Continuing Education Activity

Tofersen, a novel antisense oligonucleotide (ASO) drug, received accelerated approval from the U.S. Food and Drug Administration (FDA) in April 2023 for the treatment of amyotrophic lateral sclerosis (ALS). ALS is a progressive, fatal neurodegenerative disorder affecting motor neurons in the brain and spinal cord, leading to muscle weakness, paralysis, and eventual death. Tofersen is specifically indicated for ALS patients with a superoxide dismutase 1 (SOD1) gene mutation. The mutant SOD1 protein resulting from this gene mutation gains a toxic function and significantly increases SOD1 messenger RNA (mRNA) levels and protein in the cerebrospinal fluid (CSF). This activity provides comprehensive information about Tofersen's indications, contraindications, mechanism of action, adverse event profile, monitoring, and relevant interactions relevant to patients and healthcare team members involved in treating patients with ALS and related conditions. 

Objectives:

• Screen potential ALS patients with SOD1 gene mutations and disease severity who may benefit from tofersen treatment.

• Apply best practices for pharmacovigilance to identify and manage any adverse events associated with tofersen use in patients to avoid treatment-related complications.

• Assess the response to tofersen treatment by regularly evaluating ALS symptoms, disease progression, and changes in quality of life following the therapy.

• Communicate effectively with patients and their caregivers about the potential benefits, risks, and expectations of tofersen therapy.

Indications

Indications

Tofersen, a novel antisense oligonucleotide (ASO) drug, received accelerated approval from the U.S. Food and Drug Administration (FDA) in April 2023 for the treatment of amyotrophic lateral sclerosis (ALS). ALS is a progressive, fatal neurodegenerative disorder affecting motor neurons in the brain and spinal cord, leading to muscle weakness, paralysis, and eventual death. Tofersen is specifically indicated for ALS patients with a superoxide dismutase 1 (SOD1) gene mutation. The mutant SOD1 protein resulting from this gene mutation gains a toxic function and significantly increases the amount of SOD1 messenger RNA (mRNA) and protein in the cerebrospinal fluid (CSF).[1] 

Mutations in the SOD1 gene represent the second-most common cause of familial ALS, occurring in approximately 10% to 20% of familial cases and approximately 1% to 2% of sporadic ALS cases.[2][3] Unfortunately, ALS has no cure, and the existing treatments can only provide modest symptomatic relief.  

Tofersen is specifically indicated for ALS patients with a confirmed SOD1 mutation, which can be detected through genetic testing. The drug targets the mRNA produced from mutated SOD1 genes, effectively reducing the synthesis of toxic SOD1 proteins. These toxic proteins are known to cause protein misfolding and aggregation within motor neurons and astrocytes, contributing to the progression of the disease. The accumulation of mutant SOD1 proteins can lead to cellular dysfunction, resulting in neurodegeneration and muscle weakness in ALS patients.[4] Tofersen represents a significant advancement in neurology, as it is the first disease-modifying therapy available for ALS.  

Tofersen received accelerated FDA approval based on its ability to decrease plasma neurofilament light chain (NfL), a marker historically used to assess disease progression.[5][6] Although the FDA has approved tofersen for clinical use, ongoing trials will continue to investigate whether this drug offers significant clinical benefits. The accelerated approval process is distinct from the official FDA approval, as the drug has not been conclusively proven to be clinically beneficial yet; therefore, it will still need to undergo rigorous testing.[7] Tofersen has completed 3 phases of clinical trials, demonstrating its ability to modify the expression of the SOD1 protein and NfL marker.  

In the phase 3 clinical trial, known as the VALOR trial, the safety and efficacy of tofersen were evaluated. The study involved 108 adults diagnosed with ALS and a confirmed mutation in the SOD1 gene.[6][1] Tofersen did not achieve the primary objective of slowing the progression of the disease, as determined by the Revised Amyotrophic Lateral Sclerosis Functional Rating Scale (ALSFRS-R) after 28 weeks.[6][1] The ALSFRS-R questionnaire allows patients to self-report their physical capabilities based on balance, fine and gross motor abilities, and respiratory function.[8] Although improvements were observed in the treatment group, they were not statistically significant.[1]

During phase 1 and 2 trials, the administration of tofersen resulted in a sustained reduction of 33% in the total levels of CSF SOD1 protein in the CSF. This data demonstrate compelling evidence of the drug's ability to modify its intended target effectively. Furthermore, in phase 1 and 2 trials, tofersen administration was associated with decreased concentrations of NfL marker and phosphorylated heavy chain (pNfH) in both serum and CSF. These biomarkers are commonly utilized as indicators of neuronal degeneration.[9][10] This observation was specifically noted in the group receiving 100 mg of tofersen, not the group receiving the placebo.[10] 

A follow-up study utilizing 12 months of data from the VALOR trial and its open-label extension revealed that the earlier initiation of tofersen led to a notable deceleration in the decline of clinical and respiratory function, strength, and overall quality of life in patients with SOD1-ALS.[6] The continued approval of tofersen may rely on confirming its clinical benefit through additional confirmatory trial(s).  

Tofersen is not a cure for ALS, as its benefits are limited to a small subset of patients with SOD1 mutations. Patients with ALS without SOD1 mutation will not benefit from tofersen and, therefore, should not consider it a viable treatment option. Whether tofersen will improve ALS patients' survival or quality of life is uncertain. However, research has indicated that it could potentially slow down the progression of the disease. The clinical benefit of tofersen is currently being evaluated under the FDA's accelerated approval process and will be continuously monitored.

Further research is necessary to determine the long-term effects and optimal dosing of tofersen. Currently, tofersen is not being used for any off-label purposes. Patients considering starting tofersen treatment should consult their doctor to assess the potential benefits and risks associated with the drug. 

Mechanism of Action

Mechanism of Action

Tofersen belongs to the class of ASOs, which are short, synthetic, single strands of RNA or DNA that bind to a complementary sequence and alter the expression of mRNA.[11] Tofersen directly binds to and mediates the degradation of SOD1 mRNA produced from mutated SOD1 genes, effectively leading to a decrease in the synthesis of the SOD1 protein.[12][1] 

Mutated SOD1 protein is known to have toxic effects on motor neurons and astrocytes, the major cell types involved in ALS development and progression.[13] By lowering the levels of SOD1 protein in the CSF and blood, tofersen can slow down the rate of disease progression and enhance the quality of life of patients with SOD1 ALS. 

Pharmacokinetics

Absorption: Tofersen is administered directly into the CSF through lumbar puncture and is absorbed by the central nervous system (CNS). After the monthly maintenance dose, there is very little or no buildup of tofersen in the CSF or plasma.

Distribution: Tofersen has the ability to distribute into the tissues of the CNS.[7]

Metabolism: Tofersen is expected to undergo metabolism through (3’-5’) exonuclease-mediated hydrolysis.[7] Tofersen has not shown any evidence of interactions with cytochrome P450 enzymes.[7]

Excretion: The excretion of tofersen has not been extensively studied. However, the estimated effective half-life of the drug within the CNS is approximately 4 weeks.[7]

Administration

Administration

Tofersen is administered intrathecally using a lumbar puncture. A lumbar puncture involves using a long, thin needle to puncture the skin and its underlying structures in the lower back, allowing access to the space surrounding the spinal cord for drug delivery. ASOs do not readily pass through the blood-brain barrier and, as a result, must be administered directly into the CNS. Before administering a dose of tofersen, it is recommended to extract 10 mL of CSF from the patient. This procedure prevents fluid overload and reduces the potential risk of increased intracranial pressure. To administer tofersen in patients, it is recommended to inject the medication slowly for 1 to 3 minutes using the same lumbar needle previously employed for the removal of the CSF.  

The recommended dosage of tofersen for adults is 100 mg (per 15 mL) per administration. The administration of tofersen begins with 3 loading doses, followed by a monthly maintenance dose. The first 3 doses of 100 mg are administered to patients at 14-day intervals, with subsequent doses provided at 28-day intervals after that.[7]

Patients may be given a sedative if tofersen administration causes them severe distress. Lumbar punctures can be uncomfortable procedures and often lead to lower back discomfort, headaches, and dizziness.[14] Image guidance may be used to ensure accurate needle placement and depth during the tofersen administration.[15] Imaging techniques, such as computed tomography and ultrasound guidance, are frequently utilized to assist in precisely placing the lumbar needle, particularly in patients with orthopedic hardware, obesity, or abnormal anatomy. As not all physicians offer sedatives or use imaging techniques during the procedure, it is important to discuss with your doctor the available options before any needle placement procedure.

Specific Patient Populations  

No specific study has been conducted on administering tofersen in specific populations. In addition, clinical data regarding the pharmacokinetics of tofersen in patients with renal or hepatic impairment is currently unavailable. Tofersen treatment response in pregnant women, breastfeeding mothers, pediatric patients, and older individuals has not yet been studied in human populations. Please refer to the Monitoring section of this article for additional information.  

Missed Dosage

If the second loading dose of tofersen is delayed, it should be administered to the patient as soon as possible. The subsequent dose (third dose) should be given at the regular interval of 14 days. If the third loading or maintenance dose is missed, tofersen should be administered to the patient as soon as possible. Thereafter, the patient should continue to receive doses at 28-day intervals, following prior recommendations.  

Adverse Effects

Adverse Effects

The most common adverse effects of tofersen are headache, injection-site pain, fatigue, arthralgia (joint pain), pleocytosis (increase in CSF white blood cells), and myalgia (muscle pain).[6][10] Pleocytosis was the most significant adverse event observed between the placebo and treatment groups, with 42% of tofersen patients experiencing an increase in white blood cells compared to only 8% of placebo patients.[10] 

However, pleocytosis is not directly correlated with patients experiencing specific adverse effects. Tofersen may also cause more severe adverse events, including myelitis and radiculitis (inflammation and damage of the spinal cord and nerve roots), papilledema and elevated intracranial pressure (swelling and increased pressure in the optic nerve and brain), and aseptic meningitis (inflammation of the membranes covering the brain and spinal cord).

These adverse effects may arise due to direct drug effects or complications related to administering the drug through a lumbar puncture, which introduces foreign materials into the sterile CNS cavity. These adverse effects can be severe and potentially life-threatening necessitating an immediate diagnostic workup and prompt treatment following the standard of care. Patients experiencing these previously discussed adverse effects should recover with appropriate medical treatment (if applicable) and cease tofersen dosing. Patients are advised to consult their healthcare provider before using tofersen and promptly report any symptoms or adverse reactions they may experience. 

Drug-Drug Interactions

Drug-drug interactions with tofersen have not been extensively studied. Currently, no evidence suggests that tofersen interacts with cytochrome P450 enzymes or major cellular transporters.  

Contraindications

Contraindications

The clinical trials did not report any contraindications associated with the use of tofersen. Moreover, it is important to note that tofersen does not undergo hepatic metabolism.  

Box Warning

No box warnings are associated with tofersen at this time.

Precautions

Some adverse effects have been reported with tofersen use, including myelitis, radiculitis, papilledema, increased intracranial pressure, and aseptic meningitis. Although rare, these adverse effects can be life-threatening and require close monitoring and immediate medical attention if they occur.  

Monitoring

Monitoring 

Pregnant Patients

Tofersen has not been subjected to clinical studies to evaluate its safety in pregnant women. Currently, there is a lack of sufficient data regarding the developmental risks of tofersen, including major congenital defects, miscarriage, or other adverse maternal or fetal outcomes associated with its use during pregnancy. In animal studies involving pregnant mice and rabbits, tofersen did not demonstrate any adverse effects on pregnancy, embryo-fetal development, or prenatal or postnatal development. However, the results of animal studies may not directly translate to human pregnancy outcomes, and the risks of using tofersen in pregnant women and their children remain uncertain. Therefore, tofersen should be administered during pregnancy only when the potential benefits outweigh the potential risks to the fetus and after careful evaluation and consultation with the healthcare provider. 

Lactation Considerations

Tofersen may have an impact on breast milk and breastfed infants. However, currently, there is no available data regarding its metabolites in human milk, effects on breastfed infants, or influence on milk production. In animal studies, tofersen was detected in the milk of lactating mice after subcutaneous administration. Therefore, when a patient is breastfeeding while taking tofersen, it is crucial to carefully consider and assess both the potential benefits and possible risks of the drug on the health of both the infant and the mother. 

Pediatric Patients

The safety and effectiveness of tofersen in pediatric patients have not been established yet. ALS primarily affects older individuals aged 55 to 75. 

Older Patients

Based on the FDA drug insert information for tofersen, it was found that out of 162 clinical study participants with ALS and a SOD1 mutation, 22 patients (13.5%) were aged 65 or older, and 2 patients (1.2%) were aged 75 or older at the beginning of the treatment. Although tofersen was found to be safe and effective for these older patients, it is still important to monitor them closely as some older patients may have different reactions to the treatment. There is no evidence to suggest that specific dosage adjustments for tofersen should be made based on a patient's age.

Toxicity

Toxicity

The toxicity of tofersen has not been extensively studied. However, due to the characteristics of ASO drugs and their limited bioavailability in the CNS, the toxicity of tofersen is considered to be restricted. Notably, no antidote or specific treatment is currently available for an overdose of tofersen.

Enhancing Healthcare Team Outcomes

Enhancing Healthcare Team Outcomes

Diagnosing and treating ALS necessitates the collaboration of an interprofessional healthcare team consisting of physicians from various specialties, advanced practice practitioners, respiratory therapists, nursing staff, and pharmacists. The diagnostic process usually commences with a comprehensive history and physical examination conducted by a primary care physician. Common initial symptoms of ALS may include muscle weakness, poor coordination, slurred speech, or shortness of breath during moderate exertion. When patients present with ALS symptoms, they will be referred to a neurologist who will conduct a comprehensive set of diagnostic evaluations. These evaluations may include electrical conduction studies, pulmonary function tests, blood tests, and imaging studies to aid in reaching an accurate diagnosis.

Patients diagnosed with ALS should have regular follow-up appointments with their neurologist and pulmonologist to monitor disease progression and treatment effectiveness. These clinicians collaborate closely with pharmacists with extensive experience in current and emerging pharmacological treatments for neurological diseases. The interprofessional team of healthcare professionals ensures appropriate pharmacological management and comprehensive care for ALS patients. Furthermore, the healthcare team will include respiratory therapists and nurses responsible for monitoring vital signs and breathing function to predict clinical status and potential for decline. The treatment course may be adjusted through shared decision-making based on each healthcare professional's collective findings and assessments. The comprehensive and effective care and treatment for ALS patients require a diverse and highly competent interprofessional team of healthcare practitioners.