Novartis's Gene Therapy Zolgensma Has Durable Effects At Five Years

AveXis/Novartis’s one-time AAV9 vector-based intravenous gene therapy for spinal muscular atrophy, Zolgensma, continues to have beneficial effects up to five years after its administration to babies, and an intrathecal formulation has significant promise in older infants.

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Clinical responses to Novartis AG’s intravenous one-time gene therapy, Zolgensma (onasemnogene abeparvovec-xioi) have continued for up to five years after dosing in patients with spinal muscular atrophy (SMA) type 1, and intrathecal doses have been associated with “remarkable” increases in disease scores in patients with type 2 disease, the company has reported.

The findings are a boost for SMA patients and for Novartis although the big pharma, with a strong line-up of new products approaching major markets, may have to adjust its marketing expectations and timing of its marketing strategy in light of the COVID-19 crisis. The EU marketing application for Zolgensma, for example, comes before the EU’s Committee for Medicinal Products for Human Use (CHMP) this week, with EU approval expected within a couple of months, if successful. (Also see "Critical Juncture In Zolgensma EU Market Quest" - Pink Sheet, 24 Mar, 2020.) 

The efficacy of the investigational intrathecal formulation of Zolgensma (AVXS-1010 IT) compared favorably to the current standard of care, Biogen Inc.’s Spinraza (nusinersen)’s Phase III study, commented analysts at Credit Suisse. However, it is difficult to compare the Zolgensma intrathecal data with clinical data produced for another SMA drug candidate, PTC Therapeutics Inc./Roche’s Phase III SMA candidate, risdiplam, because of the older patient population studied, the analysts added.  (Also see "Genentech’s SMA Type 1 Data Strengthen Case Backing Risdiplam Approval" - Scrip, 23 Jan, 2020.)

Still, they expect Zolgensma will become the standard of care for newborn-screened and young type 2 SMA patients. The product has just been approved in Japan for the treatment of SMA in patients under the age of two, including those who are pre-symptomatic at diagnosis.

The US FDA put a partial clinical hold on trials of the intrathecal version of Zolgensma in October last year because of concerns about an association with neuro-inflammation seen in animal studie.  The Novartis unit, AveXis, said it had provided data indicating there had been no clinical reports of sensory neuropathy in 335 patients after intravenous or intrathecal treatment, and the FDA is expected to respond on the issue in the second quarter of 2020.   (Also see "US FDA Puts IT Zolgensma Studies On Partial Clinical Hold" - Scrip, 30 Oct, 2019.)

Durable Responses

The finding that the benefits of iv administration of single doses of onasemnogene abeparvovec-xioi have continued for up to five years after dosing in a Phase I study should go some way to ease concerns about whether responses to the gene therapy will be durable in patients.

The clinical data were released at a virtual meeting of the US’s Muscular Dystrophy Association on 24 March. The meeting, called the Clinical Trial Session, was set up after the MDA’s annual meeting was cancelled due to COVID-19 concerns. Novartis was due to provide updates on several Zolgensma studies at that meeting; the data from which will now be published online by MDA in the following weeks.

In the START long-term follow-up (LTFU) study, 10 of 12 SMA type 1 patients who received a targeted therapeutic intravenous dose of Zolgensma in the Phase I START study (cohort 2) were enrolled in a long-term observational study at the close of that 24-month trial, at which point all 10 patients were free of permanent ventilation.

As of 31 December 2019, all 10 patients were alive and free of permanent ventilation, with a mean time since gene therapy of 4.5 years (ranging from 4.1 to 5.2 years), and a mean age of 4.8 years (4.5-5.6 years), Novartis reported. Motor milestones were not lost during follow-up, and two patients were able to stand with assistance, neither of whom had received nusinersen. Six of the 10 patients do not require regular daily respiratory support.

The Basel, Switzerland-based big pharma also released interim data from the STR1VE-US study of Zolgensma in symptomatic patients with SMA type 1 (symptoms present at birth or by six months of age), who showed rapid and sustained improvement in motor function that had not been seen previously. Patients were aged less than six months of age at the time of gene therapy.

CHOP INTEND (Children's Hospital of Philadelphia Infant Test of Neuromuscular Disorders) scores increased by an average of 6.9 points at one month (N=22), 11.7 points at three months (N=22) and 14.6 points at six months (N=20) after gene therapy treatment, the company reported. 21 patients (95.5%) achieved a CHOP INTEND score of ≥40, and 14 (63.6%) achieved a CHOP INTEND score of ≥50. No new deaths were reported; one patient died from respiratory failure six months after receiving Zolgensma, assessed as due to SMA.

The most frequently reported adverse events were pyrexia (54.5%), upper respiratory tract infection (50.0%), constipation (40.9%), and scoliosis (40.9%), consistent with events experienced by children with SMA.

Novartis pointed out that STR1VE-US was the first trial in symptomatic patients with SMA type 1 to use a new clinical endpoint, involving the “ability to thrive.” Of 22 patients, nine (40.9%) achieved this co-secondary endpoint at 18 months of age (p<0.0001 vs natural history).

Intrathecal Dosing

In older patients, intrathecal administration of onasemnogene abeparvovec should allow use of smaller amounts of the virus vector than would be necessary with intravenous doses dependent on body weight.

New data from the Phase I/II STRONG study in patients aged between two and five years with SMA type 2 indicate the potential benefits of treatment. Patients who received 1.2 x 10¹⁴ vg (dose B) of the gene therapy met the primary efficacy endpoint, with a “remarkable” mean increase from baseline of 6.0 points on the Hammersmith Functional Motor Scale-Expanded (HFMSE), Novartis noted.

This is twice the clinically meaningful threshold established in previous SMA studies, and reflected improvement in three to six skills, Novartis said. The HFMSE score represents improvement in motor function, and translates into control of bodily functions such as sitting up.

Novartis is scheduled to have an investor call on 30 March to discuss the data.