Interim data from STRONG, STR1VE and SPRINT ongoing trials positive for Zolgensma to treatspinal muscular atrophy

AveXis, a Novartis company, 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 III 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 III 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: patients who are >=6 months but <24 months, and patients who are > =24 months but <60 months. The primary efficacy outcome for patients who were >=6 to <24 months is the ability to stand without support >=3 seconds; the primary efficacy outcome for patients who were >=24 to >60 months is change in Hammersmith Functional Motor Scale-Expanded (HFMSE) score from baseline. Three dosing strengths are being evaluated. Only 3/34 (8.8 percent) patients were excluded due to elevated AAV9 antibodies. Patients in the STRONG study showed improvement in motor function, with 19 patients (12/12 dosed at >=24 to <60 months and 7 who were dosed at >=6 to <24 months who then became old enough to be evaluated on the HSMSE) having a mean 4.2-point increase from baseline in HFMSE as of their most recent study visit (5-12 months post-treatment). Half of the patients (6/12) who were >=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 III 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 <6 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. 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. Of the 15 patients who could have reached 13.6 months of age or discontinued the study prior to 13.6 months of age, 13 (87 percent) survived without permanent ventilation. Untreated natural history indicates that only 50 and 25 percent of babies with SMA Type 1 will survive event-free by the time they reach 10.5 months of age and 13.6 months of age, respectively. The median age was 14.4 months. 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 III STR1VE trial are consistent with the findings in the Phase 1 START trial and on track to confirm those results.

Phase III SPR1NT Data as of March 8, 2019.: SPR1NT is a Phase III, 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 =<6 weeks of age. The primary outcome measure for patients with two copies of SMN2 is independent sitting for >=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. Among patients with two copies of SMN2 (n=8), a mean 8.9-point improvement from baseline in CHOP-INTEND was achieved one-month post dosing, and a mean score of 8.4 points in Bayley-III Gross Motor was achieved by month two. 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. Untreated natural history indicates that patients with two copies of SMN2 will never sit without assistance. The median duration of follow-up is 5.4 months and the median age is 6.1 months. 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. One patient was enrolled in to SPR1NT with four copies of SMN2 and was assessed for safety but not efficacy as this patient did not meet the intent-to-treat criteria.