A new gene therapy developed by Novartis AG's Avexis Inc. unit, Zolgensma (onasemnogene abeparvovec), has won FDA approval for the treatment of all types of spinal muscular atrophy (SMA) in children under 2 with biallelic mutations in the survival motor neuron 1 (SMN1) gene, news that was rapidly followed Friday by approval of Piqray (alpelisib), the first PI3K inhibitor to be marketed for the treatment of breast cancer.

Labeled broadly to extend therapy even to SMA patients who are presymptomatic at diagnosis, the Zolgensma decision provided "a 'best case' indication," according to Jefferies analyst Peter Welford, who predicted rapid adoption of the treatment of infants with the most common and severe variant of the disease, type 1, and as much as $2.6 billion in peak worldwide sales.

After Biogen Inc.'s Spinraza (nusinersen), Zolgensma becomes the second FDA-approved therapy for SMA in an active corner of rare disease drug development. Its approval, which Acting FDA Commissioner Ned Sharpless called "another milestone in the transformational power of gene and cell therapies," also secures for Novartis a valuable rare pediatric disease priority review voucher. (See BioWorld Today, Dec. 28, 2016.)

Novartis acquired Zolgensma by way of an $8.7 billion buyout of Avexis in May 2018, an agreement that was at the time its second big gene therapy deal. Just four months prior, it had acquired ex-U.S. commercial rights to Spark Therapeutics Inc.'s Luxturna (voretigene neparvovec), a gene therapy for patients with inherited retinal disease. Regenxbio Inc., which initially received $100 million in milestone payments under an accelerated schedule from Avexis, as part of its licensing of the AAV9 vector used in Zolgensma, will now receive an additional $3.5 million triggered by Friday's approval. Regenxbio is eligible to receive an additional $80 million milestone payment after Zolgensma reaches $1 billion in cumulative sales. (See BioWorld, April 10, 2018.)

Novartis shares (NYSE:NVS) rose 3.7% on Friday, closing at $87.52, while Regenxbio shares (NASDAQ:RGNX) rose 7.4% to close at $45.64. Shares in Biogen (NASDAQ:BIIB) fell 0.9% to $227.06.

A costly choice for parents, insurers

A one-time therapy, delivered by I.V., Zolgensma will be launching immediately with a list price of about $2.1 million, or $425,000 per year if paid over five years. The company has partnered with Express Scripts-owned specialty pharmacy Accredo Health Group Inc. to offer the pay-over-time option in an effort "to help ease possible short-term budget constraints, especially for states, small payers and self-insured employers," it said. As it moves to expand access to the therapy, Avexis has also established outcomes-based agreements up to five years, as well as providing a patient program to support affordability and access in the U.S., where median household income in 2017 was $60,336, according to the Department of Commerce.

Avexis President Dave Lennon called the price for the therapy "fair and reasonable" and within the cost-effectiveness thresholds of groups such as the Institute for Clinical and Economic Review (ICER), which has updated a draft of its value-based price benchmark for the drug.

"Zolgensma is dramatically transforming the lives of families affected by this devastating disease, and given the new efficacy data for the presymptomatic population, the price announced today falls within the upper bound of ICER's value-based price benchmark range," said Steven Pearson, president of ICER. "Insurers were going to cover Zolgensma no matter the price, and Novartis has spoken publicly about considering prices that approached $5 million. It is a positive outcome for patients and the entire health system that Novartis instead chose to price Zolgensma at a level that more fairly aligns with the benefits for these children and their families," he said.

Early intervention

SMA is a rare, genetic neuromuscular disease caused by a defective or missing SMN1 gene. Without a functional SMN1 gene, infants with SMA lose the motor neurons responsible for muscle functions such as breathing, swallowing, speaking and walking. Zolgensma is designed to provide a functional copy of SMN1 to halt disease progression by generating SMN protein expression with a single, one-time I.V. infusion.

Vas Narasimhan, CEO of Basel, Switzerland-based Novartis, said the potential for early intervention is "hugely important, because we know if you rescue motor neurons early, you have the ability to really preserve function in these children."

The therapy's approval is based on data from the ongoing phase III STR1VE trial and the completed phase I START trial, evaluating the treatment's safety and efficacy in patients with SMA type 1 who showed symptoms of SMA at less than 6 months of age, with one or two copies in the STR1VE trial or two copies in the START trial of the SMN2 backup gene and who have biallelic SMN1 gene deletion or point mutations.

The most commonly observed adverse events during trials were elevated aminotransferases and vomiting.

Novartis said it expects to see about 400 infants per year born with SMA in the U.S. that might be eligible for treatment with Zolgensma, with about 30 newborns diagnosed each month. About 700 more individuals previously diagnosed with SMA, some of whom may currently be taking Spinraza, could also be eligible for the therapy. How many of those patients receive Zolgensma instead of Spinraza is likely to be due to a variety of factors, Guggenheim Securities Yatin Suneja said.

"Since the newborn screening panel does not discriminate between differing types of SMA, and Zolgensma is approved for all types, we envision a scenario whereby all infants diagnosed with SMA will rapidly qualify for and be treated with Zolgensma (due it being a single infusion, having a good efficacy profile, and a lower cumulative cost each year through year 5)," Suneja wrote on Friday. "This could have the effect of rapidly turning off the spigot for new SMA patients for [Biogen], essentially capping Spinraza's maximum reach to patients who are currently receiving treatment and have aged out of qualifying for Zolgensma. Going forward, we believe this implies a shrinking market for Spinraza once SMA newborn screening has been established across all 50 states."

Dispelling doubts that it would be able to manufacture the medicine in sufficient quantities to meet commercial demand, Novartis said Friday that it has been manufacturing Zolgensma since early this year in an FDA-approved production site in Illinois. In addition, Lennon said, the company has three sites under development for expansion, including one in North Carolina, another in Colorado, and a third contract manufacturing operation.

A ground-breaker in breast cancer

Busy as ever in its approach to a holiday break, the FDA also approved Novartis' Piqray (alpelisib) tablets, to be used in combination with the FDA-approved endocrine therapy fulvestrant, to treat postmenopausal women, and men, with hormone receptor (HR)-positive, HER2-negative, PIK3CA-mutated, advanced or metastatic breast cancer following progression on or after an endocrine-based regimen. It was the first novel drug approved under the agency's Real-Time Oncology Review pilot program, a setup that allows the agency to begin analyzing key efficacy and safety datasets prior to official submission of an application, it said.

The approval, granted under a priority review, was accompanied by an FDA green light for Qiagen NV's companion diagnostic test, Therascreen PIK3CA RGQ PCR Kit, to detect the PIK3CA mutation in a tissue and/or a liquid biopsy.

About 40% of patients with HR-positive/HER2-negative breast cancer have PIK3CA mutations, which are associated with tumor growth, resistance to endocrine treatment and a poor overall prognosis, Novartis said.

Novartis evaluated Piqray's efficacy in the SOLAR-1 trial, a randomized trial of 572 postmenopausal women and men with HR-positive, HER2-negative, advanced or metastatic breast cancer whose cancer had progressed while on or after receiving an aromatase inhibitor. Results from the trial showed the addition of Piqray to fulvestrant helped patients whose tumors had a PIK3CA mutation achieve a median progression-free survival of 11 months vs. 5.7 months. (See BioWorld, Aug. 24, 2018.)

"Today's approval is expected to change the way we practice medicine in advanced breast cancer. For the first time, physicians can test for PIK3CA biomarkers and develop a treatment plan based on the genomic profile of a patient's cancer," said Fabrice André, a researcher and professor at Institut Gustave Roussy in Villejuif, France, who served as the principal investigator for SOLAR-1. The cost at which the advance will come wasn't immediately clear on Friday, as Novartis did not publish pricing details for Piqray.