#AANAM – Type 2 Patients Taking Well to Zolgensma, With Motor Milestones and No Safety Concerns

Type 2 patients with spinal muscular atrophy (SMA) given the gene therapy Zolgensma via spinal canal injection are showing no safety concerns so far and notable motor milestones, early results of a Phase 1 trial report.

Based on these interim but promising data, AveXis anticipates a request being made for the therapy’s approval using intrathecal (spinal cord) injection, necessary for older SMA patients. In a press release, the company said that it (and Novartis, which AveXis is now part of) will approach regulators for guidance.

These findings, “Phase 1 Study of Intrathecal Administration of AVXS-101 Gene-Replacement Therapy (GRT) for Spinal Muscular Atrophy Type 2 (SMA2) (STRONG),” were presented in a scientific poster by Richard S. Finkel at the 2019 American Academy of Neurology (AAN) Annual Meeting, running in Philadelphia through May 10.

Zolgensma, an expected one-time treatment, is designed to deliver a healthy version of the SMN1 gene — faulty in people with SMA – to motor neurons, specialized cells controlling muscle contraction. It works to enable production of the SMN protein, whose low levels are associated with progressive loss of motor nerve cells.

Zolgensma is awaiting regulatory decisions in the U.S., Europe, and Japan. The applications were largely based on results from the pivotal Phase 1 study in SMA type 1 infants (NCT02122952), where marked improvements in survival and achievements of motor milestone were seen following intravenous infusion of the therapy.

In an interview with SMA News Today, AveXis president Dave Lennon said that although the applications accepted and taken under review by the FDA are for type 1 infants up to 9 months old, the company has presented the agency with data from all Zolgensma clinical trials, opening up the possibility of a broader label. However, Lennon added, it’s premature to talk about the expectations and, should it be approved, “ultimately the decision on the label is the FDA’s.”

A multi-center Phase 1 trial, named STRONG (NCT03381729), is testing a more targeted delivery route  — intrathecal, or via the spinal canal —  in  type 2 patients up to 5 years old who are able to sit but not to stand or walk independently. All have three copies of the SMN2 gene, which makes a shorter and less effective SMN protein.

To date, 30 people are enrolled in STRONG and assigned by age to a group: group 1 is those between 6 and 24 months (18 patients), and group 2 are those ages 2 to 5 years old (24 to 60 months; 12 patients). All were followed for 12 months in this analysis.

As a safety check, the trial opened with three group 1 patients given dose A (6 x 10¹³ vg), and three in group 2 given a higher dose B (1.2 x 10¹⁴ vg). Then, with safety demonstrated, 13 group 1 patients and nine in group 2 were also treated with Zolgensma at dose B. (Eligible patients are still being enrolled for a higher dose C (up to 2.4×10¹⁴), intrathecal treatment group; contact information is here.)

The trial’s primary endpoints, or goals, are measures showing safety and tolerability, an optimal dose, the ability to stand without support for three seconds or longer (group 1), and Hammersmith Functional Motor Scale-Expanded scores of motor function, which test movement abilities, like that of sitting, standing, and laying down, with control (group 2).

To date, all patients given Zolgensma intrathecally tolerated the treatment well.

“We believe that the intravenous [delivery] is appropriate for younger children and intrathecal [delivery] is appropriate for older children,” Lennon said in a conference call-in briefing on Sunday.

Because damage to nerve cells is not reversible, “time of treatment is crucial regarding motor development in these children. Patients who are older are still going to have effects from earlier damage prior to treatment, and therefore will need different kinds of supportive care to get back on track in terms of their development,” Lennon added.

No motor milestones already present at the study’s start were subsequently lost. Nineteen patients (12 in the older groups and seven in the younger) had a mean 4.2-point increase in Hammersmith Functional Motor Scale (HFMSE) scores of motor abilities at their most recent visit (5 to 12 months after treatment). Higher scores reflect better motor control.

Half of group 2 patients showed a 3-point or better improvement in HFMSE scores at one month post-treatment.

Twenty-two motor milestones in 10 patients were recorded using the Bayley-III Gross Motor Milestone Scale — used for infants and toddlers to test developmental skills — across both treatment groups, including two younger patients who gained the ability to stand independently (one in each dose group); the higher-dose patient (dose B) went on to walk alone, the data showed. One group 2 patient given dose B is now walking without assistance.

Serious adverse events included a rise in liver enzymes levels in three patients, which is a possible sign of liver damage; acute hypoxic respiratory failure in one patient; a respiratory viral infection in one patient and pneumonia in another; and one hospitalization to treat the flu. Apart from the pneumonia and respiratory viral infection, all were resolved without further complications.

Elevated liver enzymes were considered probably related to treatment, while all other adverse events were thought unrelated. Importantly, the frequency of elevated liver enzymes appeared to be lower using intrathecal delivery than that seen with intravenous administration.

No dose-limiting toxicity was observed, and researchers will begin testing Zolgensma at dose C.

As a gene therapy, Zolgensma uses the shell of a genetically engineered virus, the adeno-associated virus (AAV) 9, to deliver a normal copy of the SMN1 gene to its motor neuron target motor. Once the SMN1 gene reaches patients’ cells, it supplements those cells’ own production of SMN protein via the SMN2 gene.

Immune reactions against AAVs typically develop in people around age 2. But, antibodies from the mothers — which usually disappear after a few months— have been found in infants. So far, low rates of AAV9 antibodies have been observed in STRONG trial patients in these trials and were not high enough to exclude them from participating.

“The STRONG study is progressing well and may support the hypothesis that [Zolgensma] is a promising treatment option for patients with SMA2,” the researchers concluded.