With the U.S. Food and Drug Administration (FDA) expected to soon decide whether Zolgensma (onasemnogene abeparvovec) can treat people with spinal muscular atrophy (SMA) type 1, clinical trials of the gene therapy are showing rapid benefits across disease types.
Those gains might justify a broader label — one allowing the treatment, if approved, to be given to a wider range of patients.
“What we’re seeing very consistently is efficacy in type 1 patients is replicated in efficacy in type 2 and efficacy in type 3 patients,” David Lennon, president of AveXis — the Novartis-owned company that developed Zolgensma said in a phone interview with SMA News Today.
The FDA application is largely based on the marked improvements in survival and motor function seen in the pivotal Phase 1 trial (NCT02122952) in SMA type 1 patients up to 6 months old and showing disease symptoms when dosed.
But data presented at the recent American Academy of Neurology (AAN) annual meeting suggest Zolgensma can help other SMA types. “We’re very confident that Zolgensma can have benefit certainly for type 2 patients and, by extrapolation, potentially for type 3 patients also,” Lennon said.
AveXis and Novartis are providing FDA regulators with clinical trial data that might support a broader label, he said, adding that he thought ongoing discussions “very productive.”
Because the potential therapy, reported to be a one-time treatment, will be quite expensive — Novartis estimates range from $1.5 million to $5 million — plans are being put in place to ensure accessibility. This includes working with payers “to define policies and contracts that allow them to cover Zolgensma,” Lennon said.
“We will have a full suite of patient assistance programs to support patients in their journey through Zolgensma treatment,” he added. Again, details await the FDA decision expected this month and, if favorable, the types and ages of SMA patients eligible for treatment.
For now, AveXis is planning to offer a three- to five-year payment installment plan, as well as a “money-back” guarantee to insurers should someone not respond to treatment. “If a patient has either died or gone onto ventilatory support, then we would provide the rebate back,” Lennon said.
Type 2 patients showing gains
SMA is caused by defects in the SMN1 gene, which lowers the levels of the SMN protein and leads to loss of motor nerve cells, muscle weakness, and atrophy. Zolgensma uses a genetically modified virus, called AAV9, to deliver a normal copy of SMN1 to motor neurons, allowing for healthy SMN protein production.
To confirm that Zolgensma boosts levels, investigators assessed protein production in the brain, spinal cord, and peripheral organs of an infant who had died in the Phase 3 trial, STR1VE (NCT03306277), of respiratory failure considered unrelated to treatment. These data were presented in a Novartis Q1 2019 investor presentation and at a recent Muscular Dystrophy Association (MDA) conference.
That analysis showed SMN protein levels, five months after intravenous (IV) treatment, comparable to those of healthy children, including — importantly — in motor nerve cells. “We’re basically seeing normal levels of SMN expression being achieved through the delivery of a gene therapy,” Lennon said.
Infants with SMA type 1 — the most common and severe form of the disease — receive Zolgensma via IV infusion, but older patients and those with other disease types undergo intrathecal (IT, spinal canal) delivery, a more targeted approach allowing for lower dosing.
“What we’ve tried to do is take a scientific approach in terms of how we think about formulation,” Lennon said. Data from both animal models of SMA and people show that high levels of SMN are required in peripheral tissues only very early in life — in a newborn’s “first weeks and months,” and then drops in those tissues.
“Our approach in using IV early in infants is to try to replicate the biological situation by giving high levels of SMN expression throughout the body,” Lennon said. In older patients, IT infusion is used to deliver SMN “where it’s needed most, which is in the motor neurons of the spine.”
Spinal delivery is used in the STRONG Phase 1 trial (NCT03381729), which is enrolling SMA type 2 infants and children up to age 5, able to sit but not stand or walk independently, at sites across the U.S.
Early and positive results at one year of follow-up were presented for a first time at the AAN meeting.
“What we’re seeing … is that half the patients have achieved at least a three-point increase in their [Hammersmith Functional Motor Scale-Expanded] scores, which is a measure of their functional improvement. And a three-point [increase] is considered clinically meaningful,” Lennon said.
“We are seeing strong efficacy … very rapidly. Most patients are responding within the first month of treatment,” he added, “and with very low rates of adverse events being reported so far.”
Importantly, most patients rapidly progressed through motor milestones that included sitting, crawling, standing with or without assistance, and walking. Two are now able to stand unassisted, one to walk independently, and another has started to walk with assistance.
But progress in younger patients, less affected by the disease, was clearly superior to that of older patients.
Treated children were divided into two groups — those 6 to 24 months old and those 2 to 5 years old — and outcomes compared. “We did see obviously better results when we treated earlier in the younger group and more patients achieving milestones in that group,” Lennon said. “That goes along with the consistency of treating earlier is better.”
Still, STRONG findings overall show “a really positive trajectory for such an early timepoint in the study, so we’re really excited about where we are,” Lennon said, and the trial is now expanding to include a third and higher “group C” dose.
Positive outcomes here will inform a further trial, to be called REACH, planned for type 1 to 3 patients up to age 18.
A trial in presymptomatic babies with SMA type 1-3 up to 6 weeks old — the global SPR1NT Phase 3 trial (NCT03505099) that is now beginning enrollment — also reported early findings of rapid motor gains like independent breathing and feeding. Likewise, 24-month results from the START long-term extension study (NCT03421977) showed no loss of motor function in 10 patients given proposed therapeutic high dose in the pivotal Phase 1 trial.
Little ‘added benefit’ to combo treatment
Spinraza (nusinersen, by Biogen), the only FDA-approved disease-modifying therapy and one that treats all SMA patients, works to raise SMN protein levels in a different way than Zolgensma. It boosts the ability of a related gene — called SMN2 — to generate full-length and stable SMN protein.
Three children treated with Zolgensma in START are also being given Spinraza, Lennon said. But the decision to go for a combination treatment was totally “at the discretion of the physician and the patients, or the parents, I should say … We don’t see a biological reason to suggest that further increasing SMN levels in these kids will lead to better outcomes.”
He added: “Of the patients that were in that trial, none have lost any milestones. … In our minds, there’s not a great story yet to suggest there’s added benefit from putting these therapies on top of each other.”
Because the potential for additional motor gains with Spinraza is still “an open question” in the SMA community, however, “I’m sure we’ll continue to look at how we might be able to study if Spinraza can add benefit,” Lennon concluded.