Zolgensma (AVXS-101) Under Priority FDA Review as Possible Gene Therapy for SMA Type 1

The U.S. Food and Drug Administration (FDA) has granted priority review to Novartis’ Biological License Application (BLA) asking that Zolgensma (onasemnogene abeparvovec-xxxx) — previously called AVXS-101 — be approved as a gene therapy for spinal muscular atrophy (SMA) type 1.

Its request is reported to specifically cover intravenous (IV) administration of Zolgensma in infants up to 9 months old. An FDA decision is expected in May, and if favorable opens to SMA patients a gene replacement therapy for a first time.

“This important step by the FDA brings us ever closer to delivering Zolgensma to patients with SMA type 1,” David Lennon, president of  AveXis, the Novartis-owned company that developed the therapy, said in a press release.

Similar reviews are underway in Europe and Japan.

Zolgensma is intended to restore production of a working and full-length SMN protein in specialized cells that control muscle contraction, called motor neurons. It contains a functional copy of the SMN1 gene, which is defective in most SMA patients, leading to markedly lower levels of a working SMN protein and subsequent loss of motor neurons, progressive muscle weakness, and atrophy (shrinkage).

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As such, it is “one-time, potentially curative therapy,” Lennon said, and one that “represents a potentially significant therapeutic advance for these patients and their families” because it “addresses the genetic root cause of SMA without the need for repeat dosing.”

In other words, it stands to free children born with type 1 from “debilitating disease progression and lifelong invasive chronic treatment,” Lennon added, working into a point that might be used to justify Zolgensma’s price, if approved. Novartis and AveXis executives discussed a $4 million to $5 million list price for the treatment in a recent R&D and Investor update.

They justified that potential price using a Novartis model that showed Zolgensma’s 10-year treatment cost, set against quality-adjusted life years, is within the range of the list price for Spinraza (nusinersen, by Biogen) — the first approved SMA treatment, and one that amounts to around $4.1 million per patient over 10 years.

“The introduction of one-time, potentially curative therapies will require rethinking how our healthcare system manages diagnosis, treatment, care and associated costs for patients with genetic disease,” Lennon largely repeated in the Dec. 3 release. “Novartis and AveXis are proud to lead the way toward a modern healthcare system built on the tremendous value of truly innovative and transformative medicines that could bend the curve of life.”

He also promised a commitment to “flexibly partnering with healthcare stakeholders to ensure appropriate access” to such medicines.

The European Medicines Agency gave Zolgensma a PRIME (PRIority MEdicines) designation, and a decision on marketing approved is expected in mid-2019. Regulators in Japan also gave it priority status — a status called SAKIGAKE  — and an approval ruling there is expected in early 2019. These are Europe and Japan’s equivalent of the FDA’s breakthrough therapy designation.

Zolgensma’s applications are largely supported by data from a Phase 1 trial (NCT02122952) that evaluated the safety and efficacy of a single intravenous dose Zolgensma in 15 SMA type 1 patients whose symptoms were evident before they were 6 months old.

SMA type 1 is the most frequent and severe disease form, with symptoms appearing at birth or within the first few months of life. Untreated, these babies are unable to raise their heads, sit upright unassisted, or to breathe, cough, or swallow normally.

Two IV doses were tested — a higher, proposed therapeutic 2.0E14 vg/kg dose in 12 patients, and the lower 6.7E13 vg/kg in three. All 15 treated infants, as toddlers, showed survival and motor function benefits at 24 months post-treatment, which contrasts to SMA’s natural history of 8% event-free survival at 20 months.

Movement skills in the 12 treated at higher dose — assessed by the maximum CHOP-INTEND scores — showed statistically significant improvements at one- and three-months post-infusion. Gains in motor function were sustained over the 24-month study period. Benefits noted included 11 children able to control their heads and hold them up for three or more seconds and to sit without support for more than five seconds. Nine could sit unassisted for more than 30 seconds. Most were also able to eat orally.

None required permanent ventilation. Among 10 higher-dose patients not dependent on daily non-invasive ventilation (NIV) at the study’s start, seven were still not using daily NIV at 24 months after treatment.

The most frequently observed adverse event was elevated liver enzymes, Novartis reported.

Results from an ongoing study observing these children for up to 15 years, called START (NCT03421977), found another two children able to stand with assistance, and two sit unassisted for more than 30 seconds. Some of these patients are four years post-infusion. One boy is “preparing to go to preschool” after entering the trial as a one-month-old headed for “a totally incapacitated life,” Lennon said in the November R&D update.

Early results from the ongoing Phase 3 STR1VE trial (NCT03306277) in type 1 children younger than 6 months show improved movement ability, as well as no need for respiratory or nutritional support.

Older patients and those with SMA types 2 and 3 may be the focus of future approval requests. A Phase 1 trial in SMA type 2, named STRONG (NCT03381729), was recently said to be fully enrolled, with results expected in May. STRONG will assessing the safety and tolerability of two doses, given as a single intrathecal (spinal cord) injection, of Zolgensma in children up to 5 years of age who are able to sit but not stand or walk.

A separate trial, called REACH, is expected to begin in 2019 and will include types 1–3 patients up to age 18 years who are ineligible for the company’s other studies.

Zolgensma could become the second therapy for SMA should it win approval; Spinraza, the first, was approval for patients with types 1–3 by the FDA in December 2016.

If a decision goes its way next year, Zolgensma would also be the second available gene therapy targeting a hereditary disease. Luxturna (voretigene neparvovec-rzyl, by Spark Therapeutics) is a one-time gene therapy for children and adults with inherited retinal dystrophy, and was approved by the FDA in December 2017.

The four-letter suffix for the compound that makes up Zolgensma — onasemnogene abeparvovec-xxxx — is yet to be added, Novartis noted in its release.