AVXS-101 is the proprietary gene therapy candidate from AveXis, designed to deliver a functional copy of a human SMN gene to motor neuron cells in order to improve motor neuron function in SMA patients.

The therapy was tested in a Phase 1 clinical trial as a treatment for SMA type 1 (NCT02122952). Carried by a harmless virus, it was able to cross the blood-brain barrier — a protective barrier that tightly regulates what substances carried in the bloodstream can enter the brain.

How AVXS-101 works

AVXS-101 has four key elements of an optimal gene therapy:

  1. A recombinant adeno-associated virus (AAV)9 capsid shell that works to deliver a functional copy of the human SMN gene across the blood-brain barrier without modifying the patient’s existing DNA (avoiding the need for intrathecal delivery, or via the spinal canal, when treating infants)
  2. a human SMN trangene, a full copy of a stable SMN gene that is introduced into the cells’ nuclei and that works to supplement the cells’ own production of the SMN protein
  3. scAAV ITR (self-complementary DNA technology), a human SMN transgene that is introduced as a self-complementary double-stranded molecule for a faster onset of therapy effects
  4. a continuous promoter, which activates the transgene and allows for continuous and sustained expression of the SMN protein

Clinical trials for AVXS-101

A Phase 1 clinical trial (NCT02122952) is evaluating the safety, tolerability and efficacy of gene transfer in 15 infants up to six months old with SMA type 1.

This open-label study assesses the effects of an intravenous injection of AVXS-101, given at a low or high dose (6.7 X 10^13 vg/kg or 2.0 X 10^14 vg/kg), through a vein in the arm or leg. Researchers evaluated the treatment’s short-term safety over a two-year period, and assessed its efficacy when all infants reached 13.6 months of age. A follow-up safety analysis will be completed when the last patient reaches two years of age post-dose. Patients will then be monitored annually as per standard of care for up to 15 years.

An interim data analysis, released in July 2016, demonstrated a favorable safety profile with no new treatment-related safety or tolerability concerns identified. Motor skill improvements were also seen, especially in the higher-dose group.

Based on these preliminary results, the U.S. Food and Drug Administration (FDA) designated AVXS-101 a Breakthrough Therapy on July 20, 2016, potentially speeding its development. This was followed on Jan. 31, 2017,  with the European Medicines Agency (EMA) granting access for AVXS-101 to its PRIority MEdicines (PRIME) program as a potential treatment of SMA type 1.

AveXis reported top-line results in March 2017 from the Phase 1 trial, showing no new treatment-related safety or tolerability findings,  and no new events reported in any patient. Researchers observed improvements in motor function in all the babies, with 11 of 12 who received the proposed therapeutic dose of AVXS-101 (2.0 X 10^14 vg/kg) achieving head control, nine being able to roll a minimum of 180 degrees from back to both left and right, and 11 being able to sit unaided.

On April 25, AveXis presented results from the Phase 1 trial at the 2017 Annual Meeting of the American Academy of Neurology (AAN) in Boston. Results from this Phase 1 trial summed up the effect that AVXS-101 appears to have on the brain and spinal cord, and on the systemic features of SMA type 1. These included videos showing the achievement of motor milestones in infants after receiving the low or the high dose of AVXS-101 and data that supports the use of AVXS-101 via intrathecal administration for neurological diseases, such as SMA types 2 and 3. Moreover, data from this Phase 1 trial revealed that infants treated earlier with AVXS-101 were able to achieve motor milestones more quickly.