AveXis, a Novartis company, recently announced that new interim data from the Phase 3 SPR1NT trial in pre-symptomatic patients as well as interim data from the ongoing Phase 3 STR1VE clinical program for Zolgensma showed positive outcomes, demonstrating age‑appropriate major milestone gain with pre‑symptomatic treatment and prolonged event-free survival* in patients with SMA Type 1. An additional oral presentation highlighted interim results from the long-term follow-up of the Phase 1 START study. These data will be presented during the 2019 European Paediatric Neurology Society (EPNS) Congress.

SPR1NT

Phase 3 SPR1NT Data as of May 31, 2019

SPR1NT is an ongoing Phase 3, open-label, single-arm, multi-center trial designed to evaluate the safety and efficacy of a one-time intravenous (IV) infusion of Zolgensma in pre-symptomatic patients with SMA and two or three copies of SMN2 who are <=6 weeks of age.

As of May 31, 10 patients with two copies of SMN2, 12 patients with three copies of SMN2 and one patient with four copies of SMN2 were treated. The mean age of patients in the two-copy cohort was 6.6 months at last follow up and 4.6 months for the three‑copy cohort. Of the two- and three-copy patients who had completed their six-month swallow evaluation, all had normal swallow function and were fed exclusively by mouth; of the 22 patients being evaluated overall, all were alive and free of permanent ventilation. All patients with two copies of SMN2 achieved or maintained a Children’s Hospital of Philadelphia Infant Test of Neuromuscular Disorders (CHOP-INTEND) score of greater than 50, with seven patients achieving a CHOP-INTEND score of greater than or equal to 60 and five patients reaching the maximum score of 64. Of patients with two copies of SMN2, six (60%) were able to sit without support for at least 30 seconds at an average age of 7.6 months. Three of these patients (30%) were able to stand with assistance at an average age of 10.1 months. The natural history of untreated patients with SMA indicates that patients with two copies of SMN2 will never sit without assistance.3

Thirteen of the 18 patients (72.2%) experienced at least one treatment-emergent adverse event (TEAE) and seven (38.9%) were reported to have a TEAE considered by the investigator to be related to Zolgensma. Three serious TEAEs were reported in three treated patients: croup (one patient), lethargy (one patient), and hypercalcemia (one patient). All serious TEAEs were resolved and considered unrelated to treatment. In addition, TEAEs of special interest were reported in four patients: hepatic enzyme increased (one patient), liver function test increased (two patients), transaminases increased (one patient). One patient had asymptomatic increases of blood creatine phosphokinase MB and troponin, both resolved.

STR1VE — GLOBAL

Phase 3 STR1VE Global Data as of May 31, 2019

The Global Phase 3 STR1VE clinical program includes ongoing, open-label, single-arm, single-dose, multi-center trials (STR1VE-US in the United States, STR1VE-EU in Europe and STR1VE-AP in Asia Pacific) designed to evaluate the efficacy and safety of a single, one-time IV infusion of Zolgensma in patients with SMA Type 1 who are less than six months of age at the time of gene therapy, with one or two copies of the SMN2 backup gene and who have bi-allelic SMN1 gene deletion or point mutations.

At the EPNS Congress, STR1VE-EU data will be presented side-by-side with STR1VE-US data. Collectively, these results demonstrate that a single, one-time treatment with Zolgensma has significant therapeutic benefit in prolonging event‑free survival compared to natural history and rapidly improving motor function in patients with SMA Type 1.

Patients treated with Zolgensma continued to gain motor milestones. The mean follow-up time since dosing was 12.1 months in STR1VE-US and 4.2 months in STR1VE-EU. Eleven patients (50%) in the STR1VE-US study and two patients (6%) in the STR1VE-EU study achieved the ability to 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 the natural history of the disease.3 Five of the six patients (83%) in STR1VE-US who reached 18 months of age (study completion) had achieved the milestone of sitting independently for 30 seconds (primary study endpoint). Additionally, one patient in the STR1VE-US study could pull to a stand and walk with assistance. In STR1VE-US, CHOP-INTEND scores increased by an average of 6.9 points one month, and 11.7 points three months after gene therapy treatment. In STR1VE-EU, scores increased by an average of 6.4 points one month, and 10.6 points three months after gene therapy treatment.

While the two trials represent the same patient population in terms of SMA type and entry criteria, e.g., age range and functional status, there were differences in the baseline characteristics in the patients from the two trials. In STR1VE-US the mean age at dosing was 3.7 months and the mean CHOP-INTEND score was 32. Whereas in STR1VE-EU, the mean age of dosing was 4.1 months and the mean CHOP-INTEND score was 28. Additionally, at the start of the trial in STR1VE-US, none of the patients needed nutritional or ventilatory support. In STR1VE-EU, nine patients needed nutritional support and seven needed ventilatory support. Lastly, none of the 25 STR1VE-US patients screened for AAV9 antibodies had exclusionary AAV9 antibody titers (>1:50), whereas six of the 40 patients screened in STR1VE-EU had titers >1:50. Upon rescreening, five STR1VE-EU patients were excluded due to elevated AAV9 antibodies.

STR1VE-US

Of the 22 patients enrolled in STR1VE-US, 20 were alive, without permanent ventilation, and continuing in the trial. Of 19 patients who had either reached 13.6 months of age or experienced an event, 17 patients (89.5%) survived without permanent ventilation. The mean age at the most recent visit was 15.8 months at an average follow-up time of 12.1 months. Natural history indicates that only 25% of Type 1 patients will survive event-free by the time they reach 13.6 months of age.4 CHOP-INTEND scores increased by an average of 6.9 points one month and 11.7 points three months after gene therapy treatment.

In the STR1VE-US trial, one patient died from respiratory failure, which was deemed by the investigator and an independent Data Safety Monitoring Board to be unrelated to treatment. Additionally, after the safety data cutoff (March 8, 2019) one patient in the STR1VE-US study was determined by the investigator to have required ≥ 16 hours of non-invasive BiPAP ventilator support for ≥ 14 consecutive days at the time of withdrawal from the study. Based on this report from the investigator, AveXis will consider this patient as having required permanent ventilatory support at the time of discontinuation.

STR1VE-EU

As of May 31, of the 10 patients who had reached 10.5 months of age or experienced an event, nine (90%) survived without permanent ventilation. The mean age at the most recent visit was 8.2 months at an average follow-up time of 4.2 months. CHOP-INTEND scores increased by an average of 6.4 points one month (n=25) and 10.6 points three months (n=22) after gene therapy treatment.

As previously reported, one patient in the STR1VE-EU trial died prior to the March 8th safety data cutoff. According to the Coroner’s report, the immediate cause of death was hypoxic-ischemic brain damage with respiratory tract infection as the underlying cause. SMA Type 1 was indicated as the underlying cause for the respiratory tract infection. In addition, there was no evidence of an inflammatory CNS process or a toxic or a treatment-related brain damage.

Following the autopsy report findings, leukoencephalopathy, which was reassessed as hypoxic-ischemic brain damage, and respiratory distress are considered unrelated to the gene therapy by the investigator. The final autopsy report has indicated the gene therapy could have potentially contributed to the concurrent events of abnormal liver function tests (elevation of liver enzymes called transaminases), abnormal blood tests (low platelets) and low blood pressure. The serious adverse events (SAE) reports will be updated accordingly and submitted to the Health Authorities.

STR1VE Global Safety

Safety observations across the STR1VE Global data are comparable to those seen in the Phase 1 START trial. Adverse events of special interest, including elevated transaminases, platelet count decrease and thrombocytopenia, were transient and did not cause any long-term sequelae.

START

START Long-Term Follow-Up Data as of May 31, 2019

START was a Phase 1 study evaluating the safety and efficacy of a one-time IV infusion of Zolgensma in SMA Type 1 patients with the onset of clinical symptoms before six months of age. At the close of the 24-month study, all 12 patients in cohort 2 (targeted therapeutic dose) were alive and free of permanent ventilation. Without treatment, most of these patients would not survive past the age of two or would require permanent ventilation.4 Ten of these 12 patients voluntarily enrolled in an ongoing observational long-term follow-up of the START study.

As of May 31, of the 10 patients who enrolled in the long-term follow-up study, all are alive and continue to maintain developmental milestones. Two patients, neither of whom have received treatment with nusinersen following Zolgensma infusion, gained the ability to stand with assistance. These milestones are in addition to the two START patients previously reported who are walking independently.

The mean age of patients was 4.2 years (range 3.7 – 5.0 years) and the mean time since gene therapy treatment was 3.9 years (range 3.5 – 4.6 years). Seven out of 10 patients (70%) are not currently receiving concomitant therapy with nusinersen. All patients have maintained or demonstrated improvements in ventilatory status. Six out of 10 patients (60%) do not require daily respiratory support.

There were no new treatment related SAEs and no adverse events of special interest occurred during the long-term follow up study. No fatal serious TEAEs have occurred during the parent study or long-term follow up study. Serious TEAEs were reported in six of 13 patients. The following serious TEAEs were reported in one or more patients: pneumonia (three patients), dehydration (two patients), acute respiratory failure (two patients), respiratory distress (two patients), bronchitis (one patient), cardiac arrest (one patient), gastroenteritis (one patient), hypoglycemia (one patient), respiratory failure (one patient).

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.