AveXis Presents Data at AAN Annual Meeting Demonstrating Efficacy of Zolgensma in Broad Spectrum of Spinal Muscular Atrophy (SMA) Patients

AveXis, a Novartis company, recently announced interim data from ongoing trials of the investigational product Zolgensma® (onasemnogene abeparvovec-xioi; AVXS-101) that showed positive results across a broad spectrum of patients with spinal muscular atrophy (SMA). These included the first presentation of data from the Phase 1 STRONG trial, which showed motor function gains and milestone achievements in patients with SMA Type 2 via intrathecal (IT) delivery; new data from the Phase 3 STR1VE trial, which continued to show prolonged event-free survival, increases in motor function and significant milestone achievement consistent with the Phase 1 START trial; and the first presentation of data from the Phase 3 SPR1NT trial, which showed motor milestone achievement consistent with normal development in SMA patients treated pre-symptomatically. These data were presented during the 2019 American Academy of Neurology (AAN) Annual Meeting.

Phase 1 STRONG Data as of March 8, 2019

STRONG is a Phase 1, open-label, dose-comparison, multi-center trial designed to evaluate the safety and tolerability of one-time IT administration of Zolgensma in patients with SMA Type 2 who have three copies of the SMN2 gene, and who are able to sit but cannot stand or walk at the time of study entry. Patients were stratified into two groups based on age at time of dosing. Three dosing strengths are being evaluated.

Patients in the STRONG study showed improvement in motor function, with 19 patients (12/12 dosed at >=24 to=6 to=24 months at dosing experienced a >=3-point improvement from baseline in HFMSE by one-month post dosing.

Since dosing, 22 motor milestones in 10 patients have been achieved according to the Bayley-III Gross Motor Milestone Scale across the Dose A and Dose B treatment groups, including two patients who gained the ability to stand independently, one of whom went on to walk alone in the younger group, and one additional patient who gained the ability to walk with assistance in the older group. The median duration of follow-up was 6.5 months. Efficacy data from Dose C are not presented because enrollment is not complete.

All patients (n=30) were alive. There were two serious treatment-related adverse events. Both were of transaminase elevation. The frequency of patients with adverse events of transaminase elevation appeared to be lower than that seen with intravenous (IV) administration of Zolgensma.

Phase 3 STR1VE Data as of March 8, 2019

STR1VE is an ongoing, open-label, single-arm, single-dose, multi-center trial in the U.S. designed to evaluate the efficacy and safety of a one-time IV infusion of Zolgensma in patients with SMA Type 1 who are

As of March 8, 2019, of the 20 patients who could have reached 10.5 months of age or discontinued the study prior to 10.5 months of age, 19 (95 percent) survived without permanent ventilation. As previously disclosed, one patient died from respiratory failure, which was deemed by the investigator and independent Data Safety Monitoring Board to be unrelated to treatment. This patient had demonstrated significant motor improvement prior to the event, with a 27-point increase in CHOP-INTEND from baseline five months post-infusion.

Children’s Hospital of Philadelphia Infant Test of Neuromuscular Disorders (CHOP-INTEND) scores increased by an average of 6.9 points one month, 11.7 points three months and 14.3 points five months after gene transfer, reflecting improvement in motor function from baseline. Twenty-one of 22 (95 percent) patients achieved a CHOP-INTEND score of >=40.

Patients treated with Zolgensma continued to gain motor milestones, including one patient who could crawl, one patient who could pull to a stand and 11 patients who could sit without support for at least 30 seconds according to Bayley-III Gross Motor criteria, an achievement babies with SMA Type 1 never reach in natural history. The 11 patients (50%) achieved the ability to sit without support at a mean age of 11.9 months and at a mean 8.2 months post treatment.

Safety observations in STR1VE are comparable to those seen in the Phase 1 START trial. Adverse events observed include elevated transaminases, platelet count decrease and thrombocytopenia.

These interim data from the multicenter, Phase 3 STR1VE trial are consistent with the findings in the Phase 1 START trial and on track to confirm those results.

Phase 3 SPR1NT Data as of March 8, 2019

SPR1NT is a Phase 3, open-label, single-arm, multi-center trial designed to evaluate the safety and efficacy of a one-time IV infusion of Zolgensma in pre-symptomatic patients with SMA and two or three copies of SMN2 who are ==30 seconds by 18 months. The primary outcome measure for patients with three copies of SMN2 is standing without support for at least three seconds by 24 months.

As of March 8, 2019, all patients (18/18)* were alive and event-free. All patients in this group achieved or maintained a CHOP-INTEND score of 50 points, with four patients achieving a score of 60 points and three patients achieving the maximum score of 64.

Patients with two copies of SMN2 reached age-appropriate motor milestones, including four patients who could sit without support for at least 30 seconds according to Bayley-III Gross Motor criteria, and one patient who could stand with assistance for >=2 seconds.

Serious adverse events were cases of croup (n=1), lethargy (n=1), and hypercalcemia (n=1), all of which resolved and were considered unrelated to treatment by investigators. Other observed adverse events included elevated transaminases, elevated blood creatine phosphokinase MB and elevated troponin.

Cure SMA Supports Multiple Gene Therapy Approaches

Beginning in 2010, Cure SMA made a series of grants to Nationwide Children’s Hospital to study gene therapy, also called gene transfer. Spinal muscular atrophy (SMA) is caused by a mutation in the survival motor neuron 1 gene (SMN1). Because of this mutation, the individual does not produce enough survival motor neuron (SMN) protein.

Gene transfer may increase SMN levels by using a virus, called a vector, to deliver the SMN1 gene to affected cells. Adeno-associated virus serotype 9 (AAV9) has the unique ability to cross the blood brain barrier and the Blood-Cerebrospinal Fluid Barrier (CSF).

Currently, two approaches are being studied: an injection into a vein, known as IV delivery, and injection directly into the CSF, a process known as IT delivery. The IV delivery approach is currently under review for approval by the FDA.

IT delivery of gene therapy has shown promise for reducing the amount of drug required for larger and older patients. This could eventually make the treatment accessible to a wider population. IT delivery of gene therapy is currently being tested in clinical trials.

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