AveXis Seeks FDA Blessing to Manufacture AVXS-101 Gene Therapy to Treat SMA Type 1 Babies

A crucial two-hour meeting between AveXis executives and officials of the U.S. Food and Drug Administration (FDA) will determine the next step for AVXS-101, a spinal muscular atrophy (SMA) treatment that has shown remarkable promise in a Phase 1 trial of babies with SMA type 1 — the most severe form of this muscle-damaging disease.

Specifically, AveXis wants the FDA to approve its manufacturing process for AVXS-101, its SMA gene therapy, at the May 1 meeting, and to assure the regulatory body that the drug’s quantity and quality is sufficient to meet demand. AveXis hopes to proceed with new clinical trials in the United States and Europe this year.

The company aims to make AVXS-101 accessible to patients “as quickly and safely as possible” said AveXis President and CEO Sean Nolan, and the FDA meeting — known as a Type B chemistry manufacturing and controls meeting — is key to achieving this goal. The FDA will announce its decision in 30 to 45 days.

Babies with SMA type 1 often never reach any developmental milestones, activities that healthy children learn to do as they grow — beginning with controlling the head and rolling over, and progressing to crawling and walking. SMA, caused by insufficient levels of the SMN (survival motor neuron) protein due to a defective or missing SMN1 gene, affects nerve cells that control muscles.  Most SMA type 1 infants require nutritional and respiratory support by 12 months because they can neither swallow nor breathe on their own.

Notably, babies with SMA type 1 cannot sit unassisted. Symptoms are usually evident before a child reaches six months of age, and for most, the odds of survival begin to decline quickly after eight months of age.

For this reason, speed is “critical in these patients, whose motor neurons are dying quickly,” Nolan said in a webinar based on trial data (through Jan. 20) that AveXis presented at the recent American Academy of Neurology conference in Boston. “We need to rescue those precious motor neurons immediately. Rapidly improving motor function is key, and time is of the essence for these patients.”

The webinar included complete results of the clinical trial (NCT02122952), which found that most infants who received a therapeutic dose of AVXS-101 reached remarkable developmental milestones in terms of head and neck strength, breathing and swallowing abilities, and sitting. Eight of 12 infants in the trial’s second cohort — who received the proposed therapeutic dose — were able to sit unassisted for 30 seconds or longer, an achievement that “approaches normal functional development,” said Dr. Sukumar Nagendran, the company’s senior vice president and chief medical officer. Children treated early, before six months of age, generally showed the best results.

“These sitting data are unprecedented,” Nagendran said. “Children with SMA type 1 simply do not achieve this level of functioning.”

Cohort 2 babies treated prior to losing the ability to breathe and swallow independently did not lose those abilities over time. These skills are crucial not only to the child but to the child’s family, Nolan said, as parents consistently rate “gains in function” — like the ability for children to feed themselves, spend time alone and engage in social activities — as their top priorities in an SMA therapy.

The data, Nolan said, support the “clinically transformative effect AVXS-101 appears have on central nervous system and systemic features of SMA type 1,” including “event-free survival, motor function, pulmonary and nutritional support, and the achievement of developmental milestones.”

Amazingly, videos included in the webinar capture infants rolling over several times on their own, controlling their heads, playing with toys as they sit up without aid, crawling quickly, and walking about with a toddler’s grace and ease — while carrying games or backpacks. The boy carrying the game even walks up to an elevator and reaches naturally to press its “down” button.

The videos also noted that these children received AVXS-101 at very early ages, from less than 1 month to 4.9 months old.

“As you can see, achievements by these children … [are] truly remarkable and completely in contrast with the natural history of this disease,”  Nagendran said, “and importantly [all] appear to demonstrate continued improvements past 13.6 months of age.”

Assuring a proper manufacturing process for AVXS-101, however, is more complicated than for conventional drugs because it is a gene therapy. Treatment with AVXS-101 involves one-time intravenous infusion of a virus carrying a healthy copy of the SMN1 gene to compensate for defective or missing gene. The non-replicating virus is able to pass the brain-blood barrier and rapidly introduce “a full copy of a fully functioning” gene into the nucleus of targeted cells that can immediately begin to produce the necessary SMN protein, AveXis reports in the webinar. (A non-replicating virus cannot modify a person’s DNA.)

That’s why the stakes are high in this FDA review of the proposed manufacturing process:  either manufacturing can go ahead and a new trial can begin as soon as possible, or certain issues will have to be resolved first.