Drug treatment for spinal muscular atrophy types II and III

Abstract

BackgroundSpinal muscular atrophy (SMA) is caused by a homozygous deletion of the survival motor neuron 1 (SMN1) gene on chromosome 5, or a heterozygous deletion in combination with a (point) mutation in the second SMN1 allele. This results in degeneration of anterior horn cells, which leads to progressive muscle weakness. Children with SMA type II do not develop the ability to walk without support and have a shortened life expectancy, whereas children with SMA type III develop the ability to walk and have a normal life expectancy. This is an update of a review first published in 2009 and previously updated in 2011. ObjectivesTo evaluate if drug treatment is able to slow or arrest the disease progression of SMA types II and III, and to assess if such therapy can be given safely. Search methodsWe searched the Cochrane Neuromuscular Specialised Register, CENTRAL, MEDLINE, Embase, and ISI Web of Science conference proceedings in October 2018. In October 2018, we also searched two trials registries to identify unpublished trials. Selection criteriaWe sought all randomised or quasi-randomised trials that examined the e icacy of drug treatment for SMA types II and III. Participants had to fulfil the clinical criteria and have a homozygous deletion or hemizygous deletion in combination with a point mutation in the second allele of the SMN1 gene (5q11.2-13.2) confirmed by genetic analysis. The primary outcome measure was change in disability score within one year a er the onset of treatment. Secondary outcome measures within one year a er the onset of treatment were change in muscle strength, ability to stand or walk, change in quality of life, time from the start of treatment until death or full-time ventilation and adverse events attributable to treatment during the trial period.Treatment strategies involving SMN1-replacement with viral vectors are out of the scope of this review, but a summary is given in Appendix 1. Drug treatment for SMA type I is the topic of a separate Cochrane Review.

Diagnosis and management of spinal muscular atrophy: Part 2: Pulmonary and acute care; medications, supplements and immunizations; other organ systems; and ethics

“…Until recently no drug treatment had proved to be able to influence the disease course of SMA. A Cochrane review published in 2012 reported six randomized placebo-controlled trials on treatment for SMA using creatine, phenylbutyrate, gabapentin, thyrotropin-releasing hormone, hydroxyurea and combination therapy with valproate and acetyl-L-carnitine [36,37]. None of these studies showed statistically significant effects on the outcome measures in participants with SMA types 2 and 3.…”

Diagnosis and management of spinal muscular atrophy: Part 2: Pulmonary and acute care; medications, supplements and immunizations; other organ systems; and ethics

“…Until recently no drug treatment had proved to be able to influence the disease course of SMA. A Cochrane review published in 2012 reported six randomized placebo-controlled trials on treatment for SMA using creatine, phenylbutyrate, gabapentin, thyrotropin-releasing hormone, hydroxyurea and combination therapy with valproate and acetyl-L-carnitine [36,37]. None of these studies showed statistically significant effects on the outcome measures in participants with SMA types 2 and 3.…”

An Overview of the Therapeutic Strategies for the Treatment of Spinal Muscular Atrophy

“…97 A phase 2/3 multicenter, randomized, double-blinded study of riluzole, thoroughly investigated its efficacy and safety in young adults with type 2 and 3 SMA; most of the results were either discouraging or did not show adequate efficacy. 98…”

Rasch analysis of clinical outcome measures in spinal muscular atrophy

“…Muscle Nerve 49:422-430, 2014 Spinal muscular atrophy (SMA) is a rare 1 inherited neuromuscular condition characterized by degeneration of spinal and bulbar anterior horn cells with resulting muscle weakness and atrophy 2 ; it is commonly classified into 1 of 3 categories. 3 Over the past 15 years increased understanding of the molecular genetics and pathophysiology of Abbreviations: AmSMART, American SMA Randomized Trial group; CHOP-INTEND, Children's Hospital of Philadelphia test of neuromuscular disorders; DIF, differential item functioning; EK2, Egen Klassifikation Scale v.2; FDA, Food SMA has provided a platform for therapeutics development and new promising clinical trials [4][5][6] whose efficacy is ultimately judged by outcome measures. Functional rating scales are being used increasingly in this important role, [7][8][9] and it is therefore essential that they provide clinically meaningful and scientifically robust data.…”

Diagnosis and management of spinal muscular atrophy: Part 2: Pulmonary and acute care; medications, supplements and immunizations; other organ systems; and ethics

“…Until recently no drug treatment had proved to be able to influence the disease course of SMA. A Cochrane review published in 2012 reported six randomized placebo-controlled trials on treatment for SMA using creatine, phenylbutyrate, gabapentin, thyrotropin-releasing hormone, hydroxyurea and combination therapy with valproate and acetyl-L-carnitine [36,37]. None of these studies showed statistically significant effects on the outcome measures in participants with SMA types 2 and 3.…”

An Overview of the Therapeutic Strategies for the Treatment of Spinal Muscular Atrophy

“…97 A phase 2/3 multicenter, randomized, double-blinded study of riluzole, thoroughly investigated its efficacy and safety in young adults with type 2 and 3 SMA; most of the results were either discouraging or did not show adequate efficacy. 98…”

Rasch analysis of clinical outcome measures in spinal muscular atrophy

“…Muscle Nerve 49:422-430, 2014 Spinal muscular atrophy (SMA) is a rare 1 inherited neuromuscular condition characterized by degeneration of spinal and bulbar anterior horn cells with resulting muscle weakness and atrophy 2 ; it is commonly classified into 1 of 3 categories. 3 Over the past 15 years increased understanding of the molecular genetics and pathophysiology of Abbreviations: AmSMART, American SMA Randomized Trial group; CHOP-INTEND, Children's Hospital of Philadelphia test of neuromuscular disorders; DIF, differential item functioning; EK2, Egen Klassifikation Scale v.2; FDA, Food SMA has provided a platform for therapeutics development and new promising clinical trials [4][5][6] whose efficacy is ultimately judged by outcome measures. Functional rating scales are being used increasingly in this important role, [7][8][9] and it is therefore essential that they provide clinically meaningful and scientifically robust data.…”

Diagnosis and management of spinal muscular atrophy: Part 2: Pulmonary and acute care; medications, supplements and immunizations; other organ systems; and ethics

“…Until recently no drug treatment had proved to be able to influence the disease course of SMA. A Cochrane review published in 2012 reported six randomized placebo-controlled trials on treatment for SMA using creatine, phenylbutyrate, gabapentin, thyrotropin-releasing hormone, hydroxyurea and combination therapy with valproate and acetyl-L-carnitine [36,37]. None of these studies showed statistically significant effects on the outcome measures in participants with SMA types 2 and 3.…”

An Overview of the Therapeutic Strategies for the Treatment of Spinal Muscular Atrophy

“…97 A phase 2/3 multicenter, randomized, double-blinded study of riluzole, thoroughly investigated its efficacy and safety in young adults with type 2 and 3 SMA; most of the results were either discouraging or did not show adequate efficacy. 98…”

Rasch analysis of clinical outcome measures in spinal muscular atrophy

“…Muscle Nerve 49:422-430, 2014 Spinal muscular atrophy (SMA) is a rare 1 inherited neuromuscular condition characterized by degeneration of spinal and bulbar anterior horn cells with resulting muscle weakness and atrophy 2 ; it is commonly classified into 1 of 3 categories. 3 Over the past 15 years increased understanding of the molecular genetics and pathophysiology of Abbreviations: AmSMART, American SMA Randomized Trial group; CHOP-INTEND, Children's Hospital of Philadelphia test of neuromuscular disorders; DIF, differential item functioning; EK2, Egen Klassifikation Scale v.2; FDA, Food SMA has provided a platform for therapeutics development and new promising clinical trials [4][5][6] whose efficacy is ultimately judged by outcome measures. Functional rating scales are being used increasingly in this important role, [7][8][9] and it is therefore essential that they provide clinically meaningful and scientifically robust data.…”