Phase 1 Trial of AVXS-101 in SMA Type 2 Fully Enrolled

Patient enrollment is complete for AveXis’ Phase 1 clinical trial testing its gene therapy candidate AVXS-101 in patients with spinal muscular atrophy (SMA) type 2.

“We are pleased that STRONG is now fully-enrolled and expect to report data from this study by May 2019,” David Lennon, PhD, the company’s president, said in an email reply to SMA News Today.

The trial, named STRONG (NCT03381729), will test the safety and tolerability of single-dose intrathecal injection (into the spinal canal) of 27 patients up to 60 months (5 years) of age who are able to sit but not  stand or walk.

Evaluation of the higher dose (1.2 X 10^14 vg) will depend on the safety of the lower dose (6.0 X 10^13 vg), each initially tested in three patients. Patients will be divided into two groups: those younger or older than two years at time of dosing. Effectiveness will be evaluated after 12 months of follow-up.

AVXS-101 is designed to deliver a functional copy of the SMN1 gene to cells that control muscle contractions, called motor neurons. SMN1 is defective in SMA patients, leading to lower levels of a working SMN protein, and subsequently to loss of motor neurons, progressive muscle weakness, and atrophy (shrinkage).

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All patients in the STRONG trial have SMN1 gene’s exon 7 deleted in both copies, or alleles. Exons are the bits of DNA with information to generate proteins. These patients also have three copies of the SMN2 gene, which produces an unstable and shorter version of the SMN protein.

AVXS-101 is now under review for approval inthe U.S. and Europe for intravenous (IV) delivery in infants up to 9 months of age who have SMA type 1. A pre-application review period also was started in Japan. Final decisions on whether to approve AVXS-101 are expected in mid-2019.

Recently acquired by Novartis, AveXis has been working to ensure adequate supply of AVXS-101 to patients in case it is approved by the U.S. Food and Drug Administration (FDA), Lennon said.

The recent filings were based mainly on the open-label, dose-escalation Phase 1 START trial (NCT02122952), testing the safety, tolerability and effectiveness of two IV-delivered doses of AVXS-101 in 15 babies with SMA type 1, the most severe and common type of the disease.

“Compared to natural history, AVXS-101 delivered rapid improvement in motor milestone achievements, a dramatic survival benefit, and a durable effect going out four years in SMA type 1 patients,” Lennon said.

Early results of the ongoing Phase 3 STR1VE trial (NCT03306277) in type 1 children younger than 6 months showed improvements in movement ability, as well as no need for respiratory or nutritional support.

Although not part of the current applications for approval, older children with SMA type 2, such as those in STRONG, as well as those with SMA type 3, may be the subject of future filings. “Based on clinical results to date for AVXS-101 in SMA type 1, we expect AVXS-101 delivered via IT [intrathecal] administration to also show a positive benefit in [other] SMA subtypes,” Lennon said.

Besides providing information on the potential benefits of AVXS-101 in SMA type 2, STRONG also will help define the next steps of AveXis’ program. “Because it is our first study of the IT formulation of AVXS-101, data from STRONG will also help determine the final design for our planned study in children up to 18 years of age with SMA types 1, 2 and 3,” Lennon said.

This trial, called REACH, is set to begin in 2019 and will include patients ineligible for the company’s other studies.

Overall, this illustrates the company’s aim to expand the indications treated by AVXS-101. In a February interview with SMA News Today, Suku Nagendran, then AveXis’ chief medical officer, mentioned how Spinraza (nusinersen, by Biogen) progressed over time as a suggestion of what may lie ahead for AVXS-101.

Spinraza became the first available SMA therapy when the FDA approved it to treat both infants and adults with SMA types 1-3.