tofersen

Action and Spectrum

Actions and Spectrum:

tofersen (BIIB067) is a synthetic antisense oligonucleotide drug designed to treat patients with amyotrophic lateral sclerosis (ALS). This neurodegenerative disease affects the nerve cells responsible for controlling voluntary muscles. tofersen works by targeting and reducing the levels of superoxide dismutase 1 (SOD1) protein, which is known to contribute to the disease.

The spectrum of tofersen refers to the drug’s range of effects on patients. In the case of tofersen, the drug is designed to target patients with ALS who have a specific mutation in the SOD1 gene, which is present in a subset of ALS patients.

The actions of tofersen involve targeting and reducing the levels of SOD1 protein in the nervous system, which is believed to be a pivotal contributor to the progression of ALS. By reducing the levels of this protein, tofersen may slow or halt the degeneration of motor neurons in the spinal cord and brain, leading to improved muscle function and increased lifespan in patients with ALS. tofersen is administered through intrathecal injection, which delivers the drug directly into the cerebrospinal fluid surrounding the spinal cord and brain, where it can reach the affected neurons.

Drug Interaction

Adverse Reaction

>10%

Pain

Arthralgia

Fatigue

Myalgia

Increased WBCs

1-10%

Neuralgia

Musculoskeletal stiffness

Increased CSF protein

Frequency not defined

Myelitis

Radiculitis

Aseptic meningitis

Pyrexia

Papilledema

Elevated intracranial pressure (ICP)

Black Box Warning

None

Contraindication / Caution

Contraindication/Caution:

One major contraindication of tofersen is a history of hypersensitivity or an allergic reaction to the drug. Patients allergic to tofersen or its components should not receive the drug.

Another caution with tofersen is that it is not recommended in patients with a history of bleeding disorders or taking anticoagulant medications, as the drug may increase the risk of bleeding.

Additionally, tofersen has not been studied in pregnant or breastfeeding women, and its safety and efficacy in these populations are unknown. Therefore, tofersen should be avoided during pregnancy and breastfeeding unless the potential benefits outweigh the risks.

Pregnancy / Lactation

Pregnancy consideration:

No data is available regarding any fetal defects caused due to drug intake during pregnancy.

Breastfeeding warnings:

No data is available regarding the excretion of the drug in breast milk.

The drug is detected in the subcutaneously injected mice, which are lactating.

Pregnancy category:

• Category A: Satisfactory and well-controlled studies show no risk to the fetus in the first or later trimester.
• Category B: No evidence of risk to the fetus is found in animal reproduction studies, and there are not enough studies on pregnant women.
• Category C: Adverse effects on the fetus found with evidence in animal reproduction studies and no adequate evidence for a human product; Pregnant women must take care of the potential risks.
• Category D: There is adequate data with sufficient evidence of human fetal risk from various platforms. However, despite potential dangers may be used only in emergencies for potential benefits.
• Category X: Drugs listed in this category outweigh the risks over benefits. The drug is not for pregnant women.

Category N: No data for the drug under this category is available.

Pharmacology

Pharmacology:

tofersen is a synthetic antisense oligonucleotide drug designed to reduce superoxide dismutase 1 (SOD1) protein levels in patients with amyotrophic lateral sclerosis (ALS). The drug is administered via intrathecal injection, which delivers it directly into the cerebrospinal fluid surrounding the spinal cord and brain.

Once administered, tofersen binds to the messenger RNA (mRNA) produced by the SOD1 gene and induces its degradation. This reduces the levels of SOD1 protein in the nervous system, which is believed to be a pivotal contributor to the progression of ALS.

tofersen is designed to target patients with ALS who have a specific mutation in the SOD1 gene, which is present in a subset of ALS patients. By reducing the levels of this mutant protein, tofersen may slow or halt the degeneration of motor neurons in the spinal cord and brain, which can lead to improved muscle function and increased lifespan in patients with ALS.

Pharmacodynamics:

tofersen is an antisense oligonucleotide designed to treat amyotrophic lateral sclerosis (ALS) caused by mutations in the SOD1 gene. The pharmacodynamics of tofersen refers to its mechanism of action and effects on the body.

tofersen works by targeting and binding to messenger RNA (mRNA) produced by the mutant SOD1 gene, which leads to the degradation of the mRNA and a decrease in the production of the toxic SOD1 protein. This reduction in toxic protein production has been shown to slow disease progression in animal models of ALS.

In clinical trials, tofersen has demonstrated a dose-dependent reduction in SOD1 protein levels in the cerebrospinal fluid (CSF) of patients with ALS carrying the SOD1 mutation. This reduction in protein levels was accompanied by a slowing of disease progression, as measured by the ALS Functional Rating Scale-Revised (ALSFRS-R) and other clinical assessments.

The pharmacodynamics of tofersen also includes its pharmacokinetic properties, such as absorption, distribution, metabolism, and elimination from the body. tofersen is administered via intrathecal injection into the spinal fluid, which allows it to reach the motor neurons affected by ALS. It has a long half-life in the CSF, which allows for once-monthly dosing.

Pharmacokinetics:

Absorption

tofersen transfers from the cerebrospinal fluid into the systemic circulation, with a median time to maximum concentration. The plasma values range from 2-6 hours.

Distribution

Intrathecal administration follows drug distribution in CNS tissues

Metabolism

The metabolism occurs through exonuclease (3′- and 5′)-mediated hydrolysis.

Elimination and Excretion

The estimated elimination half-life is weeks

Adminstartion

Administration:

tofersen is administered via intrathecal injection, injected directly into the spinal fluid. This route of administration is necessary because tofersen needs to cross the blood-brain barrier to reach the motor neurons affected by ALS.

A healthcare professional typically injects a clinical setting, such as a hospital or infusion center. Before the injection, the patient will undergo a spinal tap to collect a small cerebrospinal fluid (CSF) sample for analysis. The injection is then performed using a specialized needle inserted into the spinal canal.

The dosage and frequency of tofersen administration will depend on the patient’s condition and response to the treatment. In clinical trials, tofersen was administered once a month at 100 mg.

Patients receiving tofersen may experience side effects related to the injection, such as headache, back pain, or fever. More severe side effects, such as meningitis or encephalitis, are rare but can occur.

Patient Information Leaflet

Patient information leaflet

Generic Name: tofersen

Pronounced: toe-FER-sen

Why do we use tofersen?

tofersen is used to treat a specific type of amyotrophic lateral sclerosis (ALS) caused by mutations in the SOD1 gene. ALS, also known as Lou Gehrig’s disease, is a progressive neurological disorder that affects the motor neurons responsible for controlling voluntary muscle movement.