Novartis’ Zolgensma is at a critical juncture. A new oral rival has just arrived, and its bid to expand into older spinal muscular atrophy patients just hit an FDA roadblock. But to hear Novartis Gene Therapies President David Lennon tell it, the company has both situations under control.
Threat from an oral rival
In August, what used to be a two-way battle between Zolgensma and Biogen’s blockbuster Spinraza—two injections—had a third player. Roche won an FDA approval to market oral drug Evrysdi for patients two months of age and older. By comparison, Zolgensma’s use is currently limited to children younger than 2 years of age in the U.S.
While Evrysdi offers older patients a new option, Zolgensma is still the top choice for newborns and infants, Lennon said.
“With our indications for the younger patients, we feel very confident that gene therapy will be the best choice for most of the patients in this category,” he said in an interview Wednesday, adding that the company hasn’t seen any impact from the competitive launch so far. In the third quarter, Zolgensma’s sales in the U.S. rebounded from a COVID-related low to reach $122 million, compared with $126 million in the first quarter.
Lennon’s optimism is shared, at least, by SVB Leerink analyst Mani Foroohar, who recently projected that Evrysdi would be more of a threat to Spinraza, not Zolgensma. “Given strong data, one-time therapy, and simple IV administration, we see Zolgensma as remaining the treatment of choice for very young SMA patients,” he wrote in an investor note in August.
So far, about 75% of Evysdi scripts are going to later-onset Types 2 and 3 SMA patients, and about two-thirds of patients are switching from a mix of Spinraza or Zolgensma, Roche pharma chief Bill Anderson said on the company’s recent third-quarter earnings call.
Lennon argued that “switch” would be a mischaracterization for Zolgensma because gene therapy, once injected, is with a person for life. That means whatever new treatment a person gets later would be an add-on.
Still, these “switches” draw a picture in which patients are still trying to improve treatment outcomes from Zolgensma. And RBC Capital Markets analyst Brian Abrahams, based on an interview with a caregiver who’s highly involved in the SMA community, noticed that there’s an emerging trend among SMA families to pair treatments up. Does that mean Zolgensma’s not working?
Physician responses indicate that Zolgensma’s efficacy correlates with what was seen in its clinical trials, Lennon said. For the pricey gene therapy, Novartis has in place an outcome-based payment model and pay-over-time options up to five years. In more than a year on the market—during which time it was used to treat 700 patients globally—it hasn’t had to provide money back or stop payments because of unsatisfactory outcomes, Lennon said.
Scientifically, there’s not a great rationale for how existing treatments would further improve the performance after a gene therapy, Lennon said, though he acknowledged that it’s a question physicians and patients have.
“We also understand that parents want to do the most they can for their child even in the absence of data,” Lennon said. “I think in general there is a view that combinations can be safe, and parents are looking for that opportunity to see if their child can do even better.”
Biogen is already planning the phase 4 Respond trial to see if sequential treatment with Spinraza could further help Zolgensma patients. Although Novartis currently has no plan for such studies, Lennon pointed out Novartis has branaplam, an early-stage oral small-molecule RNA splicing modulator that works in a similar way to Evysdi by increasing the amount of functional survival motor neuron protein.
“We could consider potentially combining that with [Zolgensma] in the future if we were to explore the question [of combination therapy],” Lennon said. And before that, there are real-world data from patients who add therapies that Novartis can draw from, he added.
Intrathecal formulation delay
Even though Zolgensma’s holding its ground among younger patients, it is looking to expand into patients up to 5 years old with an intrathecal version, which is injected into the spinal fluid.
But the high-dose arm of a phase 1/2 trial was recently put on hold by the FDA after a safety flag in preclinical tests pointed to potential spinal cord inflammation and neuronal cell degeneration. Novartis was planning to run a one-year monkey trial to resolve the clinical hold and file for approval in 2021, and CEO Vas Narasimhan has said that the company believed the mid-dose was enough to support licensure.
Then, the FDA struck again in September, requiring Novartis to run a pivotal phase 3 study of the intrathecal formulation. The decision effectively pushed off the chance of an approval by at least two years.
The agency’s concern for a phase 3 isn’t about safety. Although intrathecal Zolgensma has shown strong data, the regulators still want to put those in context, according to Lennon.
“The FDA basically didn’t agree with us that the [mid-dose] in the Strong trial in and of itself was sufficient,” he said. “And largely that was based on the fact that it was an open-label study and there was no control arm.”
During Novartis’ Q3 call on Thursday, Narasimhan said the company intends to “come up with a lean program that will enable us to move extremely quickly.” Lennon wouldn’t provide more details but said Novartis is looking at a number of “innovative steps” to start the phase 3.
As for whether Novartis still intends to move the high dose forward after removal of the clinical hold, a Novartis spokesperson said the company is still exploring implications and will know more after discussing with the FDA.