Casimersen

12.1 Mechanism of Action Casimersen is designed to bind to exon 45 of dystrophin pre-mRNA resulting in exclusion of this exon during mRNA processing in patients with genetic mutations that are amenable to exon 45 skipping. Exon 45 skipping is intended to allow for production of an internally truncated dystrophin protein in patients with genetic mutations that are amenable to exon 45 skipping [see Clinical Studies ( 14 )] .

1 INDICATIONS AND USAGE AMONDYS 45 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 45 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 [see Clinical Studies ( 14 )] . Continued approval for this indication may be contingent upon verification of a clinical benefit in confirmatory trials. AMONDYS 45 is an antisense oligonucleotide 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 45 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 [see Clinical Studies ( 14 )] . Continued approval for this indication may be contingent upon verification of a clinical benefit in confirmatory trials. ( 1 )

2 DOSAGE AND ADMINISTRATION Serum cystatin C, urine dipstick, and urine protein-to-creatinine ratio should be measured before starting AMONDYS 45 ( 2.1 ) 30 milligrams per kilogram of body weight once weekly ( 2.2 ) Administer as an intravenous (IV) infusion over 35 to 60 minutes via an in-line 0.2 micron filter ( 2.2 , 2.4 ) Dilution required prior to administration ( 2.3 ) 2.1 Monitoring to Assess Safety Serum cystatin C, urine dipstick, and urine protein-to-creatinine ratio (UPCR) should be measured before starting AMONDYS 45. Consider measurement of glomerular filtration rate prior to initiation of AMONDYS 45. Monitoring for kidney toxicity during treatment is recommended. Obtain the urine sample prior to infusion of AMONDYS 45 or at least 48 hours after infusion [see Warnings and Precautions ( 5.2 )] . 2.2 Dosing Information The recommended dosage of AMONDYS 45 is 30 milligrams per kilogram administered once weekly as a 35 to 60-minute intravenous infusion via an in-line 0.2 micron filter. If a dose of AMONDYS 45 is missed, it may be administered as soon as possible after the scheduled dose. 2.3 Preparation Instructions AMONDYS 45 is supplied in single-dose vials as a preservative-free concentrated solution that requires dilution prior to administration. Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration, whenever solution and container permit. Use aseptic technique. Calculate the total dose of AMONDYS 45 to be administered based on the patient's weight and the recommended dose of 30 milligrams per kilogram. Determine the volume of AMONDYS 45 needed and the correct number of vials to supply the full calculated dose. Allow the vials to warm to room temperature. Mix the contents of each vial by gently inverting 2 or 3 times. Do not shake. Visually inspect each vial of AMONDYS 45. The solution is a clear to slightly opalescent, colorless liquid, and may contain trace amounts of small, white to off-white amorphous particles. Do not use if the solution in the vials is cloudy, discolored or contains extraneous particulate matter other than trace amounts of small, white to off-white amorphous particles. With a syringe fitted with a 21-gauge or smaller bore non-coring needle, withdraw the calculated volume of AMONDYS 45 from the appropriate number of vials. To avoid dulling the needle and fragmenting the stoppers, replace the needle periodically during preparation. Dilute the withdrawn AMONDYS 45 in 0.9% Sodium Chloride Injection, USP, to make a total volume of 100 to 150 mL. Gently invert 2 to 3 times to mix. Do not shake. Visually inspect the diluted solution. Do not use if the solution is cloudy, discolored or contains extraneous particulate matter other than trace amounts of small, white to off-white amorphous particles. Administer the diluted solution via an in-line 0.2 micron filter. AMONDYS 45 contains no preservatives and should be administered immediately after dilution. Complete infusion of diluted AMONDYS 45 within 4 hours of dilution. If immediate use is not possible the diluted product may be stored for up to 24 hours at 2 °C to 8 °C (36 °F to 46 °F). Do not freeze. Discard unused AMONDYS 45. 2.4 Administration Instructions Application of a topical anesthetic cream to the infusion site prior to administration of AMONDYS 45 may be considered. AMONDYS 45 is administered via intravenous infusion. Flush the intravenous access line with 0.9% Sodium Chloride Injection, USP, prior to and after infusion. Infuse the diluted AMONDYS 45 over 35 to 60 minutes via an in-line 0.2 micron filter. Do not mix other medication with AMONDYS 45 or infuse other medications concomitantly via the same intravenous access with AMONDYS 45. If a hypersensitivity reaction occurs, consider slowing the infusion, interrupting or discontinuing the AMONDYS 45 therapy [see Contraindications ( 4 ), Warning and Precautions ( 5.1 ) and Adverse Reactions ( 6.2 )] .

6 ADVERSE REACTIONS The following clinically significant adverse reactions are described elsewhere in the labeling: Hypersensitivity reactions [see Warnings and Precautions ( 5.1 )] The most common adverse reactions (incidence >20% and at least 5% higher than placebo) were upper respiratory tract infection, cough, pyrexia, headache, arthralgia, and oropharyngeal pain. ( 6.1 ) To report SUSPECTED ADVERSE REACTIONS, contact Sarepta Therapeutics, Inc. at 1-888-SAREPTA (1-888-727-3782) or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch . 6.1 Clinical Trials Experience Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice. In the AMONDYS 45 clinical development program, 76 patients received at least one intravenous dose of AMONDYS 45 (30 mg/kg). All patients were male and had genetically confirmed Duchenne muscular dystrophy. Age at study entry was 7 to 20 years (mean 9.9 years). Most (88%) patients were White, and 9% were Asian. AMONDYS 45 was studied in a double-blind, placebo-controlled study (Study 1). Patients in ongoing Study 1 received AMONDYS 45 (n=57) 30 mg/kg or placebo (n=31) intravenously once weekly for up to 96 weeks, after which all patients received or will receive AMONDYS 45 30 mg/kg for up to 48 weeks. Adverse reactions observed in ≥20% of patients treated with AMONDYS 45 and 5% more frequently than in the placebo group in Study 1 are shown in Table 1 . Table 1. Adverse Reactions Occurring in at Least 20% of Patients Treated with AMONDYS 45 and at a Rate at Least 5% More Frequently than in the Placebo Group in Study 1 *Includes upper respiratory infection, pharyngitis, nasopharyngitis, and rhinitis. Adverse Reaction AMONDYS 45 30 mg/kg Once Weekly (n = 57) % Placebo (n = 31) % Upper Respiratory Tract Infections* 65 55 Cough 33 26 Pyrexia 33 23 Headache 32 19 Arthralgia 21 10 Oropharyngeal Pain 21 7 Other adverse reactions that occurred in at least 10% of patients treated with AMONDYS 45, and that were reported at a rate at least 5% more frequently in the AMONDYS 45 group than in the placebo group, were: ear pain, nausea, ear infection, post-traumatic pain, and dizziness and light-headedness. 6.2 Postmarketing Experience The following adverse reactions have been identified during postapproval use of AMONDYS 45. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure. Infusion-related reactions including rash, headache, cough, abdominal pain (including upper abdominal pain), and vomiting occurred within 24 hours from the start of an infusion of AMONDYS 45. Hypersensitivity reactions, including angioedema and anaphylaxis, have occurred in patients treated with AMONDYS 45.