Dataset Information

Onasemnogene abeparvovec in spinal muscular atrophy: predictors of efficacy and safety in naive patients with spinal muscular atrophy and following switch from other therapies.

ABSTRACT:

Background

Efficacy and safety of onasemnogene abeparvovec (OA) for Spinal Muscular Atrophy infants under 7 months and <8.5 kg has been reported in clinical trials. This study examines efficacy and safety predictors in a wide age (22 days-72 months) and weight (3.2-17 kg) range, also including patients previously treated with other drugs.

Methods

46 patients were treated for 12 months between January 2020 and March 2022. Safety profile was also available for another 21 patients with at least 6 month follow-up after OA infusion. 19/67 were treatment naïve when treated with OA. Motor function was measured with the CHOP-INTEND.

Findings

CHOP-INTEND changes varied among age groups. Baseline score and age at OA treatment best predicted changes. A mixed model post-hoc analysis showed that in patients treated before the age of 24 months the CHOP-INTEND changes were already significant 3 months after OA while in those treated after the age of 24 months the difference was only significant 12 months after OA. Adverse events occurred in 51/67. The risk for elevated transaminases serum levels was higher in older patients. This was also true for weight and for pre-treatment with nusinersen when analysed individually. A binomial negative regression analysis showed that only age at OA treatment had a significant effect on the risk of elevated transaminases.

Interpretation

Our paper describes OA 12-month follow-up showing efficacy across various age and weight groups not targeted by clinical trials. The study identifies prognostic factors for safety and efficacy in treatment selection.

Funding

None.

SUBMITTER: Pane M

PROVIDER: S-EPMC10184045 | biostudies-literature | 2023 May

REPOSITORIES: biostudies-literature

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Publications

Onasemnogene abeparvovec in spinal muscular atrophy: predictors of efficacy and safety in naïve patients with spinal muscular atrophy and following switch from other therapies.

Pane Marika M Berti Beatrice B Capasso Anna A Coratti Giorgia G Varone Antonio A D'Amico Adele A Messina Sonia S Masson Riccardo R Sansone Valeria Ada VA Donati Maria Alice MA Agosto Caterina C Bruno Claudio C Ricci Federica F Pini Antonella A Gagliardi Delio D Filosto Massimiliano M Corti Stefania S Leone Daniela D Palermo Concetta C Onesimo Roberta R De Sanctis Roberto R Ricci Martina M Bitetti Ilaria I Sframeli Maria M Dosi Claudia C Albamonte Emilio E Ticci Chiara C Brolatti Noemi N Bertini Enrico E Finkel Richard R Mercuri Eugenio E

EClinicalMedicine 20230505

<h4>Background</h4>Efficacy and safety of onasemnogene abeparvovec (OA) for Spinal Muscular Atrophy infants under 7 months and <8.5 kg has been reported in clinical trials. This study examines efficacy and safety predictors in a wide age (22 days-72 months) and weight (3.2-17 kg) range, also including patients previously treated with other drugs.<h4>Methods</h4>46 patients were treated for 12 months between January 2020 and March 2022. Safety profile was also available for another 21 patients wi ...[more]

PMID: 37197706

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Project description:BackgroundRecently gene therapy with onasemnogene abeparvovec has been approved for the treatment of spinal muscular atrophy (SMA). As the experience from clinical trials is limited, there are still uncertainties for which patient population the treatment can be considered safe and effective.MethodsWe report our experience with eight consecutive patients with SMA who were treated with the standard dose of onasemnogene abeparvovec (1.1×1014 vg/kg) at the University Hospital Bonn, Germany. All patients received prophylactic immunosuppression with 1 mg/kg/d prednisolone for four weeks starting on the day before gene therapy.ResultsWe treated eight patients (4 male, 4 female, age range 10-37 months) with a body weight between 7.1 and 11.9 kg. All patients had 2 or 3 copies of the SMN2-gene and were previously treated with nusinersen. Following treatment with onasemnogene abeparvovec all patients showed a temporary increase of the body temperature and an increase of transaminase levels. In all but one patient it was necessary to increase or prolong the standard steroid dose to control the immune response. In one severe case, liver damage was associated with impaired liver function. This patient received a steroid pulse therapy for five days. Blood counts revealed asymptomatic thrombocytopenia (<150×109/L) in 6/8 patients and a significant increase of monocytes following gene therapy. Liver values and blood counts returned to almost normal levels during the post-treatment observation period. Troponin I increased above normal limit in 4/8 patients but was not associated with any abnormalities on cardiac evaluation.ConclusionsIn a broader spectrum of patients, treatment with onasemnogene abeparvovec was associated with a higher rate of adverse events. In our cases it was possible to control the immune response by close monitoring and adaptation of the immunosuppressive regimen. Further research is needed to better understand the immune response following gene therapy and ideally to identify patients at risk for a more severe reaction.

Project description:ImportanceThis ongoing study assesses long-term safety and durability of response in infants with spinal muscular atrophy (SMA) type 1 after dosing with onasemnogene abeparvovec gene replacement therapy.ObjectiveThe primary objective of this ongoing study is to assess safety. The secondary objective is to determine whether developmental milestones achieved in the START phase 1 clinical trial were maintained and new milestones gained.Design, setting, and participantsThis study is an ongoing, observational, follow-up study for continuous safety monitoring for 15 years in patients from the START phase I study (conducted May 5, 2014, through December 15, 2017) at Nationwide Children's Hospital in Columbus, Ohio. Participants were symptomatic infants with SMA type 1 and 2 copies of SMN2 previously treated with an intravenous dose of onasemnogene abeparvovec (low dose, 6.7 × 1013 vg/kg; or therapeutic dose, 1.1 × 1014 vg/kg) in START. Thirteen of 15 original START patients are included in this analysis; 2 patients' families declined follow-up participation. Data were analyzed from September 21, 2017, to June 11, 2020.ExposuresMedian time since dosing of 5.2 (range, 4.6-6.2) years; 5.9 (range, 5.8-6.2) years in the low-dose cohort and 4.8 (range, 4.6-5.6) years in the therapeutic-dose cohort.Main outcomes and measuresThe primary outcome measure was the incidence of serious adverse events (SAEs).ResultsAt data cutoff on June 11, 2020, 13 patients treated in START were enrolled in this study (median age, 38.9 [range, 25.4-48.0] months; 7 females; low-dose cohort, n = 3; and therapeutic-dose cohort, n = 10). Serious adverse events occurred in 8 patients (62%), none of which resulted in study discontinuation or death. The most frequently reported SAEs were acute respiratory failure (n = 4 [31%]), pneumonia (n = 4 [31%]), dehydration (n = 3 [23%]), respiratory distress (n = 2 [15%]), and bronchiolitis (n = 2 [15%]). All 10 patients in the therapeutic-dose cohort remained alive and without the need for permanent ventilation. Prior to baseline, 4 patients (40%) in the therapeutic-dose cohort required noninvasive ventilatory support, and 6 patients (60%) did not require regular ventilatory support, which did not change in long-term follow-up. All 10 patients treated with the therapeutic dose maintained previously acquired motor milestones. Two patients attained the new milestone of "standing with assistance" without the use of nusinersen.Conclusions and relevanceThe findings of this ongoing clinical follow-up of patients with SMA type 1 treated with onasemnogene abeparvovec supports the long-term favorable safety profile up to 6 years of age and provides evidence for sustained clinical durability of the therapeutic dose.Trial registrationClinicalTrials.gov Identifier: NCT03421977.