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sit up, roll over or walk, and muscles for breathing don’t develop properly, forcing the use of ventilators or tubes inserted into their windpipe (what’s known as a tracheostomy), and the risk of deadly respiratory infections.
The stakes are also high in other forms of SMA. More time untreated could mean abilities lost—like being able to lift your arm over your head, or type on a computer—that are never regained.
Delays in getting Spinraza after its 2016 launch have been ironed out, says Dastgir. She has treated about 30 SMA patients total, and a couple of them have received their first Spinraza dose two weeks after diagnosis. (Dastgir is on the AveXis scientific advisory board and has accepted speaking fees from Biogen.)
One little boy Fay treated was already on a ventilator when he got Spinraza. He still needed a tracheostomy. Novartis has to be ready with Zolgensma. “If there’s any chance of delays early on I’m just going to put kids on Spinraza,” Fay says.
The FDA Label: The FDA approved Spinraza for all forms of SMA, before Biogen had evidence for many of those patients.
How will clinicians and insurers react if the FDA approves Zolgensma for all SMA patients? The plan is to infuse it into the spine of Type 2 or 3 patients and into the bloodstream of babies with Type 1. Fay wants to see if one method will be as effective as the other.
Positive data at AAN from the STRONG study (in Type 2 patients) and the SPR1NT study (in pre-symptomatic patients) would help Zolgensma’s case. Fay will wait for more follow-up. “I don’t want to use Zolgensma prematurely,” he says.
Durability: The main selling point for gene therapy is staying power, which Novartis is counting on with Zolgensma. The longer it works, the more it should stave off downstream healthcare costs. But perhaps not as much as one might expect. In older patients, their SMA might not advance, which is “huge and possibly life-saving of itself,” says Dastgir. “But the damage has been done.” They’ll still need monitoring and treatment.
For newborns who receive treatment, the goal is to have them “walk and run,” says Dastgir, “but honestly, I have no idea what to expect.”
It’s also not clear if Zolgensma’s savings would include avoiding the cost of Spinraza. It would need to prove as effective as Spinraza, and last long enough to be worth its cost. That evidence will require years of patient follow-up.
Getting the right dose of Zolgensma will be important. A second shot might not work because the patient would develop an immune defense against the virus used as a delivery system. Some SMA patients will have that defense before any treatment. Nine of 177 (5 percent) of children under five screened for Zolgensma thus far have had these traits and weren’t eligible for treatment. There’s a test for pre-existing immunity, but how will practitioners deal with results that come back in a gray area? Will insurers refuse to pay for treatment?
“If costs were not an issue then we would want to do combination therapy,” Fay says. But they will be. “I honestly don’t know how insurance is going to handle it,” he says.
Safety: Thus far, Spinraza has proven largely safe. But there are important caveats. Patients need to get multiple spinal taps per year, for life. It’s an uncomfortable procedure, at best. Some patients might require sedation, which is worrisome because of potential long-term effects on developing brains. “We try to avoid repeated anesthesia in kids, as there are some risks,” Fay says.
Dastgir has avoided sedation in all her patients so far, using unconventional methods such as letting parents, gowned and masked, stay with their kids. But she acknowledges treatments that don’t require sedation—at least not repeated sedation—will be attractive: “Psychologically, Zolgensma will be more appealing to parents, as a one-time dose.”
Biogen last year published a retrospective study of eight patients in their Spinraza clinical trials and concluded that the anesthesia, over 61 procedures, was “safe and effective.” (Biogen did not respond to requests for comment by press time.)
[Update: A spokeswoman later responded via email that, based on Biogen trials and patient experience, lumbar puncture was “generally well tolerated with no serious complications.” She did not address potential side effects of sedation. “Clinical decisions, including how to administer a therapy, are made by physicians based on their evaluation of each patient,” she wrote. “As such, we do not track the different protocols they use in the clinical management of their patients.“]
Zolgensma has also appeared safe. The most consistent issue has been a spike in liver enzymes, alleviated with a short course of steroids. It’s a common occurrence in gene therapies that are delivered, like Zolgensma, with the help of adeno-associated viruses (AAVs).
However, Novartis reported in April that one Type 1 patient died in a trial in Europe, and the investigator deemed it “possibly” related to treatment. Novartis executives later said the death could have been due to the steroids and that regulators weren’t concerned. But as SVB Leerink analyst Mani Foroohar mentioned recently in a research note, “steroid treatment is part and parcel of AAV administration,” leaving the question whether the steroid course could limit Zolgensma’s reach, he wrote.
Noting how sick Type 1 patients are, Fay of UCSF said he’ll be more concerned if it’s determined the death was caused by an immune attack against the gene therapy. The autopsy results have yet to be released.
Alex Lash contributed to this report.
Image of a spinal cord motor neuron courtesy of Berkshire Community College.