Introduction
Qalsody (tofersen) is an antisense oligonucleotide therapy developed by Biogen for the treatment of amyotrophic lateral sclerosis (ALS) in adults with a mutation in the superoxide dismutase 1 (SOD1) gene. Approved by the FDA in April 2023 under the accelerated approval pathway, Qalsody represents a targeted therapeutic approach for this specific genetic subtype of ALS, marking a significant advancement in precision medicine for neurodegenerative disorders.
Mechanism of Action
Qalsody works through an antisense mechanism targeting SOD1 mRNA. The drug is designed to bind to SOD1 mRNA, leading to its degradation by RNase H1 enzyme. This reduces the production of mutant SOD1 protein, which is believed to be toxic and contribute to motor neuron degeneration in SOD1-ALS. By decreasing levels of the pathogenic protein, Qalsody aims to slow disease progression in this genetically defined patient population.
Indications
Qalsody is indicated for the treatment of amyotrophic lateral sclerosis (ALS) in adults who have a mutation in the superoxide dismutase 1 (SOD1) gene. This represents approximately 2% of all ALS cases. Diagnosis must be confirmed through genetic testing demonstrating a pathogenic SOD1 variant before treatment initiation.
Dosage and Administration
Standard dosing: 100 mg administered via intrathecal injection once every 14 days for three loading doses, followed by 100 mg once every 28 days as maintenance therapy. Administration:- Administered by healthcare professionals trained in intrathecal injection procedures
- Must be delivered directly into the cerebrospinal fluid via lumbar puncture
- Requires proper aseptic technique and appropriate monitoring during administration
- Renal impairment: No dosage adjustment recommended
- Hepatic impairment: No dosage adjustment recommended
- Elderly: No specific dosage adjustment recommended
- Pregnancy: Use only if potential benefit justifies potential risk
Pharmacokinetics
Absorption: Administered directly into the intrathecal space; achieves distribution throughout the central nervous system. Distribution: Primarily distributed within the central nervous system with minimal systemic exposure. Cerebrospinal fluid concentrations are substantially higher than plasma concentrations. Metabolism: Undergoes metabolism by exo- and endonucleases to shorter oligonucleotides. Elimination: Primarily eliminated renally with a half-life of approximately 1-2 months in cerebrospinal fluid.Contraindications
- Hypersensitivity to tofersen or any component of the formulation
- Active infection at the injection site or systemic infection
- History of severe hypersensitivity reactions to antisense oligonucleotides
Warnings and Precautions
Serious neurological events: May include myelitis, radiculitis, aseptic meningitis, and papilledema. Monitor patients closely. Intrathecal administration risks: Includes post-lumbar puncture syndrome, headache, and procedural complications. Elevated CSF protein: May occur during treatment; monitor regularly. Hypersensitivity reactions: May occur, including angioedema and urticaria. Coagulation abnormalities: Monitor for signs of bleeding or coagulation disorders.Drug Interactions
Formal drug interaction studies have not been conducted. However, theoretical interactions may include:
- Anticoagulants and antiplatelet agents (potential increased bleeding risk)
- Other intrathecal medications (avoid concurrent administration)
- Medications that affect CSF dynamics or pressure
Adverse Effects
Most common adverse reactions (≥10%):- Fatigue (48%)
- Arthralgia (39%)
- Increased CSF white blood cell count (26%)
- Myalgia (22%)
- Increased CSF protein (17%)
- Pain (17%)
- Headache (13%)
- Myelitis (2%)
- Radiculitis (2%)
- Aseptic meningitis (2%)
- Papilledema (2%)
- Elevated intracranial pressure
Monitoring Parameters
Baseline assessment:- Genetic confirmation of SOD1 mutation
- Neurological examination
- CSF analysis (cell count, protein)
- Ophthalmological examination
- Coagulation parameters
- Neurological status at each visit
- CSF analysis every 3-6 months
- Regular ophthalmological exams
- Signs of hypersensitivity reactions
- Monitoring for bleeding tendencies
- Assessment of injection site reactions
Patient Education
- Qalsody is not a cure for ALS but may slow disease progression
- Treatment requires regular intrathecal injections administered by healthcare professionals
- Report any signs of infection, neurological changes, or vision problems immediately
- Inform all healthcare providers about Qalsody treatment
- Understand potential benefits and risks of treatment
- Regular monitoring is essential throughout therapy
- Report any signs of bleeding or bruising unusually
- Keep all scheduled appointments for injections and monitoring
References
1. FDA prescribing information: Qalsody (tofersen). April 2023. 2. Miller TM, et al. Phase 1-2 Trial of Antisense Oligonucleotide Tofersen for SOD1 ALS. N Engl J Med. 2020;383(2):109-119. 3. Biogen Inc. Qalsody clinical trial data. 2023. 4. Brown RH, Al-Chalabi A. Amyotrophic Lateral Sclerosis. N Engl J Med. 2017;377(2):162-172. 5. Kiernan MC, et al. Amyotrophic lateral sclerosis. Lancet. 2011;377(9769):942-955. 6. ClinicalTrials.gov: NCT02623699 (VALOR study). 7. EMA assessment report: Qalsody (tofersen). 2023.