Going for Phase 4 with Spinraza in spinal muscular atrophy

Biogen to evaluate benefit of drug in patients treated with gene therapy Zolgensma

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CAMBRIDGE, Mass.—Biogen Inc. has announced plans to initiate a global Phase 4 clinical study called RESPOND to examine the clinical benefit and assess the safety of Spinraza (nusinersen) in infants and children with spinal muscular atrophy (SMA) who still have unmet clinical needs following treatment with gene therapy Zolgensma (onasemnogene abeparvovec).
SMA is a rare, genetic, neuromuscular disease that is characterized by a loss of motor neurons in the spinal cord and lower brain stem that can result in severe, progressive muscle atrophy and weakness. Approximately one in 10,000 live births have a diagnosis of SMA, and people of all ages are impacted by the disease. It is a leading genetic cause of infant mortality.
“As clinicians, we continue to pursue improved outcomes for infants and children with SMA, and the need for additional benefit in some patients treated with gene therapy has been observed. There is compelling clinical rationale for the potential for additional efficacy with Spinraza in these patients,” said Dr. Crystal Proud, a pediatric neuromuscular neurologist at Children’s Hospital of The King’s Daughters in Virginia and a member of the RESPOND study steering committee. “We expect that the RESPOND study will generate valuable data to help inform future treatment decisions for our youngest SMA patients.”
People with SMA do not produce enough survival motor neuron (SMN) protein, which is critical for the maintenance of motor neurons that support sitting, walking and basic functions of life, including breathing and swallowing. The RESPOND study will seek to understand if the proven efficacy of Spinraza and its continuous production of SMN protein may also benefit patients previously treated with gene therapy.
“Available data now show that some patients in the long-term study of Zolgensma have moved on to treatment with Spinraza. We believe that, for certain patients, motor neurons may be insufficiently treated by this gene therapy, and we plan to initiate this study to understand the extent to which Spinraza may potentially improve outcomes,” said Dr. Maha Radhakrishnan, chief medical officer at Biogen. “The impact of Spinraza since its launch has been unprecedented compared to the natural history of the disease, with 100 percent of pre-symptomatic infants in the NURTURE study alive after nearly five years of treatment. More than 10,000 SMA patients have now been treated globally.”
In the long-term study of Zolgensma, it has been reported that, to date, four out of 10 patients have been subsequently treated with Spinraza. Based on the planned study design, RESPOND will be a two-year, open-label study to evaluate the efficacy and safety of Spinraza in SMA patients previously treated with Zolgensma to further inform treatment decisions. Efficacy will be assessed by change from baseline on motor function measures, additional clinical outcomes (e.g., swallowing) and caregiver burden. Neurofilament levels, an exploratory endpoint, will also be evaluated as a marker of biological disease activity.
The primary study group aims to include 40 infants aged 9 months or younger (at the time of first Spinraza dose) who have rwo copies of SMN2 (likely to develop SMA Type 1) and received Zolgensma at 6 months old or younger. A second study group will include 20 children and will generate data in patients with a broader age range (up to 3 years old at the time of first Spinraza dose).
As noted by Philippa Salter—a neurology analyst at data and analytics company GlobalData—before Zolgensma was approved in 2019, Spinraza was the only treatment option for SMA. Because of that, it experienced rapid uptake and reached blockbuster status with $2.1 billion in global revenue in 2019.
“Zolgensma’s supposed ‘one-time’ treatment challenged Spinraza’s dominance by giving a better quality of life compared with Spinraza’s intrathecal route of administration, which requires a lumbar puncture every time the drug needs to be administered,” she explained. “This reduced the number of patients who would need to take Spinraza and had a negative impact on its sales.
However, since Zolgensma’s approval, it has become apparent that the gene therapy may not be the ‘one-time’ treatment everybody hoped—as highlighted by some key opinion leaders interviewed by GlobalData, who also flagged a lack of long-term data.”
Therefore, if Biogen’s Phase 4 trial can demonstrate that Spinraza can provide benefit by improving motor function and reducing need for respiratory support, it will strengthen Spinraza’s position and reduce the impact from the launch of Zolgensma.
“Even if there are positive results from this Phase 4 trial, Spinraza is still expected to face competition in the future from other products entering the market, particularly from Roche and PTC Therapeutics risdiplam, which is currently waiting for a decision from the FDA expected later this year,” Salter  adds, though. “Risdiplam has a similar mechanism of action to Spinraza but a much more favorable oral route of administration, which should give it an advantage.”

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