AveXis Asking FDA, EU to Approve AVXS-101 as 1st Gene Therapy for SMA Type 1

AveXis has filed a first request for approval of its highly-anticipated gene therapy, AVXS-101, to treat infants with spinal muscular atrophy (SMA) type 1 with the U.S. Food and Drug Administration, CureSMA announced on its website.

Similar applications were filed with regulatory authorities in the European Union and Japan, AveXis said in a statement to the SMA community posted on the group’s website.

These three requests, first reported by the patient advocacy group that was an early supporter of the therapy, applies only to type 1 infants up to 9 months treated via intravenous (IV) delivery. Further requests for older patients and those with other disease types are anticipated.

Sukumar Nagendran, then AveXis’ chief medical officer, hinted at such a development, predicting this year could be one “of significant clinical progress as we continue toward our ultimate goal of bringing AVXS-101 to the patients and families devastated by SMA” in January.

In the next 60 days, the FDA will decide whether to accept the application, known as a Biologics License Application (BLA), CureSMA reported. If it moves ahead, its review process is expected to take six months.

Decisions by all three regulatory agencies are expected by mid-2019.

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Pivotal data supporting the applications are drawn largely on the company’s Phase 1 study (NCT02122952) in type 1 babies that is now in a long-term extension called START (NCT03421977).

Infants in that first trial given the proposed therapeutic dose — 1.1 x 10¹⁴ vector genomes per kilogram — had increases of 9.8 points at one month and 15.4 points at three months in mean CHOP-INTEND scores, which assess movement ability, the company had reported.

“At 13.6 months of age from birth, only 25% of [type 1] children survive event-free,” Sukumar Nagendran, the chief medical officer of AveXis, said in an interview with SMA News Today, describing SMA’s natural history in type 1 babies. “And at 20 months, only 8% survive event-free.”

The Phase 1 study, which formally concluded in January 2018, upended those natural history patterns.

“What was remarkable and what we consider transformative — and frankly all the experts in the SMA field also feel the same — is that we had 100% survival of the children at 13.6 months of age, and 100% survival of the children at 20 months of age,” Nagendran said of study outcomes in the February interview.

A separate and pivotal Phase 3 trial, STR1VE Phase 3 (NCT03306277), now underway, is also assessing the effectiveness and safety of a one-time intravenous infusion of AVXS-101 in type 1 SMA children younger than 6 months.

Novartis acquired AveXis, largely on the basis of this promising therapy and the series of pivotal clinical trials underway, for $8.7 billion in cash, it announced in April.

Type 1 SMA is the most severe and common type of spinal muscular atrophy. Symptoms appear between birth and 6 months of age, and are characterized by serious muscle weakness, including an inability to raise the head to breathe, cough or swallow normally. Children with type 1 SMA can only sit upright with support.

“We congratulate AveXis and Novartis on reaching this milestone,” Kenneth Hobby, president of Cure SMA, said in the announcement. “The IV clinical trial data shows that a one-time dose of gene therapy has the potential for a transformative impact on this life-threatening disease.”

Trials in a broader range of patients — including testing of intrathecal delivery (injection into the spinal cord) in patients up to 5 years old — are ongoing.

• The SPR1NT (NCT03505099) Phase 3 trial is testing AVXS-101 ing pre-symptomatic infants with SMA types 1, 2, and 3, using IV administration.
• The STR1VE-EU (NCT03461289) Phase 3 trial is the European equivalent of the STR1VE trial in the U.S., testing IV dosing in infants with SMA type 1.
• STRONG (NCT03381729), a Phase 1 study, is testing intrathecal dosing in SMA type 2 patients up to 60 months of age.
• The REACH trial is slated to begin in 2019, and will test an intrathecal dose of AVXS-101 in SMA types 1-3 patients ages 6 months to 18 years, including those ineligible for other trials.

AVXS-101 consists of a harmless AAV virus, serving as a carrier, and a normal version of the SMN gene, which is defective in SMA. The lower levels of the SMN protein cause the loss of specialized nerve cells called motor neurons, ultimately leading to progressive muscle weakness and atrophy.

Researchers presented “unheard of” preliminary data from STR1VE at the American Academy of Neurology (AAN) Annual Meeting that ran in Los Angeles in April. The treatment appeared to be safe, with no reported serious adverse events. In the six babies who had received AVXS-101, mean CHOP-INTEND scores rose by an average of 7.8 one month after dosing.

After three months, half of those patients had improved 17.3 points. By 24 months post-treatment, 11 out of 12 babies were able to sit unassisted for 30 seconds or more.

“We look forward to a rapid approval by the FDA, and then future positive results from the ongoing intrathecal clinical trials,” Hobby said in the CureSMA announcement.

SMA had no disease-modifying treatment prior to Spinraza (nusinersen), by Biogen, which was approved by the FDA in December 2016.