Nusinersen treatment of Spinal Muscular Atrophy Type 1 — results of expanded access programme in Poland
, 2, 3, 4, 5, 2, 3, 2, 3, 3, 1, 1, 1
Abstract
Aim of the study. This study aimed to evaluate the effects of nusinersen therapy in Polish children with SMA type 1.
Clinical rationale of study. Spinal muscular atrophy (SMA) is a neuromuscular disorder that is characterised by the loss of motor neurons, progressive muscle weakness and atrophy, leading to increased disability and mortality. Nusinersen, an antisense oligonucleotide that promotes production of the functional survival motor neuron protein is approved for the treatment of SMA 5q in the European Union. In 2017, an early access programme (EAP) for nusinersen was launched in Poland. In this study, we present the results of nusinersen treatment in Polish patients participating in the EAP.
Materials and methods. We collected prospectively clinical data including mutational analysis of SMN1 and SMN2 genes, motor function outcomes as measured on a standardized scales, ventilatory and nutritional status, on SMA type 1 patients receiving nusinersen in three EAP centres in Poland. Scores on the CHOP-INTEND scale after 18–26 months of treatment were compared to baseline.
Results. We analysed data from 26 patients with SMA type 1, mean age 4.79 (2–15) years. The mutational analysis revealed two SMN2 gene copies in the majority of patients (61.54%). Three and four copies were found in 34.62% and 3.84%, respectively. Median disease duration was 21 months. Half (n = 13) of the patients required mechanical ventilation at baseline and 57.69% (n = 15) were fed by nasogastric tube or percutaneous endoscopic gastrostomy. No patient worsened during the follow-up. Mean improvement in CHOP-INTEND from baseline to the last follow-up was 7.38 points (p < 0.001). CHOP-INTEND scores did not decline for any patient. Patients with three or more SMN2 gene copies had higher scores than did the patients with two copies (p = 0.013), and they tended to show greater improvement over time, but the difference was not significant (p = 0.324). Shorter disease duration and higher CHOP-INTEND baseline score were associated with a better response (p = 0.015). Patients with a CHOP-INTEND score above the median had higher scores overall than the rest (p < 0.0013), and they improved significantly more than the rest (p = 0.037). Nusinersen was well tolerated, no new safety findings were identified.
Conclusions and clinical implications. Our data indicates that nusinersen treatment might be effective in SMA type 1 patients, regardless of their age and functional status.
Keywords: nusinersenspinal muscular atrophyantisense oligonucleotideexpanded access programme
References
- Wang CH, Xu J, Carter TA, et al. Characterization of survival motor neuron (SMNT) gene deletions in asymptomatic carriers of spinal muscular atrophy. Hum Mol Genet. 1996; 5(3): 359–365.
- Zerres K, Rudnik-Schöneborn S, Forrest E, et al. A collaborative study on the natural history of childhood and juvenile onset proximal spinal muscular atrophy (type II and III SMA): 569 patients. Journal of the Neurological Sciences. 1997; 146(1): 67–72.
- Frączek A, Potulska-Chromik A, Bednarska-Makaruk M, et al. Spinal muscular atrophy with an overlapping syndrome - "double trouble" or a potentially better outcome? Neurol Neurochir Pol. 2020; 54(5): 475–477.
- Jędrzejowska M, Kostera-Pruszczyk A. Spinal muscular atrophy - new therapies, new challenges. Neurol Neurochir Pol. 2020; 54(1): 8–13.
- Lorson CL, Hahnen E, Androphy EJ, et al. A single nucleotide in the SMN gene regulates splicing and is responsible for spinal muscular atrophy. Proc Natl Acad Sci U S A. 1999; 96(11): 6307–6311.
- Monani UR, Lorson CL, Parsons DW, et al. A single nucleotide difference that alters splicing patterns distinguishes the SMA gene SMN1 from the copy gene SMN2. Hum Mol Genet. 1999; 8(7): 1177–1183.
- Finkel RS, Mercuri E, Darras BT, et al. ENDEAR Study Group. Nusinersen versus Sham Control in Infantile-Onset Spinal Muscular Atrophy. N Engl J Med. 2017; 377(18): 1723–1732.
- Chiriboga CA, Swoboda KJ, Darras BT, et al. Results from a phase 1 study of nusinersen (ISIS-SMN(Rx)) in children with spinal muscular atrophy. Neurology. 2016; 86(10): 890–897.
- Gidaro T, Servais L. Nusinersen treatment of spinal muscular atrophy: current knowledge and existing gaps. Dev Med Child Neurol. 2019; 61(1): 19–24.
- Jedrzejowska M, Milewski M, Zimowski J, et al. Incidence of spinal muscular atrophy in Poland--more frequent than predicted? Neuroepidemiology. 2010; 34(3): 152–157.
- Verhaart IEC, Robertson A, Leary R, et al. A multi-source approach to determine SMA incidence and research ready population. J Neurol. 2017; 264(7): 1465–1473.
- Kolb SJ, Kissel JT. Spinal Muscular Atrophy. Neurol Clin. 2015; 33(4): 831–846.
- Wang CH, Finkel RS, Bertini ES, et al. Participants of the International Conference on SMA Standard of Care. Consensus statement for standard of care in spinal muscular atrophy. J Child Neurol. 2007; 22(8): 1027–1049.
- D'Amico A, Mercuri E, Tiziano FD, et al. Spinal muscular atrophy. Orphanet J Rare Dis. 2011; 6: 71.
- Finkel RS, McDermott MP, Kaufmann P, et al. Observational study of spinal muscular atrophy type I and implications for clinical trials. Neurology. 2014; 83(9): 810–817.
- De Sanctis R, Coratti G, Pasternak A, et al. Developmental milestones in type I spinal muscular atrophy. Neuromuscul Disord. 2016; 26(11): 754–759.
- Sick Fund Data. ; 2020.
- Yong J, Moffett M, Lucas S. Implementing a Global Expanded Access Program (EAP) for Infantile-Onset Spinal Muscular Atrophy (Type I): Understanding the Imperative, Impact and Challenges. J Neuromuscul Dis. 2019; 6(2): 227–231.
- Engelborghs S, Niemantsverdriet E, Struyfs H, et al. Consensus guidelines for lumbar puncture in patients with neurological diseases. Alzheimer's & Dementia: Diagnosis, Assessment & Disease Monitoring. 2017; 8(1): 111–126.
- Darras BT, Farrar MA, Mercuri E, et al. An Integrated Safety Analysis of Infants and Children with Symptomatic Spinal Muscular Atrophy (SMA) Treated with Nusinersen in Seven Clinical Trials. CNS Drugs. 2019; 33(9): 919–932.
- Meylemans A, De Bleecker J. Current evidence for treatment with nusinersen for spinal muscular atrophy: a systematic review. Acta Neurol Belg. 2019; 119(4): 523–533.
- Pechmann A, Langer T, Schorling D, et al. Evaluation of Children with SMA Type 1 Under Treatment with Nusinersen within the Expanded Access Program in Germany. J Neuromuscul Dis. 2018; 5(2): 135–143.
- Farrar MA, Teoh HL, Carey KA, et al. Nusinersen for SMA: expanded access programme. J Neurol Neurosurg Psychiatry. 2018; 89(9): 937–942.
