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), and being carried on a harmless virus, was able to cross the blood-brain barrier — a protective barrier that tightly regulates what substances carried in the bloodstream can cross the barrier to enter the brain.

How AVXS-101 works

AVXS-101 was developed to possess 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 works to supplement cells’ 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 SMN protein expression

Clinical trials for AVXS-101

The Phase 1 clinical trial was recently completed. Its purpose was to evaluate the safety, tolerability, and efficacy of gene transfer in 15 infants up to 6 months old with SMA type 1.

This open-label study assessed 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. The treatment’s short-term safety was evaluated over a two-year period. Its efficacy was initially assessed when all patients 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 topline results from the Phase 1 trial, showing no new treatment-related safety or tolerability findings,  and no new events reported in any patient, in March 2017. Improvements in motor function were observed 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.

Next Steps for AVXS-101

AveXis is planning a meeting with the FDA in the second quarter of 2017 to discuss chemistry manufacturing, and controls of AVXS-101. If the meeting is successful, the company is hoping to initiate a pivotal trial of AVXS-101 via intravenous delivery in patients with SMA Type 1  in the U.S. in the second quarter of 2017.

Similarly, depending on FDA meeting, the company is also hoping to initiate a Phase 1 safety and dose-escalation study of AVXS-101 in patients with SMA type 2 in mid-2017, and to start a pivotal EU trial in SMA type 1 patients later in the year.

In mid-2017, AveXis will conduct an end-of-Phase 1 meeting with the FDA, and a comprehensive clinical program review with the EMA.

Read the latest AVXS-101 news on SMA News Today.

Follow the latest developments for all experimental Spinal Muscular Atrophy treatments on the SMA Therapy Tracker.

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