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Gene Therapy as a Novel Approach to Treating Spinal Muscular Atrophy: Health-System and Managed Care Pharmacist Perspectives


Gene therapy is a treatment that seeks to modify a person’s genetics in an effort to treat or cure a disease process.1 It is felt to be a particularly desirable treatment option for monogenic diseases, which are diseases that result from an abnormality of a single gene. There are various targeted approaches to gene therapy treatment, including the direct substitution of a mutated gene with a healthy replacement; inactivating a gene that is malfunctioning or predisposes a patient to disease; or adding missing genetic material.

The carrier of the gene is an important consideration for achieving successful gene therapy. These carriers, known as ‘vectors,’ transfer the genetic material to a patient’s cells. The optimal vector is identified on the basis of the target location for delivery of the genetic material, the duration of gene expression required, and the quantity and size of the material the vector needs to carry.

Gene therapy can occur in vivo, which involves a direct injection of a viral vector-mediated product into the body, or it can be conducted through an ex vivo mechanism. In ex vivo processes, genes are manipulated external to the patient, often involving exposure to a viral vector carrying the desired genetic material, and are then reintroduced back into the body. This is also referred to as patient-derived cellular gene therapy.

Viral vectors

Over the years, many viruses have been studied as potential vectors for genetic material. Some viruses integrate into the host genome, while others do not. Examples of integrating viral vectors include gammaretrovirus- and lentivirus-mediated therapies.2 In the late 1990s, gene therapy trials were initiated for severe combined immunodeficiency (SCID), an inherited disorder of the immune system that leaves an individual unable to fight off infections due to a lack of adequate immune cells.3 Several patients were treated with a gammaretrovirus-mediated in vivo vector therapy in an attempt to restore the missing interleukin-2 receptor gamma chain gene in CD34+ bone marrow precursor cells. While the treatment was considered successful in 9 patients, 4 eventually developed T-cell leukemia in the 31 to 68 months after treatment. The unanticipated cause of this cancer was the activation of proto-oncogenes (normally functioning genes that contribute to cancer development when altered) resulting from vector integration.3 Lentiviral and gammaretroviral vectors have been further modified in an attempt to lessen such adverse effects. Both vectors continue to be used today, most notably in 2 ex vivo CD19-directed genetically modified autologous T-cell immunotherapies, tisagenlecleucel (Kymriah) and axicabtagene ciloleucel (Yescarta).4,5 

Another setback in the advancement of gene therapy occurred a few years later with the death of a young man with partial ornithine transcarbamoylase (OTC) deficiency.6 Jesse Gelsinger was an 18-year-old male who was controlling his disease with a protein-limited diet and medication therapy. However, seeing a chance to participate in a study that might help individuals born with a more severe form of the deficiency—one that typically resulted in the death of 75% of affected patients before the age of 5 years—he agreed to take part. He received a hepatic artery infusion of the OTC gene enclosed in an attenuated recombinant adenoviral vector. Adenoviral vectors are considered advantageous in that they possess a high capacity for cloning and are capable of affecting both dividing and non-dividing host cells.7 However, they are now known to potentially result in a high immunogenic response after delivery.8,9 After exhibiting a severe immune reaction to the vector, Jesse succumbed 4 days after the infusion and became the first viral vector-associated death.10 As a result, the trial was suspended, as were multiple other ongoing gene-related studies.

To increase the monitoring and oversight of these types of trials, the United States (U.S.) Food and Drug Administration (FDA) and the National Institutes of Health (NIH) created the Gene Therapy Clinical Trial Monitoring Plan and the Gene Transfer Safety Symposia in 2000.6 It would be nearly 2 decades before the first in vivo viral vector-mediated gene therapy would finally receive market approval in the U.S. Voretigene neparvovec-rzyl (Luxturna), used in the treatment of inherited retinal dystrophy, was approved in 2017. This viral vector-mediated gene therapy is composed of a modified adeno-associated virus (AAV) capsid that expresses the RPE65 gene—a gene that provides instructions for making a protein essential for normal vision.11

Compared to other viral vectors, AAV vectors have demonstrated significantly lower pathogenicity and immunogenicity. AAV vectors have been engineered from a parvovirus that is naturally non-replicating. In order for the AAV to replicate, a helper virus is necessary; thus, AAV is non-pathogenic on its own.12 AAVs possess non-enveloped capsids that store single-stranded DNA. For therapeutic purposes, viral DNA sequences are replaced by the genetic material that is to be introduced into the host cell. The vector itself is incapable of integrating into the DNA of the host.13 This makes AAVs ideal vectors for non-dividing cells while allowing for long-term expression.14 After reaching the cell nucleus, the DNA remains in stable episomal form. One disadvantage of AAVs is that they are small in size and, therefore, cannot carry large amounts of genetic material.15

Non-viral vectors

Due to the potential adverse effects of immunogenicity and oncogenicity associated with viral vectors, non-viral vectors have been studied as an alternative. However, as a whole, non-viral vectors have proven to be underperformers in terms of delivery efficiency.16 Categories of non-viral vectors include physical methods, which are designed to use force to bypass a cell membrane barrier (e.g., needles, particle bombardment, ultrasound waves), and chemical carriers, which may be inorganic particles or lipid-based, polymer-based, or peptide-based particles. In many cases, increasing efficiency results in a corresponding increase in the toxicological profile of a non-viral vector, as is the case with electroporation (using an electrical pulse to open pores in cell membranes). Other non-viral vectors have limited in vivo efficacy, such as that seen with magnetofection, which utilizes magnetic fields to concentrate particles into the target cells. While non-viral vectors are attractive in theory and are improving with continued research, overall, viral vectors are currently more effective for the application of gene therapy.16

Unique considerations for handling viral-mediated gene therapy

The recent advancements and FDA approvals of novel gene therapy treatments have brought to light the need for further guidance for the healthcare worker who is caring for patients who have received these agents. To date, there are no universal guidance documents available in the U.S. for the handling of gene therapy or biohazardous medications in a clinical setting.17 Without guidance from regulatory bodies, each health system will need to develop its own set of policies and procedures to ensure safe handling. Pharmacists can consult the United States Pharmacopoeia General Chapter 800 (USP800), Hazardous Drugs—Handling in Healthcare Settings, for guidance on the handling of hazardous drugs.18

If safety data for a particular drug are limited or unavailable, USP800 recommends that the drug be treated under hazardous precautions until further safety data become available. In order to ensure occupational safe handling and administration of these agents, consideration must be given to all aspects of gene therapy handling, including receipt from the shipper; internal storage; transport through the health system; administration technique; precautions for patients, healthcare personnel, and close contacts; disposal of waste; disinfection of the workspace; and global surveillance.17 

The personal protective equipment (PPE) requirements outlined in USP800 are sufficient for the handling of the majority of gene therapy products expected to be manipulated in a pharmacy environment.18 This includes gowns, head covers, masks, shoe covers, and gloves. The addition of goggles should be considered if formulations are apt to splash or spray. PPE should be disposed of in accordance with policies for biological waste. Pharmacists should make sure they are well-versed on all aspects of the biological agents they are compounding or dispensing. It is important to know the pathogenicity of any viral agent involved in therapy and care should be taken to ensure that the cellular material is incapable of causing infection.

In order to prevent exposure, the engineering controls recommended within USP800 outline the need for a biological safety cabinet (BSC) or other containment primary engineering control when the pharmacist is manipulating hazardous agents. High-efficiency particulate air (HEPA)-filtered exhaust from a Class II BSC can be recirculated into the general pharmacy environment unless the agent being manipulated is a volatile hazard or a radionucleotide.18

Policies pertaining to the prevention of accidental exposure and detailed guidance for when such exposure occurs should be in place for all viral agents. Safety data sheets should also be readily available.18 Transport of viral agents from one part of a building to another should not be completed using pneumatic tube systems due to the risk of spillage and contamination, and consideration should be given to having spill kits at the ready when transport occurs. 


Spinal muscular atrophy (SMA) is an autosomal recessive neurodegenerative disorder. It is the most common fatal genetic disease in infancy, occurring in approximately 1 in 6000 to 11,000 live births.19,20 In approximately 95% of cases, there is a homozygous deletion or conversion of the SMN1 gene located on chromosome 5q.21 The remaining cases are typically due to a de novo deletion. The SMN1 gene is crucial for the creation of SMN protein, which is necessary for normal motor development. SMA affects the motor neurons in the anterior horn of the spinal cord and the brainstem resulting in progressive motor weakness.22 Unlike other motor neuron diseases, SMA is unique in that the highest rate of loss of strength and function happens near the time of onset. This is followed by continued, but slower, progression. Depending on the type, SMA may result in early mortality.23

A nearly identical gene to SMN1, SMN2, is also located on chromosome 5q. This gene encodes the same protein as SMN1, but, because of a critical substitution of cysteine with thymidine at position 6 in exon 7, gene splicing is disrupted. The result is that approximately 90% of mRNA transcripts exclude exon 7. This causes the creation of an unstable truncated protein, which undergoes rapid enzymatic degradation.24 While some mRNA transcripts (10%-15%) do contain all exons, which results in a stable, full-length SMN protein, the SMN2 genes are incapable of reversing the deficiency entirely. However, as a general rule, the severity of SMA is reduced in the presence of a higher number of SMN2 copies.25,26 Without SMN2, the loss of SMN1 would be universally fatal.27

Diagnosis of SMA is divided into 5 separate types according to the timing of symptom onset and the maximum motor function achieved by a patient. The SMN2 copy number can be predictive of phenotype, though some patients may deviate from this prediction.20 An increasing number of states are implementing newborn screening for SMA, which results in most patients being diagnosed and treated prior to symptom onset. As a result, many patients meet milestones never expected and delay or avoid symptom onset altogether. This results in an increased difficulty in disease typing due to the fact that the disorder does not cause abnormal sensation or cognitive compromise.28 

SMA type 0 (SMA0) is the earliest-manifesting form, with symptoms that begin in utero and present as severe disease at the time of birth. This type occurs in less than 5% of patients. Patients with SMA0 typically display joint contractures, respiratory distress, and diffuse hypotonia. Without immediate intervention, these individuals will not survive the neonatal period.23 For this reason, and because patients usually have only 1 SMN2 gene copy, it is considered the most severe form of the disease. 

SMA type 1 (SMA1), also known as Werdnig-Hoffmann disease, is the most common form, accounting for approximately 60% of all cases of SMA.29 Most patients with SMA1 have 2 copies of SMN2. Patients with SMA1 develop symptoms within the first 6 months of life.20,30 Common symptoms in these individuals include symmetrical limb weakness, tongue fasciculations, absent deep tendon reflexes, fatigue, joint contractures, scoliosis and weak cries.26,27,31,32 SMA1 patients will never acquire the strength necessary to sit up unaided. Difficulty breathing is a major concern and continuous mechanical ventilation is frequently required.33 Pulmonary compromise leading to respiratory failure is often the fatal complication of SMA1.34,35 Bulbar dysfunction is also possible, causing further respiratory compromise through aspiration, as well as nutritional compromise due to dysphagia. Failure to thrive is a common finding in SMA1 patients and feeding tube placement frequently becomes necessary. Mechanical augmentation for cough may be required to help clear secretions.26 Gastrointestinal dysmotility can also cause gastroesophageal reflux, which may, in turn, lead to aspiration. This complication may require surgical intervention. Delay in diagnosis is common in SMA1 in the absence of newborn screening. Without any intervention, death by the age of 2 years would be a near certainty.

Patients with SMA type 2 (SMA2), or Dubowitz disease, manifest symptoms by the age of 18 months. SMA2 patients make up approximately 10% of the SMA population. Pulmonary complications are the primary cause of mortality in this group, as well, though symptoms tend to be less severe than those seen in SMA1.36 Many SMA2 patients will require assisted non-invasive ventilation during nighttime hours. These individuals are frequently able to sit but will not walk. With supportive care available today, most patients with SMA2 will survive into adulthood. It is typical for patients with SMA2 to possess 3 copies of the SMN2 gene. 

Patients with SMA type 3 (SMA3), or Kugelberg-Welander disease, develop symptoms after 18 months of age and make up less than 5% of the SMA population. Overall, their symptoms are milder than those of patients with other types of SMA, and they can typically stand independently. However, any ability to ambulate may be lost by the teenage or early adult years. Most patients with this type of SMA have 3 or 4 copies of SMN2. Length of survival is typically not affected in SMA3.34,35 

The mildest form of SMA is type 4 (SMA4), which occurs in approximately 1 in 5 people with SMA. They have at least 4 copies of SMN2, and they may have 6 or more, which often results in a phenotypically normal appearance. When present, symptoms are not noted until adulthood, are slowly progressive, and do not interfere with a patient’s ability to stand. Most will continue to walk and, like those with SMA3, their lifespan is unaffected.29

Functional assessments

Evaluating therapies in children comes with a unique set of challenges. Several specific tools to evaluate the functional assessment of infants and young children with neuromuscular disorders have been developed. These include the Hammersmith Infant Neurologic Exam (HINE), the Hammersmith Functional Motor Scale-Expanded (HFMSE), and the Children’s Hospital of Philadelphia Infant Test of Neuromuscular Disorders (CHOP-INTEND). Many of these tools were incorporated into recent trials that evaluated the efficacy and safety of 2 newly approved SMA therapies—a viral vector-mediated gene therapy and an antisense oligonucleotide.

The HINE is a useful assessment for neurologic function in patients aged 2 months to 2 years. Part 2 of the exam (HINE-2) is specific to motor milestones. Each of the 8 items on the exam is scored from 0 to 4, with the lower number indicating a worse function. For example, someone with severe SMA (e.g., SMA1) might have a score of zero for the entire section.37,38

The HFMSE is useful in the evaluation of an individual with SMA2 or SMA3.39 In general, lower scores indicate poorer function. Clinically meaningful change on the HFMSE is difficult to quantify given the wide variety of symptom presentation in the disease types.

For the assessment of motor skills in children with SMA1 between the ages of 4 months and 4 years, CHOP-INTEND may be used. Again, the lower the score, the lesser the functional ability. Most individuals with severe SMA will score below 40 on the scale, which ranges from 0 to 64 points, with the average baseline score being in the low 20s.40

Onasemnogene abeparvovec-xioi

Onasemnogene abeparvovec-xioi (Zolgensma) is the first viral vector-mediated gene therapy agent approved for the treatment of SMA. It was developed using an AAV vector platform capable of carrying the target SNM1 transgene, which encodes the full-length human SMN protein, to motor neurons in the CNS.41 The AAV9 serotype was deliberately chosen for its ability to cross the blood-brain barrier more readily than the other 12 serotypes. Additionally, compared with other serotypes, the number of pre-existing antibodies to AAV9 is typically minimal. The use of a complimentary vector allows for bypassing the need for the patient’s own system to synthesize a second strand of DNA.42 The non-integrating nature of the treatment allows for a stable, extranuclear episome that decreases the risk of insertional mutagenesis. The therapy includes a hybrid cytomegalovirus (CMV) enhancer/chicken beta-actin promoter to drive high and robust SMN expression in motor neurons.43 CMV infection is not possible due to the construct being replication incompetent. Owing to the non-dividing nature of motor neurons, a single treatment is expected to provide life-long efficacy. This treatment was approved for use in SMA patients under the age of 2 years in May of 2019.

In the first clinical trial of this agent, 15 patients with SMA1 and 2 copies of SMN2 were enrolled in a study utilizing a single dose of onasemnogene abeparvovec. A historical cohort was used for comparison, in which only 8% of patients were alive at 20 months.44 Three patients received what was expected to be a minimally effective dose (6.7 x 1013 vector genomes/kilogram [vg/kg]), while the remaining 12 were given the proposed therapeutic dose (2 x 1014 vg/kg). All enrollees were alive and without permanent ventilation at or beyond the 20-month timeframe. The mean increases in CHOP-INTEND scores were 7.7 and 24.6 points for the low-dose and high-dose groups, respectively. Improvements of 9.8 and 15.4 points were noted at 1 and 3 months, respectively, in the therapeutic-dose cohort, as well (p<0.001 compared to baseline). Regardless of baseline motor function, individuals receiving earlier dosing (before 3 months of age) achieved more significant improvements in motor function compared to those who were dosed later. Long-term assessment of motor function appears to demonstrate that improvements were sustained, as noted in the 24-month follow-up data45: all patients were alive and none were utilizing permanent ventilation at that time, and all subjects in the therapeutic-dose group maintained a CHOP-INTEND score of at least 40.

Another ongoing open-label, phase III study (STRIVE) of 22 patients aged 6 months or younger with SMA1 and 1 or 2 copies of SMN2 supported the initial efficacy findings.46 Mean improvements in CHOP-INTEND scores at 1, 3, and 5 months post-infusion were 6.9, 11.7, and 14.3 points, respectively. Nearly all patients (95%) achieved a score of 40 points or better, with 50% reaching at least 50 points, and 9% reaching 60 points or more. One death in the cohort was unrelated to study medication.

Data have also been gathered in SMA2 patients receiving onasemnogene abeparvovec. In the ongoing STRONG study, 28 patients are being evaluated, 16 of whom are between 6 months and 2 years of age, and 12 who are between 2 and 5 years of age.47,48 Seven patients in the younger cohort and all patients at least 2 years of age were evaluated with the HFMSE. The mean improvement was 4.2 points over baseline at time points between 5 and 12 months post-infusion.

Another open-label phase III study (SPRINT) was designed to evaluate pre-symptomatic SMA patients 6 weeks of age or younger with 2 or 3 SMN2 copies who had received onasemnogene abeparvovec.49  Eight patients who were followed-up at a median age of 6.1 months achieved CHOP-INTEND scores of 50 points universally, with 75% reaching 60 points or more. Mean improvements from baseline were 8.9 and 14.4 points at 1 and 3 months, respectively. Publication of final outcomes is pending.

Common side effects associated with onasemnogene abeparvovec therapy seen in at least 5% of people in clinical trials include vomiting and aminotransferase elevations.50 A 30-day course of systemic corticosteroids is recommended to prevent liver abnormalities associated with treatment. Antibody titers to AAV9 measured using an enzyme-linked immunosorbent assay (ELISA) are recommended prior to dosing, with a cutoff level of greater than 1:50. Additional recommendations for monitoring include platelet counts at baseline, weekly for the first month, and bi-weekly for 2 to 3 months until platelet counts return to baseline. In addition, monitoring troponin I is recommended before treatment, weekly for the first month, and then monthly for the following 2 months until the level normalizes. A one-time, single, weight-based intravenous infusion is indicated for eligible patients (Table 1).50

Table 1. Administration Guidelines for Gene Therapies Currently Approved for the Treatment of Spinal Muscular Atrophy50,60
Drug (brand name) Dose Considerations
Nusinersen (Spinraza) 12 mg intrathecally every 14 days x 3 doses, followed by 12 mg 30 days later; administer maintenance doses of 12 mg every 4 months thereafter Administer at room temperature.
Remove 5 mL of cerebrospinal fluid from intrathecal space prior to administration.
Administer over 1-3 minutes using a spinal anesthesia needle.
Onasemnogene abeparvovec (Zolgensma) 1.1 x 1014 vector genomes/kg intravenously x 1 dose Administer intravenously over 60 minutes.
One day prior to dosing, begin systemic corticosteroid therapy equivalent to 1 mg/kg prednisolone for 30 days. Check liver function tests. Continue until findings are unremarkable, then taper steroid over an additional 28 days.


Although they contain no viral-mediated or biologically active properties, antisense oligonucleotides (ASO) were first discovered more than 2 decades ago to have the ability to manipulate RNA processing.51 Often considered a close relative of traditional gene therapy agents, these single-stranded DNA molecules target mRNA and prevent genetic translation. Nusinersen (Spinraza) is an ASO that was approved in December 2016 for the treatment of SMA in both pediatric and adult patients regardless of type. Because ASO cannot cross the blood-brain barrier, nusinersen must be given via intrathecal administration in order to ensure delivery to its desired site of action in the central nervous system (CNS). Progression of disease may result in compromised access to the lumbar intraspinal space necessitating high cervical or intraventricular administration.33 Nusinersen binds to pre-mRNA, preventing the splicing of exon 7 from SMN2 and resulting in more complete full-length copies of the SMN protein.52,53 While nusinersen is not a cure for SMA, it has demonstrated the ability to improve functional outcomes in clinical trials.

The first trial of nusinersen was an open-label, dose-escalation study in patients with SMA1.54 Those enrolled included 20 individuals ranging from 3 weeks to 7 months of age. Dosing differed among the participants, with 4 patients receiving a loading dose of 6 mg on days 1, 15, and 85; the dose was then increased to 12 mg beginning every 4 months from day 253. The remaining 16 patients received doses according to the same schedule but were administered 12 mg at each interval. Compared to baseline data, improvements in motor function were demonstrated using CHOP-INTEND (p=0.0013) and HINE-2 (p<0·0001) scales. Additionally, compared to data gathered from a natural history case series of individuals with SMA, the Kaplan-Meier survival curves diverged significantly (p=0.0014).26

The second study (ENDEAR) was a phase III, double-blind, sham-controlled trial for determination of efficacy. Enrollment included 121 infants under 7 months of age who were not mechanically ventilated and had SMA1 with 2 copies of SMN2.55 Sham administration technique was accomplished utilizing a needle stick with bandage placement. The standard 12-mg dose was adjusted according to anticipated cerebrospinal fluid (CSF) volume for the age of the individual receiving the treatment. Doses were given on days 1, 15, 29, and 64 (loading period), followed by doses on days 183 and 302. Motor milestone response was higher in the treated patients (41%) than in those receiving sham treatments (0%) in an interim analysis using CHOP-INTEND and HINE-2 (p<0.001) scales to assess response. Surviving patients not needing permanent assisted ventilation (tracheostomy or ventilatory support for ≥ 16 hours per day) met criteria for event-free survival. The number of patients in this group was higher than among those who received the sham therapy (p=0.005). The overall survival rate was also better in the nusinersen group (p=0.004). Additionally, those who began therapy sooner after diagnosis fared better. Due to the robust response of individuals randomized to the treatment arm, the study was terminated early. This interim data, in combination with other trial data available at the time, led directly to the approval of nusinersen. 

Studies evaluating the effectiveness of nusinersen in patients with longer time since diagnosis have also been completed. One such study evaluated the effectiveness of the therapy via a phase I, open-label, escalating-dose trial that enrolled 28 patients diagnosed with SMA2 or SMA3 who were between the ages of 2 and 14 years.56 Each patient had 3 to 5 copies of SMN2. The HFMSE was utilized for assessment. Doses varied, with 1-mg, 3-mg, 6-mg, and 9-mg doses utilized for one-time administrations. Those receiving the highest dose reported a minimum improvement of at least 3 points on the HFMSE at 3 months (p=0.016), with further improvement seen at the 9-to-14-month evaluation during the extension study (5.8 points; p=0.008).

Another group of anticipated SMA2 or SMA3 patients was enrolled in a phase III study (CHERISH).57 A total of 126 individuals who developed symptoms at 6 months of age or older who were between the ages of 2 and 12 years entered the double-blind, sham-controlled study. All patients received a 12-mg dose of nusinersen. The active-treatment group achieved significantly better scores on the HFMSE at 15 months post-enrollment than the control group (4 points vs. -1.9 points; p<0.001). This trial was terminated early due to this difference. The p-value remained stable at what would have been the time of final analysis.

Lastly, a phase 1b/2a trial, which was designed as a 253-day, ascending-dose (3 mg, 6 mg, 9 mg, and 12 mg), open-label study that enrolled children with SMA aged 2 to 15 years led to a 715-day, single-dose-level (12 mg) extension study.58 A total of 28 patients were enrolled (11 patients with SMN2 and 17 with SMA3). HFMSE scores were improved in both groups (SMA2, +10.8 points; SMA3, +1.8 points) after approximately 3 years of treatment, indicating the drug was beneficial beyond ages and treatment lengths previously studied. Improvements were also seen in the 6-minute walk test, and 1 previously non-ambulatory patient began walking during the trial.

Because it has been recognized that earlier treatment of SMA produces better outcomes and limits disability, a study of 25 diagnosed patients (SMA1 or SMA2) who were not yet exhibiting symptoms was undertaken (NURTURE).59 Initial doses were administered at or before 6 weeks of age. The primary endpoint was defined as time to death or respiratory intervention (≥ 6 hours/day continuously for ≥ 7 days or tracheostomy); this parameter was met by 4 patients, though each required assistance only during an acute, reversible illness. At a mean age of 26 months, all enrollees were able to sit without assistance and 88% were walking, 17 of them unaided. These data appear to solidify the importance of early intervention in eligible patients.

Monitoring parameters for nusinersen include platelet counts and coagulation parameters (prothrombin time and partial thromboplastin time) to monitor for signs of bleeding, as significant thrombocytopenia (below the normal limit) was observed in 11% of patients with normal baseline values during clinical studies.60 Glomerulonephritis has also been observed, necessitating monitoring of quantitative urine protein at the same intervals. Antibody development is possible, but, at present, there are insufficient data to determine what, if any, effect this might have on treatment efficacy.33

The most common side effects associated with nusinersen administration include respiratory tract infection and constipation, as well as those anticipated with intrathecal injection (headache, back pain, and post-lumbar puncture syndrome) (Table 1).60,61


Onasemnogene abeparvovec has the designation of being the world’s most expensive therapy, with a price tag of $2,125,000. It has been argued that the cost is more than justified by the healthcare costs that would otherwise be incurred by a patient with ongoing, progressive SMA, given the fact that it is administered only once and is expected to have a lifetime therapeutic benefit. Still, some insurance companies are reticent to pay for the therapy. The manufacturer is in discussions with the insurance industry to allow for alternative types of payment, including paying in installments, but this is not yet a standard practice. Another option that is being discussed and spearheaded by The Massachusetts Institute of Technology would not only allow for payment by installments, but the ultimate cost of the drug would be determined by an individual patient’s response.62

The cost of nusinersen is $750,000 for the first year of therapy, followed by annual costs of $375,000.63 Given the fact that the drug requires continued dosing, its cost will exceed that of onasemnogene abeparvovec after 5 years. A cost utility analysis conducted from the perspective of a U.S. commercial payor placed onasemnogene abeparvovec ahead of nusinersen in terms of effectiveness relative to cost using a willingness-to-pay threshold based on cost per quality-adjusted life-year (QALY).64 For hospitals and health systems, a single misstep in the process whereby any therapy is wasted due to mismanagement could have critical consequences from a financial standpoint, making the handling of these treatments and training of all involved personnel that much more essential.

Pipeline agents

There are several additional agents currently being explored for the treatment of SMA. The first of these is reldesemtiv, which is an orally administered agent being evaluated for use in SMA2, SMA3, and SMA4. The therapy is thought to work by slowing the rate of calcium release from the regulatory troponin complex, which plays a role in sensitizing proteins that respond by contracting or relaxing. Reldesmtiv is believed to partially overcome reduced nerve signaling by increasing the capacity of skeletal muscles to contract.65

Myostatin is a protein that inhibits the growth of skeletal muscle. Another pipeline agent, SRK-015, is being developed as a selective and local inhibitor of latent myostatin in hopes that it will improve strength in patients with SMA2 and SMA3. It is administered by the intravenous route.66

Two additional agents, risdiplam (approval anticipated in 2020)67 and branaplam are orally administered pyridazine derivatives that work by modifying the splicing of pre-mRNA to allow for the generation of a stable SMN protein by SMN2. Risdiplam is being studied for all SMA types, while SMA1 is the current focus for branaplam.68


Gene therapy for SMA promises to change the lives of patients and families, but it also comes with challenges for stakeholders, including pharmacies and payors. Once motor neurons are lost, the damage is irreversible. As such, if these treatments are to be employed, it is essential that therapy begin as close to the time of diagnosis as possible to ensure the best outcomes. Pharmacies should consult USP800 for guidance on how to handle these agents until official safety guidance documents are developed.


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