AVXS-101, the proprietary gene therapy candidate from AveXis, is designed to treat spinal muscular atrophy (SMA).

How AVXS-101 works

SMA is caused by a mutation in the SMN1 gene, which encodes for a protein that motor neurons — or nerve cells that control muscle contraction — need in order to survive. The mutation prevents this gene from producing any functional SMN protein.

AVXS-101 is a gene therapy designed to deliver a functional copy of the SMN1 gene to motor neuron cells in SMA patients.

AVXS-101 comprises the shell of a genetically engineered virus, the adeno-associated virus (AAV) 9, called a capsid, that delivers a normal copy of the SMN1 gene to the brain via the bloodstream. This avoids delivery via the spinal canal when treating infants. Once the SMN1 gene (called a transgene because it comes from an external source) reaches patients’ cells, it supplements those cells’ own production of SMN protein.

The SMN1 transgene in AVXS-101 consists of double-stranded DNA, meaning it takes the same form as natural genes and can be activated more quickly, producing faster, more efficient therapy. AVXS-101 includes the genetic instructions to activate the transgene so that SMN protein production is continuous and sustainable.

AVXS-101 in clinical trials

A Phase 1 clinical trial (NCT02122952) is evaluating the safety, tolerability and efficacy of AVXS-101 in 15 infants up to six months old with SMA type 1This open-label study is assessing the effects of an intravenous injection of AVXS-101, given at a low or high dose through a vein in the arm or leg.

Researchers already 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 2 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 in July 2016, potentially speeding its development. Likewise, the European Medicines Agency (EMA) granted access in January 2017 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 impressive improvements in motor function in all patients who took part in the trial. Eleven of the 12 infants who received the proposed therapeutic dose of AVXS-101 were able to achieve head control. Nine were able to roll at least 180 degrees from the back to both the left and the right, and 11 were able to sit unaided — something that is normally never seen in babies with SMA type 1.

AveXis presented results from the Phase 1 trial last April at the 2017 annual meeting of the American Academy of Neurology in Boston. These results summarized the effect that AVXS-101 appears to have on the brain and spinal cord, and on the systemic features of SMA type 1. They included videos showing the achievement of motor developmental milestones in infants after receiving either the low or the high dose of AVXS-10. The company also presented data supporting the use of AVXS-101 via administration into the spinal canal for SMA types 2 and 3. Finally, data from the Phase 1 trial revealed that the earlier infants received AVXS-101, the quicker they achieved motor milestones.

AveXis is now running a Phase 3 trial, called STR1VE (NCT03306277) in infants with SMA type 1. The company aims to recruit up to 15 U.S. participants and continue it through March 2020. AveXis announced in September 2017 that it plans to initiate a similar trial in Europe called STR1VE EU.

Researchers recently dosed the first patient in a second study, the Phase 1 STRONG trial (NCT03381729) in children with SMA type 2. During this trial, patients will receive a one-time injection into the spinal canal. The trial is recruiting U.S. participants.

AveXis announced in January 2018 that it is expanding the clinical development program of AVXS-101 and that it plans to launch two new trials in coming months. One of these will be a trial in patients who do not yet show symptoms of SMA types 1, 2, or 3, called SPRINT. The other so-called pediatric “all comers” trial, called REACH, will include patients aged 6 months to 18 years who are not eligible for other studies.

Other information

In 2017, AveXis officials met with the FDA for permission to begin the AVXS-101 manufacturing process. At this meeting, AveXis  showed the FDA it can produce the drug in quantities sufficient to meet the demands of SMA patients.


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