AveXis, a Novartis company, announced that new data from the Phase 1/2 STRONG study demonstrated a one-time intrathecal (IT) administration of AVXS-101 in patients ≥2 years and <5 years of age with spinal muscular atrophy (SMA) Type 2 who received Dose B (1.2 x 1014 vg) met the primary efficacy endpoint, achieving a remarkable mean increase from a baseline of 6.0 points in the Hammersmith Functional Motor Scale-Expanded (HFMSE), twice the clinically meaningful threshold established in previous SMA studies and reflecting improvement in three to six skills.

In addition, nearly all patients (92%) in this group achieved a clinically meaningful ≥3-point increase in HFMSE at any post-baseline visit during the study period, demonstrating a consistent response and a dramatic difference from the natural history control group (P <0.0001). Increases observed in HFMSE reflect the preservation of motor neurons connected to key muscle groups impacted in SMA Type 2, allowing for motor development such as trunk control when rolling and sitting, and transitioning from lying to sitting. In contrast to these findings, according to natural history, untreated SMA Type 2 patients typically experience a steady decline in motor function, and more than 30% die by age 25.

Phase 1/2 STRONG Data as of December 2, 2019

STRONG is an ongoing, open-label, multi-center trial designed to evaluate the efficacy, safety, and tolerability of one-time IT administration of AVXS-101 in SMA Type 2 patients who have three copies of the SMN2 gene, and who are able to sit but unable to stand or walk at the time of study entry. Patients were divided into two groups based on age at time of treatment: patients who are ≥6 months but <2 years of age, and patients who are ≥2 years but <5 years of age. As of the data cut-off, 32 patients were enrolled and have been treated with one of three doses: Dose A (6.0 x 1013 vg), Dose B (1.2 x 1014 vg) and Dose C (2.4 x 1014 vg).

In patients ≥2 years to <5 years old (n=12):

  • The primary efficacy endpoint of change in HFMSE score from baseline was achieved (P <0.0021) compared to a natural history control group.
    • To ensure appropriate comparison, a natural history group was matched with the treatment group inclusion criteria using the Pediatric Neuromuscular Clinical Research Network (PNCR) database.
  • Patients achieved clinically meaningful improvements in motor function, as demonstrated by 6.0-point increase from baseline in HFMSE scores at 12 months post-dosing.
  • Nearly all (11/12) patients in this group achieved a clinically meaningful ≥3-point increase in HFMSE during the study period.
  • Four motor milestones have been achieved among three patients in the Dose B group using Bayley-III, which is a scale created to assess normal development, including one patient who gained the ability to walk with assistance.
  • The secondary efficacy endpoint of the ability to walk independently for ≥5 steps was not achieved by any patient.

In Dose B patients ≥6 months to <2 years old (n=13)

  • The primary and secondary efficacy endpoints were the ability to stand without support for ≥3 seconds and walk independently for ≥5 steps, respectively. One patient achieved the ability to stand alone and walk independently
  • Five of the six (83%) patients who became old enough to be evaluated on the HFMSE achieved a 3.0-point increase from baseline at any time after 24 months of age, in-line with the older cohort.
  • 18 motor milestones were achieved among six out of the 13 patients, including one patient who gained the ability to stand independently, and went on to walk alone.

Efficacy data from four patients currently enrolled in Dose C were not presented, and further enrollment has been suspended. In October 2019, the U.S. Food and Drug Administration (FDA) placed a partial hold on the AVXS-101 IT program following findings from a small, AveXis-initiated pre-clinical study in which animals treated with intrathecal AXVS-101 showed dorsal root ganglia mononuclear cell inflammation, sometimes accompanied by neuronal cell degeneration or loss. AveXis submitted a response to the FDA with further characterization and a commitment to further study these preclinical findings, along with a thorough analysis of clinical safety to date showing no clinical reports of sensory neuronopathy in 335 patients following treatment with AVXS-101 (intravenous and intrathecal administration) as of December 31, 2019. The FDA is expected to respond to the submission by Q2 2020.

Adverse events (AEs) observed in STRONG were consistent with the intravenous AVXS-101 program. No new clinical safety signals were detected in the study. Nearly all patients in STRONG study experienced at least one adverse event (AE) and 12 patients (38%) were reported to have an AE considered by the investigator to be related to treatment. Serious AEs were reported in 22% (n=7) of patients. A total of 13 serious AEs were reported in seven patients: pneumonia (n=2), influenza, bronchitis, rhinovirus infection, respiratory tract infection, elevated ALT, elevated AST, acute respiratory failure, asthma, respiratory failure (n=1 each), blood alkaline phosphatase increased (n=2). Many of these AEs (i.e. respiratory infections) are consistent with events experienced by children with SMA and the general population. Transaminitis events in two patients were considered probably related to treatment and resolved completely. There were no deaths reported.

About AVXS-101 Intrathecal Administration

Investigational IT administration of AVXS-101 is being evaluated in SMA Type 2 patients in a Phase 1/2 clinical trial. AveXis has an exclusive, worldwide license with Nationwide Children’s Hospital to both the intravenous and intrathecal delivery of AAV9 gene therapy for the treatment of all types of SMA; has an exclusive, worldwide license from REGENXBIO for any recombinant AAV vector in its intellectual property portfolio for the in vivo gene therapy treatment of SMA in humans; an exclusive, worldwide licensing agreement with Généthon for in vivo delivery of AAV9 vector into the central nervous system for the treatment of SMA; and a non-exclusive, worldwide license agreement with AskBio for the use of its self-complementary DNA technology for the treatment of SMA.