Spinraza-Zolgensma Combination Well-tolerated in Children with SMA Type 1, Study Shows

Combining Spinraza (nusinersen) with the gene therapy Zolgensma (onasemnogene abeparvovec-xioi) is generally well-tolerated and sustains motor improvements in children with spinal muscular atrophy (SMA) type 1, according to a case series study.

The data, which included children treated with Zolgensma at older ages than those reported in clinical trials, suggested that older patients may be at a higher risk of developing gene therapies’ known side effects, such as liver dysfunction and low platelet counts.

However, further studies are needed to better characterize combination therapies’ safety and determine whether it is more beneficial than single therapy, especially considering their high cost, researchers noted.

The case series study, “Combination molecular therapies for type 1 spinal muscular atrophy,” was published in the journal Muscle & Nerve.

Currently available SMA therapies — Biogen’s Spinraza and Novartis’ Zolgensma — both work to restore the levels of SMN, the protein lacking in SMA patients due to mutations in the SMN1 gene.

Spinraza, the first approved disease-modifying therapy for all SMA patients, targets SMN2, a backup gene that can compensate partially for the loss of SMN1-derived SMN. The therapy is given directly into the spinal canal every four months.

In contrast, Zolgensma is administered directly into the bloodstream and delivers a functional copy of SMN1 to cells. It is available to children up to age 2 in the U.S. and Japan, and to almost all SMA types in those weighing up to 21 kilograms (about 46 pounds) in Europe.

The gene therapy can be given only once, due to the body’s natural immune reaction and production of antibodies against the modified virus it uses to deliver the gene to cells.

Nevertheless, immune reactions can still occur after the single dose, which can raise the levels of liver enzymes — an indicator of liver damage — and drop those of platelets. For that reason, it is recommended that patient’s liver function and platelet counts are monitored before, and at regular periods after, treatment.

While treatment combination aiming at increasing or sustaining motor function improvements is likely to occur in these patients, there is limited data on its safety and effectiveness.

Researchers now have reported the effects of combination therapy in five children with type 1 SMA followed at the Arkansas Children’s Hospital of the University of Arkansas for Medical Sciences and the Ann and Robert H. Lurie Children’s Hospital of Chicago.

Patients, who were 17 to 29 months of age at last assessment, received first treatment between 1.5 and 7 months and second therapy between 9 and 23 months.

Four children were treated first with Spinraza and then with Zolgensma, and three of them continued Spinraza treatment after that. One child received Zolgensma first, followed by Spinraza, and was the only one to receive the gene therapy within the age range (6.5 months) studied in clinical trials.

After the combination therapy, all patients continued to show motor function improvements, as assessed by the Children’s Hospital of Philadelphia Infant Test of Neuromuscular Disorders and the Hammersmith Infant Neurological Examination Part 2.

Increased levels of liver enzymes, indicating liver dysfunction, were detected in the four children who received Zolgensma after Spinraza and were successfully normalized with prednisolone treatment (recommended when given gene therapy).

Prednisolone therapy was prolonged beyond the previously reported duration range with Zolgensma (one to four months) in two patients who were hospitalized due to liver problems.

The researchers suspected that this rise in liver enzymes was related mainly to Zolgensma and noted that the fast reintroduction of Spinraza after Zolgensma may result in cumulative liver toxicity.

Interestingly, the two children receiving the gene therapy the latest (23 months, nearly 2 years) also showed asymptomatic low levels of platelets, which “could possibly be explained by a more “experienced” immune system posing a robust immune response,” the researchers wrote.

The child who received Zolgensma after Spinraza experienced no side effects.

These findings suggest that combining Spinraza with Zolgensma is generally well-tolerated in type 1 patients, but prolonged prednisolone use and liver toxicity monitoring may be necessary, the team noted.

“It is unclear whether combination therapy augments SMN expression levels above either monotherapy approach, and, if so, whether the augmented level is more beneficial that that achieved with either monotherapy,” the researchers wrote.

Further studies involving more patients are needed to better understand the effects of combination therapy in liver function and to “determine whether there are circumstances in which combination therapy would be more efficacious than either monotherapy,” the them concluded.

Recently, Biogen announced plans to launch a Phase 4 clinical trial, called RESPOND, evaluating the benefits of Spinraza in approximately 60 infants and children with SMA who were treated previously with Zolgensma.