A pair of clinical data sets gives Novartis confidence in a new formulation of the company’s gene therapy Zolgensma for the treatment of older patients with spinal muscular atrophy (SMA).
Among SMA patients aged 2 to below 18 years, an injection of Zolgensma directly into the fluid of the spine led to a 2.39-point improvement on a motor ability scale a year after treatment, according to results from the phase 3 Steer trial. The drug’s performance was significantly better than the 0.51-point improvement seen among patients who received a sham procedure.
The measurement, called the Hammersmith Functional Motor Scale Expanded (HFMSE), is clinically validated to evaluate motor ability for patients with SMA types 2 and 3 and has a total possible score of 66, with higher scores indicating better motor function. An HFMSE change above two points is generally considered clinically relevant, according to a 2020 study published in the European Journal of Neurology.
While the Steer trial enrolled treatment-naïve patients, Novartis also tested the one-time intrathecal gene therapy, coded OAV101 IT, in individuals who had tried but discontinued treatment with Biogen’s Spinraza or Roche’s Evrysdi in the phase 3b Strength trial.
Among those treatment-experienced SMA patients aged 2 to less than 18 years, intrathecal Zolgensma showed consistent safety as in Steer as well as stabilization in motor function over a one-year period, the company said.
Both data sets will be presented at the Muscular Dystrophy Association’s annual conference. Novartis plans to file the intrathecal form of Zolgensma with regulatory agencies in the first half of 2025.
Findings from the two trials “support the potential for OAV101 IT to be a meaningful treatment option for people living with SMA with a goal of maintaining or improving motor function through a one-time therapy,” Crystal Proud, M.D., a principal investigator at the Children’s Hospital of the King’s Daughters, said in a statement.
It’s been a long road for intrathecal Zolgensma since the FDA in 2021 knocked back Novartis’ plan to pursue approval with the dosing format based on data from a phase 1/2 trial called Strong.
Novartis developed the intrathecal version to reach older SMA patients, because the large amount of Zolgensma required in the original intravenous formulation would pose a safety risk for heavier people. As it stands, intravenous Zolgensma is approved for children less than 2 years of age in the U.S. or patients who weigh up to 21 kilograms in Europe. By comparison, the intrathecal formulation needs a much lower dosage to get enough drug to the brain and spinal cord, where it’s actually needed.
By Novartis’ estimate, intrathecal Zolgensma could be a multibillion-dollar product at peak.
Previously, in the phase 1/2 Strong trial, Zolgensma IT achieved a six-point improvement in HFMSE from baseline to one year in patients between 2 to less than 5 years old. That trial tested three dosage strengths of the intrathecal candidate, and the data came from the same dose used in Steer.
In the current phase 3 Steer trial, Zolgensma IT pulled off a three-point increase on HFMSE in a subgroup of patients in that same age range, versus an improvement of 1.56 points in the comparator group. Among patients aged 5 to less than 18 years, Zolgensma IT delivered a 1.6-point improvement, whereas the sham control group saw a 0.86-point deterioration.
The two trials have different populations and designs, with Steer being a blinded and controlled study and Strong an open-label trial without a different comparator arm.
Overall, in Steer, 39.2% of Zolgensma IT recipients achieved at least a three-point increase in HFMSE. In the control group, 26% of patients saw that level of improvement.
The differences may seem small, but the Steer trial met its primary endpoint of improving HFMSE outcomes in a broad SMA patient population. Since HFMSE consists of multiple functions with a maximum of two points each, a two-point improvement for certain domains means going from not having a certain function at all to being fully independent, Norman Putzki, M.D., who heads up neuroscience drug development at Novartis, noted in an interview with Fierce Pharma.
In terms of safety, the most frequent side effects of Zolgensma IT were respiratory infections, fever and vomiting.
Liver toxicity is a known problem with Zolgensma IV, and it’s highlighted in an FDA boxed warning. In Steer, the rate of liver toxicity was similar at 9.3% and 9.8% for Zolgensma IT and sham control, respectively. Most liver enzyme increases—which indicate abnormal liver function—were mild and transient. There were no cases that met Hy’s law, which represents a serious reaction of drug-induced liver injury.
In Strength, Zolgensma IT recorded four (14.8%) cases of liver toxicity. These include one patient with ALT enzymes that at one point shot above 10 times the normal level, but they later returned to normal after a retest. No patients met Hy’s law criteria.
The different safety profiles underline the point that Zolgensma IT is distinct from IV despite their same biology, Putzki said.
“The [IV] one is weight-based dosing in newborn children primarily, and here we’re looking at a single administration of one flat dose intrathecally that comes with a very ephemeral safety profile,” he said.
As to efficacy, treatment-experienced patients in the Strength trial saw incremental gains of an average 0.17 points and overall stable motor function as measured by HFMSE.
Putzki said the Strength results are remarkable because the one-time gene therapy removes some of the burden related to chronic treatment and comes with a favorable safety profile and motor function stabilization.
https://www.fiercepharma.com/pharma/novartis-details-intrathecal-zolgensma-data-gene-therapy-bid-reach-more-sma-patients
