Children with spinal muscular atrophy (SMA) type 1, who likely would have died before age 2 only a few years back, were seen to walk after being treated with Spinraza (nusinersen).
This approved therapy, and others with the potential to one day be a treatment option — like a gene therapy — are bringing considerable hope to the SMA community, Jill Jarecki, chief scientific officer for Cure SMA, said in an interview with SMA News Today.
Her interview coincides with a separate interview with Robert Finkel, chief of the Division of Neurology at Nemours Children’s Hospital in Florida, and principal investigator of the pivotal Phase 3 ENDEAR (NCT02193074) study — data from which has now been published in the New England Journal of Medicine, along with results from an SMA gene therapy trial and an accompanying editorial.
ENDEAR “was a very successful randomized controlled study in symptomatic babies with SMA type 1, and would emphasize … symptomatic,” Finkel said. “We were able to show not only a stabilization in their motor function, meaning that they did not decline further, which is what their natural history would have been. … We actually showed improvement.”
Still, the editorial reminds us that these approaches — while offering unprecedented benefits — have notable limitations.
Ans van der Ploeg, a professor at the Center for Lysosomal and Metabolic Diseases at Erasmus University Medical Center in the Netherlands, pointed to several in her editorial, “The Dilemma of Two Innovative Therapies for Spinal Muscular Atrophy.”
While some babies born with SMA type 1 were able to walk, stand, roll over, and lift their heads after Spinraza treatment — all exceptional achievements — others died, she wrote. Researchers also do not know how well treatment effects will hold up as these children grow older and gain in muscle mass.
These same limitations likely apply to gene therapy, van der Ploeg wrote.
But let us back up a bit to examine the studies that van der Ploeg is discussing.
Highly successful trial
ENDEAR enrolled over 120 SMA type 1 infants into a study where babies were randomly assigned treatment with Spinraza or a so-called sham procedure as a control group. Spinraza is administered through an injection into the spinal canal; control infants had a needle inserted in the back without an injection.
Data in the newly published report, “Nusinersen versus Sham Control in Infantile-Onset Spinal Muscular Atrophy,” showed that 41 percent of Spinraza-treated infants had reached motor development milestones at a six-month interim analysis. None in the control group did.
That data, first revealed in 2016, resulted in the trial being stopped early, which allowed infants in the control group to get Spinraza treatment in an open-label study. It also resulted in a rapid approval of Spinraza in the U.S. only four months later, followed by European approval in 2017.
A final analysis raised to 51 percent the number of treated type 1 infants reaching motor milestones, while those on the sham treatment remained at 0 percent.
Gene therapy shows promise
Many may view the technology behind Spinraza — increasing the production of SMN protein from the “backup” SMN2 gene using so-called antisense oligonucleotides — as catching up with the future.
But positive results from gene therapy trials imply the future is already here, giving a sense of the pace at which therapy development can occur.
The second report in the journal, “Single-Dose Gene-Replacement Therapy for Spinal Muscular Atrophy,” described the outcomes of SMA type 1 infants treated with AVXS-101 in a Phase 1 study (NCT02122952).
AVXS-101 is a gene therapy, delivering a functional copy of the SMN gene with the help of a harmless virus, called AAV9. In the study’s 15 infants, three received a lower dose of the therapy and 12 a higher dose.
Results, which were also reported earlier, demonstrated that the treatment was safe, which was the trial’s main goal. But they also showed that all 15 patients were alive without the need for permanent mechanical ventilation at 20 months of age — a rather atypical scenario for SMA type 1 babies.
Without treatment, only about 8 percent of these infants were seen in earlier studies to be able to breathe without permanent ventilation at 20 months.
Gene therapy trial results also clearly pointed to benefits being mainly in the high-dose group.
Is the glass half full?
Van der Ploeg spent a large part of her editorial pointing out the room for treatment improvement — for instance, if the effects of gene therapy do not hold up as the children age, researchers do not know if a second administration is possible.
Finkel preferred to view the advances in a positive, yet sober, light.
Speaking of the Spinraza data, he underscored that in most progressive neurodegenerative disorders, stabilization is considered an adequate treatment response.
“Here, we went beyond that and we actually showed improvement,” he said.
Yet Finkel agreed with the limitations noted by van der Ploeg, and with several unknowns for both Spinraza and the gene therapy, developed by AveXis. But important strengths, he clearly thought, should not be overlooked.
Spinraza is designed in a way that should give no off-target effects — potential side effects — since the drug only binds to one specific location in the entire human genome, he said.
He noted a possible problem in that Spinraza is administered into the spinal canal, meaning that tissues outside the brain and spinal cord are not be exposed to the treatment. Despite its name, SMN (short for survival motor neuron) is not a protein that is exclusive to motor neurons. It exists in other organs and tissues, such as muscle.
“And it may be that you do need systemic exposure, particularly in muscle,” Finkel said. “That’s a topic that is still under study.”
The gene therapy, in contrast, is delivered intravenously and reaches all organs and tissues, including muscles, brain and spinal cord. While this could overcome Spinraza’s constraints, researchers do not now know if it is possible to re-administer the treatment. It is intended for a one-time administration.
Less a limitation than a point, Finkel also noted that the Spinraza study showed — as did other SMA trials — that babies treated earlier in their disease course had a more robust response to the therapy.
“That would suggest that earlier treatment makes a difference. And you see the same information from the gene therapy report,” said Finkel, who served as chair of the data safety monitoring board for the Phase 1 study of AVXS-101.
In fact, Spinraza is being explored in infants with genetically confirmed SMA who are yet to show symptoms. The NURTURE trial (NCT02386553) includes 25 such babies treated within the first six weeks of life. Outcomes seem promising.
“Based on the most recent data … those babies are normal,” Finkel said. “So not only are those babies, who were genetically destined to be a type 1, not only are they sitting — meaning type 2 — but they’re walking, they’re running, they’re showing normal motor development.”
He believes the same — early treatment bringing best results — will also be true for other therapies currently in clinical trials, including AveXis’ gene therapy and oral drugs being developed by Roche or Novartis.
The emergence of a treatment that clearly appears most beneficial when started early has prompted efforts, both in the U.S. and Europe, to add SMA to the list of diseases for which newborn screening is recommended, Finkel said.
Cure SMA nominated SMA to the recommended uniformed screening panel (RUSP) in February 2016, and it now is in the evidence review phase, Jarecki said.
A vote on whether to include SMA in the screening panel is likely in February 2018, but individual states will be free to choose to adopt the RUSP recommendations or not, she added.
Still aiming for ‘best response’
Researchers are starting to accumulate long-term data, Finkel said, with data on type 2 SMA children now reaching out six years and type 1 four years.
But how might Spinraza’s benefits play out as people treated at very young ages mature?
“We don’t know yet. Is this improvement we’re seeing in these babies going to continue, is it sustainable? I honestly have my fingers crossed,” Finkel said.
As children grow, they put on more muscle, which requires a larger pool of functioning motor neurons, he explained.
The gene therapy has a related, but treatment-specific, issue: The virus, although harmless, triggers an immune response that may prevent a second treatment round if effects start to wane as a child ages. At this time, researchers still do not know if a second round is possible.
The editorial noted that the gene therapy — should it be proven effective and approved — could be combined with Spinraza. But Finkel points out that, given the very high costs of these treatments, it may not be feasible for health authorities or insurers to cover both.
Jarecki underscored that ongoing trials may lead to other options. “Neither Spinraza nor gene therapy is a cure,” she said. “So we really believe in combination therapies, and we’d like to explore other types of therapy … that could be used in combination with SMN-enhancing drugs.”
It appears these researchers are in agreement that the entire issue of SMA therapy boils down to these considerations:
“We now have the opportunity to treat these babies — how do we do so intelligently to get the best response. And how do we do it to service the needs of the healthcare system of each country,” said Finkel, placing the complexity of treating rare diseases in the spotlight.
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