Combining Spinraza(nusinersen) with the gene therapyZolgensma(onasemnogene abeparvovec-xioi) is generally well-tolerated and sustains motor improvements in children withspinal muscular atrophy(SMA) type1, 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 therapiesknown 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 Biogens Spinraza andNovartis Zolgensma both work to restore the levels ofSMN, the protein lacking in SMA patients due tomutations in theSMN1gene.

Spinraza, the firstapproved disease-modifying therapy for all SMA patients, targetsSMN2, a backup gene that can compensate partially for the loss ofSMN1-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 ofSMN1to cells. It is available to children up to age 2 in theU.S.andJapan,and to almost all SMA types in those weighing up to 21 kilograms (about 46 pounds) inEurope.

The gene therapy can be given only once, due to the bodys 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 patients 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 Childrens Hospital of the University of Arkansas for Medical Sciences and the Ann and Robert H. Lurie Childrens 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 theChildrens 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 withprednisolone 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 ofSpinrazain approximately 60 infants and children withSMA who were treated previously with Zolgensma.

Marta Figueiredo holds a BSc in Biology and a MSc in Evolutionary and Developmental Biology from the University of Lisbon, Portugal. She is currently finishing her PhD in Biomedical Sciences at the University of Lisbon, where she focused her research on the role of several signalling pathways in thymus and parathyroid glands embryonic development.

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Ana holds a PhD in Immunology from the University of Lisbon and worked as a postdoctoral researcher at Instituto de Medicina Molecular (iMM) in Lisbon, Portugal. She graduated with a BSc in Genetics from the University of Newcastle and received a Masters in Biomolecular Archaeology from the University of Manchester, England. After leaving the lab to pursue a career in Science Communication, she served as the Director of Science Communication at iMM.

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Spinraza-Zolgensma Combination Well-tolerated in Children with SMA... - SMA News Today