A single administration of Zolgensma continues to extend the survival of patients with spinal muscular atrophy (SMA) type 1 while halting motor neuron loss several years after dosing, according to long-term clinical data.
Zolgensma, developed by AveXis — later purchased by Novartis in 2018 — is a one-time treatment intended to deliver a normal version of the SMN1 gene, which is defective in SMA patients, to specialized cells called motor neurons, which control muscle contractions.
The company is awaiting decisions in the U.S., Europe, and Japan on whether to approve intravenous infusion of Zolgensma in infants up to 9 months old with SMA type 1, the most common and severe form of the disease.
Novartis’ applications were largely based on results from a Phase 1 trial (NCT02122952), which included 15 SMA type 1 patients whose onset of clinical symptoms began before six months of age — 12 received a higher, proposed therapeutic dose of Zolgensma (2.0×1014 vg/kg) and three received a lower dose (6.7×1013 vg/kg).
Patients in this trial could subsequently enter into a long-term follow-up study (NCT03421977), the START trial, which continued to evaluate the safety and efficacy of intravenous (IV) delivery of Zolgensma.
In the study, “AVXS-101 Gene-Replacement Therapy (GRT) in Spinal Muscular Atrophy Type 1 (SMA1): Long-Term Follow-Up From the Phase 1 Clinical Trial,” presented during the 2019 American Academy of Neurology (AAN) Annual Meeting, Jerry R. Mendell talked about the latest results from the AveXis Phase 1 and START trials.
At the 24 months of Phase 1 study closeout, all patients in the therapeutic dose group were alive and free of permanent ventilation. This is in striking contrast to only 8% of patients who are expected to reach such achievement as per natural history of the disease.
Four patients had treatment-related adverse events, mainly elevated liver enzymes, which may indicate liver damage.
There was robust SMN1 gene expression in treated motor neurons — those that are affected or lost in SMA — however, improvement was dependent on the existing motor neuron pool. Because motor neuron loss occurs early during disease progression, early treatment is key, noted Mendell, who is the principal investigator across Zolgensma’s clinical program.
“The apparent relationship between age at treatment and efficacy emphasizes the importance of [genetic] screening and early treatment,” Mendell said.
Gene expression is the process by which information in a gene is synthesized to create a working product, like a protein.
CHOP-INTEND scores — an assessment of motor function — were increased by nine points as early as a month after treatment. Mean increase in CHOP-INTEND scores was 25.4 points.
Eleven of the 12 patients in the therapeutic dose group were able to hold their heads up for more than three seconds and sit unassisted for more than five seconds. Ten patients were able to sit without support for more than 10 seconds, nine patients for more than 30 seconds, and two patients were able to stand alone, walk with assistance and walk alone.
The long-term, follow-up START trial included 10 patients who received the therapeutic dose of Zolgensma in the parent Phase 1 study.
As of March 8, 2019, no previously achieved motor milestone had been lost during long-term follow- up and no patients had any additional requirements for ventilatory or nutritional support. In fact, two of the four patients who required ventilatory support at the beginning of the START trial no longer required it on a regular basis.
The mean age at last follow-up was 3.9 years (range of 3.4 to 4.8 years) and mean time since start of treatment was 3.7 years (range of 3.3 to 4.3 years).
During long-term follow-up, serious adverse events were reported in five out of 10 patients. These included pneumonia, respiratory distress or failure, bronchitis, and gastroenteritis. However, these were transient and manageable.
Importantly, all patients have remained alive and without loss of therapeutic benefit for as long as 4.3 years after Zolgensma treatment.
No patient was treated with concomitant Spinraza during the parent Phase 1 study; however, as of March 8, 2019, three started Spinraza (nusinersen) treatment after 24 months of the study. The decision to initiate combination therapy was at parental and physician discretion and not due to loss of motor function.
“We don’t see a biological reason to suggest that further increasing SMN levels in these kids will lead to better outcomes in these kids, and there’s no clinical data to suggest that’s the case either, to date. 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, or putting Spinraza after gene therapy,” Dave Lennon, AveXis president, said in an interview with SMA News Today.
“But certainly there’s some open question that still exists in the community, and I’m sure we’ll continue to look at how we might be able to study if Spinraza can add benefit on top of gene therapy,” he added.
Overall, “patients treated with a one-time dose of [Zolgensma] continue to gain strength, develop, and achieve new milestones, demonstrating a long-term, durable response.”