Perspectives on clinical trials in spinal muscular atrophy

Abstract

Spinal muscular atrophy is one of the most heterogeneous of the single-gene neuromuscular disorders. The broad spectrum of severity, with onset from the prenatal period to adulthood, presents unique challenges in the design and implementation of clinical trials. The clinical classification of subjects into severe (type 1), intermediate (type 2), and mild (type 3) subtypes has proved useful both in enhancing communication among clinicians internationally and in forging the collaborative development of outcome measures for clinical trials. Ideally, clinical trial design in spinal muscular atrophy must take into account the spinal muscular atrophy type, patient age, severity-of-affection status, nature of the therapeutic approach, timing of the proposed intervention relative to disease progression, and relative homogeneity of the cohort to be studied. Following is an overview of the challenges and opportunities, current and future therapeutic strategies, and progress to date in clinical trials in spinal muscular atrophy.

Figure 1

Ulnar compound muscle action potential (CMAP) versus age in 46 infants with spinal muscular atrophy type 1. Control values from a single unaffected sibling (SMN1 deletion carrier) are depicted by squares. Solid triangles indicate data from the first assessment in 8 subjects diagnosed with spinal muscular atrophy type 1 prenatally or early in the postnatal period due to a history of an affected sibling. Open triangles indicate data from symptomatic spinal muscular atrophy type 1 infants presenting at various ages. All data represent natural history data for subjects not yet enrolled in treatment protocols. The progressive decrease in compound muscle action potential values during the first 6 months of age represent the most active phase of progressive motor unit loss in these subjects, encompassing the preclinical and subacute phases of disease progression (see Figure 2). A less precipitous loss of compound muscle action potential amplitudes and motor units, of later onset, is observed in spinal muscular atrophy type 2 and 3 subjects.

Figure 2

Acquisition of gross motor milestones in controls versus infants with spinal muscular atrophy (SMA). Preclinical and subacute phases are characterized by more rapid loss of motor units. Loss of functional motor skills is modified by compensatory mechanisms for motor unit loss, including collateral reinnervation, central nervous system maturation and myelination, and peripheral nerve myelination.

Figure 3

Estimated spinal muscular atrophy (SMA) prevalence by age and type. Although an estimated 60% to 70% of children with a homozygous SMN deletion will manifest clinically with spinal muscular atrophy type 1, the prevalence of spinal muscular atrophy type 2 is higher because of significantly increased mortality in more severely affected infants.