Natural history of Type 1 spinal muscular atrophy: a retrospective, global, multicenter study

Claude Cances, Dmitry Vlodavets, Giacomo Pietro Comi, Riccardo Masson, Maria Mazurkiewicz-Bełdzińska, Kayoko Saito, Edmar Zanoteli, Angela Dodman, Muna El-Khairi, Ksenija Gorni, Isaac Gravestock, Janine Hoffart, Renata S Scalco, Basil T Darras, ANCHOVY Working Group, Katia Alberti, Giovanni Baranello, Nina Barisic, Noemi Brolatti, Claudio Bruno, Claude Cances, Giacomo Pietro Comi, Basil T Darras, Nicolas Deconinck, Elke Vos, Liesbeth De Waele, Angela Dodman, Claudia Dosi, Muna El-Khairi, Amanda Engelbrekt, Nathalie Goemans, Ksenija Gorni, Alessandra Govoni, Isaac Gravestock, Kazuhiro Haginoya, Janine Hoffart, Katarzyna Kotulska-Jozwiak, Laure Le Goff, Alexis Levine, Saidi Manel, Riccardo Masson, Chiara Mastella, Eleonora Mauri, Maria Mazurkiewicz-Bełdzińska, Megi Meneri, Isabella Moroni, Katarzyna Pierzchlewicz, Aurelie Portefaix, Alexandra Prufer, Myriam Rauso, Kayoko Saito, Renata S Scalco, Veronica Schembri, Mariangela Sicolo, Valentine Tahon, Josipa Tomas, Dominique Vincent-Genod, Dmitry Vlodavets, Carole Vuillerot, Kazuyuki Yotsumata, Edmar Zanoteli, Claude Cances, Dmitry Vlodavets, Giacomo Pietro Comi, Riccardo Masson, Maria Mazurkiewicz-Bełdzińska, Kayoko Saito, Edmar Zanoteli, Angela Dodman, Muna El-Khairi, Ksenija Gorni, Isaac Gravestock, Janine Hoffart, Renata S Scalco, Basil T Darras, ANCHOVY Working Group, Katia Alberti, Giovanni Baranello, Nina Barisic, Noemi Brolatti, Claudio Bruno, Claude Cances, Giacomo Pietro Comi, Basil T Darras, Nicolas Deconinck, Elke Vos, Liesbeth De Waele, Angela Dodman, Claudia Dosi, Muna El-Khairi, Amanda Engelbrekt, Nathalie Goemans, Ksenija Gorni, Alessandra Govoni, Isaac Gravestock, Kazuhiro Haginoya, Janine Hoffart, Katarzyna Kotulska-Jozwiak, Laure Le Goff, Alexis Levine, Saidi Manel, Riccardo Masson, Chiara Mastella, Eleonora Mauri, Maria Mazurkiewicz-Bełdzińska, Megi Meneri, Isabella Moroni, Katarzyna Pierzchlewicz, Aurelie Portefaix, Alexandra Prufer, Myriam Rauso, Kayoko Saito, Renata S Scalco, Veronica Schembri, Mariangela Sicolo, Valentine Tahon, Josipa Tomas, Dominique Vincent-Genod, Dmitry Vlodavets, Carole Vuillerot, Kazuyuki Yotsumata, Edmar Zanoteli

Abstract

Background: ANCHOVY was a global, multicenter, chart-review study that aimed to describe the natural history of Type 1 spinal muscular atrophy (SMA) from a broad geographical area and provide further contextualization of results from the FIREFISH (NCT02913482) interventional study of risdiplam treatment in Type 1 SMA.

Methods: Data were extracted from medical records of patients with first symptoms attributable to Type 1 SMA between 28 days and 3 months of age, genetic confirmation of SMA, and confirmed survival of motor neuron 2 copy number of two or unknown. The study period started on 1 January 2008 for all sites; study end dates were site-specific due to local treatment availabilities. Primary endpoints were time to death and/or permanent ventilation and proportion of patients achieving motor milestones. Secondary endpoints included time to initiation of respiratory and feeding support.

Results: Data for 60 patients from nine countries across Asia, Europe and North and South America were analyzed. The median age (interquartile range [IQR]) for reaching death or permanent ventilation was ~ 7.3 (5.9-10.5) months. The median age (IQR) at permanent ventilation was ~ 12.7 (6.9-16.4) months and at death was ~ 41.2 (7.3-not applicable) months. No patients were able to sit without support or achieved any level of crawling, standing or walking.

Interpretation: Findings from ANCHOVY were consistent with published natural history data on Type 1 SMA demonstrating the disease's devastating course, which markedly differed from risdiplam-treated infants (FIREFISH Part 2). The results provide meaningful additions to the literature, including a broader geographical representation.

Keywords: ANCHOVY; FIREFISH; SMA natural history; Spinal muscular atrophy; Type 1 SMA.

Conflict of interest statement

CC is a site principal investigator for Biogen and F. Hoffmann-La Roche Ltd clinical trials, and has received advisory fees from Novartis TG. VD and GPC have no conflicts of interest. RM has received fees from Biogen, F. Hoffmann-La Roche Ltd and Novartis Gene Therapies. MMB is a site principal investigator for Biogen and F. Hoffmann-La Roche Ltd clinical trials, and has received honoraria for advisory boards and speaker's fees from Biogen, F. Hoffmann-La Roche Ltd, and Novartis. KS is a site principal investigator for Biogen and Novartis Gene Therapies clinical trials, has received honoraria for advisory boards from Biogen, Novartis, and Roche/Chugai and speaker’s fees from Biogen and Novartis. IG and JH are employees of F. Hoffmann-La Roche Ltd. AD, MEK, KG and RSS are employees of, and hold shares in, F. Hoffmann-La Roche Ltd. BTD has received grants from Biogen, CureSMA, F. Hoffmann-La Roche Ltd, Fibrogen, Ionis Pharmaceuticals, U.S. National Institutes of Health/National Institute of Neurological Disorders and Stroke, PTC Therapeutics, Sarepta Pharmaceuticals, Slaney Family Fund for SMA, Spinal Muscular Atrophy Foundation, Summit and Working on Walking Fund; and is a board member for Amicus Inc., AveXis, Biogen, F. Hoffmann-La Roche Ltd grants, Genentech, Sarepta Pharmaceuticals and Vertex.

© 2022. The Author(s).

Figures

Fig. 1
Fig. 1
Time to death or permanent ventilation*: ANCHOVY. *Permanent ventilation was defined as ≥ 16 h of non-invasive ventilation per day for > 21 consecutive days, intubation for > 21 consecutive days, or tracheostomy. 90% CIs are calculated with a complementary log–log transformation for the estimated survival function, with standard errors computed via Greenwood’s formula. Patients with no recorded event are censored at the last age they were known to be event free. Two additional patients died after 24 months of age. CI, confidence interval
Fig. 2
Fig. 2
Time to respiratory support including permanent ventilation*: ANCHOVY. *Time from birth to first occurrence of awake-assisted, night-time-assisted, or nap-time-assisted ventilation, airway clearance through cough assistance or permanent ventilation (defined as ≥ 16 h of non-invasive ventilation per day for > 21 consecutive days, intubation for > 21 consecutive days, or tracheostomy). 90% CIs are calculated with a complementary log–log transformation for the estimated survival function, with standard errors computed via Greenwood’s formula. Patients with no recorded events are censored at the last age they were known to be event free. One additional patient required respiratory support after 24 months of age. CI, confidence interval
Fig. 3
Fig. 3
Time to feeding support*: ANCHOVY. *Feeding support included placement of nasogastric or nasojejunal tube or gastrostomy. 90% CIs are calculated with a complementary log–log transformation for the estimated survival function, with standard errors computed via Greenwood’s formula. Patients with no recorded events are censored at the last age they were known to be event free. There were no additional events recorded after 24 months of age. CI, confidence interval
Fig. 4
Fig. 4
Landmark comparison of time to death or permanent ventilation: ANCHOVY and FIREFISH Part 2. Kaplan–Meier curves are shown for FIREFISH (n = 41; solid black) and ANCHOVY (n = 40; solid blue). To compensate for the differences in age at the start of the risk period in the FIREFISH Part 2 and ANCHOVY studies, the landmark (dotted red vertical line) was set at the youngest age that a patient had an event in the FIREFISH Part 2 study, which was at an age of 6.1 months (186 days). ANCHOVY patients who had events before this time point are excluded. CI, confidence interval

References

    1. Darras B, Monani U, De Vivo D. Genetic disorders affecting the motor neuron: spinal muscular atrophy. In: Swaiman K, Ashwal S, Ferriero D, Schor N, Finkel R, Gropman A, editors. Swaiman’s pediatric neurology: principles and practice. 6. Elsevier; 2017. pp. 1057–1064.
    1. Farrar MA, Kiernan MC. The genetics of spinal muscular atrophy: progress and challenges. Neurotherapeutics. 2015;12(2):290–302. doi: 10.1007/s13311-014-0314-x.
    1. Lefebvre S, Burglen L, Reboullet S, Clermont O, Burlet P, Viollet L, et al. Identification and characterization of a spinal muscular atrophy-determining gene. Cell. 1995;80(1):155–165. doi: 10.1016/0092-8674(95)90460-3.
    1. Singh RN, Howell MD, Ottesen EW, Singh NN. Diverse role of survival motor neuron protein. Biochim Biophys Acta Gene Regul Mech. 2017;1860(3):299–315. doi: 10.1016/j.bbagrm.2016.12.008.
    1. Lorson CL, Hahnen E, Androphy EJ, Wirth B. 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. doi: 10.1073/pnas.96.11.6307.
    1. Finkel RS, Sejersen T, Mercuri E. 218th ENMC International Workshop: Revisiting the consensus on standards of care in SMA Naarden, The Netherlands, 19–21 February 2016. Neuromuscul Disord. 2017;27(6):596–605. doi: 10.1016/j.nmd.2017.02.014.
    1. Yeo CJJ, Darras BT. Overturning the paradigm of spinal muscular atrophy as just a motor neuron disease. Pediatr Neurol. 2020;109:12–19. doi: 10.1016/j.pediatrneurol.2020.01.003.
    1. Wirth B, Karakaya M, Kye MJ, Mendoza-Ferreira N. Twenty-five years of spinal muscular atrophy research: from phenotype to genotype to therapy, and what comes next. Annu Rev Genom Hum Genet. 2020;21:231–261. doi: 10.1146/annurev-genom-102319-103602.
    1. Munsat TL, Davies KE. International SMA consortium meeting (26–28 June 1992, Bonn, Germany) Neuromuscul Disord. 1992;2(5–6):423–428. doi: 10.1016/S0960-8966(06)80015-5.
    1. Finkel RS, McDermott MP, Kaufmann P, Darras BT, Chung WK, Sproule DM, et al. Observational study of spinal muscular atrophy type I and implications for clinical trials. Neurology. 2014;83(9):810–817. doi: 10.1212/WNL.0000000000000741.
    1. Kolb SJ, Coffey CS, Yankey JW. Natural history of infantile-onset spinal muscular atrophy. Ann Neurol. 2017;82:883–891. doi: 10.1002/ana.25101.
    1. De Sanctis R, Pane M, Coratti G, Palermo C, Leone D, Pera MC, et al. Clinical phenotypes and trajectories of disease progression in type 1 spinal muscular atrophy. Neuromuscul Disord. 2018;28(1):24–28. doi: 10.1016/j.nmd.2017.09.015.
    1. Arnold WD, Kassar D, Kissel JT. Spinal muscular atrophy: diagnosis and management in a new therapeutic era. Muscle Nerve. 2015;51(2):157–167. doi: 10.1002/mus.24497.
    1. D'Amico A, Mercuri E, Tiziano FD, Bertini E. Spinal muscular atrophy. Orphanet J Rare Dis. 2011;6:71. doi: 10.1186/1750-1172-6-71.
    1. Mercuri E, Finkel RS, Muntoni F, Wirth B, Montes J, Main M, et al. Diagnosis and management of spinal muscular atrophy: Part 1: Recommendations for diagnosis, rehabilitation, orthopedic and nutritional care. Neuromuscul Disord. 2018;28(2):103–115. doi: 10.1016/j.nmd.2017.11.005.
    1. Finkel RS, Mercuri E, Meyer OH, Simonds AK, Schroth MK, Graham RJ, et al. Diagnosis and management of spinal muscular atrophy: part 2: pulmonary and acute care; medications, supplements and immunizations; other organ systems; and ethics. Neuromuscul Disord. 2018;28(3):197–207. doi: 10.1016/j.nmd.2017.11.004.
    1. Poirier A, Weetall M, Heinig K, Bucheli F, Schoenlein K, Alsenz J, et al. Risdiplam distributes and increases SMN protein in both the central nervous system and peripheral organs. Pharmacol Res Perspect. 2018;6:e00447. doi: 10.1002/prp2.447.
    1. Ratni H, Ebeling M, Baird J, Bendels S, Bylund J, Chen KS, et al. Discovery of risdiplam, a selective survival of motor neuron-2 (SMN2) gene splicing modifier for the treatment of spinal muscular atrophy (SMA) J Med Chem. 2018;61(15):6501–6517. doi: 10.1021/acs.jmedchem.8b00741.
    1. Genentech. EVRYSDI (risdiplam) US prescribing information 2020. . Accessed June 2022.
    1. Roche. Evrysdi (risdiplam) EMA prescribing information 2021. . Accessed June 2022.
    1. AveXis Inc. ZOLGENSMA® (onasemnogene abeparvovec-xioi) US prescribing information 2019. Updated May 2019. . Accessed June 2022.
    1. AveXis Inc. ZOLGENSMA® (onasemnogene abeparvovec-xioi) EMA prescribing information 2020. Updated July 2022. . Accessed July 2022.
    1. Biogen Inc. SPINRAZA® (nusinersen) US prescribing information 2016. Updated December 2016. . Accessed June 2022.
    1. Biogen Inc. SPINRAZA® (nusinersen) EMA prescribing information 2017. Updated December 2017. . Accessed June 2022.
    1. Finkel RS, Mercuri E, Darras BT, Connolly AM, Kuntz NL, Kirschner J, et al. Nusinersen versus sham control in infantile-onset spinal muscular atrophy. N Engl J Med. 2017;377(18):1723–1732. doi: 10.1056/NEJMoa1702752.
    1. Mendell JR. Single-dose gene-replacement therapy for spinal muscular atrophy. N Engl J Med. 2017;377:1713–1722. doi: 10.1056/NEJMoa1706198.
    1. Baranello G, Darras BT, Day JW, Deconinck N, Klein A, Masson R, et al. Risdiplam in Type 1 spinal muscular atrophy. N Engl J Med. 2021;384(10):915–923. doi: 10.1056/NEJMoa2009965.
    1. Darras BT, Masson R, Mazurkiewicz-Bełdzińska M, Rose K, Xiong H, Zanoteli E, et al. Risdiplam-treated infants with Type 1 spinal muscular atrophy versus historical controls. N Engl J Med. 2021;385(5):427–435. doi: 10.1056/NEJMoa2102047.
    1. Lemoine TJ, Swoboda KJ, Bratton SL, Holubkov R, Mundorff M, Srivastava R. Spinal muscular atrophy type 1: are proactive respiratory interventions associated with longer survival? Pediatr Crit Care Med. 2012;13(3):e161–e165. doi: 10.1097/PCC.0b013e3182388ad1.
    1. Ou SF, Ho CS, Lee WT, Lin KL, Jones CC, Jong YJ. Natural history in spinal muscular atrophy Type I in Taiwanese population: a longitudinal study. Brain Dev. 2021;43(1):127–134. doi: 10.1016/j.braindev.2020.07.012.
    1. De Sanctis R, Coratti G, Pasternak A, Montes J, Pane M, Mazzone ES, et al. Developmental milestones in type I spinal muscular atrophy. Neuromuscul Disord. 2016;26(11):754–759. doi: 10.1016/j.nmd.2016.10.002.
    1. Kolb SJ. Baseline results of the NeuroNEXT spinal muscular atrophy infant biomarker study. Ann Clin Transl Neurol. 2016;3(2):132–145. doi: 10.1002/acn3.283.
    1. WHO Child Growth Standards: Length/height-for-age, weight-for-age, weight-for-length, weight-for-height and body mass index-for-age: methods and development. Geneva: World Health Organization; 2006. . Accessed June 2022.
    1. WHO child growth standards: head circumference-for-age, arm circumference-for-age, triceps skinfold-for-age and subscapular skinfold-for-age: methods and development: World Health Organization; 2007. . Accessed June 2022.
    1. Haataja L, Mercuri E, Regev R, Cowan F, Rutherford M, Dubowitz V, et al. Optimality score for the neurologic examination of the infant at 12 and 18 months of age. J Pediatr. 1999;135(2):153–161. doi: 10.1016/S0022-3476(99)70016-8.
    1. Bishop KM, Montes J, Finkel RS. Motor milestone assessment of infants with spinal muscular atrophy using the Hammersmith infant neurological exam-part 2: experience from a Nusinersen clinical study. Muscle Nerve. 2018;57(1):142–146. doi: 10.1002/mus.25705.
    1. R Core Team. R: a language and environment for statistical computing Vienna, Austria: R Foundation for Statistical Computing; 2019. . Accessed June 2022.

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