Improving clinical trial outcomes in amyotrophic lateral sclerosis

Abstract

Individuals who are diagnosed with amyotrophic lateral sclerosis (ALS) today face the same historically intransigent problem that has existed since the initial description of the disease in the 1860s - a lack of effective therapies. In part, the development of new treatments has been hampered by an imperfect understanding of the biological processes that trigger ALS and promote disease progression. Advances in our understanding of these biological processes, including the causative genetic mutations, and of the influence of environmental factors have deepened our appreciation of disease pathophysiology. The consequent identification of pathogenic targets means that the introduction of effective therapies is becoming a realistic prospect. Progress in precision medicine, including genetically targeted therapies, will undoubtedly change the natural history of ALS. The evolution of clinical trial designs combined with improved methods for patient stratification will facilitate the translation of novel therapies into the clinic. In addition, the refinement of emerging biomarkers of therapeutic benefits is critical to the streamlining of care for individuals. In this Review, we synthesize these developments in ALS and discuss the further developments and refinements needed to accelerate the introduction of effective therapeutic approaches.

Fig. 1. The pathophysiology of ALS.

Amyotrophic lateral sclerosis (ALS) preferentially involves the descending corticospinal motor neurons that synapse with spinal motor neurons and project to skeletal muscles via the neuromuscular junction. The processes of neurodegeneration in amyotrophic lateral sclerosis involve a complex array of molecular and genetic pathways. Glutamate-induced excitotoxicity can result from the overactivation of ionotropic glutamate receptors that allow excessive influx of Na⁺ and Ca²⁺ ions (step 1) and ultimately neurodegeneration through the activation of Ca²⁺-dependent enzymatic pathways. Glutamate excitotoxicity also generates free radicals, which further contribute to the process of neurodegeneration via oxidative stress. Na⁺–K⁺ pump dysfunction (step 2) disrupts the resting membrane potential and leads to secondary effects of altered intracellular Na⁺ levels. Ion channel dysfunction (step 3) also leads to altered intracellular Na⁺ levels. Altered Na⁺ levels result in the reversal of the Na⁺–Ca²⁺ exchanger (step 4), thereby increasing the intracellular Ca²⁺ levels that can cause neuronal toxicity. Defects in RNA processing, RNA metabolism and protein synthesis lead to defects in nucleocytoplasmic trafficking associated with neuronal degeneration (step 5). Mutant SOD1 enzymes increase oxidative stress, induce mitochondrial dysfunction, form intracellular aggregates, and adversely affect neurofilament and axonal transport processes (step 6). Mutations in TARDBP, FUS and C9orf72 can result in the formation of intracellular aggregates of their protein products (step 7), leading to increased oxidative stress, mitochondrial dysfunction, defects in axonal transport and, consequently, in neuronal death. Defects in protein folding and degradation also lead to protein aggregates (step 8). The activation of microglia promotes the secretion of pro-inflammatory cytokines and neurotoxic substances, such as glutamate, which promote neuroinflammation and neuronal death (step 9). Reduced expression and activity of the astrocytic glutamate transporter excitatory amino acid transporter 2 (EAAT2) (step 10) is associated with motor neuron degeneration owing to glutamate toxicity. Accumulation of mutant SOD1 protein in Schwann cells (step 11) are thought to mediate synaptic denervation, which precedes the onset of anterior horn cell degeneration.

Fig. 2. Model of precision medicine for ALS.

A one-size-fits-all approach (left) in amyotrophic lateral sclerosis (ALS) leads to the use of a single treatment in heterogeneous populations. In this scenario, some patients benefit from therapy but others do not. Stratified medicine (centre) improves on the one-size-fits-all approach by enabling patients to be separated into more homogeneous groups based on demographics, clinical phenotype and molecular subtypes of ALS. However, advances in knowledge and technology are enabling a transition to a precision medicine paradigm (right) in ALS. Precision medicine incorporates individual phenotypic and genotypic data to guide individualized therapy. In this scenario, all patients can benefit from treatment.

Fig. 3. MAMS adaptive platform trial design.

In this multi-arm, multi-stage (MAMS) platform trial, eligible patients are randomly assigned to one of four sub-studies and subsequently randomly assigned to receive active treatment or placebo. A master protocol determines patient selection criteria, logistics, outcome measures, biomarkers and data management in all four sub-studies. Genotype and molecular markers can also be collected systematically. The platform consists of five arms (treatments 1–4 and a pooled placebo arm). Pre-planned interim analyses are built into the design at points A and B. At point A, treatment 2 is found to have a favourable efficacy signal, so the arm seamlessly moves into phase III and more patients are recruited into that arm (thicker arrow). At the same point, futility criteria are met with treatment 3 and this arm is dropped (cross). New arms can be added over time such as treatment 4 here.