Novartis’ Zolgensma has First-Line Potential in Spinal Muscular Atrophy (SMA)

Biopharmaceutical Report II


Issue19_August 2019




Novartis’ (SIX:NOVN) Zolgensma (onasemnogene abeparvovec-xioi) has strong potential to be used as a first-line treatment in spinal muscular atrophy (SMA), but it is unclear how durable it will be despite being designed as a one-time treatment, experts said. Second-line options including Biogen’s (NASDAQ:BIBB) Spinraza (nusinersen) are being considered, but lack of clinical data attesting to post-Zolgensma use could cause payer resistance.


Analyst reports suggest strong uptake sentiment for IV Zolgensma due to its broad label, but some experts interviewed by this news service noted there are still unaddressed efficacy questions for Zolgensma, as pivotal data fails to account for older patients that fall within the label. While ongoing and upcoming trials seek to address some of those efficacy shortcomings, including use in older patients or patients with neutralizing antibodies, there is no guarantee of success in those trials.


This news service reported on 28 June that Novartis has plans for a 2020 Phase I trial in SMA infants who present neutralizing antibodies. At the recent American Academy of Neurology (AAN) annual meeting in May, Novartis announced positive interim data from its Phase I STRONG trial (NCT03381729) testing intrathecal Zolgensma delivery in older patients, and trial completion is expected in September 2020. The company also presented results from the STR1VE, SPRINT and STRONG trials at the recently concluded Cure SMA conference, although details have not been publicly released.


Analysts’ impressions of Zolgensma include optimism about its intrathecal formulation. Zolgensma’s projected 2023 sales are USD 1.4bn, and Novartis has a market cap of CHF 228bn (USD 229bn).


Novartis did not respond to a request for comment.


Second-line options desirable but likely restricted


While patients who are diagnosed with SMA early will likely be recommended Zolgensma in the first line, there is no guarantee that they will not need any other treatments as they age, despite Zolgensma being designed as a one-time treatment, experts agreed. This has led physicians to wonder about second-line treatments in case of a failure, said a pediatric neurologist.


There are concerns that the effects of the therapy, which are nonintegrating, might dilute with increasing age or that it might spontaneously shut off, said Dr Darryl De Vivo, professor of neurology, Columbia University, New York. Data over 10 years would help answer those concerns, but at least current trends are promising, as some type 1 patients from the 15-patient Phase I START trial (NCT02122952) were followed for over four years and have needed no other intervention, the pediatric neurologist noted. The fact these patients are still thriving represents a big achievement, as type 1 SMA patients typically do not live beyond two years and require lifelong ventilation, he added.


However, another neurologist pointed out that some patients from the START trial had already gone back to a combination therapy, casting doubts on its durability. AAN data showed that three of the 10 patients who enrolled in START’s follow-up resumed combination therapy at parental and physician discretion, but not due to loss of motor function. The other seven patients did not have any other treatment intervention, and none of the 10 needed ventilation support. START was a safety trial exploring tolerability, while STR1VE measured developmental milestones as a primary efficacy endpoint.


As Spinraza, which was approved in 2016, has been shown to improve symptoms across all SMA types, many physicians are considering the drug as an additional line of treatment, the second neurologist said. However, the lack of data on Spinraza use following Zolgensma’s failure will further arm payers to restrict access as they are both expensive, she added.


Spinraza has a list price of about USD 750,000 for the first year of treatment and USD 375,000 annually for maintenance thereafter, while Zolgensma is slated to cost over USD 2m, according to prices obtained online.


Ongoing trials closely watched for much needed additional evidence


There are ongoing and upcoming efforts to address unanswered efficacy questions, but Zolgensma’s previous successes are no guarantee ongoing trials will succeed, said Dr Alexander Fay, assistant professor of neurology, University of California, San Francisco. These questions include how patients ages six months to two years might fare with intravenous Zolgensma, as the FDA has approved it for these patients, but registrational

data only examined type 1 patients up to six months, he noted. Zolgensma was approved on 24 May based on data from the 20-patient Phase III trial STR1VE (NCT03306277) for patients who were under two years old with bi-allelic mutations in the survival motor neuron 1 gene.


Type 1 patients tend to have symptom onset at around six months of age, and the disease progresses rapidly and aggressively within months, leading to a significant amount of motor neuron loss even at one year old, experts said. Similarly,while type 2 and type 3 SMA patients have a later symptom onset, neuronal degeneration could already have occurred even at two years old, they added.


The pediatric neurologist pointed out that the ongoing STRONG study, which is examining type 2 patients from ages six months up to 60 months, would help answer efficacy questions in older patients. STRONG is examining an intrathecal administration of Zolgensma. Mechanistically, while an intrathecal administration allows more direct access to the motor neurons than intravenous delivery, older patients might have already lost a significant amount of motor neurons, De Vivo noted.


An intrathecal administration could lead to fewer side effects, as less vector might be required, Fay said. Although the intrathecal delivery could mitigate some of the liver abnormalities that were observed with the IV treatment, these abnormalities were transient and easily controlled with corticosteroids in past trials and are thus of low concern, the second neurologist noted.


The upcoming 2020 Phase I trial could help address patients who were excluded from previous clinical trials due to having neutralizing antibodies, but current confidence for success stems from preclinical data, the pediatric neurologist said. Approximately 5–10% of patients might present neutralizing antibodies, he added.




Shuan Sim

Reporter, New York


Shuan Sim has a Bachelors degree in linguistics and journalism from New York University. He had previously worked in various trade publications covering technology, precious metals and diamond trade and more. Shuan has worked as a breaking news reporter covering Asia and an international reporter in the Czech Republic. He’s also fluent in Mandarin and proficient in Japanese.

  • Grey Facebook Icon
  • Grey Twitter Icon
  • Grey LinkedIn Icon

Subscribe to Our Journal

Email: wgroup@wmedical.org
Tel: 201-402-1400