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Spinal muscular atrophy (SMA) is an autosomal recessive degenerative neuromuscular disorder caused by a mutation in the SMN1 gene, characterized by loss of spinal motor neurons leading to progressive muscle weakness. Advances in the molecular biology of SMA have resulted in the development of therapeutic agents that target survival motor neuron (SMN) protein production. These SMN-modifying treatments include mRNA therapies and gene transfer therapy. Treatments that modulate SMN2 mRNA alternative splicing include antisense oligonucleotide (ASO) and small-molecule agents. The best studied is nusinersen (Spinraza), an ASO approved for use to treat patients with SMA of all types. Small molecules (risdiplam and branaplam) act systemically and centrally to increase SMN protein levels via alternative splicing. Another SMN-modifying treatment is gene transfer therapy with AAV9 (adeno-associated virus 9) with AVXS-101, which has recently been approved in the U.S. under the name onasemnogene abeparvovec (Zolgensma). Risdiplam and AVXS-101 are currently in advanced phase III trials. Data on risdiplam is soon to be submitted to regulatory agencies for approval. This article discusses risdiplam?s preliminary clinical trial results and contrasts risdiplam with other SMN-modifying therapies with respect to mechanism of action, tissue distribution and drug delivery. Preliminary data from patients treated with risdiplam show a strong clinical response in motor, respiratory and swallowing function in type 1 infants. These robust effects were observed despite the fact that risdiplam-treated infants (when comparing median mean age at time of first dose) were older than the infants enrolled in either the nusinersen or in the AVXS-101 studies. Effects were also seen even among later-onset SMA in patients who were significantly older and had more advanced disease with chronic changes (e.g., severe scoliosis) than did other later-onset SMA patients studied. The level of response at this stage of disease would indicate perhaps a therapeutic advantage to systemic treatment compared to a CNS-restricted site of action. Risdiplam, thus far, has been shown to be safe and well tolerated with no drug-related adverse events resulting in drug discontinuation reported. As risdiplam and other SMN-modifying therapies are proven effective and approved for use, understanding the differences in mechanism of action, drug distribution and method of delivery gains relevance with regards to future therapeutic decisions. Results of the ongoing presymptomatic studies currently underway using each of the SMN-modifying therapies (risdiplam, nusinersen and AVXS-101) in a homogenous population (presymptomatic) are likely to shed light as to whether any one specific treatment offers a therapeutic advantage.
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Reference：
Pyridazine – Wikipedia,
Pyridazine | C4H4N1060 – PubChem