New Frontiers in the Treatment of Spinal Muscular Atrophy

CL Power, DJ O’Rourke
Dept of Neurology, Children’s University Hospital, Temple Street, Dublin 1

Spinal muscular atrophy (SMA) is an autosomal recessive neuromuscular disorder, with a current estimated incidence of 1 in 11,000 live births. Although there is a variable phenotype, 60% of patients with SMA have type 1 disease. Typically diagnosed by the age of six months, this severe form of the condition is characterised by progressive weakness and the failure to meet motor milestones. There is an early need for permanent assisted ventilation, without which the median life expectancy is less than two years.

Proper maintenance and function of motor neurons in the brainstem and spinal cord is dependent on optimum production of survival motor neuron (SMN) protein. Two genes are responsible for this production: SMN1 and SMN2. SMN1 codes for approximately 90% of SMN protein; homozygous deletion or mutation of this gene results in the clinical presentation of SMA. Copy number variability has been observed with SMN2; those with a higher copy number tend to present with a less severe phenotype. Therefore, increasing the production of SMN protein by SMN2 represents a clear therapeutic approach to SMA.

Two recent studies explored innovative, targeted treatment strategies for SMA type 1. Although SMN2 can code for SMN protein, incorrect splicing of the pre-mRNA is common. This results in a high proportion of defunct SMN protein. Nusinersen is an antisense oligonucleotide drug targeting the SMN2 gene. It binds to an area downstream of exon seven in the pre-mRNA, preventing aberrant splicing and resulting in the increased translation of full-length, functional SMN protein. Finkell et al. conducted a phase three efficacy and control trial exploring the use of Nusinersen in patients less than 7 months of age with symptomatic type 1 SMA and two copies of the SMN2 gene: the ENDEAR study1. In this study, two primary end points were identified: motor milestone response and event-free survival. Motor milestone response was evaluated using the Hammersmith Infant Neurological Examination Section 2 (HINE-2) score. Event-free survival was defined as time to death or the use of permanent assisted ventilation. Mean age at first treatment dose was 163 days.

Patients in the control group showed significant improvement in event-free survival and motor response compared to the control group; a significant improvement in motor response at a pre-specified interim analysis resulted in early termination of the trial for ethical reasons. Of note, at day 394, patients in the Nusinersen group achieved motor milestones not reached by any patients in the control group: 22% achieved full head control, 10% could roll over, 8% could sit without support, and one percent could stand.

A different, and equally innovative, treatment method for SMA 1 is described by Mendell et al: a single intravenous dose of self-complementary adeno-associated virus serotype 9 (scAAV9), which carries SMN complementary DNA2. This treatment encodes and replaces the missing SMN protein. A small treatment group was identified: fifteen patients, of which three received a low dose of scAAV9 and twelve received a high dose. Thus, these groups were compared to each other and to historical controls. Mean age of enrolment in the high dose group was 3.4 months. End points were similar to the ENDEAR study: safety was the primary end point, with motor response primarily measured with CHOP INTEND. As with ENDEAR, survival was positively affected with treatment. At trial conclusion, all patients had reached the age of 20 months and none required permanent assisted ventilation. Motor response was increased in all patients compared with historical controls, most markedly in the high dose cohort. As in the ENDEAR study, patients who underwent treatment achieved motor milestones not reached by controls (in this case, historical controls). Of the twelve patients in the high dose cohort, 11 could sit without support for at least 5 seconds, 10 for at least 10 seconds, and 9 for at least 30 seconds. Eleven patients achieved head control, 9 were able to roll over, and two patients could crawl, pull to stand, stand and walk independently. Eleven patients achieved speech.

Both of these studies represent remarkable new possibilities in the field of SMA treatment, and the relevance of this is most notable when discussing a new diagnosis with parents in clinical practice. For the first time, we are in a position to offer treatment for a condition that could previously be managed only in a palliative fashion. As lifespan increases, other considerations will arise.

Nusinersen is available commercially via the Food and Drug Administration; it has received a commercial license for use through the European Medicines Agency, and is currently going through the regulatory drug approval process in various European countries including Ireland. At present there are five children in Ireland with a diagnosis of SMA 1, receiving nusinersen through an Early Access Program. Should the scope of treatment expand to include those with SMA 2, there will be approximately 20 further patients (<18years). Nusinersen is a highly expensive drug, requiring repeated dosing; and though it has been shown to be an effective treatment, it is not a cure. The expansion of treatment and the possibility of commercial availability will require consistent review of these considerations, along with adherence to the strictest standards of care for this patient cohort3,4.

Although scAAV9 is designed as a once-off treatment, we are also faced with questions and considerations: patients will likely develop antibodies, which could necessitate further intervention; as SMN protein is found in multiple systems, we do not know the full extent of the effects of this treatment in the patient as their lifespan increases. Similar issues arise with cost and availability; and as with nusinersen, this is not a cure for SMA.

In both studies, earlier intervention was found to produce better results in terms of motor milestones. Thus another question arises: that of newborn screening and pre-symptomatic treatment – something that is being explored, in terms of nusinersen, in the NURTURE study5. As follow up increases, and treatments become more readily available, the practice of screening to ensure the earliest intervention possible may well become a cornerstone of management. For the first time, SMA is a treatable condition. This raises daunting challenges, but also a host of possibilities for clinicians, our patients and their families.

Dr. Declan O’Rourke, Dept of Paediatric Neurology, Children’s University Hospital, Temple Street, Dublin 1
Phone: 01 8784200

1. Finkel RS, Mercuri E, Darras BT, Connolly AM, Kuntz NL, Kirschner J, Chiriboga CA, Saito K, Servais L, Tizzano E, Topaloglu H, Tulinius M, Montes J, Glanzman AM, Bishop K, Zhong ZJ, Gheuens S, Bennett CF, Schneider E, Farwell W, De Vivo DC; ENDEAR Study Group. Nusinersen versus Sham Control in Infantile-Onset Spinal Muscular Atrophy. N Engl J Med. 2017;377:1723-1732.

2. Mendell JR, Al-Zaidy S, Shell R, Arnold WD, Rodino-Klapac LR, Prior TW, Lowes L, Alfano L, Berry K, Church K, Kissel JT, Nagendran S, L’Italien J, Sproule DM, Wells C, Cardenas JA, Heitzer MD, Kaspar A, Corcoran S, Braun L, Likhite S, Miranda C, Meyer K, Foust KD, Burghes AHM, Kaspar BK. Single-Dose Gene-Replacement Therapy for Spinal Muscular Atrophy. N Engl J Med. 2017;377:1713-1722.

3. Mercuri E, Finkel RS, Muntoni F, Wirth B, Montes J, Main M, Mazzone ES, Vitale M, Snyder B, Quijano-Roy S, Bertini E, Davis RH, Meyer OH, Simonds AK, Schroth MK, Graham RJ, Kirschner J, Iannaccone ST, Crawford TO, Woods S, Qian Y, Sejersen T; SMA Care Group. Diagnosis and management of spinal muscular atrophy: Part 1: Recommendations for diagnosis, rehabilitation, orthopedic and nutritional care. Neuromuscul Disord. 2017 Nov 23. [Epub ahead of print]

4. Finkel RS, Mercuri E, Meyer OH, Simonds AK, Schroth MK, Graham RJ, Kirschner J, Iannaccone ST, Crawford TO, Woods S, Muntoni F, Wirth B, Montes J, Main M, Mazzone ES, Vitale M, Snyder B, Quijano-Roy S, Bertini E, Davis RH, Qian Y, Sejersen T; SMA Care group. Diagnosis and management of spinal muscular atrophy: Part 2: Pulmonary and acute care; medications, supplements and immunizations; other organ systems; and ethics. Neuromuscul Disord. 2017 Nov 23. [Epub ahead of print]

5. De Vivo DC, Hwu WL, Reyna SP, Farwell W, Gheuens S, Sun P, Zhong ZJ, Su J, Schneider E, Bertini E. Interim Efficacy and Safety Results from the Phase 2 NURTURE Study Evaluating Nusinersen in Presymptomatic Infants with Spinal Muscular Atrophy. Neurology 2017;88(16 Supplement):S46.003.