Novartis acknowledged today that the FDA has imposed a partial hold on clinical trials for intrathecal administration of AVXS-101, the gene therapy that won the FDA’s first approval for treating some forms of spinal muscular atrophy (SMA) in May under the name Zolgensma® (onasemnogene abeparvovec-xioi).

The partial hold does not affect the marketing of Zolgensma or clinical trials assessing intravenous (IV) delivery of AVXS-101, Novartis emphasized. However, the hold affects studies assessing AVXS-101 administered as an injection into the spinal canal in patients with SMA Type 2.

As a result of the hold, enrollment in the high dose cohort has been stopped in the Phase I STRONG trial (NCT03381729), an ongoing, open-label, dose-comparison, multi-center trial designed to evaluate the efficacy, safety, and tolerability of one-time intrathecal administration of AVXS-101. The low- and mid-dose cohort enrollment has previously been completed and interim results have been presented.

The pharma giant said the partial hold followed AveXis, A Novartis Company, alerting authorities and clinical trial investigators about animal findings from a small, AveXis-launched preclinical study showing dorsal root ganglia (DRG) mononuclear cell inflammation, sometimes accompanied by neuronal cell body degeneration or loss.

“The clinical significance of the DRG inflammation observed in this preclinical animal study is not known and was not seen in prior animal studies with AVXS-101,” Novartis said in a statement, adding that DRG inflammation can be associated with sensory effects. “We have completed a thorough review of human safety data from all available sources to date and no adverse effects related to sensory changes have been seen in AVXS-101 intrathecal or Zolgensma. We are working with health authorities to confirm further guidance to clinical investigators.”

“We remain confident”

Novartis also said it will continue to closely monitor for any reports of related safety events in patients, adding: “We remain confident that the overall benefit-risk profile for patients on treatment is favorable.”

The partial clinical hold comes a month after another safety issue related to the gene therapy. Last month, Novartis acknowledged the death of a six-month-old patient treated with Zolgensma in the European Phase III clinical trial STRIVE-EU (NCT03461289)—but insisted that the death was not the result of toxicity within the gene therapy.

“According to the coroner’s report, the immediate cause of death was hypoxic-ischemic brain damage with respiratory tract infection as the underlying cause,” AveXis stated on September 19. “SMA Type 1 was indicated as the underlying cause for the respiratory tract infection. In addition, there was no evidence of an inflammatory CNS process or a toxic or a treatment-related brain damage.”

Zolgensma is an adeno-associated virus vector-based gene therapy that won FDA approval on May 24. Zolgensma is indicated for the treatment of SMA in pediatric patients less than two years of age with SMA with bi-allelic mutations in the survival motor neuron 1 (SMN1) gene.

$175M in sales

Since its launch in late May, Zolgensma has racked up $175 million in sales, most of which was the $160 million generated during the third quarter. “Zolgensma is off to a strong start,” CEO Vas Narasimhan stated in a presentation during Novartis’ quarterly conference with analysts following release of Q3 results.

While much public attention on Zolgensma has focused on its $2.1 million list price, Novartis attributes the strong launch to its discounted patient-access programs with insurers. The gene therapy is accessible to 90% of commercial patients and 30% of Medicaid patients, Narasimhan told analysts.

“We are now still seeing 99% final approval rates for patients that are on label after we go through the appropriate [payer] appeals processes,” Narasimhan added. “We are seeing solid demand in a broad base of institutions. Over 50 treating institutions now in the United States, including many leading academic centers of excellence, have prescribed now Zolgensma.”

AveXis has also sought to ensure it can manufacture the gene therapy by using the Harmans, MD, facility of Catalent-owned Paragon Gene Therapy—as well as by lining up four of its own U.S. production sites, including AstraZeneca’s former advanced biologics therapy manufacturing campus in Longmont, CO, which AveXis agreed to acquire in April.

Faulty animal data was at the center of a controversy that arose in August, when the FDA announced AveXis’ acknowledgement that the accuracy of data from product testing performed in animals submitted in its BLA for Zolgensma had been impacted by an unspecified manipulation of data intended to support the development of its production process for the gene therapy.

Novartis has said it was first informed about the data manipulation in mid-March, and internally confirmed the problem in May, before alerting the FDA. AveXis replaced its two top scientific executives—Brian Kaspar, PhD, previously CSO and Allan Kaspar, PhD, previously senior vice president research and development—with a single executive, Page Bouchard, DVM, who was appointed senior vice president of research and CSO, effective August 5. Bouchard was previously global head of preclinical safety for Novartis Institutes for BioMedical Research. Through an attorney, Brian Kaspar has issued a statement saying he “categorically” denied any wrongdoing, and was “prepared to assert his rights and defend his conduct accordingly.”

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