Efficacy and safety of onasemnogene abeparvovec in children with spinal muscular atrophy type 1: real-world evidence from 6 infusion centres in the United Kingdom

Vasantha Gowda; Mark Atherton; Archana Murugan; Laurent Servais; Jennie Sheehan; Emma Standing; Adnan Manzur; Mariacristina Scoto; Giovanni Baranello; Pinki Munot; Gary McCullagh; Tracey Willis; Sandya Tirupathi; Iain Horrocks; Anil Dhawan; Michael Eyre; Maria Vanegas; Miguel A. Fernandez-Garcia; Amy Wolfe; Laura Pinches; Marjorie Illingworth; Marion Main; Lianne Abbott; Hayley Smith; Emily Milton; Sarah D'Urso; Kayal Vijayakumar; Silvia Sanchez Marco; Sinead Warner; Emily Reading; Isobel Douglas; Francesco Muntoni; Min Ong; Anirban Majumdar; Imelda Hughes; Heinz Jungbluth; Elizabeth Wraige

doi:10.1016/j.lanepe.2023.100817

Efficacy and safety of onasemnogene abeparvovec in children with spinal muscular atrophy type 1: real-world evidence from 6 infusion centres in the United Kingdom

Vasantha Gowda^*, Mark Atherton, Archana Murugan, Laurent Servais, Jennie Sheehan, Emma Standing, Adnan Manzur, Mariacristina Scoto, Giovanni Baranello, Pinki Munot, Gary McCullagh, Tracey Willis, Sandya Tirupathi, Iain Horrocks, Anil Dhawan, Michael Eyre, Maria Vanegas, Miguel A. Fernandez-Garcia, Amy Wolfe, Laura PinchesMarjorie Illingworth, Marion Main, Lianne Abbott, Hayley Smith, Emily Milton, Sarah D'Urso, Kayal Vijayakumar, Silvia Sanchez Marco, Sinead Warner, Emily Reading, Isobel Douglas, Francesco Muntoni, Min Ong, Anirban Majumdar, Imelda Hughes, Heinz Jungbluth, Elizabeth Wraige

^*Corresponding author for this work

Research output: Contribution to journal › Article › peer-review

20 Citations (Scopus)

Abstract

Background: Real-world data on the efficacy and safety of onasemnogene abeparvovec (OA) in spinal muscular atrophy (SMA) are needed, especially to overcome uncertainties around its use in older and heavier children. This study evaluated the efficacy and safety of OA in patients with SMA type 1 in the UK, including patients ≥2 years old and weighing ≥13.5 kg. Methods: This observational cohort study used data from patients with genetically confirmed SMA type 1 treated with OA between May 2021 and January 2023, at 6 infusion centres in the United Kingdom. Functional outcomes were assessed using age-appropriate functional scales. Safety analyses included review of liver function, platelet count, cardiac assessments, and steroid requirements. Findings: Ninety-nine patients (45 SMA therapy-naïve) were treated with OA (median age at infusion: 10 [range, 0.6–89] months; median weight: 7.86 [range, 3.2–20.2] kg; duration of follow-up: 3–22 months). After OA infusion, mean ± SD change in CHOP-INTEND score was 11.0 ± 10.3 with increased score in 66/78 patients (84.6%); patients aged <6 months had a 13.9 points higher gain in CHOP-INTEND score than patients ≥2 years (95% CI, 6.8–21.0; P < 0.001). Asymptomatic thrombocytopenia (71/99 patients; 71.7%), asymptomatic troponin-I elevation (30/89 patients; 33.7%) and transaminitis (87/99 patients; 87.9%) were reported. No thrombotic microangiopathy was observed. Median steroid treatment duration was 97 (range, 28–548) days with dose doubled in 35/99 patients (35.4%). There were 22.5-fold increased odds of having a transaminase peak >100 U/L (95% CI, 2.3–223.7; P = 0.008) and 21.2-fold increased odds of steroid doubling, as per treatment protocol (95% CI, 2.2–209.2; P = 0.009) in patients weighing ≥13.5 kg versus <8.5 kg. Weight at infusion was positively correlated with steroid treatment duration (r = 0.43; P < 0.001). Worsening transaminitis, despite doubling of oral prednisolone, led to treatment with intravenous methylprednisolone in 5 children. Steroid-sparing immunosuppressants were used in 5 children to enable steroid weaning. Two deaths apparently unrelated to OA were reported. Interpretation: OA led to functional improvements and was well tolerated with no persistent clinical complications, including in older and heavier patients. Funding: Novartis Innovative Therapies AG provided a grant for independent medical writing services.

Original language	English
Article number	100817
Journal	The Lancet Regional Health - Europe
Volume	37
DOIs	https://doi.org/10.1016/j.lanepe.2023.100817
Publication status	Published - Feb 2024

Keywords

Efficacy
Follow-up
Gene therapy
Longitudinal
Motor neuron disorder
Onasemnogene abeparvovec
Real-world experience
Safety
SMA
Spinal muscular atrophy
United Kingdom
Zolgensma

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Gowda, V., Atherton, M., Murugan, A., Servais, L., Sheehan, J., Standing, E., Manzur, A., Scoto, M., Baranello, G., Munot, P., McCullagh, G., Willis, T., Tirupathi, S., Horrocks, I., Dhawan, A., Eyre, M., Vanegas, M., Fernandez-Garcia, M. A., Wolfe, A., ... Wraige, E. (2024). Efficacy and safety of onasemnogene abeparvovec in children with spinal muscular atrophy type 1: real-world evidence from 6 infusion centres in the United Kingdom. The Lancet Regional Health - Europe, 37, Article 100817. https://doi.org/10.1016/j.lanepe.2023.100817

@article{0f0bf86c4a374dcba7bf8ef5e9a2c931,

title = "Efficacy and safety of onasemnogene abeparvovec in children with spinal muscular atrophy type 1: real-world evidence from 6 infusion centres in the United Kingdom",

abstract = "Background: Real-world data on the efficacy and safety of onasemnogene abeparvovec (OA) in spinal muscular atrophy (SMA) are needed, especially to overcome uncertainties around its use in older and heavier children. This study evaluated the efficacy and safety of OA in patients with SMA type 1 in the UK, including patients ≥2 years old and weighing ≥13.5 kg. Methods: This observational cohort study used data from patients with genetically confirmed SMA type 1 treated with OA between May 2021 and January 2023, at 6 infusion centres in the United Kingdom. Functional outcomes were assessed using age-appropriate functional scales. Safety analyses included review of liver function, platelet count, cardiac assessments, and steroid requirements. Findings: Ninety-nine patients (45 SMA therapy-na{\"i}ve) were treated with OA (median age at infusion: 10 [range, 0.6–89] months; median weight: 7.86 [range, 3.2–20.2] kg; duration of follow-up: 3–22 months). After OA infusion, mean ± SD change in CHOP-INTEND score was 11.0 ± 10.3 with increased score in 66/78 patients (84.6%); patients aged <6 months had a 13.9 points higher gain in CHOP-INTEND score than patients ≥2 years (95% CI, 6.8–21.0; P < 0.001). Asymptomatic thrombocytopenia (71/99 patients; 71.7%), asymptomatic troponin-I elevation (30/89 patients; 33.7%) and transaminitis (87/99 patients; 87.9%) were reported. No thrombotic microangiopathy was observed. Median steroid treatment duration was 97 (range, 28–548) days with dose doubled in 35/99 patients (35.4%). There were 22.5-fold increased odds of having a transaminase peak >100 U/L (95% CI, 2.3–223.7; P = 0.008) and 21.2-fold increased odds of steroid doubling, as per treatment protocol (95% CI, 2.2–209.2; P = 0.009) in patients weighing ≥13.5 kg versus <8.5 kg. Weight at infusion was positively correlated with steroid treatment duration (r = 0.43; P < 0.001). Worsening transaminitis, despite doubling of oral prednisolone, led to treatment with intravenous methylprednisolone in 5 children. Steroid-sparing immunosuppressants were used in 5 children to enable steroid weaning. Two deaths apparently unrelated to OA were reported. Interpretation: OA led to functional improvements and was well tolerated with no persistent clinical complications, including in older and heavier patients. Funding: Novartis Innovative Therapies AG provided a grant for independent medical writing services.",

keywords = "Efficacy, Follow-up, Gene therapy, Longitudinal, Motor neuron disorder, Onasemnogene abeparvovec, Real-world experience, Safety, SMA, Spinal muscular atrophy, United Kingdom, Zolgensma",

author = "Vasantha Gowda and Mark Atherton and Archana Murugan and Laurent Servais and Jennie Sheehan and Emma Standing and Adnan Manzur and Mariacristina Scoto and Giovanni Baranello and Pinki Munot and Gary McCullagh and Tracey Willis and Sandya Tirupathi and Iain Horrocks and Anil Dhawan and Michael Eyre and Maria Vanegas and Fernandez-Garcia, {Miguel A.} and Amy Wolfe and Laura Pinches and Marjorie Illingworth and Marion Main and Lianne Abbott and Hayley Smith and Emily Milton and Sarah D'Urso and Kayal Vijayakumar and Marco, {Silvia Sanchez} and Sinead Warner and Emily Reading and Isobel Douglas and Francesco Muntoni and Min Ong and Anirban Majumdar and Imelda Hughes and Heinz Jungbluth and Elizabeth Wraige",

note = "Publisher Copyright: {\textcopyright} 2023 The Author(s)",

year = "2024",

month = feb,

doi = "10.1016/j.lanepe.2023.100817",

language = "English",

volume = "37",

journal = "The Lancet Regional Health - Europe",

issn = "2666-7762",

publisher = "Elsevier Ltd",

}

Gowda, V, Atherton, M, Murugan, A, Servais, L, Sheehan, J, Standing, E, Manzur, A, Scoto, M, Baranello, G, Munot, P, McCullagh, G, Willis, T, Tirupathi, S, Horrocks, I, Dhawan, A , Eyre, M, Vanegas, M, Fernandez-Garcia, MA, Wolfe, A, Pinches, L, Illingworth, M, Main, M, Abbott, L, Smith, H, Milton, E, D'Urso, S, Vijayakumar, K, Marco, SS, Warner, S, Reading, E, Douglas, I, Muntoni, F, Ong, M, Majumdar, A, Hughes, I, Jungbluth, H & Wraige, E 2024, 'Efficacy and safety of onasemnogene abeparvovec in children with spinal muscular atrophy type 1: real-world evidence from 6 infusion centres in the United Kingdom', The Lancet Regional Health - Europe, vol. 37, 100817. https://doi.org/10.1016/j.lanepe.2023.100817

TY - JOUR

T1 - Efficacy and safety of onasemnogene abeparvovec in children with spinal muscular atrophy type 1

T2 - real-world evidence from 6 infusion centres in the United Kingdom

AU - Gowda, Vasantha

AU - Atherton, Mark

AU - Murugan, Archana

AU - Servais, Laurent

AU - Sheehan, Jennie

AU - Standing, Emma

AU - Manzur, Adnan

AU - Scoto, Mariacristina

AU - Baranello, Giovanni

AU - Munot, Pinki

AU - McCullagh, Gary

AU - Willis, Tracey

AU - Tirupathi, Sandya

AU - Horrocks, Iain

AU - Dhawan, Anil

AU - Eyre, Michael

AU - Vanegas, Maria

AU - Fernandez-Garcia, Miguel A.

AU - Wolfe, Amy

AU - Pinches, Laura

AU - Illingworth, Marjorie

AU - Main, Marion

AU - Abbott, Lianne

AU - Smith, Hayley

AU - Milton, Emily

AU - D'Urso, Sarah

AU - Vijayakumar, Kayal

AU - Marco, Silvia Sanchez

AU - Warner, Sinead

AU - Reading, Emily

AU - Douglas, Isobel

AU - Muntoni, Francesco

AU - Ong, Min

AU - Majumdar, Anirban

AU - Hughes, Imelda

AU - Jungbluth, Heinz

AU - Wraige, Elizabeth

PY - 2024/2

Y1 - 2024/2

N2 - Background: Real-world data on the efficacy and safety of onasemnogene abeparvovec (OA) in spinal muscular atrophy (SMA) are needed, especially to overcome uncertainties around its use in older and heavier children. This study evaluated the efficacy and safety of OA in patients with SMA type 1 in the UK, including patients ≥2 years old and weighing ≥13.5 kg. Methods: This observational cohort study used data from patients with genetically confirmed SMA type 1 treated with OA between May 2021 and January 2023, at 6 infusion centres in the United Kingdom. Functional outcomes were assessed using age-appropriate functional scales. Safety analyses included review of liver function, platelet count, cardiac assessments, and steroid requirements. Findings: Ninety-nine patients (45 SMA therapy-naïve) were treated with OA (median age at infusion: 10 [range, 0.6–89] months; median weight: 7.86 [range, 3.2–20.2] kg; duration of follow-up: 3–22 months). After OA infusion, mean ± SD change in CHOP-INTEND score was 11.0 ± 10.3 with increased score in 66/78 patients (84.6%); patients aged <6 months had a 13.9 points higher gain in CHOP-INTEND score than patients ≥2 years (95% CI, 6.8–21.0; P < 0.001). Asymptomatic thrombocytopenia (71/99 patients; 71.7%), asymptomatic troponin-I elevation (30/89 patients; 33.7%) and transaminitis (87/99 patients; 87.9%) were reported. No thrombotic microangiopathy was observed. Median steroid treatment duration was 97 (range, 28–548) days with dose doubled in 35/99 patients (35.4%). There were 22.5-fold increased odds of having a transaminase peak >100 U/L (95% CI, 2.3–223.7; P = 0.008) and 21.2-fold increased odds of steroid doubling, as per treatment protocol (95% CI, 2.2–209.2; P = 0.009) in patients weighing ≥13.5 kg versus <8.5 kg. Weight at infusion was positively correlated with steroid treatment duration (r = 0.43; P < 0.001). Worsening transaminitis, despite doubling of oral prednisolone, led to treatment with intravenous methylprednisolone in 5 children. Steroid-sparing immunosuppressants were used in 5 children to enable steroid weaning. Two deaths apparently unrelated to OA were reported. Interpretation: OA led to functional improvements and was well tolerated with no persistent clinical complications, including in older and heavier patients. Funding: Novartis Innovative Therapies AG provided a grant for independent medical writing services.

AB - Background: Real-world data on the efficacy and safety of onasemnogene abeparvovec (OA) in spinal muscular atrophy (SMA) are needed, especially to overcome uncertainties around its use in older and heavier children. This study evaluated the efficacy and safety of OA in patients with SMA type 1 in the UK, including patients ≥2 years old and weighing ≥13.5 kg. Methods: This observational cohort study used data from patients with genetically confirmed SMA type 1 treated with OA between May 2021 and January 2023, at 6 infusion centres in the United Kingdom. Functional outcomes were assessed using age-appropriate functional scales. Safety analyses included review of liver function, platelet count, cardiac assessments, and steroid requirements. Findings: Ninety-nine patients (45 SMA therapy-naïve) were treated with OA (median age at infusion: 10 [range, 0.6–89] months; median weight: 7.86 [range, 3.2–20.2] kg; duration of follow-up: 3–22 months). After OA infusion, mean ± SD change in CHOP-INTEND score was 11.0 ± 10.3 with increased score in 66/78 patients (84.6%); patients aged <6 months had a 13.9 points higher gain in CHOP-INTEND score than patients ≥2 years (95% CI, 6.8–21.0; P < 0.001). Asymptomatic thrombocytopenia (71/99 patients; 71.7%), asymptomatic troponin-I elevation (30/89 patients; 33.7%) and transaminitis (87/99 patients; 87.9%) were reported. No thrombotic microangiopathy was observed. Median steroid treatment duration was 97 (range, 28–548) days with dose doubled in 35/99 patients (35.4%). There were 22.5-fold increased odds of having a transaminase peak >100 U/L (95% CI, 2.3–223.7; P = 0.008) and 21.2-fold increased odds of steroid doubling, as per treatment protocol (95% CI, 2.2–209.2; P = 0.009) in patients weighing ≥13.5 kg versus <8.5 kg. Weight at infusion was positively correlated with steroid treatment duration (r = 0.43; P < 0.001). Worsening transaminitis, despite doubling of oral prednisolone, led to treatment with intravenous methylprednisolone in 5 children. Steroid-sparing immunosuppressants were used in 5 children to enable steroid weaning. Two deaths apparently unrelated to OA were reported. Interpretation: OA led to functional improvements and was well tolerated with no persistent clinical complications, including in older and heavier patients. Funding: Novartis Innovative Therapies AG provided a grant for independent medical writing services.

KW - Efficacy

KW - Follow-up

KW - Gene therapy

KW - Longitudinal

KW - Motor neuron disorder

KW - Onasemnogene abeparvovec

KW - Real-world experience

KW - Safety

KW - SMA

KW - Spinal muscular atrophy

KW - United Kingdom

KW - Zolgensma

UR - http://www.scopus.com/inward/record.url?scp=85179618322&partnerID=8YFLogxK

U2 - 10.1016/j.lanepe.2023.100817

DO - 10.1016/j.lanepe.2023.100817

M3 - Article

AN - SCOPUS:85179618322

SN - 2666-7762

VL - 37

JO - The Lancet Regional Health - Europe

JF - The Lancet Regional Health - Europe

M1 - 100817

ER -

Efficacy and safety of onasemnogene abeparvovec in children with spinal muscular atrophy type 1: real-world evidence from 6 infusion centres in the United Kingdom

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