Casimersen - Drug Monograph

Introduction

Casimersen (brand name Amondys 45) is a phosphorodiamidate morpholino oligomer antisense therapy approved by the FDA in February 2021. It represents a significant advancement in the treatment of Duchenne muscular dystrophy (DMD) in patients with specific genetic mutations. This targeted therapy addresses the underlying cause of disease progression in a subset of DMD patients.

Mechanism of Action

Casimersen works through an antisense mechanism targeting exon 45 of the dystrophin pre-mRNA. The drug is designed to bind to exon 45 of the dystrophin pre-mRNA, resulting in exclusion of this exon during mRNA processing. This allows for the production of an internally truncated but functional dystrophin protein in patients amenable to exon 45 skipping. By promoting the production of this modified dystrophin protein, casimersen helps stabilize muscle cell membranes and slow disease progression.

Indications

Casimersen 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 represents approximately 8% of the DMD patient population.

Dosage and Administration

• Recommended dosage: 30 mg/kg administered once weekly as an intravenous infusion
• Route: Intravenous infusion over 35-60 minutes
• Preparation: Requires dilution in 0.9% Sodium Chloride Injection, USP
• Administration: Use an in-line 0.2 micron filter during infusion
• Special populations: No dosage adjustment recommended for renal or hepatic impairment
• Pediatric use: Safety and effectiveness established in patients 6 years and older

Pharmacokinetics

• Absorption: Administered intravenously, resulting in complete bioavailability
• Distribution: Primarily distributes to peripheral tissues with limited CNS penetration
• Metabolism: Undergoes minimal metabolism; primarily eliminated unchanged
• Elimination: Renal excretion is the primary elimination pathway
• Half-life: Approximately 3-4 hours in plasma

Contraindications

Casimersen is contraindicated in patients with:

• History of hypersensitivity reactions to casimersen or its excipients
• No other absolute contraindications have been identified

Warnings and Precautions

• Renal toxicity: Monitor renal function before initiation and during treatment
• Infusion reactions: May occur during or following infusion; monitor patients closely
• Hepatic impairment: Use with caution in patients with hepatic dysfunction
• Fever: Pyrexia has been observed; monitor and manage appropriately
• Cardiac monitoring: Regular cardiac assessment recommended due to underlying DMD cardiomyopathy

Drug Interactions

• No formal drug interaction studies have been conducted
• Theoretical potential for interactions with other nephrotoxic agents
• Use caution when administering with medications that affect renal function
• No known interactions with cytochrome P450 substrates, inhibitors, or inducers

Adverse Effects

• Upper respiratory tract infections
• Cough
• Fever
• Headache
• Arthralgia
• Oropharyngeal pain

• Renal toxicity (elevated serum creatinine)
• Hypersensitivity reactions
• Cardiotoxicity (related to underlying disease)

Monitoring Parameters

• Renal function: Serum creatinine before starting treatment and regularly during therapy
• Renal biomarkers: Urine protein-to-creatinine ratio
• Infusion reactions: Monitor during and for at least 60 minutes after infusion
• Hepatic function: Liver enzymes periodically
• Cardiac function: Echocardiogram and ECG as clinically indicated
• Disease progression: Regular assessment of motor function and muscle strength

Patient Education

• Understand that this is a disease-modifying treatment, not a cure
• Report any signs of infusion reactions (fever, chills, rash, breathing difficulties)
• Maintain regular follow-up appointments for safety monitoring
• Inform all healthcare providers about casimersen therapy
• Understand the importance of adherence to weekly infusion schedule
• Report any changes in urinary output or color
• Be aware that response to treatment may vary between individuals

References

1. FDA prescribing information: Amondys 45 (casimersen) injection. February 2021. 2. Clemens PR, Rao VK, Connolly AM, et al. Safety, tolerability, and efficacy of casimersen in patients with Duchenne muscular dystrophy amenable to exon 45 skipping: A randomized clinical trial. JAMA Neurol. 2022;79(2):152-161. 3. Charleston JS, Schnell FJ, Dworzak J, et al. Eteplirsen treatment for Duchenne muscular dystrophy: Exon skipping and dystrophin production. Neurology. 2018;90(24):e2146-e2154. 4. Mendell JR, Khan N, Sha N, et al. Comparison of long-term ambulatory function in patients with Duchenne muscular dystrophy treated with eteplirsen and matched natural history controls. J Neuromuscul Dis. 2021;8(3):469-479. 5. ClinicalTrials.gov: Study of SRP-4045 and SRP-4053 in DMD Patients (ESSENCE). NCT02500381.