AveXis, a Novartis company, announced on October 5, 2019 new interim data from the Phase 1/2 STRONG study for intrathecal (IT) administration of AVXS-101, demonstrating older patients (≥ 2 years and < 5 years) with spinal muscular atrophy (SMA) Type 2 achieved a mean increase of 5.9 points from baseline in HFMSE scores, nearly double the clinically meaningful threshold, at a mean duration of follow-up time of 9.3 months. This is up from a mean increase of 4.2 points from baseline in HFMSE scores presented in May 2019 at the American Academy of Neurology Annual Meeting.
Half of the older patients with SMA Type 2 experienced a clinically meaningful response in motor function gains starting at one month post-treatment. Gains are defined as a ≥ 3-point increase from baseline in HFMSE scores. HFMSE is a well-recognized functional scale used clinically and in clinical trials to measure physical abilities and motor function in non-ambulatory and ambulatory individuals with SMA Type 2 and 3. These data were presented at the 24th World Muscle Society (WMS) annual congress.
Phase 1/2 STRONG Data as of May 31, 2019
STRONG is an ongoing, open-label, dose-comparison, multi-center trial designed to evaluate the efficacy, safety and tolerability of one-time IT administration of AVXS-101 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 divided into two groups based on age at time of treatment: patients who are ≥6 months but < 2 years and patients who are ≥ 2 years but < 5 years. As of the data cut-off, 31 patients are enrolled and have been treated with one of three doses: Dose A (6.0 x 10 vg), Dose B (1.2 x 10 vg) and Dose C (2.4 x 10 vg). Data from Dose C were not presented at WMS. Three of 36 (8.3%) of patients screened were excluded due to elevated titers of anti-AAV9 antibodies.
In patients ≥ 6 months to < 2 years old:
- The primary efficacy endpoint is the ability to stand without support for ≥ 3 seconds
- The secondary efficacy endpoint is the ability to walk independently for ≥ 5 steps, according to the Bayley-III Gross Motor Milestone Scale
- Since treatment, 18 motor milestones were achieved among the 16 patients who received Dose A or Dose B, including two patients who gained the ability to stand independently, one of whom went on to walk alone
In patients ≥ 2 years to < 5 years old:
- The primary efficacy endpoint is change in HFMSE score from baseline
- The secondary efficacy endpoint is the ability to walk independently for ≥ 5 steps according to the Bayley-III Gross Motor Milestone Scale
- Patients showed a clinically meaningful improvement in motor function, having a mean 5.9-point increase from baseline in HFMSE scores at their most recent visit, at a mean duration of follow-up time of 9.3 months
- In a responder analysis, half of patients (6/12) had a ≥ 3-point increase, which was observed starting at one month post-treatment
- Since treatment, four motor milestones have been achieved among 12 patients in the Dose B group, including one patient who gained the ability to walk with assistance
All patients in STRONG study experienced at least one treatment emergent adverse event (TEAE) and 13 patients (43%) were reported to have a TEAE considered by the investigator to be related to treatment. Serious TEAEs were reported in 13% (n=4) of patients. A total of seven serious TEAEs were reported in four patients (n=1 each): influenza, pneumonia, respiratory syncytial virus infection, elevated ALT, elevated AST, blood alkaline phosphatase increased, and respiratory failure. Elevated ALT and AST (in one patient) were considered probably related to treatment. None of the serious TEAEs resulted in discontinuation from the study and no deaths were reported.
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.