Published Phase 3 Data Demonstrates Unprecedented Improvements in SMA Type 1 Compared With Natural History


The senior vice president and chief medical officer at Novartis Gene Therapies shared his perspective on the recent clinical trial results for Zolgensma in SMA type 1.

Shephard Mpofu, MD, Senior Vice President and Chief Medical Officer, Novartis Gene Therapies

Shephard Mpofu, MD

The leading genetic cause of infant death, spinal muscular atrophy (SMA) is a rare disease that leads to progressive muscle weakness, paralysis, and death in its most severe forms.1,2 Until just a few years ago, there were no treatment options for SMA, and parents were told to take their babies home and love them. Left untreated, children diagnosed with SMA type 1—one of the most severe, and common types of the disease – passed away or required permanent ventilation in 90% of cases by their second birthday.3,4

Thankfully, recent years have brought about dramatic scientific innovation for this devastating disease, including multiple FDA-approved treatment options. As disease-modifying therapies emerged, the expectation for what treatment could achieve has increased. Achievements of survival, and survival without the need for permanent ventilation, have since made way to the ability to feed orally, and the achievement of developmental milestones, such as head control and even the ability to sit, stand and walk—outcomes never experienced in the untreated natural history of the disease. Data published last week in The Lancet Neurology reported such outcomes in children with SMA type 1 treated after symptom onset.

The study, “Onasemnogene abeparvovec gene therapy for symptomatic infantile-onset spinal muscular atrophy in patients with 2 copies of SMN2 (STR1VE; NCT03306277): an open-label, single-arm, multicentre, phase 3 trial” was designed to evaluate the efficacy and safety of Zolgensma (onasemnogene abeparvovec-xioi) in patients with SMA type 1—the most prevalent form of the disease, accounting for 60% of all diagnoses — who were less than six months of age, had one or two copies of the SMN2 backup gene and a bi-allelic SMN1 gene deletion or point mutation.5

READ MORE: Wearable Gait Technology Shows Promise in SMA and DMD

Zolgensma is the first-and-only gene therapy approved for the treatment of SMA in children younger than 2 years old, delivered as a one-time infusion (see prescribing and Important Safety Information, including a Boxed Warning for Acute Serious Liver Injury, here). In the completed STR1VE-US trial, patients who received Zolgensma demonstrated significant event-free survival compared with natural history; 91% (20 of 22) of patients were alive and free of permanent ventilation at the 14-months-of-age study visit, a primary end point. Patients in the trial also demonstrated motor milestone achievements compared with the natural history of the disease—including sitting without support for 30 seconds or more at 18 months of age visit (59%, a primary end point)—as well as rapid and clinically meaningful improvements in motor function following a one-time infusion of Zolgensma.5

In addition to the primary endpoints, the study evaluated the “ability to thrive” in children with SMA type 1, a stringent composite endpoint, inclusive of functions of swallowing, feeding, and age-appropriate weight maintenance.5 SMA is a disease that, when left untreated, often robs children of their most basic muscle functions, resulting in the loss of movement and lung function. Children often need breathing assistance and or a feeding tube. In contrast, of the 22 patients studied in the STR1VE-US trial, nine (41%) reached this co-secondary end point at 18 months of age (P <.0001 vs natural history), including 19 patients (86%) who did not receive nutrition through any feeding tube or other non-oral method, 14 patients (64%) who maintained weight (at least the third percentile) consistent with gender and age and 12 patients (55%) who were able to tolerate thin liquids.5

These are the transformative outcomes we should be constantly striving for as we seek to advance the treatment of SMA, not just for those currently diagnosed with SMA—but for the countless others who may face a diagnosis in the future.

Shepard Mpofu, MD, is the senior vice president and chief medical officer at Novartis Gene Therapies.

1. Anderton RS, Mastaglia FL.Advances and challenges in developing a therapy for spinal muscular atrophy. Expert Rev Neurother. 2015;15(8):895-908. doi: 10.1586/14737175.2015.1059757
2. Mendell, JR, Al-Zaidy S, Shell, R, et al. Single-Dose Gene-Replacement Therapy for Spinal Muscular Atrophy. N Engl J Med 2017;377(18):1713-1722. doi: 10.1056/NEJMoa1706198
3. Sugarman EA, Nagan N, Zhu H, et al. Pan-ethnic carrier screening and prenatal diagnosis for spinal muscular atrophy: clinical laboratory analysis of >72,400 specimens. Eur J Hum Genet. 2012;20(1):27-32. doi: 10.1038/ejhg.2011.134
4. 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. doi: 10.1212/WNL.0000000000000741.
5. Day JW, Finkel RS, Chiriboga CA, et al. Onasemnogene abeparvovec gene therapy for symptomatic infantile-onset spinal muscular atrophy in patients with two copies of SMN2 (STR1VE): an open-label, single-arm, multicentre phase 3 trial. Lancet Neurol. 2021;20(4):28493. doi: 10.1016/S1474-4422(21)00001-6.

ZOLGENSMA is an adeno-associated virus vector-based gene therapy indicated for the treatment of pediatric patients less than 2 years of age with spinal muscular atrophy (SMA) with bi-allelic mutations in the survival motor neuron 1 (SMN1) gene.

The safety and effectiveness of repeat administration or the use in patients with advanced SMA (e.g., complete paralysis of limbs, permanent ventilator dependence) has not been evaluated with ZOLGENSMA.
Important Safety Information
BOXED WARNING: Acute Serious Liver Injury
Acute serious liver injury and elevated aminotransferases can occur with ZOLGENSMA. Patients with pre-existing liver impairment may be at higher risk. Prior to infusion, assess liver function of all patients by clinical examination and laboratory testing (e.g., hepatic aminotransferases [aspartate aminotransferase (AST) and alanine aminotransferase (ALT)], total bilirubin, and prothrombin time). Administer a systemic corticosteroid to all patients before and after ZOLGENSMA infusion. Continue to monitor liver function for at least 3 months after infusion.
Transient decreases in platelet counts, some of which met the criteria for thrombocytopenia, were observed at different time points after ZOLGENSMA infusion. Monitor platelet counts before ZOLGENSMA infusion and on a regular basis for at least 3 months afterwards.
Thrombotic Microangiopathy
Cases of thrombotic microangiopathy (TMA) were reported approximately 1 week after ZOLGENSMA infusion. Obtain baseline creatinine and complete blood count before ZOLGENSMA infusion. Following infusion, monitor for thrombocytopenia as well as other signs and symptoms of TMA. Consult a pediatric hematologist and/or pediatric nephrologist immediately to manage if clinically indicated.

Elevated Troponin-I
Transient increases in cardiac troponin-I levels were observed following ZOLGENSMA infusion. Monitor troponin-I before ZOLGENSMA infusion and on a regular basis for at least 3 months afterwards.
The most commonly observed adverse reactions (incidence ≥5%) in clinical studies were elevated aminotransferases and vomiting.
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