AveXis Gene Therapy Used in Series of SMA Clinical Trials Both Safe and ‘Transformative,’ Executives Say in Interview

The modified viral vector being used by AveXis in a range of new or upcoming clinical trials in babies and children with spinal muscular atrophy (SMA) is safe and effective — with distinct differences from the vector used in a recent mammal study that warned of toxicity, company executives said in an interview.

“It’s a totally different capsule,” Sukumar Nagendran, chief medical officer at AveXis, said in a telephone interview with SMA News Today, referring to the virus shell being used in its pivotal trials in patients, and that used by researchers at the University of Pennsylvania in a recently reported study.

The Penn study found severe liver and motor neuron toxicity, respectively, in the three monkeys and three piglets it treated at high dose with an AAVhu68 vector used to deliver a gene therapy. That vector is a variant of the AAV9 vectors being used in the SMA patient trials.

“There’s a lot of nuances,” Brian Kaspar, the company’s chief scientific officer, also said in the interview.

Chief among them, he and Nagendran said, were differences in amino acids used in the mammal study and in AveXis trials, differences in manufacturing processes, the purity of the product, and the nature of the capsids that could have rendered it “immunogenic,” or capable of producing a potentially toxic immune response.

“There’s a two-amino-acid difference with the AAVhu68 compared to the AAV9,” Kaspar said. “And, simply put, if you make one amino acid change, and the field recognizes this, … you can change the receptors to which the AAV particle binds. And I think, in this case, there is a possibility that you could develop a more immunogenic AAV vector.”

Differences in the manufacturing process could also explain the toxicity reported with AAVhu68.

“The FDA clearly defines that the manufacturing process defines the product, and that is very important to pay attention to,” Nagendran said. The standard is good manufacturing practice (GMP), ensuring the quality and conformity of a product, “and Dr. [James] Wilson’s manufacturing process is non-GMP, and it is not the AveXis process.”

The safety issue raised in the mammal study, “Severe toxicity in nonhuman primates and piglets following high-dose intravenous administration of an AAV vector expressing human SMN,” published in the journal Human Gene Therapy, is particularly sensitive for AveXis. The company is using its gene therapy — AVXS-101 — at an equivalent high-dose to the dose (2×10¹⁴ vg/kg) spotted as being toxic to the monkeys and piglets within five days of treatment.

But toxicity has not been an issue in any AAV9 vector studies, spanning years of preclinical and clinical trials, the researchers said.

The likelihood is — as a related editorial published with the Penn study also suggested — that crucial differences between the AAVhu68 and AAV9 vectors may well exist.

“We have studied AAV9 over the course of years in efficacy as well as safety studies in mice, in pigs and piglets, as well as non-human primates, and now 18 children,” Kaspar said, without toxicity or other key safety issues being raised.

“And some of the children have been on the therapy for nearly four years,” he added.

AveXis follows a GMP system in its production of AVXS-101. The scientists use analytical methods to ensure purity of their product, and quantify the vector using a technique the company developed called Digital Droplet PCR, which guarantees greater consistency in the number of AVXS-101 vectors, Kaspar said.

Using the new technique, the researchers recalibrated the quantity of AVXS-101 that children are receiving in current and upcoming trials. The initial optimal dose set for type 1 SMA patients — those with the most severe disease — of 2×10¹⁴ vg/kg has been reset to 1.1×10¹⁴ vg/kg.

In its initial, dose-finding Phase 1 clinical trial (NCT02122952) in 15 infants with type 1 SMA, 12 were given a one-time injection of the original 2×10¹⁴ vg/kg high dose and three a low dose (6.7 x10¹³ vg/kg). All responded, though those in the high dose showed the greatest improvements in motor control, strength, and independence — responses unheard of in the natural history of this disease.

And at two years or more of follow-up, “all these children are all doing fine,” Nagendran said.

Even the low-dose group’s three children “are alive and continue to be alive, but they also have function,” he said. “Even though the response in the low-dose group is not similar to the second [high-dose] cohort … that they’re able to use iPads and they’re able to drive their scooters.”

Their most recent follow-up exam was in December 2017, and all continued to show both motor milestones and good health, Nagendran said, adding that these findings will be detailed in an upcoming scientific conference.

Results of the Phase 1 trial supported the design of the company’s pivotal trials. These include STR1VE (NCT03306277), which compares AVXS-101 treatment in type 1 SMA infants in the U.S. with the well-established natural history of the disease. All will be given a single intravenous dose, at the new high-dose level, of AVXS-101. The Phase 1 STRONG trial (NCT03381729), will test a lower, intrathecal (spinal infusion) dose of AVXS-101 in children with SMA type 2.

A study to take place in type 1 infants in Europe, STR1VE EU, is also planned, as is a trial in presymptomatic patients to be called SPRINT. And REACH will be a kind of “all-comers” trial, open to children ages six months to 18 years not eligible for other studies.

Possible outcomes of these trials are yet to be determined. But reflecting on what has been seen in the Phase 1 study, there’s reason for hope, Nagendran said.

“In our Phase 1 trial, we showed that 92 percent of children are able to sit five seconds or greater, and 75 percent of children are able to sit 30 seconds or greater,” Nagendran said, noting that the natural history of SMA type 1 has “zero children” ever being able to sit independently. Sitting independently for 30 seconds might seem unexceptional to those unfamiliar with SMA, but for type 1, it is.

“As far as I’m concerned as the chief medical officer,” Nagendran added, “AVXS-101 continues to show transformative impact.”