Amyotrophic lateral sclerosis - Emerging treatments

Stem cells

There has been substantial interest in the potential of stem cells to treat ALS. Trials have used different types and methods of delivery of stem cells. One phase 1/2 trial of implantation of human spinal cord-derived neural stem cells in the ventral horn of both cervical and lumbar spine of patients with ALS showed that injections can be performed safely.[107] Studies have been carried out on both peripheral and intrathecal injections of treated adult bone marrow-derived mesenchymal stromal cells (MSCs) designed to produce a variety of neurotrophic factors. One phase 3 study using intrathecally administered neurotrophic factor-secreting stem cells failed to reach its primary end point, but there was some improvement noted in biochemical markers.[108] Expert opinion is mixed as to whether this method and mechanism of stem cell delivery should continue to be developed or abandoned. One systematic review concluded there is a lack of high-quality evidence to recommend stem-based therapies and that further trials are needed.[109]

Masitinib

Masitinib is an anti-inflammatory agent that targets mast cells and microglia. One randomized controlled phase 2/3 trial reported slowing of decline of function in patients receiving masitinib in combination with riluzole, compared with placebo plus riluzole. Adverse events included maculopapular rash and peripheral edema.[110][111] A phase 3 trial is under way.[112]

Ibudilast

Ibudilast is an oral, small-molecule phosphodiesterase and a macrophage migration inhibitory factor inhibitor, which suppresses pro-inflammatory cytokines and promotes neurotrophic factors. The pharmacokinetics, safety, tolerability, and efficacy of ibudilast on function, muscle strength, quality of life, and survival in ALS patients are being investigated in a randomized, double-blind, placebo-controlled, multicenter phase 2b/3 study.[113]

Tofersen

Tofersen (also known as BIIB067) is an investigational antisense oligonucleotide that reduces the levels of the abnormal protein superoxide dismutase 1 (SOD1) by binding to SOD1 mRNA. In one phase 1/2 trial, SOD1 concentrations were reduced in cerebrospinal fluid following intrathecal administration of tofersen over 12 weeks in adults with ALS due to SOD1 gene mutations.[114] Although a placebo-controlled phase 3 trial of intrathecal tofersen did not improve clinical end points, data from the open-label extension phase suggest that patients randomized to the treatment arm had improved outcomes during the open-label phase compared with patients receiving placebo initially.[115] The potential effects of earlier compared with later initiation of tofersen are being evaluated in an ongoing extension study.[116] The ATLAS study evaluating early treatment with tofersen in presymptomatic patients carrying a SOD1 mutation is under way.[117]

Reldesemtiv

Reldesemtiv is an activator of fast skeletal muscle troponin, which may improve the efficiency of muscle contraction in weak muscles. An international phase 3 study is evaluating whether reldesemtiv may slow the reduction in vital capacity or hand grip in patients with ALS.[118]

AP-101

AP-101 is a human monoclonal antibody designed to selectively target and reduce levels of misfolded SOD1, which can be seen in the pathology of both sporadic ALS and SOD1 hereditary ALS. This intravenous therapy is currently undergoing a phase 2 trial.[119]

SAR443820

SAR443820 (also known as DNL788) is an oral central nervous system-penetrant inhibitor of receptor-interacting protein kinase 1 (RIPK1), a signaling protein in the tumor necrosis factor pathway, which may reduce neuroinflammation and slow neuronal death. A phase 2 trial is under way.[120]

Trehalose

Trehalose is a low molecular weight disaccharide that crosses the blood-brain barrier and may reduce aggregation of misfolded proteins and activate autophagy to clear aggregated proteins. An intravenous formulation of trehalose is being evaluated as part of the Healey ALS platform trial.[121]