Myasthenia gravis (MG) is a chronic and debilitating autoimmune disease mediated by pathogenic IgG autoantibodies directed against the neuromuscular junction. The resulting muscle weakness and fatiguability are highly burdensome for patients. Decreasing autoantibody levels is an effective therapeutic strategy via plasma exchange, intravenous immunoglobulin, or immunoadsorption.¹ However, the high costs and adverse events associated with these treatments have necessitated investigations into safer and more convenient alternatives.

Efgartigimod is a human IgG1 antibody Fc-fragment that blocks the neonatal Fc receptor (FcRn). FcRn is involved in IgG recycling.¹ IgG pinocytosed into FcRn-expressing cells binds to FcRn in early acidified endosomes, causing IgG to be recycled or transcytosed to the cell surface and released. Efgartigimod, engineered an with increased affinity to FcRn, can outcompete endogenous IgG to block recycling and subsequently reduce IgG autoantibody levels. Such capacity has been demonstrated in murine models of autoimmunity.

James F. Howard, Jr., MD, FAAN, University of North Carolina School of Medicine, Chapel Hill, NC, discusses the findings of the Phase III ADAPT trial (NCT03669588) evaluating the efficacy, safety, and tolerability of efgartigimod in patients with generalized MG.² ADAPT was a double-blind, placebo-controlled trial that randomized 167 patients 1:1 to receive four weekly efgartigimod infusions or placebo. Subsequent treatment cycles were determined based on clinical responses. The trial assessed participant responses using the Myasthenia Gravis Activities of Daily Living (MG-ADL) profile, defining responders as those who improved by ≥2 points sustained for ≥4 weeks.

Ablative surgery has been used for the treatment of Parkinson’s disease (PD) for many years and has well-documented evidence supporting its ability to reduce parkinsonian motor symptoms. However, traditional approaches come with a notable risk of surgical complications, including bleeding, dysarthria and impaired balance.³ A wealth of literature supporting deep brain stimulation (DBS), particularly in the subthalamic nucleus (STN) has seen DBS overtake ablation as the most popular surgical approach for amelioration of PD symptoms.⁴ While highly efficacious and associated with a reduced risk of complications when compared to ablative surgery, STN DBS relies on very strict patient selection criteria, leaving it underutilized.

A novel technique using magnetic resonance–guided focused ultrasound (FUS) to create therapeutic lesions has started to gain attention as a promising therapeutic option in PD. FUS ablation avoids craniotomy, electrode penetration and other potential surgical complications. It has been approved for the treatment of essential tremor and tremor-dominant PD based on safety and efficacy data collected in randomized trials.⁴

Amyotrophic lateral sclerosis (ALS) is a fatal disease in which efficacious therapies directly targeting pathogenic processes are severely lacking. Characterized by motor neuron degeneration and resultant progressive muscle weakness and atrophy, symptom management is the predominant goal of ALS treatment. Riluzole and edaravone are FDA-approved treatment options shown to modulate disease course to a degree, but a substantial unmet need remains.

The Phase II CENTAUR trial (NCT03127514) is a randomized, placebo-controlled trial investigating the safety and efficacy of AMX0035, an investigational sodium phenylbutyrate-taurursodiol coformulation.⁵ AMX0035 is designed to reduce neuronal death, combining the individual activities of sodium phenylbutyrate and taurursodiol on the endoplasmic reticulum (ER) and mitochondria, respectively. Both ER stress and mitochondrial dysfunction have been strongly implicated in the pathogenesis of ALS. Sodium phenylbutyrate is a histone deacetylase inhibitor shown to mitigate endoplasmic reticulum stress via upregulation of heat shock proteins and small molecule chaperone capabilities.⁶ Taurursodiol ameliorates mitochondrial dysfunction through several mechanisms, including the prevention of Bax translocation into the mitochondrial membrane, reducing mitochondrial permeability and thus, increasing cells’ apoptotic threshold.

Sodium phenylbutyrate and taurursodiol have demonstrated their ability to reduce neuronal death in pre-clinical models, both individually and in combination. Pilot trials have reported safety data for the individual agents, and CENTAUR represents the first trial to assess the safety and efficacy of the combination.

At AAN 2021, Sabrina Paganoni, MD, PhD, Massachusetts General Hospital, Harvard Medical School, Boston, MA, shared the results of a long‐term overall survival analysis of participants in the CENTAUR trials.⁵ A total of 137 patients were randomized in a 2:1 ratio to receive AMX0035 or matching placebo for 24 weeks.