Novartis’ Intrathecal Zolgensma Effective in Older Children

Six years ago, the FDA approved Novartis’ Zolgensma as the first gene therapy for children under two years of age with spinal muscular atrophy. Wednesday, the company reported late-stage data from an intrathecal form of the gene therapy that appears to be effective in treating the rare, neuromuscular disease in older patients.

“Everything was in a positive direction,” John W. Day, a professor of neurology and neurological sciences and pediatric genetics at Stanford Medicine who was not involved in Novartis’ studies, told BioSpace. “It looks like [the gene therapy is] safe. It looks like you’re seeing a signal of treatment efficacy.”

Indeed, although the trial missed its secondary endpoints, intrathecal (IT) Zolgensma (onasemnogene abeparvovec or OAV101 IT) elicited a 2.39-point improvement on the Hammersmith Functional Motor Scale Expanded (HFMSE)—a gold standard spinal muscular atrophy (SMA) assessment tool—in the Phase III STEER trial. That’s compared to 0.51 points for those who received a sham surgery. In a second Phase IIIb study, dubbed STRENGTH, OAV101 IT led to stabilization of motor function over 52 weeks in patients who have discontinued treatment with Biogen’s antisense oligonucleotide Spinraza or Roche’s SMN2 splicing modifier Evrysdi.

Based on these data, presented Wednesday at the Muscular Dystrophy Association’s Clinical & Scientific Conference in Dallas, Novartis plans to file for approval of the IT formulation with regulatory agencies in the first half of 2025.

Both formulations of Zolgensma address the genetic root cause of SMA by providing a functional copy of the human SMN1 gene, which is lacking in these patients. If approved, OAV101 IT would be the first gene replacement therapy for patients with SMA over the age of two years.

Spinraza is FDA-approved for patients of all ages with all types of SMA, while Roche’s recently approved Evrysdi tablet is indicated for patients two years or older who weigh more than 20 kgs.

Novartis broke through in May 2019 with the FDA approval of Zolgensma, the first gene therapy for SMA. “When it comes to the mostly newborn, the young kids, we have seen transformative results there,” Norman Putzki, the company’s global development head of neuroscience and gene therapy, told BioSpace prior to Wednesday’s presentation. However, a more prevalent group of patients were “already too old . . . or too heavy to receive the treatment,” Putzki said.

Enter OAV101 IT, which is delivered intrathecally (IT), making it safe for older, heavier patients, according to Putzki.

With these patients, “You have a massively larger exposure, particularly towards the high end of the spectrum . . . that would require very high doses,” he continued. “So we can mitigate everything that is a dose-related toxicity by going IT with a small, flat dose into the [cerebrospinal fluid].” Sure enough, Novartis reported that the rate of adverse events was similar between treatment and placebo groups in both the STEER and STRENGTH studies.

As for efficacy, Putzki said Novartis has seen motor gains that were “clinically meaningful,” but he emphasized the significance of preserving the function the patients have left. In the STEER and STRENGTH studies, SMA had already taken its toll on this older patient population, who were able to sit but not walk independently. With OAV101 IT, Putzki said, “you see there’s a prevention of further progression of the disease, further decline, losing these motor abilities that patients need in order to take care of themselves.”

Of the 75 patients treated with Novartis’ gene therapy in the STEER trial, two patients were able to stand independently, while 15 were able to walk with assistance, according to the company’s presentation.

For Day, however, the results seen with OAV101 IT in STEER and STRENGTH were more “nuanced” than the “dramatic” results seen in infants treated with Zolgensma, as well as Spinraza and Evrysdi. Indeed, the gene therapy did not achieve statistical significance on the trial’s secondary endpoints—an additional scale called the Revised Upper Limb Module (RULM) or a 3-point response on the HFMSE. Novartis attributed these misses to the prioritization of a subgroup analysis in the preplanned testing procedure.

This older population is “a hard group to see a very dramatic response in,” Day said, “because they’re pretty significantly affected patients.”

But despite failing to meet these secondary endpoints, Novartis did say they trended in the right direction so as to “consistently favor OAV101 IT.”

When asked how long the treatment effects could be expected to last, Putzki pointed to the aggregate data from STEER, STRENGTH and the Phase I/II STRONG study, in which patients treated with OAV101 IT have been followed for up to six years. So far, “we haven’t seen a loss of treatment effect over time,” he said. And in the long-term, follow-up study of the Phase I START trial of Zolgensma, a single intravenous infusion of the gene therapy continued to demonstrate a favorable benefit-risk profile and durable efficacy up to 10 years after dosing, according to Novartis.

“I think it’s biologically plausible to assume that’s also true for [OAV101 IT],” Putzki said.

From the FDA’s 2016 approval of Spinraza—the first treatment for SMA—to the greenlighting of a tablet version of Evrysdi last month, the past decade has seen considerable progress in treating the disease.

“We have come from no treatment available to multiple treatment options available, and we have seen that the adoption in the community has been really rapid, and the treatment paradigm has evolved really quickly,” Putzki said.

Also at the MDA conference, Scholar Rock presented new data from a Phase III trial of apitegromab, an antibody that inhibits myostatin activation in the hopes of providing a clinically meaningful improvement in motor function for SMA patients. In the SAPPHIRE trial, apitegromab met the primary endpoint, demonstrating a clinically meaningful improvement on the HFMSE. In a prespecified secondary endpoint, 30.4% of patients receiving apitegromab saw at least a 3-point improvement on this scale, versus 12.5% of placebo patients.

Other companies with SMA drugs in development include Biohaven, which is developing a myostatin and activin receptor blocker called taldefgrobep alfa—though the candidate stumbled in Phase III in November 2024—and NMD Pharma, which is testing NMDP-02, a ClC-1 ion channel inhibitor, in Phase II trials.

Despite the progress, however, Putzki and Day agreed that there is still room for improvement.

Day spoke of the need for better biomarkers. Almost all patients who receive a course-modifying treatment for SMA have residual motor deficits, he said. The question, he continued, is whether those residual deficits reflect a persistent deficiency of SMN or whether other factors are at play. If, for example, there is “an inadequate [number] of motor neurons . . . all the [SMN restoration] in the world is not [going to] resolve that.”

Neurofilament light (NfL) has recently garnered attention as a possible biomarker to show disease progression and monitor treatment responses in SMA patients. But Day isn’t buying it. “I just find it non-specific and insensitive,” he said. “Ideally, we would have biomarkers that really reflected SMN content in different cell types.”

For Putzki, the next step in SMA is to cover “the entire range of patients”—exactly what Novartis aims to do with OAV101 IT. “Currently, patients in that category, two to 18 years or older, they have to rely on chronic treatments” that “come with a significant burden on the patients and their families,” he said. “So having a one-time gene therapy available, I think takes a lot of this burden away.”