A broad range of clinical studies into AveXis’s gene therapy AVXS-101 is likely to decide whether it is indeed a “transformative” treatment for babies and children with spinal muscular atrophy (SMA) types 1-3.
Five trials — ongoing or soon to start worldwide — are planned, including a study in pre-symptomatic infants likely to develop SMA, and one in those unable to take part in other trials.
AVXS-101’s potential is supported by results of a Phase 1 study (NCT02122952) that addressed the safety and efficacy of intravenous AVXS-101 in 15 type 1 SMA infants, enrolled before they were 6 months of age. Efficacy was evaluated when they reached 13.6 months old, a timeline that will continue to be used across the new trials.
“At 13.6 months of age from birth, only 25% of 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 added.
Most children, especially those treated with the higher dose, also showed unheard-of improvements, including an ability to sit 30 seconds or longer unassisted, to roll over and even, in some cases, to walk. No child with type 1 SMA has ever been able to sit independently, he said.
Even those receiving the low dose showed improved motor control, able to press keys on a laptop or ride a scooter. “When you talk to the parents and the patients themselves, they will tell us that any improvement in function has huge impact on their quality of life,” Nagendran said.
A durable, one-time therapy
Brian Kaspar, chief scientific officer at AveXis, has long studied how best to deliver a therapy into the central nervous system. “Throughout my two decades of being in the gene therapy field, we have been actively trying to work on ways to be the least invasive to get into the brain and spinal cord as possible,” he said in the interview.
This goal made Kaspar’s team focus on adeno-associated viruses (AAVs), as other research showed these vectors could cross blood vessels and get into muscles. The researchers ultimately found that an AAV subtype – called AAV9 – could target cells in the brain and spinal cord “at unprecedented levels, in ways we had never seen before,” he said.
It quickly became clear they were on the verge of developing a potential treatment for SMA. Kaspar at the time was at Ohio State University, and a colleague “right next-door, literally,” Dr. Arthur Burghes, was “one of the world-class experts in SMA research” and creator of the widely used Delta 7 SMN mouse model.
Animals responded well to the gene therapy Kaspar was advancing: Disease mice that typically die at 15 days old had “median survival surpassing 200 days,” he said.
The therapy to come out of this work —AVXS-101 — is designed not only to be safe, but to also be a one-time treatment with the potential to prevent muscle degeneration throughout a person’s life.
As Kaspar noted, children in the Phase 1 trial treated once with AVXS-101 as long as four years ago still show no signs of “losing any motor milestones.” He also pointed to gene therapies in hemophilia and Parkinson’s patients with “evidence of durability and expression 10 to 15 years out from dosing.”
“I think,” he said, “this really is a one-time therapy.”
AVXS-101 contains the human SMN gene, which is defective in SMA patients, and targets the motor neurons dependent on this gene to survive and thrive. Importantly, the company has analyzed SMN protein levels produced by the newly replaced gene in repeat animal models, and found no decrease or dilution over time.
Sustained levels of SMN are supported by evidence of a stable population of motor neurons in treated animals and — to date — in treated children with SMA. Motor neurons do not divide, meaning that the number of these cells a person is born with holds for life in the absence of disease.
“We have confidence that our therapy has durability, and that is not a concern,” Nagendran said. “We have confidence that our therapy has significant transformative impact, based on the data that we have generated.”
Trials for the ‘broader’ SMA population
According to that data, which is as recent as of August 2017 and published in the New England Journal of Medicine, all 15 Phase 1 children were event-free at age 20 months — compared to a natural history that gives only 8% of type 1 children such a chance at that age — and 11 of the high-dose 12 could sit unassisted, be fed orally and speak. Nine were able to roll over at 20 months, and two could walk independently.
“All remarkable, transformative clinical outcomes,” Nagendran said, adding that all “continue to improve” in the most recent follow-up at 24 months post-treatment, completed between December and January.
He declined to share fuller results from the high-dose group, saying only to “stay tuned.” AveXis plans to present this data at a scientific conference soon.
With the results in hand, the company met with the U.S. Food and Drug Administration (FDA), and plans were put in place for a series of pivotal trials.
Because of its greater effectiveness, the high dose will be used in most new trials, although the means of producing it have changed. That Phase 1 dose — 2.0×10^14 vg per kilogram of body weight — is now 1.1 x 10^14 vg per kilogram, a difference in calibration only, Kaspar said. “Simply put, the 2.0 number turned into a 1.1 number.”
The first trial — now under way in the U.S. and recruiting — is an open-label Phase 3 study, STR1VE (NCT03306277). It too is focused on treating type 1 SMA babies under 6 months old with a nonfunctional SMN1 gene, and on comparing the therapy’s efficacy and safety against the well-established natural history of the disease.
So far, three children have been dosed and are being evaluated before others might be treated. (In an open-label trial, there is no placebo group.) Preliminary data shows similar safety and efficacy to results seen in Phase 1, Nagendran said. This trial has two primary measures of effectiveness: independent sitting for 30 seconds at 18 months of age, and event-free survival at 13.6 months, both of which, again, would defy natural history if realized.
“If these children by 18 months of age can sit 30 seconds or greater, that will be a remarkable achievement,” Nagendran said. It will also be a “quality of life-changing observation. Because when you can sit 30 seconds or greater, this allows the children to function independently.”
STR1VE is expected to end in March 2020. Enrollment information is available by clicking on its identification number.
A similar trial in type 1 infants is planned to open across Europe by mid-year, appropriately called STR1VE-EU.
Although the majority of AveXis’ studies focus on type 1 SMA — the disease‘s most severe and common form — a trial is also under way in type 2 children up to 60 months of age, called STRONG (NCT03381729). It too is currently recruiting — a total of 27 such children — at sites across the United States. (The trial’s identification number links to information on eligibility and enrollment.)
But type 2 children in STRONG will receive AVXS-101 at a lesser dose and using an intrathecal route (via the spinal canal) — rather than the more systemwide intravenous route used with type 1 and, likely, in presymptomatic infants. In type 2 children, a more targeted treatment is preferred, the AveXis researchers said.
“We believe that targeting motor neurons is the central component of [type 2] disease, and there is little systemic or peripheral involvement,” Kaspar said, in explaining the choice of administration.
Presymptomatic infants under 6 weeks of age, but likely to develop SMA types 1, 2, or 3, will be treated with AVXS-101 intravenously in the SPRINT trial that is also planned to start by mid-year.
SPRINT, like REACH — a trial planned for types 1 to 3 SMA patients ages 6 months to 18 years and not eligible for the other studies — will be worldwide trials. REACH’s final design — including details on patients eligible for inclusion and how the treatment will be given — will be determined based on STRONG study results. It is expected to open in late 2018 or early 2019.
“In the REACH trial, what we want and hope to do is to be as comprehensive when it comes to understanding AVXS-101 in SMA subtypes in the broader, more prevalent patient population,” Nagendran said.
Newborn screening an ideal
SPRINT will treat babies before SMA symptoms appear, Nagendran said, because repeat evidence shows that “the earlier you treat these children, the much greater the impact that the therapy has.”
This makes universal newborn screening a priority — for the SMA community, clearly, but also for those treating or working to treat these children.
Disease onset in the most severe forms of SMA is within the first months of life, which provides a small window at best for treatment that is often missed due to reasons that can include diagnostic delays.
“If you talk to the experts, it’s very clear that newborn screening is absolutely important — that children are identified in a presymptomatic state, regardless of subtype, and can be intervened upon,” Nagendran said.
AveXis, with other pharmaceutical and biotech companies, has been working with CureSMA to foster newborn screening at U.S. federal and state levels. “We are making very rapid progress, I think,” he said.
He pointed specifically to the recent recommendation by the Advisory Committee on Health Disorders in Newborns and Children (ACHDNC) for nationwide newborn SMA screening. It now awaits Health and Human Services Secretary Alex Azar’s signature.
This recommendation is strongly supported by CureSMA, which called for its “speedy approval” in a recent release.
AveXis clearly has its sights set on winning U.S., and likely EU, approval of AVXS-101 as a gene therapy across all SMA types, although final decisions are up to the regulatory agencies. The breadth of AVXS-101’s label — specifying what types of the disease it might treat — is also to be decided, should approval be warranted.
The AveXis executives declined to discuss how the company might approach a Biologics License Application (BLA) filing, although it is planning to request a pre-BLA meeting by mid-2018.
Available STR1VE data will be given the FDA at that meeting for review, Nagendran said.
But whatever the outcome of these sweeping SMA trials, he added, the best parents and physicians can do is trust their own judgment, based on what is available.
“Obviously, our responsibility is to develop the therapy, collect the dataset from a clinical and preclinical standpoint, make sure we get the gene therapy approved so that patients, children have access to it,” Nagendran said.
“But I think the final position as these children evolve over time, on what is the optimal therapy when it comes to optimal intervention — further down the road — I think time will tell.”
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