Biogen to Launch First Trial Testing Spinraza in Children Previously Given Zolgensma

Biogen has announced plans to launch a Phase 4 clinical trial evaluating the benefits of Spinraza (nusinersen) in infants and children with spinal muscular atrophy (SMA) who were previously treated with the gene therapy Zolgensma (onasemnogene abeparvovec-xioi).

The company expects to enroll the first patients in the trial, which will be named RESPOND (NCT04488133), between January and March 2021.

“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,” Crystal Proud, MD, a pediatric neuromuscular neurologist at Children’s Hospital of The King’s Daughters, in Virginia, and member of the study’s steering committee, said in a press release. “There is compelling clinical rationale for the potential for additional efficacy with Spinraza in these patients.”

“We expect that the RESPOND study will generate valuable data to help inform future treatment decisions for our youngest SMA patients,” she added.

Biogen’s Spinraza and Novartis’ Zolgensma both work to restore the levels of the SMN protein, which is lacking in SMA patients due to mutations in the SMN1 gene. SMN is found in virtually every cell in the body, but motor neurons — the nerve cells that control voluntary muscle movement — appear to be highly sensitive to SMN deficiency, dying as a result.

Spinraza, given directly into the spinal canal every four months, boosts SMN production by targeting SMN2, a backup gene that can partially compensate for the loss of SMN1-derived SMN.

On the other hand, the one-time gene therapy Zolgensma, given directly into the bloodstream, delivers a functional copy of SMN1 to cells. A single administration is expected to promote a sustained production of SMN in cells (like motor neurons) that do not divide into new cells , and as such are less likely to lose the newly introduced gene.

Zolgensma can be given only once, due to the body’s natural production of antibodies against the viral vector it uses to deliver the gene to cells.

In addition, while Spinraza is approved for all SMA types, without restrictions, Zolgensma is limited to children with SMA up to age 2 in the U.S. and Japan, and to almost all SMA types in children weighing up to 21 kilograms (about 46 pounds) in Europe.

Data from real-world experience and from Zolgensma’s long-term extension study (NCT03421977) indicate that some patients treated with Zolgensma have subsequently received Spinraza. This includes four of the 10 patients who participated in Zolgensma’s Phase 1 START study (NCT02122952) and entered the extension study.

“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 Maha Radhakrishnan, MD, Biogen’s chief medical officer.

The open-label RESPOND study will evaluate Spinraza’s safety and effectiveness in approximately 60 children up to 3 years old who still have unmet clinical needs following Zolgensma treatment.

Such suboptimal response will be determined by one or more of the following criteria: suboptimal motor function, the need for respiratory support, abnormal swallowing or feeding ability, or other factors considered relevant by the investigator.

The first group of patients is expected to include 40 infants up to nine months of age with two SMN2 copies (likely to develop type 1 disease) and who have received Zolgensma at six months or younger. The second group will include 20 children up to 3 years old.

Participants will receive four 12 mg loading doses of Spinraza, followed by similar maintenance doses every four months, over the two-year study period.

Spinraza’s effectiveness will be assessed by changes in motor function measures, additional clinical outcomes (such as swallowing), and caregiver burden. The levels of neurofilaments — proteins that provide structure to neurons and have been suggested as biomarkers of neurodegeneration — will also be measured in these patients as an exploratory goal.

The company plans to submit RESPOND’s protocol to the regulatory authorities in the coming months and to start enrollment in early 2021.

The safety, tolerability, and effectiveness of a higher Spinraza dose (28 mg) is currently being evaluated in the Phase 2/3 DEVOTE trial (NCT04089566), which is still recruiting SMA patients of all ages at approximately 50 clinical sites worldwide. More information on contacts and recruitment sites can be found here.