design. In such settings, Bayesian adaptive trial methods can often pay dividends, allowing the sensible incorporation of auxiliary data and other relevant information to bolster that collected by the trial itself. Previous work has also included the use of one-arm trials augmented by the participants' own natural history data, from which the future course of the disease in the absence of intervention can be predicted. Patient response can then be defined by the degree to which post-intervention observations are inconsistent with the predicted "natural" trajectory. While such trials offer obvious advantages in efficiency and ethical hazard (since they expose no new patients to a placebo, anathema to patients or their parents and caregivers), they can offer no protection against bias arising from the presence of any "placebo effect," the tendency of patients to improve merely by being in the trial. In this paper, we investigate the impact of both static and transient placebo effects on one-arm responder studies of this type, as well as two-arm versions that incorporate a small concurrent placebo group but still borrow strength from the natural history data. We also propose more traditional Bayesian changepoint models that specify a parametric functional form for the patient's post-intervention trajectory, which in turn allow quantification of the treatment benefit in terms of the model parameters, rather than semi-parametrically in terms of a response relative to some "null" model. We compare the operating characteristics of our designs in the context of an ongoing investigation of centronuclear myopathies (CNMs), a group of congenital neuromuscular diseases whose most common and severe form is X-linked, affecting approximately 1 in 50,000 newborn boys. Our results indicate our two-arm responder and changepoint methods can offer protection against placebo effects, improving power while protecting the trial's Type I error rate. However, further research into innovative trial designs as well as ongoing dialog with regulatory authorities remain critically important in rare disease research. [ABSTRACT FROM AUTHOR]

BACKGROUND: Frexalimab is a second-generation anti-CD40L monoclonal antibody that blocks the costimulatory CD40/CD40L pathway, which is important for activation and function of adaptive and innate immunity. In a phase 2 trial (NCT04879628) of participants with relapsing multiple sclerosis (RMS), frexalimab was well-tolerated and showed an 89% reduction in new gadolinium-enhancing (Gd+) T1 lesions in the high-dose arm vs placebo at week 12. In the ongoing open-label extension, 96% of participants in the high-dose arm were free of Gd+ T1 lesions at week 48. OBJECTIVES: Describe the design of 2 global, multicenter, randomized, double-blind, phase 3 frexalimab trials, FREXALT (NCT06141473) and FREVIVA (NCT06141486), in participants with RMS and nonrelapsing secondary progressive MS (nrSPMS), respectively. METHODS: FREXALT (comprising 2 trials, FREXALT-1 and FREXALT-2) is a double-dummy, active-controlled, event-driven (6-month composite confirmed disability worsening [cCDW] pooled across studies) trial with variable treatment duration of approximately 20 to 40 months in participants with RMS. Planned enrollment is 1400 participants randomly assigned 1:1 to frexalimab or teriflunomide. Key eligibility criteria include RMS diagnosis, Expanded Disability Status Scale (EDSS) ≤ 5.5, and ≥ 1 relapse within 1 year or ≥ 2 relapses within 2 years or ≥ 1 Gd+ lesion within 1 year. Primary end point is adjudicated annualized relapse rate, and key secondary end point is time to onset of 6-month cCDW (as assessed by the composite of EDSS, Timed 25-Foot Walk, and Nine-Hole Peg Test scores). FREVIVA is a placebo-controlled, event-driven (6-month composite confirmed disability progression [cCDP]) trial with variable treatment duration of approximately 27 to 51 months in participants with nrSPMS. Planned enrollment is 858 participants randomly assigned 2:1 to frexalimab or placebo. Key eligibility criteria include previous diagnosis of relapsing-remitting MS, current SPMS diagnosis, CDP within 1 year, EDSS 3 to 6.5, and no relapse within 2 years. Primary end point is time to onset of 6-month cCDP, and secondary end points include time to onset of 3-month cCDP and time to onset of 3-month/6-month CDP. Other secondary end points in both trials include clinical/MRI assessments, patient-reported outcomes, and safety evaluation. RESULTS: Enrollment started in December 2023. CONCLUSIONS: These phase 3 trials will assess the efficacy and safety of frexalimab in patients with RMS and nrSPMS, which is a population with no approved therapeutic options. [ABSTRACT FROM AUTHOR]

Background: Centronuclear myopathies are severe rare congenital diseases. The clinical variability and genetic heterogeneity of these myopathies result in major challenges in clinical trial design. Alternative strategies to large placebo-controlled trials that have been used in other rare diseases (e.g., the use of surrogate markers or of historical controls) have limitations that Bayesian statistics may address. Here we present a Bayesian model that uses each patient's own natural history study data to predict progression in the absence of treatment. This prospective multicentre natural history evaluated 4-year follow-up data from 59 patients carrying mutations in the MTM1 or DNM2 genes.Methods: Our approach focused on evaluation of forced expiratory volume in 1 s (FEV1) in 6- to 18-year-old children. A patient was defined as a responder if an improvement was observed after treatment and the predictive probability of such improvement in absence of intervention was less than 0.01. An FEV1 response was considered clinically relevant if it corresponded to an increase of more than 8%.Results: The key endpoint of a clinical trial using this model is the rate of response. The power of the study is based on the posterior probability that the rate of response observed is greater than the rate of response that would be observed in the absence of treatment predicted based on the individual patient's previous natural history. In order to appropriately control for Type 1 error, the threshold probability by which the difference in response rates exceeds zero was adapted to 91%, ensuring a 5% overall Type 1 error rate for the trial.Conclusions: Bayesian statistical analysis of natural history data allowed us to reliably simulate the evolution of symptoms for individual patients over time and to probabilistically compare these simulated trajectories to actual observed post-treatment outcomes. The proposed model adequately predicted the natural evolution of patients over the duration of the study and will facilitate a sufficiently powerful trial design that can cope with the disease's rarity. Further research and ongoing dialog with regulatory authorities are needed to allow for more applications of Bayesian statistics in orphan disease research. [ABSTRACT FROM AUTHOR]

In skeletal muscle, long noncoding RNAs (lncRNAs) are involved in dystrophin protein stabilization but also in the regulation of myocytes proliferation and differentiation. Hence, they could represent promising therapeutic targets and/or biomarkers for Duchenne and Becker muscular dystrophy (DMD/BMD). DMD and BMD are X-linked myopathies characterized by a progressive muscular dystrophy with or without dilatative cardiomyopathy. Two-thirds of DMD gene mutations are represented by deletions, and 63% of patients carrying DMD deletions are eligible for 45 to 55 multi-exons skipping (MES), becoming BMD patients (BMDΔ45-55). We analyzed the genomic lncRNA presence in 38 BMDΔ45-55 patients and characterized the lncRNA localized in introns 44 and 55 of the DMD gene. We highlighted that all four lncRNA are differentially expressed during myogenesis in immortalized and primary human myoblasts. In addition, the lncRNA44s2 was pointed out as a possible accelerator of differentiation. Interestingly, lncRNA44s expression was associated with a favorable clinical phenotype. These findings suggest that lncRNA44s2 could be involved in muscle differentiation process and become a potential disease progression biomarker. Based on these results, we support MES45-55 therapy and propose that the design of the CRISPR/Cas9 MES45-55 assay consider the lncRNA sequences bordering the exonic 45 to 55 deletion. [ABSTRACT FROM AUTHOR]

Nemaline myopathies are clinically and genetically heterogeneous muscle diseases characterized by the presence of nemaline bodies (rods) in muscle fibers. Mutations in the KLHL40 (kelch-like family member 40) gene (NEM 8) are common cause of severe/lethal nemaline myopathy. We report an 8-year-old girl born to consanguineous Moroccan parents, who presented with hypotonia and poor sucking at birth, delayed motor development, and further mild difficulties in walking and fatigability. A muscle biopsy revealed the presence of nemaline bodies. KLHL40 gene Sanger sequencing disclosed a never before reported pathogenic homozygous mutation which resulted in absent KLHL40 protein expression in the muscle. This further expands the phenotypical spectrum of KLHL40 related nemaline myopathy. [ABSTRACT FROM AUTHOR]

Duchenne Muscular Dystrophy (DMD) is the most frequent muscular dystrophy in childhood, with a worldwide incidence of one in 5000 live male births. It is due to mutations in the dystrophin gene leading to absence of full-length dystrophin protein. Central nervous system involvement is well-known in Duchenne Muscular Dystrophy. The multiple dystrophin isoforms expressed in brain have important roles in cerebral development and functioning. The association of Duchenne Muscular Dystrophy with seizures has been reported, and there is a higher prevalence of epilepsy in Duchenne Muscular Dystrophy patients (between 6.3% and 12.3%) than in the general pediatric population (0.5–1%). Duchenne Muscular Dystrophy patients may present with focal seizures, generalized tonic-clonic seizures or absences. We report on two boys in whom Duchenne Muscular Dystrophy is associated with epileptic spasms and hypsarrhythmia that fulfil the criteria for West syndrome, thus extending the spectrum of seizure types described in Duchenne Muscular Dystrophy patients. [ABSTRACT FROM AUTHOR]