Novartis announces results of Phase I START trial for Zolgensma for spinal muscular atrophy type 1.

With FDA acceptance of the BLA for Zolgensma Novartis has announced details of the START trial. START was a Phase 1 study evaluating safety and efficacy of Zolgensma in SMA Type 1 patients genetically tested to confirm bi-allelic SMN1 deletions, 2 copies of survival motor neuron 2 (SMN2), negative findings for the c.859G>C modification in exon 7 and with the onset of clinical symptoms before 6 months of age. Zolgensma was delivered intravenously during a single-dose infusion in patients 0.9 to 7.9 months of age.

Two cohorts were dosed: Cohort 1 (n=3) received the low dose used in this study and Cohort 2 (n=12) received the high dose used in this study. At the 24-month follow up, all 15 patients (100%), who were over all 24 months of age, were event-free, as opposed to only 8% of patients in a natural history study. This indicates a significant and clinically meaningful increase in overall survival for patients infused with Zolgensma when compared to untreated patients. At two years following infusion, no patient deaths were reported. The most commonly observed side effect in the Zolgensma clinical trial was elevated liver enzymes. The reported study outcomes reflect Cohort 2 and includes follow-up of all patients out to 24 months following Zolgensma infusion. Patients in Cohort 2 consistently achieved and maintained key developmental motor milestones. At 24 months of follow-up post-infusion, 11 patients (91.7%) were able to hold their head erect for greater than = 3 seconds and sit without support for greater than = 5 seconds, 10 patients (83.3%) were able to sit without support for geater than = 10 seconds, 9 patients (75.0%) were able to sit without support for greater than than= 30 seconds and 2 patients each (16.7%) were able to stand alone, walk with assistance and walk alone.

Of the 10 patients in Cohort 2 that were not using non-invasive ventilation (NIV) at baseline, 7 were free of daily NIV use at 24 months of follow-up. Nearly all patients experienced common childhood respiratory illnesses that, in children with SMA Type 1, typically result in tracheostomy or death. All patients survived respiratory hospitalizations without tracheostomy or the need for permanent ventilation.

Nutritional gains were also observed. In Cohort 2, seven patients did not receive enteral feeding prior to Zolgensma infusion. One of these 7 patients had nutritional support post-Zolgensma infusion to assist wound healing following a difficult recovery from scoliosis surgery but was also feeding orally. Four of the 5 patients in Cohort 2 who received enteral feeding prior to Zolgensma infusion were able to feed orally at end of study; thus, a total of 11 of the 12 patients in Cohort 2 were able to feed orally, 6 exclusively. Patients receiving the therapeutic dose achieved statistically significant motor function improvements by month 1 and month 3; Children's Hospital of Philadelphia Infant Test of Neuromuscular Disorders (CHOP-INTEND) mean increases from baseline were 9.8 points (n=12, P < 0.001) and 15.4 points (n=12, P < 0.001), respectively. Motor function improvements were sustained over time in patients infused with Zolgensma . Eleven of twelve (91.7%) Cohort 2 patients achieved a greater than = 50 CHOP-INTEND during the 24-month study period. Early intervention and dose appear to positively affect the response.

In general clinical practice, untreated SMA Type 1 children 6 months of age or older do not surpass a score of 40 points on the CHOP-INTEND. Furthermore, an average decline of 10.7 points between the ages of 6 and 12 months were reported amongst untreated infants followed as part of a prospective natural history. Cohort 2 patients who are currently voluntarily enrolled in an ongoing observational long-term follow-up of this study have maintained their developmental motor milestones - including patients who are four years post infusion - with some achieving additional motor milestones. Four patients attained new milestones, including 2 patients who sat unassisted for greater than 30 seconds and two patients were able to stand with support.