Nusinersen - Indications, Pharmacology, Warnings, and Precautions

Overview

Nusinersen is a peculiar medicine that is employed for the treatment of an inborn medical condition called spinal muscular atrophy (SMA), where the affected person elicits appreciable compromise in muscular movements and strength as the neurons concerned with motor activities are impaired. The Nusinersen therapy for individuals who are detected with spinal muscular atrophy is endorsed by the drug regulatory body of the United States, the Food and Drug Administration (FDA). Nusinersen received authorization from the FDA in the year 2016. It holds the privilege of being the first approved medicine to deal with spinal muscular atrophy. It is proven to be effective in treating patients of both younger and adult age groups.

Drug Group:

Nusinersen falls under the antisense oligonucleotide drug class. It is a peculiar drug class that works on the genetic level by revising the splicing process in such a way as to enhance the expression of its protein production.

Available Doses and Dosage Forms:

• Dosage Forms: It is marketed only in the form of injection medicine. Other forms of Nusinersen are neither approved nor marketed for treatment purposes.

• Available Dose: Nusinersen is available as an injection solution with a dosage of 12 milligrams of Nusinersen dissolved in a five-milliliter injection solution.

For Patients:

What Is Spinal Muscular Atrophy?

Spinal muscular atrophy (SMA) is quite an unfamiliar and peculiar inborn condition, where the person is born with errors in the gene, which is clinically flagged as weakened and atrophic (collapse in size) muscles. It impairs the nervous system as well as the muscular system. Muscular actions and movements are primarily regulated by the nervous system, especially the skeletal muscles, which are concerned with mobility. Many such nerve cells are rooted in the spinal cord, which conveys the signal from the brain to the concerned muscles to elicit movement. In spinal muscular atrophy, the signal transmission gets hindered, and the impulse for eliciting movement does not strike the muscles.

It develops due to trouble with a crucial protein concerned with motor neuron functions - survival motor neuron protein (SMN protein). SMN protein insufficiency arises from a faulty gene that is responsible for its production. Shoulder muscles, back muscles, thigh muscles, and muscles in the hip region elicit weakness within the initial stages. However, the intensity of failing muscles varies on an individual basis, and it is on par with the severity of protein insufficiency. A shortfall in the SMN protein not only impairs the functionalities of motor neurons but it also wrecks the neuron and murders it.

The treatment strategy for spinal muscular atrophy focuses on checking complications and extending the longevity of the affected person. Earlier, individuals who were reported with spinal muscular atrophy hardly lived for another couple of years, but with the advancement in medical therapies and treatment interventions, novel medicines like Nusinersen came into being that can improve longevity.

How Does Nusinersen Work?

Nusinersen works by enhancing the amount of SMN (survival motor neuron) protein. Abnormal functioning of the SMN1 gene directly hinders the production of SMN protein in spinal muscular atrophy patients. Nusinersen works to counterbalance the deficit by enhancing the productivity of the variant SMN gene, SMN2. It facilitates the functioning of the SMN2 gene, which is otherwise concerned with minimal SMN protein production. In this way, Nusinersen works to bring up the collapsed SMN protein level, which in turn aids in motor neuron survival and functions.

What Is the Dosage of Nusinersen?

12 milligrams of Nusinersen per five milliliters of injection solution is considered to be the ideal dosage for spinal muscular atrophy. The treatment regime with Nusinersen encompasses loading doses and maintenance doses. The loading doses are the initial four doses, where the first three are given with a gap of 14 days, while the final loading dose requires a 30 days break following the third one. Maintenance doses are given every four months following the last loading dose.

How Effective Is Nusinersen?

Nusinersen offers promising results and outcomes in spinal muscular atrophy patients. There will be a drastic improvement in muscular strength. The patient becomes more capable of carrying out day-to-day life activities, which demands motor skills. Certain clinical trials in spinal muscular atrophy patients concluded the efficacy of Nusinersen in bringing up motor skills. In addition, it acts as a check on the disease advancement and further worsening of the condition. Thus, it helps in tackling the condition to an extent and improves longevity.

What Are the Things to Inform the Doctor Before Taking the Drug?

• Previous allergic encounters with Nusinersen or its related drug should be discussed with the doctor so that the potential risk associated with further exposure can be assessed.

• The entire drug history, as well as medical history, should be made available to the concerned doctor. In case the person suffers from some other illness or ailments in addition to spinal muscular atrophy, complete information regarding the underlying conditions should be disclosed to the doctor. The doctors then assess all these medical conditions and plan the treatment accordingly. Pre-existing kidney disease should be informed without fail as it can precipitate serious kidney disorders.

• Similarly, for patients who are undertaking other medications or therapies, the treating doctor should be made aware of those medicines so that the doctor can look for anticipated interaction of the Nusinersen with other medicines. Certain drug-drug associations impair the effectiveness and demand dose or drug modifications.

• Pregnancy and lactating status are the two important factors that need to be disclosed prior to the commencement of Nusinersen therapy. Even if the patient conceives during the therapy regime, it should be immediately reported to the concerned doctor to assess the safety of the medicine under these two specific situations.

How Is Nusinersen Administered?

The intrathecal route is the only accepted method of Nusinersen drug administration in spinal muscular atrophy patients, where the medicine is deposited into the fluid envelope of the spinal cord. It is done by a procedure called lumbar puncture in which the specific medicine is introduced into the site with the help of long-needled syringes. It requires precise knowledge of the human anatomy, and hence, it can only be done by trained and qualified healthcare professionals. This injection is done after numbing the intended area with local anesthetics to ease the discomfort during the procedure.

What Are the Side Effects of Nusinersen?

Nusinersen can bring about certain undesirable side effects upon administration. Some of the widely reported side effects include the following:

• The patients elicit an unexplainable bleeding tendency and trouble with blood clotting. It is often the result of Nusinersen-induced thrombocytopenia, which is depicted as a remarkable collapse in the platelet count.

• Nusinersen is capable of deteriorating kidney functions, especially when administered to patients with active kidney diseases. The patients may experience trouble in passing urine, often accompanied by pain and strain. There will be a pronounced elevation in the urgency and frequency of urination. Impaired kidney functioning precipitates swollen and puffy legs, indicating the gathering of fluid over the leg region.

• Chills, fever, and trouble breathing with persistent cough are also reported with Nusinersen administration.

• Back pain, headache, and vomiting are the routinely encountered milder side effects of Nusinersen. There will be associated weight loss during the treatment period. Bloating (gas disturbances) and constipation may develop on and off.

Dietary Considerations:

Nusinersen is introduced into the body via lumbar injections, and hence, there are no specific dietary considerations to be followed for Nusinersen administration. No oral intake is advised, and it is not marketed in tablets or any other form other than the injection medicine.

Missed Dose:

At times, the patient may miss taking the loading or maintenance doses on the stipulated date. In such cases, it is advised to get a Nusinersen injection once the patient realizes the delay. Further care should be employed to maintain the 14-day gap for the next loading dose and four months gap for the next maintenance dose. Even if the previous dose was delayed, the interval should be promptly maintained, calculated from the day of injection.

Overdose:

There is minimal risk of Nusinersen overdose as the medicine is injected by healthcare professionals directly. However, in the event of an overdose, the patients require prompt medical attention and should be maintained under close monitoring to look for signs of complications.

Storage:

Nusinersen should be refrigerated at a temperature range of two to eight degrees Celsius (46.4 degrees Fahrenheit). However, it should never be frozen as it can alter the component structure and its effectiveness. Exposure to high temperatures and light also spoils the medicine, and hence, it should be kept away from those agents. Nusinersen stays in good condition for about 14 days, even without refrigeration, provided the exposed temperature should fall below 30 degrees Celsius (86 degrees Fahrenheit). Long-term storage of Nusinersen clearly mandates refrigeration.

For Doctors:

Indication:

• Spinal muscular atrophy.

Dose:

The dosage of Nusinersen is fixed at 12 milligrams per milliliter (mg per ml) of injection solution. The dosage remains the same for the pediatric as well as the adult population. The drug is intrathecally deposited by the lumbar puncture technique. The treatment therapy lasts for a specific period during which the patient initially receives three loading doses of 12 mg per ml Nusinersen, maintaining a 14 days gap between each dose. Following the third dose, the final loading dose of Nusinersen is advised post-30 days. Once the four loading doses are given, the maintenance dose regime commences, with an interval of four months.

Dosing Considerations:

A spinal anesthesia needle is employed for the Nusinersen intrathecal injection. No dose alteration is generally indicated. Prior to the injection of Nusinersen, five milliliters of the cerebrospinal fluid (CSF) should be drained to accommodate the injection solution and to reduce the soreness at the injection area post the procedure.

What Are the Pharmacological Aspects of Nusinersen?

• Mechanism: Nusinersen works on the survival motor neuron 2 (SMN2) gene, which is also involved in the SMN protein synthesis, but its contribution is much less in comparison with the SMN1 gene. In spinal muscular atrophy patients, the primary contributor of SMN protein, the SMN1 gene, is defective due to alteration in the gene makeup of chromosome 5q. As a result, there will be a collapse in the SMN protein level, which is identified as an integral element for motor nerves, especially in the spinal cord. Nusinersen counterbalances this depreciation by enhancing SMN protein productivity. It is achieved by revising and modifying the splicing process of the SMN2 gene, which enables the incorporation of exon 7. This facilitates the efficacy of SMN protein production by the SMN2 gene to cover up the protein deficit in spinal muscular atrophy patients, and hence Nusinersen is categorized as an antisense oligonucleotide (ASO).

• Pharmacodynamics: Nusinersen enhances the concentration of SMN2 mRNA (messenger ribonucleic acid) with add-on exon 7. This upsurge in concentration is highly appreciated in the spinal cord, especially in the thoracic segments.

• Pharmacokinetics: Unlike other medicines, Nusinersen is directly infused into the cerebrospinal fluid to ensure immediate access to the central nervous system. However, the utmost plasma concentration of Nusinersen is reported hours later, and it is evaluated to be within the range of 1.7 to six hours post intrathecal administration. In addition to the central nervous system, Nusinersen also gets distributed to other organs like skeletal muscles, kidneys, and liver. Nusinersen is broken down by the hydrolysis process. Nusinersen removal is quite a prolonged process and lasts for several days. The major bulk of elimination happens via urine.

Toxicity:

There is no reliable data about the clinical toxicology concerning the use of Nusinersen. However, few animal studies were conducted in mice, and no potential mutagenicity and infertility issues were reported in those studies. The carcinogenicity of Nusinersen in animals could not be demonstrated because of the absence of study reports.

Clinical Studies:

Human trials were executed to demonstrate the potency as well as safety concerning the use of Nusinersen. Patients who were diagnosed with infantile-onset spinal muscular atrophy were chosen for the case group. Randomization and double-blinding were employed to check all forms of bias in the research results. The study results concluded the effectiveness of Nusinersen in enhancing the motor skills of the patients. A better response is obtained from patients who were in the initial phase of the disease.

What Are the Contraindications of Nusinersen?

There is no specific contraindication for the use of Nusinersen; however, a person with hyper-reactivity or sensitivity to any of the elements in the Nusinersen injection solution should not be given the medicine. In suspected patients, the allergy test for Nusinersen should be employed to check grave allergic responses and to clear off the suspicion.

Warnings and Precautions:

• Bleeding Complications - Being an antisense oligonucleotide, Nusinersen poses the risk of developing bleeding issues. Coagulopathies were reported with various antisense oligonucleotides, and hence, caution should be employed during the therapy period. Acute episodes of thrombocytopenia may also get precipitated with Nusinersen therapy, and therefore, it is advised to keep track of the blood profile, typically the platelet count and coagulation status, to monitor the likelihood of thrombocytopenia or impaired coagulation. The healthcare professional should ensure that the blood profile is within the normal anticipated range before exposing the patient to the subsequent dose of Nusinersen.

• Renal Impairment - Nusinersen can also impair the functions of the kidney, especially in patients with compromised kidney function and pre-existing kidney pathologies. Cases of grave glomerulonephritis were reported with the use of antisense oligonucleotides. Clinical trials also concluded the presence of an appreciable proportion of proteins in the urine samples of patients undergoing therapy using Nusinersen. A periodic assessment of the urine sample of the patients should be followed to rule out proteinuria while undergoing Nusinersen therapy.

The intrathecal introduction of Nusinersen can give rise to certain sorts of discomforts in the form of back pain, headache, and vomiting. The lumbar puncture technique employed in Nusinersen therapy also poses challenges in patients with skeletal deformities like scoliosis, and in such cases, imaging techniques help guide the concerned healthcare professional.

What Are the Drug Interactions of Nusinersen?

No obvious and potential drug interactions have been demonstrated with Nusinersen, and neither such studies were conducted. Since it does not interfere with the liver's cytochrome enzymes, it is less likely to elicit interactions with the actions and metabolism of other drugs.

Specific Considerations:

• Nusinersen During Pregnancy: The use of Nusinersen in expectant mothers is still doubtful as it lacks scientific evidence exposing Nusinersen’s impact on the fetus as well as on the pregnant lady. However, animal studies were in favor and failed to identify potential birth defects.

• Nusinersen During Lactation: Lack of information concerning the consequences of Nusinersen therapy during breastfeeding makes it challenging to demonstrate a conclusive opinion. However, the doctor possesses the discrete authority to analyze such cases and to evaluate the risk-benefit ratio. Nusinersen therapy will be initiated only after taking into account all the possibilities for ill effects.

• Nusinersen in the Pediatric Population: Nusinersen is proven to be efficacious and safer for the pediatric population, from the newborn stage to 17 years of age.