ADAPT analysis: efgartigimod for generalized myasthenia gravis


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.


It was found that 67.7% of AChR-Ab+ patients treated with efgartigimod compared to 29.7% of patients in the placebo arm achieved MG-ADL responder status (p<0.0001). Significant improvements were also seen with several other scoring systems: the Myasthenia Gravis Composite (MGC) scale, which measures symptoms and signs of MG; the Quantitative Myasthenia Gravis Score (QMG), assessing disease severity; and the Myasthenia Gravis Quality of Life 15-item Scale (MG-QoL15). The efficacy and safety demonstrated by efgartigamod in the ADAPT trial suggest it may represent a more efficacious alternative to current MG management techniques.

Randomized Trial of Focused Ultrasound Subthalamotomy for Parkinson’s Disease


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


However, rigidity and bradykinesia are not improved with thalamic interventions. The subthalamic nucleus plays an essential role in the pathophysiology of PD, with its abnormal activity shown to play a role in the development and persistence of motor symptoms. Deep brain stimulation and ablation of subthalamic regions have shown striking efficacy against all cardinal symptoms of PD. Thus, investigations of FUS subthalamotomy have promise for the treatment of all major motor symptoms in PD.

Raúl Martínez-Fernandez, MD, PhD, and José Obeso, MD, PhD, University Hospital HM Puerta del Sur, Madrid, Spain, discuss the results from a prospective, randomized trial (NCT03454425), assessing the safety and efficacy of one-sided focused ultrasound (FUS) subthalamotomy for PD.4 In total, 40 patients with asymmetric PD were randomized 2:1 to undergo FUS subthalamotomy or a sham procedure. All participants had motor symptoms not fully controlled by medication or were ineligible for DBS. The mean change in the Movement Disorder Society–Unified Parkinson’s Disease Rating Scale motor score (MDS-UPDRS III) from baseline to 4 months was assessed as the primary endpoint.

A mean decrease from 19.9 points at baseline to 9.9 at 4 months was achieved in the active-treatment group, compared to a change from 18.7 points to 17.1 in those in the control arm.4 Follow-up to 12 months revealed a sustained benefit of FUS subthalamotomy, with continued monitoring ongoing. Adverse events were frequent; namely motor weakness, dyskinesias and gait and speech disturbances. Despite their commonality, side effects were mainly mild in severity and transient, with few persisting to 12 months. The trial findings demonstrate the ability of FUS ablation to improve motor symptoms in PD. However, longer-term and larger trials are needed to further investigate its use and compare it with other available treatments, including DBS.

Long-term Survival of Participants in the CENTAUR Trials of AMX0035 for ALS


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.


Rate of functional decline measured by the ALS Functional Rating Scale-Revised (ALSFRS-R) was assessed as the primary study outcome. Previously reported results showed a slower functional decline in patients receiving AMX0035 compared to the placebo arm.6

Following the 24-week randomization phase, all participants completing the trial were eligible to receive AMX0035 in an open-label extension (NCT03488524), of whom 92% opted to do so. When participants originally randomized to AMX0035 were compared to patients originally randomized to placebo, a prolonged median overall survival of 25.0 months was reached, compared to 18.5 months in those randomized to placebo. Notably, most participants originally randomized to placebo received AMX0035 in the extension study, making it possible the survival benefit attributed to AMX0035 was underestimated. Long-term risk of death or tracheostomy/permanent assisted ventilation and risk of first hospitalization were also significantly lower among participants originally randomized to AMX0035 than among those originally randomized to placebo.7

Overall, the long-term survival analysis demonstrated a survival benefit attributable to AMX0035, suggestive of a neuroprotective effect in ALS.

Written by Juliet Lawrence


  1. P Ulrichts, A Guglietta, T Dreier, et al. Neonatal Fc receptor antagonist efgartigimod safely and sustainably reduces IgGs in humans. J Clin Invest. Oct 2018; 128(10): 4372-4386.
  2. J Howard, V Bril, T Vu, et al. Efficacy, Safety, and Tolerability of Efgartigimod in Patients With Generalized Myasthenia Gravis: Analysis of the Phase 3 ADAPT Study. Apr 2021; 96 (15 Supplement).
  3. R Dallapiazza, D Lee, P De Vloo, et al. Outcomes from stereotactic surgery for essential tremor. J Neurol Neurosurg Psychiatry. Apr 2019; 90(4): 474–482.
  4. R Martínez-Fernández, J Máñez-Miró, R Rodríguez-Rojas, et al. Randomized Trial of Focused Ultrasound Subthalamotomy for Parkinson’s Disease. N Engl J Med. Dec 2020; 383(26): 2501-2513.
  5. S Paganoni, S Hendrix, S Dickson, et al. Long-term survival of participants in the CENTAUR trial of sodium phenylbutyrate-taurursodiol in amyotrophic lateral sclerosis. Muscle Nerve. Jan 2021; 63(1): 31-39.
  6. S Paganoni, E Macklin, S Hendrix, et al. Trial of Sodium Phenylbutyrate-Taurursodiol for Amyotrophic Lateral Sclerosis. N Engl J Med. Sep 2020; 383(10):919-930.
  7. S Paganoni. Long-Term Survival of Participants in the CENTAUR Trials of AMX0035 for ALS [Conference presentation]. AAN 2021, 17-22 Apr 2021.