Risdiplam

Treatment of Spinal Muscular Atrophy

Risdiplam is used to treat spinal muscular atrophy (SMA), a rare genetic disorder that affects the central nervous system and voluntary muscle movement. SMA causes the nerve cells in the spinal cord to break down, leading to muscle weakness and wasting (atrophy). This can interfere with essential activities such as walking, breathing, and swallowing.

Patient Population

This medication is approved for use in a wide range of patients, including:

• Adults
• Children
• Infants (including those under two months of age)

Risdiplam is used for various forms of the condition, including Type 1, Type 2, and Type 3 SMA. It is typically prescribed after a diagnosis has been confirmed through genetic testing. The goal of treatment is to help improve muscle function or slow the progression of the disease.

Treating the Cause of Spinal Muscular Atrophy

Spinal muscular atrophy (SMA) is a genetic condition caused by a deficiency of a protein called survival motor neuron (SMN). This protein is critical for the health of motor neurons, which are the nerve cells in the spinal cord that send signals to the muscles. When SMN protein levels are too low, these nerve cells break down and die, leading to progressive muscle weakness and wasting.

How Risdiplam Increases Protein Levels

Most people have two genes that can produce SMN protein: SMN1 and SMN2. People with SMA have a mutation in the SMN1 gene, meaning they must rely on the SMN2 gene. However, the SMN2 gene normally produces only a small amount of functional protein because of a splicing error in its genetic instructions.

Risdiplam is a survival motor neuron 2 (SMN2)-directed RNA splicing modifier. It works by:

• Targeting the SMN2 gene: It interacts with the genetic instructions produced by the SMN2 gene.
• Correcting the splicing process: It helps the gene produce a full-length, functional version of the SMN protein instead of a shortened, unstable version.
• Boosting protein levels: By correcting this process, the medication increases the total amount of functional SMN protein available throughout the body, including the central nervous system.

By increasing the levels of functional SMN protein, risdiplam helps support the survival of motor neurons and may improve muscle function and motor milestones in individuals with SMA.

Common Side Effects

The most frequently reported side effects of risdiplam vary slightly depending on the age of the patient. Common side effects include:

• Fever
• Diarrhea
• Skin rash
• Mouth sores
• Joint pain
• Bladder infections
• Upper respiratory tract infections, such as the common cold, sore throat, or cough
• Vomiting
• Constipation

In infants, common side effects often include fever, diarrhea, rash, and lower respiratory tract infections like pneumonia or bronchitis.

Serious Side Effects

Some side effects can be serious and require immediate medical attention. Contact a doctor right away if you notice:

• Signs of a severe allergic reaction, including hives, swelling of the face, lips, or tongue, and difficulty breathing.
• Symptoms of liver problems, such as yellowing of the skin or the whites of the eyes (jaundice) or dark-colored urine.

Pregnancy and Fetal Risk

Risdiplam may cause harm to a developing fetus. Animal studies have shown that the medication can lead to birth defects or fetal death. Healthcare providers typically require a pregnancy test for individuals of childbearing potential before starting the medication. Effective contraception is necessary during treatment and for at least one month after the last dose.

Male Fertility

Animal studies suggest that risdiplam may affect male fertility by reducing sperm count and impacting sperm quality. Men with partners of childbearing potential are advised to use effective contraception during treatment and for at least four months after the final dose.

Drug Interactions

Risdiplam can increase the concentration of certain drugs in the body, specifically those that are substrates of multidrug and toxin extrusion (MATE) transporters, such as metformin. This may increase the risk of side effects from those medications.

Safe Handling

The oral solution should be handled carefully. If the medication contacts the skin or eyes, the area should be washed immediately with soap and water or rinsed thoroughly with water. The medication must be prepared by a pharmacist and should not be mixed with formula or milk.

Pregnancy Considerations

Risdiplam can cause harm to a fetus based on findings from animal studies. Before starting this medication, healthcare providers typically require a pregnancy test for individuals who can become pregnant. If you are pregnant or planning to become pregnant, discuss the potential risks and benefits with your doctor.

Contraception Requirements

Because of the risk of fetal harm, specific birth control measures are recommended for both men and women:

• Females: Use effective contraception during treatment and for at least 1 month after the last dose.
• Males: Use effective contraception during treatment and for at least 4 months after the last dose to prevent potential risks to a partner's pregnancy. This medication may also affect male fertility.

Breastfeeding

It is not known whether risdiplam passes into human breast milk or how it might affect a nursing infant. Due to the potential for serious adverse reactions in a breastfed child, breastfeeding is generally not recommended while taking this medication. Consult a healthcare provider to discuss the best way to feed your baby during treatment.

Available Forms

Risdiplam is available in the following form:

• Powder for Oral Solution: This medication is supplied as a powder that must be mixed with water by a pharmacist to create a liquid solution.

The resulting liquid is taken by mouth or administered through a feeding tube.

FDA Approval History

The U.S. Food and Drug Administration (FDA) first approved risdiplam in August 2020. It was initially indicated for the treatment of spinal muscular atrophy (SMA) in patients 2 months of age and older. In May 2022, the FDA expanded the approval to include infants under 2 months of age, making it available for patients of all ages with SMA.

Regulatory Designations

During its development and review process, risdiplam received several special designations from the FDA, including:

• Fast Track designation: Intended to facilitate the development and expedite the review of drugs to treat serious conditions and fill an unmet medical need.
• Priority Review: Granted to applications for drugs that, if approved, would offer significant improvements in the safety or effectiveness of the treatment, diagnosis, or prevention of serious conditions.
• Orphan Drug designation: Provides incentives to assist and encourage the development of drugs for rare diseases.

Safety and Monitoring

There are currently no boxed warnings or Risk Evaluation and Mitigation Strategies (REMS) required by the FDA for risdiplam. The approval was based on clinical trials evaluating the drug's efficacy in improving motor function and survival in patients with different types of SMA.

Insurance and Prior Authorization

Risdiplam is generally classified as a specialty drug. Most insurance providers require prior authorization before covering the treatment. This process requires healthcare providers to submit medical documentation to the insurance company to confirm that the patient meets the specific criteria for the medication.

Specialty Pharmacy Services

Because of its specialized handling requirements, risdiplam is usually obtained through a specialty pharmacy rather than a standard community pharmacy. Specialty pharmacies work with patients and insurance companies to coordinate delivery and may provide additional support for managing the treatment regimen.

Financial Assistance Programs

Patients may have access to financial assistance programs to help cover out-of-pocket expenses. These may include manufacturer-sponsored programs for those with commercial insurance or assistance for individuals who are uninsured. Healthcare providers or specialty pharmacy staff can often assist in identifying these resources.