| Coordinating Panel on Rare Neurological Diseases  

Combination molecular therapies for type 1 spinal muscular atrophy

SMA is a perfect example of rare neurological disease, and should be regarded as a prototype concerning the medical and social aspects of its management, because we must be aware that every new molecule that will be discovered to work in other rare diseases will be an expensive one.

The authors describe their experience in treating five children with type 1 SMA with both nusinersen and onasemnogene aboparvovec. There are a few important pieces of information in this article: 4 patients (as well as 2 other patients mentioned in the reference article below) started with nusinersen, then onasemnogene was added because, although they experienced some improvement, they continued to need respiratory support and/or to present bulbar dysfunction. All patients continued to show clinical improvement, but there are no data to prove that combined therapy has higher efficacy compared to monotherapy.  The side effects weren’t different to those related to each molecule.  More studies are needed to draw firm conclusions regarding the efficacy of the combined therapy and the correct timing of administration of the two drugs. 
Besides the raw data, this topic raises a few interesting issues:
After years of nothing else than supportive therapy, in the last years we have witnessed extraordinary progress, with no less than three therapies discovered and approved: nusinersen, onasmenogene, and risdiplam. Thus, the therapeutical approach in patients with SMA should have been simplified, but this isn't the case because the medical decision is influenced by other factors: financial, social, and ethical.
All these medications have a very high cost, which influences the accessibility of patients. These costs represent an important financial effort for society. 
The medications in this article have different mechanisms of action, so that their combinations make sense; but then, what about the costs? Is it ethical to treat one patient with two drugs, while many cannot afford even one? Is this a point where medicine and ethics are divergent?
At some point families might request the administration of the second drug.  Which will be our answer to them, as doctors and healthcare authorities advisors?
Will the combined therapy be included in future guidelines?



Combination therapy with nusinersen and AVXS- 101 in SMA type 1. Bo Hoon Lee, Erin Collins, Leann Lewis, Debra Guntrum, Katy Eichinger, Karen Voter, Hoda Z. Abdel-Hamid, and Emma Ciafaloni. Neurology 2019;93:640-641. doi:10.1212/WNL.0000000000008207