LGMD2I/R9 is caused by bi-allelic partial loss-of-function of the fukutin-related protein (FKRP) gene, resulting in hypoglycosylation of alpha-dystroglycan (αDG) and progressive muscle damage in skeletal muscle and cardiac myocytes. Alongside the skeletal myopathy resulting in progressive extremity weakness, symptomatic respiratory weakness and left ventricular dysfunction may develop and can be a major cause of morbidity and mortality in LGMD2I/R9. BBP-418 is an investigational oral substrate supplementation intended to saturate the partially functional FKRP enzyme, intended to drive increased glycosylation of αDG, and potentially stabilizing or improving muscle integrity. FORTIFY (NCT05775848) is a Phase 3 multinational, multicenter, double-blind placebo-controlled study enrolling ∼81 individuals with genetically confirmed LGMD2I/R9, aged 12 to 60 years in US, UK and Australia and 18 to 60 years in EU to assess the clinical efficacy and safety of BBP-418. Individuals will be randomized in a 2:1 ratio to receive oral BBP-418 or placebo, respectively. The primary endpoint will be change in NSAD from baseline in BBP-418-treated individuals relative to placebo at 36 months. Secondary endpoints evaluated will include FVC, PUL 2.0, and ambulatory measures (100mTT and 10mWT). Troponin I, electrocardiograms and echocardiograms will be obtained to assess cardiomyopathy. An interim analysis of at least 42 participants will evaluate change in glycosylated αDG levels, and selected clinical measures, at 12 months. The FORTIFY study will assess the safety, tolerability, and efficacy of BBP-418 in LGMD2I/R9. In addition to evaluating the effect of BBP-418 on motor performance, cardiac, and respiratory function, the effect of BBP-418 treatment on glycosylated αDG levels, the hallmark of disease at the molecular level, will be investigated at 12 months with potential to use this biomarker as a surrogate endpoint in LGMD2I/R9.

S192gene.Currently no disease-modifying therapies exist.AOC 1001, as an antibody oligonucleotide conjugate (AOCTM) comprised of a DMPK siRNA conjugated to a humanized antibody targeting human transferrin receptor 1, was designed for functional delivery to muscle cells, where it can reduce the toxic mutant DMPK mRNA and potentially address the pathology of DM1.The MARINA phase 1/2 study (NCT05027269) is a randomized, placebo-controlled, double-blind trial in two parts.Part A was a single dose design.Part B was a multiple-ascending dose design with 3 cohorts (dose levels), with quarterly doses and 1 booster after the first 6 weeks.The cohorts were initiated in a staggered fashion based on a safety data review of the preceding cohort(s).The primary objective is safety and tolerability.Secondary objectives include spliceopathy, pharmacokinetics, and pharmacodynamics.Exploratory objectives include efficacy measures and patientreported outcomes.The study enrolled 38 adults aged 18-65 years with a genetic diagnosis of DM1.As the first complete trial of AOC 1001, the MARINA data analysis includes safety, tolerability, and functional endpoints.This includes investigation of a single serious adverse event reported as a related event of thalamic hemorrhage observed in a participant after their first dose at 4mg/kg.AOC 1001 was found to be delivered to the muscle, reduce DMPK mRNA, modify splicing profiles, and improve multiple functional endpoints.AOC 1001 represents a novel potential therapy addressing the underlying cause of DM1.

Limb-girdle muscular dystrophy (LGMD) type 2I is an autosomal recessive muscle disease caused by partial loss of function mutations of the fukutin-related protein (FKRP) leading to hypo glycosylation of alpha dystroglycan (αDG). Diminished glycosylation of αDG leads to contraction induced injury in myocytes leading to impairment of muscle performance. Identify and develop a method for evaluating the extent of glycosylation of αDG in striated muscle biopsies from patients with LGMD2I. A multiplex western blot (WB) method was employed to assess the extent of glycosylation in αDG by detecting both total αDG and a specific glyco-epitope. In LGMD2I, the biochemical impairment of FKRP leads to reduced glycosylation, which can be measured by diminished levels of the glyco-epitope. The ability to detect both forms of αDG generates a ratio of αDG-glycan to total αDG as an estimate of the extent of glycosylation. Several commercially available antibodies were evaluated using several healthy control muscles to assess their utility in a multiplexed WB to detect total αDG and glycosylated αDG. Two suitable antibodies were identified that were compatible with the LiCor platform. The specificity of these antibodies was assessed using parental HEK293T and DAG1 HEK293T knockout cell lysates. The signal linearity in both detection channels was evaluated using a dilution series of the control tibialis anterior (TA) muscle and was found to have good linearity (r2 > 0.85) and dilutional linearity. A commercially available recombinantly produced human αDG (rh-αDG) with little to no detectable glyco-epitope was identified and evaluated. Healthy TA control muscle is present on each blot and used to normalize the calculated ratios from test articles. This WB method will be used to assess the extent of glycosylated αDG in a subset of participants in our ongoing LGMD2I natural history study and results will be presented. A multiplexed method was developed for determining the extent of glycosylation of αDG. This approach has the potential to inform on the extent of αDG glycosylation in LGMD2I patients and to assess cellular response to a therapeutic intervention.

To assess the cost-effectiveness of both single-dose gene-replacement therapy with AVXS-101 (onasemnogene abeparvovec) and current standard of care (nusinersen) in patients with Spinal Muscular Atrophy Type 1 (SMA1) in Japan.

The treatment landscape for spinal muscular atrophy type 1 (SMA1), a severe, rapidly progressing genetic neuromuscular disease, has evolved in recent years. However, data on the economic burden of SMA1 since FDA approval of the first effective disease-modifying therapy (nusinersen, 12/23/2016) are limited. We previously conducted a retrospective evaluation of healthcare resource utilization (HCRU) and costs in patients with SMA1, overall and following nusinersen initiation; however, this study was limited by short follow-up duration (median, 7.9 months). Here, we expand these findings with additional/updated observations and greater follow-up. Patients with SMA1 were identified in Symphony Health's Integrated Dataverse® (09/01/2016–08/31/2019). HCRU was assessed from the index date (first SMA diagnosis date after 12/23/2016) until the last date of clinical activity or end of available data. For nusinersen-treated patients, HCRU was also assessed following treatment initiation. We identified 449 patients with SMA1 (55.2% female; median follow-up, 12.4 months). Patients with SMA1 overall and nusinersen-treated patients (n=59) averaged, respectively, 50.6 vs. 46.8 days with medical visits/year (inpatient, 8.2 vs. 4.7; respiratory failure–related, 9.5 vs. 7.4). All of these values, with the exception of average inpatient days/year among nusinersen-treated patients, are lower compared with our earlier analysis. HCRU is expected to translate into substantial healthcare costs, both overall and in nusinersen-treated patients. Updated cost data available at the time of the conference will be presented. An important limitation is that, while >59 patients may have received nusinersen, HCRU could only accurately be assessed among patients with recorded nusinersen-associated procedures or drug codes. When evaluated over a longer follow-up period, HCRU was generally lower than previously estimated, suggesting that the burden of SMA1 may be higher around date of diagnosis. Nonetheless, results indicate that the burden associated with SMA1 remains substantial, including among patients receiving ongoing disease-modifying therapy.

Spinal muscular atrophy (SMA) is a severe genetic neuromuscular disease for which there is limited data on the burden of illness, particularly since the approval of new treatment options. We have previously described the burden of SMA type 1. Here, we expand this work using more recent data covering a longer follow-up period and including SMA types 2 and 3. Patients with SMA types 1, 2, and 3 were identified in Symphony Health's Integrated Dataverse® (09/01/2016–11/30/2019). For each SMA type, healthcare resource utilization (HCRU) and healthcare costs (excluding nusinersen-related costs) were assessed from the first SMA diagnosis post-nusinersen FDA approval (12/23/2016) until end of clinical activity or data availability. For nusinersen-treated patients, HCRU and healthcare costs were also assessed separately following treatment initiation. Nusinersen treatment was identified based on recorded nusinersen-associated procedures or drug codes, which may not capture all nusinersen-treated patients. Median follow-up for patients with SMA type 1 (N=495), 2 (N=551), and 3 (N=3,644) was 14.8-25.5 months; nusinersen-treated patients with SMA type 1 (N=62), 2 (N=116), and 3 (N=495) had median follow-up between 15.7-17.8 months. Across SMA types, patients averaged 45.5-66.0 days with medical visits per patient per year (PPPY; inpatient days: 1.7-7.6) overall, and 50.9-92.4 days (inpatient days: 2.0-6.4) among nusinersen-treated patients. Healthcare costs PPPY averaged $105,467, $93,016, and $55,877 for SMA type 1, 2, and 3, respectively; among nusinersen-treated patients, these figures were $85,765, $142,735, and $71,696. Across SMA types, respiratory failure accounted for 16.3%-29.3% of healthcare costs, and 16.3%-32.9% among nusinersen-treated patients. When observed over a longer follow-up, healthcare costs tended to be lower, suggesting that costs may be higher around SMA diagnosis. SMA carries a substantial economic burden across SMA types 1, 2, and 3, both overall and among nusinersen-treated patients.

SMA1 is a rapidly progressing neurologic disease resulting from biallelic survival motor neuron 1 (SMN1) gene deletion/mutation. This study describes the clinical outcomes of onasemnogene abeparvovec (AVXS-101), a one-time SMN gene-replacement therapy, in SMA1 patients contrasted with nusinersen and untreated patients. SMA1 patients (2xSMN2) were treated with AVXS-101 (CL-101; NCT02122952; Cohort 2; n=12) or nusinersen (ENDEAR; NCT02193074; N=80). Event-free survival (EFS, composite endpoint of time to death or permanent ventilation), motor milestone achievement, and nutritional/ventilatory support (CL-101, ≥20 months; ENDEAR, ≥14 months of age) were contrasted with two comparable natural history studies (up to 14 months of age): Pediatric Neuromuscular Clinical Research network (PNCR; N=23) and NeuroNEXT (NN101, NCT01736553; N=16). The proportions of patients achieving EFS at ≥14 months were 30% (PNCR), 50% (NN101), 61% (nusinersen-treated), and 100% (AVXS-101-treated). No patient in PNCR or NN101 achieved motor milestones. In ENDEAR, 8% of patients sat independently; 1% stood. In CL-101, 92% of patients sat unassisted; 17% stood with assistance; 17% walked independently. The maintenance of highest acquired developmental motor milestones in long-term follow-up supports AVXS-101 durability. Seventy percent of PNCR patients received nutritional support. In contrast, 86% of AVXS-101-treated patients who were independent of nutritional support at baseline continued to eat exclusively by mouth; 92% of all AVXS-101-treated patients achieved the ability to speak or had stable/improved swallowing function. AVXS-101 in the CL-101 study improved clinical outcomes, including survival, motor milestone achievement, and reduced ventilatory/nutritional support relative to nusinersen (ENDEAR study) and natural history cohorts.