공고 • Jun 30
Sarepta Therapeutics Announces FDA Acceptance Of Supplemental New Drug Applications For Amondys 45 And Vyondys 53 For Duchenne Muscular Dystrophy
Sarepta Therapeutics announced that the U.S. Food and Drug Administration (FDA) has accepted for filing the supplemental New Drug Applications (sNDAs) for AMONDYS 45 (casimersen) and VYONDYS 53 (golodirsen) for the treatment of Duchenne muscular dystrophy (DMD). The FDA has assigned a Prescription Drug User Fee Act (PDUFA) target action date of February 28, 2027. The sNDA submissions seek conversion of the accelerated approvals of AMONDYS 45 and VYONDYS 53 to traditional approvals. The applications are supported by data from the ESSENCE confirmatory study, as well as substantial published real-world evidence and the favorable and consistent safety profiles of both exon-skipping therapies. EXONDYS 51 (eteplirsen), AMONDYS 45 (casimersen) and VYONDYS 53 (golodirsen) are exon-skipping therapies approved under the FDA’s accelerated approval pathway for patients with DMD who have mutations amenable to exon 51, exon 45 and exon 53 skipping, respectively. For more than a decade, Sarepta’s exon-skipping therapies have been used to treat over 1,800 amenable patients worldwide, from infants as young as 7 months to adults well into their 30s. In the Phase 3 ESSENCE study evaluating casimersen and golodirsen versus placebo, the primary endpoint was not met; however, numerical trends favored treatment. Additional post-hoc analyses were performed to evaluate heterogeneity challenges related to DMD progression and the impact of conducting ESSENCE during COVID-19. At week 96, treatment was associated with increased dystrophin expression and a consistent reduction in 4-step ascend decline across multiple analyses. The therapies were well tolerated over 144 weeks with no new safety signals observed, consistent with established clinical and real-world experience. Results from ESSENCE add to the available evidence for VYONDYS 53 and AMONDYS 45, including real-world studies demonstrating that treatment with VYONDYS 53 is associated with a 7.5 year delay in the need for nighttime ventilation and treatment with AMONDYS 45 is associated with a statistically significant slowing of lung function decline and a potentially meaningful benefit in the predicted time to use of a cough assist device. Across our PMO portfolio, real-world evidence indicates a multi-year benefit on survival, delays in time to loss of ambulation of 3 and 4 years, a substantial reduction in risk of reaching a left ventricular ejection fraction (LVEF) of less than 55%, and a significant reduction in emergency room and other hospital visits. EXONDYS 51 uses Sarepta’s proprietary phosphorodiamidate morpholino oligomer (PMO) chemistry and exon-skipping technology to bind to exon 51 of dystrophin pre-mRNA, resulting in exclusion, or “skipping”, of this exon during mRNA processing in patients with genetic mutations that are amenable to exon 51 skipping. EXONDYS 51 is indicated for the treatment of Duchenne muscular dystrophy (DMD) in patients who have a confirmed mutation of the DMD gene that is amenable to exon 51 skipping. This indication is approved under accelerated approval based on an increase in dystrophin in skeletal muscle observed in some patients treated with EXONDYS 51. Continued approval for this indication may be contingent upon verification of a clinical benefit in confirmatory trials. EXONDYS 51 has met the full statutory standards for safety and effectiveness and as such is not considered investigational or experimental. Hypersensitivity reactions, including bronchospasm, chest pain, cough, tachycardia, and urticaria have occurred in patients who were treated with EXONDYS 51. If a hypersensitivity reaction occurs, institute appropriate medical treatment and consider slowing the infusion or interrupting the EXONDYS 51 therapy. Adverse reactions in DMD patients (N=8) treated with EXONDYS 51 30 mg or 50 mg/kg/week by intravenous (IV) infusion with an incidence of at least 25% more than placebo (N=4) (Study 1, 24 weeks) were (EXONDYS 51, placebo): balance disorder (38%, 0%), vomiting (38%, 0%) and contact dermatitis (25%, 0%). The most common adverse reactions were balance disorder and vomiting. Because of the small numbers of patients, these represent crude frequencies that may not reflect the frequencies observed in practice. The 50 mg/kg once weekly dosing regimen of EXONDYS 51 is not recommended. The most common adverse reactions from observational clinical studies (N=163) seen in greater than 10% of patients were headache, cough, rash, and vomiting. Other adverse events may occur. VYONDYS 53 (golodirsen) uses Sarepta’s proprietary phosphorodiamidate morpholino oligomer (PMO) chemistry and exon-skipping technology to bind to exon 53 of dystrophin pre-mRNA, resulting in exclusion, or “skipping,” of this exon during mRNA processing in patients with genetic mutations that are amenable to exon 53 skipping. This indication is approved under accelerated approval based on an increase in dystrophin production in skeletal muscle observed in patients treated with AMONDYS 45. Continued approval for this indication may be contingent upon verification of a clinical benefit in confirmatory trials. Because of the effect of reduced skeletal muscle mass on creatinine measurements, creatinine may not be a reliable measure of kidney function in DMD patients. Serum cystatin C, urine dipstick, and urine protein-to-creatinine ratio should be measured before starting AMONDYS 45. Consider also measuring glomerular filtration rate using an exogenous filtration marker before starting AMONDYS 45. During treatment, monitor urine dipstick every month, and serum cystatin C and urine protein-to-creatinine ratio (UPCR) every three months. Only urine expected to be free of excreted AMONDYS 45 should be used for monitoring of urine protein. Urine obtained on the day of AMONDYS 45 infusion prior to the infusion, or urine obtained at least 48 hours after the most recent infusion, may be used. Alternatively, use a laboratory test that does not use the reagent pyrogallol red, as this reagent has the potential to cross react with any AMONDYS 45 that is excreted in the urine and thus lead to a false positive result for urine protein. If a persistent increase in serum cystatin C or proteinuria is detected, refer to a pediatric nephrologist for further evaluation. Adverse reactions occurring in at least 20% of patients treated with AMONDYS 45 and at least 5% more frequently than in the placebo group were (AMONDYS 45, placebo): upper respiratory infections (65%, 55%), cough (33%, 26%), pyrexia (33%, 23%), headache (32%, 19%), arthralgia (21%, 10%), and oropharyngeal pain (21%, 7%). Other adverse reactions that occurred in at least 10% of patients treated with AMONDYS 45 and at least 5% more frequently than in the placebo group were: ear pain, nausea, ear infection, post-traumatic pain, and dizziness and light-headedness. Other adverse events may occur.