New developments in treatments for spinal muscular atrophy (SMA) over the last few years have changed what is possible for people with SMA, allowing them to achieve new developmental milestones. However, these treatment advances have also raised new questions for the community, including whether combining treatments is safe and offers additional efficacy.

To better understand the complex topic of combining therapies, Cure SMA developed a resource booklet for individuals with SMA, their families, and healthcare providers, titled “Scientific Considerations for Drug Combinations.” In this, we define the term “combination therapy” in the context of SMA, discuss SMN-independent and SMN-dependent therapeutic options, and outline potential risks and benefits to consider when thinking about combining treatments for SMA.

There are several approaches to gathering the information needed to answer the questions about the feasibility of combination therapy for individuals with SMA. The first is through controlled clinical trials, where combinations of therapies are assessed for safety and efficacy. This strategy allows studies to be designed using testing protocols and inclusion criteria most likely to yield conclusive results. Another way is through the collection of evidence using the real-world experiences of people taking a combination of U.S. Food and Drug Administration (FDA) approved treatments, either at the same time or sequentially.  This allows for the assessment of how combinations of therapies perform in less controlled settings, with broader and more inclusive groups of patients.

It is believed that combinations of treatments can be done with two drugs that have similar mechanisms of action, or MOA’s. For SMA, often this is focused on taking two treatments that increase the level of SMN protein by replacement of the SMN1 gene or by manipulation of the SMN2 “back-up” gene. One of the key questions with this type of combination therapy that uses treatments with similar MOAs is whether the different treatments are impacting different subsets of cells—in the case of SMA likely motor neurons—in the body at different times.

A new Phase 4 clinical trial, called RESPOND, has just been initiated by Biogen to assess the benefit and the safety of Spinraza in infants and children with SMA following treatment with the gene replacement therapy Zolgensma. The RESPOND study will be conducted at approximately 20 sites worldwide and aims to enroll up to 60 children with SMA. It will begin to provide meaningful answers for some of the questions needed by the SMA community to support informed treatment decisions.

Another angle to combining treatments is to use two therapies that work in more different ways. One approach is combining a drug that increases the level of SMN protein with another that focuses on increasing muscle function that has been lost. This approach is one currently being studied in a clinical trial by Scholar Rock, which is investigating the efficacy and safety of combining a new muscle targeted treatment with the approved SMN-enhancing therapy approach of Spinraza. Cure SMA is also funding studies to explore novel targets that affect motor neuron survival or neuromuscular transmission.

Cure SMA is excited to see our industry partners starting these trials for the SMA community and are pleased to partner with Biogen and Scholar Rock to move these respective studies forward. We are also focused on adding to the evidence collected in these clinical trials with the information from  real-world experiences through the Cure SMA Care Center Network and Clinical Data Registry.