Decision-making and challenges within the evolving treatment algorithm in spinal muscular atrophy: a clinical perspective

ABSTRACT

Introduction

The clinical application of disease modifying therapies has dramatically changed the paradigm of the management of people with spinal muscular atrophy (SMA), from sole reliance on symptomatic care directed toward the downstream consequences of muscle weakness, to proactive intervention and even preventative care.

Areas covered

In this perspective, the authors evaluate the contemporary therapeutic landscape of SMA and discuss the evolution of novel phenotypes and the treatment algorithm, including the key factors that define individual treatment choice and treatment response. The benefits achieved by early diagnosis and treatment through newborn screening are highlighted, alongside an appraisal of emerging prognostic methods and classification frameworks to inform clinicians, patients, and families about disease course, manage expectations, and improve care planning. A future perspective of unmet needs and challenges is provided, emphasizing the key role of research.

Expert opinion

SMN-augmenting therapies have improved health outcomes for people with SMA and powered the practice of personalized medicine. Within this new proactive diagnostic and treatment paradigm, new phenotypes and different disease trajectories are emerging. Ongoing collaborative research efforts to understand the biology of SMA and define optimal response are critical to refining future approaches.

Plain Language Summary

The outlook for individuals with Spinal Muscular Atrophy (SMA) has transformed with the approval of three effective disease modifying therapies in the past seven years. This group of genetic diseases that cause progressive muscle weakness and present as a broad range of severity – from mild disease with near normal lifespan to severe with abbreviated lifespan and comorbidities – now have gene-based therapies that have shown (motor) functional gains, ameliorated comorbidities, and improved overall quality of life of patients and prolonged survival. With the rapid translation of early diagnostic paradigms through newborn screening and the acceleration of a therapeutic pipeline, uncertainties within clinical practice arise including the optimal time to treat, the changing clinical characteristics of the treated population, monitoring of disease progression and therapeutic response in the post-treatment era. In this article, we review the evidence base to address these challenges. The key factors that determine individual treatment choice and response are discussed. The changed clinical characteristics in treated children that need early identification and appropriate management are discussed in depth. A new classification system in keeping with the changed paradigm is provided. In these early times of the treatment era, the evidence from clinical trials and real world is combined to generate evidence base to guide management. The reader would be apprised of the recent therapeutic developments, their applications, and outcomes. Finally, the challenges to be expected along the uncharted path of prolonged lifespan are discussed and care guidelines provided.

KEYWORDS:

• Spinal Muscular Atrophy
• phenotypes
• disease modifying therapies
• newborn screening
• gene therapy
• RNA therapy

Article highlights

• All three therapies (nusinersen, onasemnogene abeparvovec, and risdiplam) have shown consistent stabilization or improvements of disease; however, variable response patterns have been observed among treated individuals.

• The best efficacy has been observed with presymptomatic and early treatment, prompting the addition of SMA to newborn screening programs.

• Substantial differences in study populations have meant that definitive conclusions on superior efficacy and tolerability between the agents cannot be established.

• The modality, frequency of administration, side effect profile, and duration of therapy, all factor into treatment choice.

• Scientific and clinical consensus is lacking as to when to consider additional disease modification and the therapeutic combinations to use to attain additional long-term gains.

• New phenotypes and different disease trajectories are emerging with SMA therapies. To more accurately guide prognosis and treatment algorithms, a contemporary classification may include modality of diagnosis, clinical status at therapeutic initiation and current motor function.

• Age and phenotype at treatment initiation are important determinants for the outcome of all current therapies. The magnitude and rate of the observed benefit is greatest in the youngest and in those with the lowest disease burden and shorter disease duration.

• Ongoing multidisciplinary care is critical for patients with SMA.

• Defining optimal response will be critical to refining future approaches. Biomarkers are key to understanding individual differences, ascertaining if and when greater gains are to be had, and evaluating treatment effect.

Declaration of interest

M Farrar is a site principal investigator for clinical trials Biogen Idec, Roche, and Novartis Gene Therapies Inc. She has received honoraria for advisory board participation from Biogen Idec, Novartis, and Roche, and received speaker’s fees from Biogen Idec and Novartis. D Kariyawasam is sub-investigator in Roche clinical trials and has received honoraria for advisory board participation from Biogen Idec and speaker’s fees from Biogen Idec and Novartis. A D’Silva is study coordinator in Roche clinical trials and has received honoraria for educational activities from Biogen Idec.

Reviewer disclosures

Peer reviewers on this manuscript have no relevant financial or other relationships to disclose.

Additional information

Funding

This work was supported by the National Health and Medical Research Council under Grant number 1194940, the University of New South Wales RNA Institute seed funding, Research Training Program Scholarship from the University of New South Wales and philanthropic giving from the “Move 4 Bella and Ride 4 Bella Challenge” to raise awareness and support for spinal muscular atrophy and rare diseases.