Pharmacology

Nusinersen is a 2'-O-methoxyethyl phosphorothioate-modified antisense oligonucleotide designed to treat spinal muscular atrophy caused by mutations in chromosome 5q that lead to survival motor neuron (SMN) protein deficiency. Normally, the SMN1 gene produces a full-length protein that is active, but in a spinal muscular atrophy patient, the SMN1 gene is affected by a mutation or deletion. These changes reduce or abolish protein expression, leading to spinal muscular atrophy with varying severity. The SMN2 gene has an identical coding sequence to SMN1, but one of the nucleotide changes is a C to T transition within exon 7. Exclusion of exon 7 markedly reduces the production of full-length protein that cannot compensate for the loss of the SMN1 gene.

Pharmacodynamics. Antisense oligonucleotides bind their targets by Watson-Crickbase-pairing, which is an infinitely versatile approach for recognizing and modulating any RNA. Nusinersen binds to SMN pre-mRNA to direct alternative splicing and increase inclusion of exon 7 in SMN2. This increases the amount of full-length SMN protein (06).

SMN is expressed ubiquitously, and in mouse models of spinal muscular atrophy, full recovery is only observed when SMN protein is restored in both the CNS and systemically (11). In human patients, intrathecal injection of nusinersen results in increased levels of SMN protein only in the neurons. It is unknown whether findings in mice also translate to humans as mice possess only one SMN gene. Following restoration of SMN deficit in neurons, it is uncertain whether systemic symptoms will become more apparent later in life (01).

Pharmacokinetics. Following intrathecal administration, nusinersen is distributed within the CNS and peripheral tissues. Important features of the pharmacokinetics include the following:

Routes of administration. Intrathecal administration can be difficult due to scoliosis, spinal fusion, and contractures of joints often encountered in patients with spinal muscular atrophy. A study that analyzed various factors involved in lumbar punctures on these patients including the use of CT of the spine concluded that the procedure can be performed safely, but a multidisciplinary team of neurologists, anesthesiologists, orthopedic surgeons, and neuroradiologists to guarantee the quality of the procedure was recommended (17). Cervical puncture has been used as alternative delivery route to administer intrathecal nusinersen in patients with spine anatomy precluding lumbar access but expertise is required in this procedure (16). Cervical puncture in patients with spinal muscular atrophy has been guided by ultrasound (15).

Clinical trials

In an open-label phase 1 study and its long-term extension, nusinersen was delivered by intrathecal injection to medically stable patients aged 2 to 14 years with type 2 and type 3 spinal muscular atrophy (04). This study provided Class IV evidence that intrathecal nusinersen is not associated with safety or tolerability concerns in children with spinal muscular atrophy, and phase 2 studies are warranted.

Part 1 of an open study assessed the tolerability and pharmacokinetics of nusinersen in subjects with presymptomatic spinal muscular atrophy who were not eligible to participate in clinical trials (NCT02386553). Part 2 of this study, NURTURE, assessed the long-term safety in those who had completed part 1. The completion date was in 2015, but no updated information is available, and the current status is not known.

A phase 2, randomized, double-blind, sham-procedure controlled study, EMBRACE, is assessing the safety as well as tolerability, and exploring the efficacy, of nusinersen administered intrathecally in subjects with spinal muscular atrophy who are not eligible to participate in other clinical trials (NCT02462759).

An open-label, phase 2, escalating dose clinical study has assessed the safety and tolerability, pharmacokinetics, and clinical efficacy of multiple intrathecal doses of nusinersen (6 mg and 12 mg dose equivalents) in patients with infantile-onset spinal muscular atrophy (07). Results showed that nusinersen was well tolerated, and clinical efficacy was consistent with its intended mechanism of action. This information was used for the design of sham-controlled phase 3 clinical study, CHERISH, in infantile-onset spinal muscular atrophy (NCT02292537). Results after 15 months of treatment starting at 6 months of age showed that 57% of the children in the nusinersen group as compared with 26% in the control group had significant and clinically meaningful improvement in motor function (14).

Phase 3 studies enrolled 173 patients, of which 121 patients participated in a multicenter, randomized, double-blind, sham-controlled investigation. Interim data of the study, submitted to the FDA, formed part of the documents reviewed for the decision to approve nusinersen. Of the 82 patients who had been treated for at least 183 days, 40% of the nusinersen-treated patients achieved a motor milestone response versus none of the sham-treated patients. The study is still ongoing, and the results have not been published.

The primary objective of an ongoing phase 3 study is to evaluate the long-term safety and tolerability of nusinersen administered by intrathecal injection to participants with spinal muscular atrophy who previously participated in investigational studies of nusinersen (NCT02594124). The secondary objective of this nonrandomized study is to examine the long-term efficacy of nusinersen.

The primary end points of ENDEAR, a randomized, double-blind, sham-controlled, phase 3 efficacy and safety trial of nusinersen in infants with spinal muscular atrophy, were a motor-milestone response (defined according to results on the Hammersmith Infant Neurological Examination) and event-free survival, ie, time to death or the use of permanent assisted ventilation (NCT02193074). Interim analysis showed that a significantly higher percentage of infants in the nusinersen group than in the control group had a motor-milestone response, and this result prompted early termination of the trial (08). Infants with spinal muscular atrophy who received nusinersen were more likely to be alive and have improvements in motor function than those in the control group. Early treatment may be necessary to maximize the benefit of the drug. A systematic review of randomized controlled trials and cohort studies concluded that nusinersen increased survival without permanent ventilatory support in children with spinal muscular atrophy type 1, whereas improvements in spinal muscular atrophy type 2 and 3 were less evident (02). Better outcomes were seen in young children with a short disease duration, particularly in children receiving nusinersen before symptom onset.

A study titled “Pre-symptomatic study of intravenous onasemnogene abeparvovec-xioi in spinal muscular atrophy (SMA) for patients with multiple copies of SMN2 (SPR1NT)” is ongoing (NCT03505099). This is an open-label, phase 3, single-arm study of a single, one-time dose of onasemnogene abeparvovec-xioi (gene replacement therapy) in patients with spinal muscular atrophy who are genetically defined by biallelic deletion of survival motor neuron 1 gene (SMN1) with 2 or 3 copies of survival motor neuron 2 gene (SMN2). Patients with survival motor neuron 1 point mutations or the survival motor neuron 2 gene modifier mutation (c.859G> C) may enroll but will not be included in the efficacy analysis sets. The study starting in infancy will have a follow-up period up to the age of 2 years.

Indications

Nusinersen is indicated for the treatment of spinal muscular atrophy in pediatric and adult patients.

Contraindications

No contraindications have been identified.

Goals and duration of treatment

Nusinersen is effective in alleviating spinal muscular atrophy, but is not a cure, and continuous treatment is required. Presymptomatic treatment of infants with spinal muscular atrophy may be possible because of reliable genetic diagnosis and prediction of disease severity by SMN2 copy numbers (03). Long-term safety results are not available yet. Postmarketing studies will be needed to determine both positive and negative effects after years of treatment.

It remains to be determined if the high degree of efficacy observed in infants and small children in clinical trials can also be achieved in adults. Data from clinical centers in Germany show therapeutic benefit of nusinersen in adult spinal muscular atrophy patients of both sexes leading to independence in activities of daily life with improvement of quality of life (10). Assessment of motor status with validated instruments is required for monitoring of the therapeutic effects in these patients.

A prospective proof-of-concept study has evaluated nontargeted CSF proteomic profiles by mass spectrometry along with basic CSF parameters of adult patients with spinal muscular atrophy types 2 or 3 before and after 10 months of nusinersen therapy in comparison with age- and gender-matched controls (12). Comparative CSF proteomic analysis identified differences among subgroups and treatment-related changes that may be suitable for diagnostic and predictive analyses.

Dosing

The recommended dose of nusinersen is 12 mg (5 mL) per administration. The treatment is initiated with 4 loading doses. The first 3 loading doses should be administered at 14-day intervals, and the fourth loading dose should be administered 30 days after the third dose. A maintenance dose should be administered once every 4 months thereafter.

Special considerations

Pediatric. The pharmacokinetics of nusinersen is similar in children and adults. Nusinersen treatment appears to be equally effective and tolerated in children and adolescents.

Geriatric. Because spinal muscular atrophy is mostly a disease of children and young adults, use of nusinersen has not been evaluated in the geriatric population.

Pregnancy. There are inadequate data on the developmental risk associated with the use of nusinersen in pregnant women. No adverse effects on embryo development were observed in animal studies in which nusinersen was administered by subcutaneous injection to mice and rabbits during pregnancy. There are no data on the presence of nusinersen in human milk, or the effects on the breastfed infant. The developmental and health benefits of breastfeeding should be considered along with the mother’s clinical need for nusinersen.

Anesthesia. No adverse interaction of nusinersen with anesthetic agents has been reported so far.

Interactions

No drug interactions have been reported.

Adverse effects

Adverse effects of nusinersen are class effects of antisense oligonucleotides with a phosphorothioate backbone. Patients treated with nusinersen may be at increased risk of bleeding complications because of thrombocytopenia and coagulation abnormalities that may result from its use. Platelet count and coagulation laboratory testing should be performed at baseline and prior to each administration of nusinersen as clinically indicated.

Renal toxicity, including potentially fatal glomerulonephritis, may occur with use of antisense oligonucleotides. Spot urine protein testing at baseline and prior to each dose of nusinersen is recommended.

The most common adverse effects reported in clinical trials were respiratory tract infections, headache, and back pain (05). Other adverse effects are procedural complications of lumbar puncture required for drug administration, such as headache, back pain, and transient or persistent cerebrospinal fluid leakage (postlumbar puncture syndrome). In a subgroup analysis of a phase 1 open trial, adverse events were more frequent in older children, in children with type 3 spinal muscular atrophy, and when using a 21- or 22-gauge needle compared to a 24-gauge or smaller needle (09).