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inflammation in dorsal root ganglia, which are neurons at the dorsal root of the spinal nerve that detect sensation and pain. No sensory injuries were observed in the monkeys in that study, or in patients who received either the intravenous or intrathecal formulations of Zolgensma to date.
“The finding we had, while it did occur, was not in every dorsal root ganglia and then even in the dorsal root ganglia that we did see it in, it only occurred in a few cells,” Lennon says. “We do believe it’s a limited effect.”
The clinical hold affects the high dose of the gene therapy; enrollment in the low- and middle-dose groups was already complete. During the conference call, Narasimhan said that the FDA last Friday told the company it needed to provide more preclinical data before the partial hold on tests of the high dose could be lifted. He added that the data requested are expected to come from studies AveXis already planned. But the regulator’s request for more data extends the timeline for seeking approval of intrathecal Zolgensma. Narasimhan said a filing could be made with the FDA in the second half of this year, or sometime in 2021 depending on what the regulator says.
AveXis envisions the intrathecal formulation of Zolgensma becoming a treatment for all SMA patients 2 or older, Lennon says. There’s a reason AveXis developed intravenous and intrathecal versions of the gene therapy. The company says the highest level of SMN expression is needed while a fetus is still in the uterus and then soon after birth. AveXis believes giving Zolgensma intravenously early in a newborn’s life gets the SMN protein to all potentially affected organs, and at the highest levels, according to a company spokesperson. One of the Zolgensma clinical trials underway is testing the therapy in babies younger than six weeks old. For older patients, the intrathecal administration delivers less of the engineered virus per dose of Zolgensma, the spokesperson says. That could reduce potential risks of side effects associated with the viruses used to deliver gene therapies.
Novartis has new clinical data supporting intrathecal Zolgensma for older patients. Last week, during a presentation that was made digitally after the coronavirus pandemic prompted the cancellation of the Muscular Dystrophy Association’s annual meeting, the company reported results for SMA type 2 patients between 2 and 5 years of age who were treated with the middle-dose of the gene therapy. Patients showed an average six point increase according to a motor function assessment for SMA. Novartis says the score change is twice the increase needed to be clinically meaningful, and it reflects the preservation of motor neurons connected to muscles affected by SMA. Importantly, Novartis reported no new side effects associated with intrathecal Zolgensma.
Intravenous Zolgensma is currently under regulatory review in Europe, Canada, and Australia. It was recently approved in Japan. Meanwhile, AveXis’s manufacturing capacity is struggling to keep up with demand. AveXis makes the gene therapy at a facility north of Chicago. Last year, the company acquired an AstraZeneca (NYSE: AZN) biologics manufacturing plant in Longmont, CO. As AveXis’s largest site, the Colorado facility will be used to make large quantities of Zolgensma, Lennon says. That site, as well as the company’s third manufacturing plant in Durham, are awaiting FDA clearance to commence manufacturing.
Zolgensma is one of several gene therapies AveXis plans to produce in Durham. Lennon says the North Carolina facility was designed for flexibility. It can make up to seven different products simultaneously and will become the company’s manufacturing site for gene therapies still in development. The company’s preclinical pipeline includes experimental treatments for Rett syndrome, a genetic neurological disorder; a form of amyotrophic lateral sclerosis caused by a genetic mutation; and Friedreich’s ataxia, a rare inherited neuromuscular disease. Lennon says AveXis has four additional programs for diseases that are still undisclosed.
Novartis expects to apply for FDA clearance to begin clinical testing of the Rett syndrome treatment by the middle of this year. An application for the ALS gene therapy could come by the end of 2020. By then, Lennon expects the Durham site will have the FDA go-ahead for manufacturing Zolgensma, as well as the experimental therapies in the AveXis pipeline. [Paragraph updated with additional detail about manufacturing capabilities.]
“WE BARELY MADE IT”
Approval of intrathecal Zolgensma is key for Novartis to compete with Biogen’s Spinraza. Competition is also on the way from Roche, which has reported encouraging data from its experimental SMA drug risdiplam. In a recent research note, SVB Leerink analyst Mani Foroohar wrote that a physician told the firm the strongest determinant of how someone responds to these SMA therapies is the patient’s age when treatment starts—younger patients treated soon after the onset of the disease have the best outcomes. Foroohar added that the efficacy of the three SMA therapies are similar, “however if one agent is able to demonstrate a clear benefit over the others, it would quickly become the treatment of choice given the devastating nature of disease progression.”
The Hewitts chose Zolgensma. Duke University Medical Center, a short drive from the Hewitts’ home, was one of the clinical trial sites. The study was designed for patients younger than 6 months old. Cameron received the gene therapy just in the nick of time. “Two days later, she would have aged out of the trial,” Josh Hewitt said. “We barely made it.”
After receiving Zolgensma, the Hewitts watched Cameron catch up on her developmental milestones. Her breathing became normal and she was able to lift her head, according to her father. She learned how to sit up and roll over. She also gained a healthy appetite. Cameron undergoes physical therapy twice a week and at home, she loves to talk and play with her older sister.
“Cameron would not be here if not for AveXis,” Josh Hewitt said.