FDA Decision Alerts January 8, 2021

EMA-Approved application for ZOLGENSMA® (onasemnogene abeparvovec-xioi)

Nick Honig and Ray Harvey
Contributing writers, Aetion

On March 26, 2020, the European Medicines Agency (EMA) approved AveXis’s ZOLGENSMA® (onasemnogene abeparvovec-xioi) for “the treatment of patients with 5q spinal muscular atrophy (SMA) with a bi-allelic mutation in the SMN1 gene and a clinical diagnosis of SMA Type 1, or patients with 5q SMA with a bi-allelic mutation in the SMN1 gene and up to 3 copies of the SMN2 gene.” Of note: the EMA granted onasemnogene abeparvovec-xioi a conditional marketing authorisation, valid for one year. To maintain marketing authorization, a sponsor must conduct certain post-marketing requirements.

Key findings from the EMA’s Public Assessment Report:

The results of a phase 3, open-label, single-arm trial, CL-303 (NCT03306277; n=22) served as the pivotal study for the EMA’s efficacy assessment.  An uncontrolled, phase 1 trial, CL-101 (NCT02122952; n=15), provided supportive evidence for the agency’s efficacy determination. The applicant provided two natural history studies to serve as external controls. The applicant also submitted expanded access data and post-marketing data.

Intent of the RWE studies

Natural history studies
The intent of the Pediatric Neuromuscular Clinical Research Network (PNCR) study (source: Finkel et al.) and the NeuroNext study (source: Kolb et al., and Kolb et al.) was to provide historical control data for comparison to CL-303 and CL-101. The natural history studies provided control data for survival rate, motor function, and The Children’s Hospital of Philadelphia Infant Test of Neuromuscular Disorders (CHOP-INTEND) scores.

Expanded access program and post-marketing data
The purpose of the expanded access and post-marketing data was to provide supportive evidence of safety and effectiveness.

Protocols for RWE generation

PNCR Study
The PNCR study collected data from 337 patients in the Pediatric Neuromuscular Clinical Research database. The original study collected information on the natural history of any type of SMA. For the purposes of this study, the applicant created a PNCR natural history cohort with the following criteria: “age of onset ≤ 6 months, bi-allelic deletion of SMN1 and 2 copies of SMN2” (n=23). The primary endpoints of the study were age at death and age reaching either death or 16 hours of ventilation support per day. The study also collected CHOP-INTEND scores and motor function data.

The EMA determined that survival, motor milestone, and CHOP-INTEND data derived from the PNCR study were relevant to comparison to the clinical studies submitted by the applicant. The survival rate from the PNCR study was 25 percent at 13.6 months. The PNCR study showed that no patient was able to sit without support for more than 10 seconds. The PNCR study also showed that no patient was able to score higher than 40 on the CHOP-INTEND scale after six months (with one transient exception).

NeuroNext Study
The NeuroNext study enrolled 26 patients younger than six months old. The study collected motor function data using the CHOP-INTEND and compound motor action potential (CMAP) measurements. The NeuroNext study also captured survival data, defining survival as being alive without tracheostomy.

The EMA determined that the survival, motor milestone, and CHOP-INTEND data derived from the PNCR study were relevant for the clinical comparison. The NeuroNext survival rate was 37.5 percent at 14 months. The EMA noted that the NeuroNext definition of survival was more lenient and therefore led to a higher survival rate. The NeuroNext study showed that no patient was able to sit with or without support, crawl, or stand or walk with assistance or alone. Following the six-month visit, no patient scored higher than 33 on the CHOP-INTEND score.

Expanded access program and post-marketing data
The applicant provided expanded access data to support the safety profile of onasemnogene abeparvovec-xioi (n=51). The applicant also provided 192 cases containing 488 adverse events from its post-marketing database.

Outcome of the RWE submissions

Natural history studies
The EMA determined that onasemnogene abeparvovec-xioi compared favorably to the natural history data for both survival and motor function. In the experimental arm of CL-303, where the survival endpoint was defined as death or permanent ventilator support, the survival rate was 90.9 percent (20 out of 22 patients).

The EMA stated onasemnogene abeparvovec-xioi “compares favorably to PNCR natural history where 25% were alive at 13.6 months.“ The experimental arm of CL-303 also demonstrated improved motor function compared to the PNCR natural history cohort. In CL-303, 59 percent of patients were able to sit without support at 14 months of age. In the PNCR study, no patient was able to meet that endpoint. 

The EMA noted some issues with the PNCR cohort, namely that patients may have had less severe disease. The EMA stated that while this may create bias, it is acceptable because it is not in favor of onasemnogene abeparvovec-xioi. The EMA also noted issues with subtype classification of SMA type 1.

In evaluating CL-101, the EMA concluded that “compared with the historical survival rate, the survival rates for patients treated with onasemnogene abeparvovec-xioi were statistically significantly higher for both cohorts and for all patients combined.”

In conclusion, the natural history studies provided substantial evidence of efficacy. The EMA notes that “the difference in survival during and at the end of the study between the patients treated with onasemnogene abeparvovec-xioi and natural history in the patient population with 2 copies of SMN2 is evident in all submitted clinical studies in which patients have a long enough follow-up.”

Expanded access program and post-marketing data
The EMA included expanded access data from 43 patients in the safety update. The data provided one case of acute serious liver failure. This case led to a warning of treating patients with hepatic impairment. 

The adverse events from post-marketing experience were consistent with the known safety profile of onasemnogene abeparvovec-xioi. The EMA noted that due to the limited information available, “no firm conclusions that confirm or deviated from the known safety profile of onasemnogene abeparvovec-xioi can be drawn.”

The EMA also issued a post-marketing requirement involving RWE. The applicant will use the RESTORE registry and available literature to help complete study CL-304 (NCT03505099, n=30), which is a condition of the agency’s conditional marketing authorization. 

Comparison to the FDA’s review of onasemnogene abeparvovec-xioi

As described in a previous FDA Decision Alert, the FDA approved onasemnogene abeparvovec-xioi on May 24, 2019 for the “treatment of pediatric patients less than two years of age with spinal muscular atrophy (SMA) with bi-allelic mutations in the survival motor neuron 1 (SMN1) gene.”

The applicant used the same natural history studies for both submissions, comparing them to trial CL-303 and CL-101 in both applications. The applicant also included expanded access data in both submissions. However, the applicant included post-market data in the EMA application, but not the FDA application. This difference is due to onasemnogene abeparvovec-xioi not being approved in any jurisdiction prior to the FDA approval.

The FDA and the EMA came to similar conclusions about the RWE, finding that it contributed to substantial evidence of safety and efficacy, playing an integral role in the approval decision. The agencies both discussed potential issues about historic subtype classification. The reviews differed in one notable area: the EMA noted the potential for bias in the PNCR cohort stemming from disease severity of the included patients. The FDA did not discuss this issue.


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.

Kolb SJ, Coffey CS, Yankey JW, et al. 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

Kolb SJ, Coffey CS, Yankey JW, et al. Natural history of infantile-onset spinal muscular atrophy. Ann Neurol. 2017;82(6):883-891. doi:10.1002/ana.25101

Honig N, Purpura C, Garry L, CBER-Approved BLA for ZOLGENSMA (onasemnogene abeparvovec-xioi). https://aetion.com/evidence-hub/fda-decision-alerts/cder-approved-bla-for-zolgensma-onasemnogene-abeparvovec-xioi/

eBook: 2021 update

The Role of Real-World Evidence in FDA Approvals

Download here