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Patients with amyotrophic lateral sclerosis (ALS) often have questions about why they developed the disease and the likelihood that family members will also be affected. In recent years, providing answers to these questions has become more complex with the identification of multiple novel genes, the newly recognized etiologic link between ALS and frontotemporal dementia (FTD), and the increased availability of commercial genetic testing. A genetic diagnosis is particularly important to establish in the era of emerging gene-based therapies, such as SOD1 antisense oligonucleotide trials. In the span of a few years, ALS genetic testing options have progressed from testing of a single gene to multigene next-generation sequencing panels and whole-exome sequencing. This article provides suggestions for genetic counseling and genetic testing for ALS in this new environment. Genet Med19 3, 267–274.

Sodium phenylbutyrate combined with taurursodiol reduces neuronal endoplasmic reticulum stress and mitochondrial dysfunction in experimental models. In a randomized trial, the combination slowed the rate of progression of ALS but did not affect the slow vital capacity or isometric muscle strength.

Chronic inflammatory demyelinating polyradiculoneuropathy (CIDP) is an autoimmune disease of the peripheral nervous system that can lead to severe disability from muscle weakness and sensory disturbances. Around a third of patients do not respond to currently available treatments, and many patients with a partial response have residual neurological impairment, highlighting the need for effective alternatives. Efgartigimod alfa, a human IgG1 antibody Fc fragment, has demonstrated efficacy and safety in patients with generalised myasthenia gravis. We evaluated the safety, tolerability, and efficacy of subcutaneous efgartigimod PH20 in adults with CIDP. ADHERE, a multistage, double-blind, placebo-controlled trial, enrolled participants with CIDP from 146 clinical sites from Asia–Pacific, Europe, and North America. Participants with evidence of clinically meaningful deterioration entered an open-label phase of weekly 1000 mg subcutaneous efgartigimod PH20 for no longer than 12 weeks (stage A). Those with confirmed evidence of clinical improvement (ECI; treatment responders) entered a randomised-withdrawal phase of 1000 mg subcutaneous efgartigimod PH20 weekly treatment versus placebo for a maximum of 48 weeks (stage B). Participants were randomised (1:1) through interactive response technology and stratified by their adjusted Inflammatory Neuropathy Cause and Treatment (aINCAT) score change during stage A and their most recent CIDP medication within 6 months before screening. Investigators, the clinical research organisation, and participants were masked to the treatment. The primary endpoint in stage A, evaluated in the stage A safety population, was confirmed ECI (≥1 points aINCAT decrease, ≥4 points [centile metric] Inflammatory Rasch-built Overall Disability Scale increase, or ≥8 kPa grip strength increase after four injections and two consecutive visits). The primary endpoint in stage B, evaluated in the modified intention-to-treat population, was the risk of relapse (time to first aINCAT increase of ≥1 points). ADHERE is registered with ClinicalTrials.gov (NCT04281472) and EudraCT (2019-003076-39) and is completed. Between April 15, 2020, and May 11, 2023, 629 participants were screened; 322 (114 female, 208 male) entered stage A, of whom 214 (66%, 95% CI 61·0−71·6) had confirmed ECI. In stage B, 221 participants were randomised (79 female, 142 male; 111 to subcutaneous efgartigimod PH20, 110 to placebo). Subcutaneous efgartigimod PH20 significantly reduced the risk of relapse versus placebo (hazard ratio 0·39 [95% CI 0·25−0·61]; p<0·0001). 31 (27·9% [19·6–36·3]) participants given subcutaneous efgartigimod PH20 had a relapse versus 59 (53·6% [44·3–63·0]) given placebo. In stage A, treatment-emergent adverse events (TEAEs) occurred in 204 (63%) participants and serious TEAEs in 21 (7%). In stage B, TEAEs occurred in 71 (64%) participants on subcutaneous efgartigimod PH20 and 62 (56%) participants on placebo, and serious TEAEs in six (5%) on subcutaneous efgartigimod PH20 and six (5%) on placebo. Three deaths occurred: two in stage A (one non-related and one unlikely related to treatment) and one in stage B (placebo group). ADHERE showed the efficacy of subcutaneous efgartigimod PH20 in reducing the risk of relapse versus placebo in people with CIDP who responded to treatment. Further studies are needed to provide data on the longer-term effects of efgartigimod alfa and how it compares with currently available treatment options. argenx.

BackgroundCoformulated sodium phenylbutyrate/taurursodiol (PB/TURSO) was shown to prolong survival and slow functional decline in amyotrophic lateral sclerosis (ALS).ObjectiveDetermine whether PB/TURSO prolonged tracheostomy/ventilation-free survival and/or reduced first hospitalisation in participants with ALS in the CENTAUR trial.MethodsAdults with El Escorial Definite ALS ≤18 months from symptom onset were randomised to PB/ TURSO or placebo for 6 months. Those completing randomised treatment could enrol in an open-label extension (OLE) phase and receive PB/TURSO for ≤30 months. Times to the following individual or combined key events were compared in the originally randomised treatment groups over a period spanning trial start through July 2020 (longest postrandomisation follow-up, 35 months): death, tracheostomy, permanent assisted ventilation (PAV) and first hospitalisation.ResultsRisk of any key event was 47% lower in those originally randomised to PB/TURSO (n=87) versus placebo (n=48, 71% of whom received delayed-start PB/TURSO in the OLE phase) (HR=0.53; 95% CI 0.35 to 0.81; p=0.003). Risks of death or tracheostomy/PAV (HR=0.51; 95% CI 0.32 to 0.84; p=0.007) and first hospitalisation (HR=0.56; 95% CI 0.34 to 0.95; p=0.03) were also decreased in those originally randomised to PB/TURSO.ConclusionsEarly PB/TURSO prolonged tracheostomy/PAV-free survival and delayed first hospitalisation in ALS.Trial registration number NCT03127514; NCT03488524.

Trehalose is a disaccharide that activates autophagy pathways in animal models of neurodegenerative diseases, with the potential to catalyse clearance of toxic, misfolded proteins in motor neurons and slow disease progression in amyotrophic lateral sclerosis (ALS). We aimed to evaluate the safety and efficacy of trehalose in individuals with ALS. The HEALEY ALS Platform Trial is a perpetual, adaptive, phase 2/3, randomised, double-blind, multi-regimen trial conducted at 60 geographically diverse sites in the USA. In the current regimen, adults with clinically possible, probable, laboratory-supported probable, or definite ALS, defined by the revised El Escorial criteria, were randomly allocated (3:1), stratified by use of edaravone and riluzole, to receive trehalose 0·75 g per kg intravenously weekly over 24 weeks, or matching placebo. The primary outcome was a composite of the relative rate of disease progression, as measured by the Revised ALS Functional Rating Scale (ALSFRS-R), and survival over 24 weeks, estimated in a Bayesian shared-parameter model. The study included prespecified stopping rules for futility; interim analyses occurred every 12 weeks. The primary outcome was analysed according to the intention-to-treat principle in all participants in the trehalose group, the placebo group within the regimen, and placebo groups from other contributing regimens; the safety analysis population was comprised of all participants who initiated treatment. This study is registered with ClinicalTrials.gov, NCT05136885. Between Feb 21, 2022, and Feb 17, 2023, 1021 participants were screened for the platform trial and 171 were assigned to the trehalose regimen. Of these, 161 participants met eligibility criteria, with 120 randomly allocated to trehalose and 41 to regimen-specific placebo. 164 participants randomly allocated to placebo in other regimens were added for analysis (totalling 205 placebo recipients). The disease rate ratio for change in ALSFRS-R and survival was 0·87 (95% credible interval 0·665–1·102, posterior probability of superiority 0·877). Serious adverse events occurred in 19 (16%) participants in the trehalose group and three (7%) participants in the regimen-only placebo group, leading to premature discontinuations in 14 (12%) versus one (2%), respectively. Fatal treatment-emergent adverse events occurred in seven participants in the trehalose group and none in the regimen-only placebo group. No death was considered related to the trial drug. The most common cause of death was respiratory failure, consistent with the natural history of ALS. Trehalose was well tolerated but there was no evidence to suggest a difference in ALS disease progression compared with placebo in this study. No statistical benefit was seen in secondary clinical or biomarker measures, suggesting that trehalose at this dosage is unlikely to be efficacious for treatment of ALS. AMG Charitable Foundation, Tackle ALS, the ALS Association, ALS Finding a Cure, the Muscular Dystrophy Association, ALS ONE, the Arthur M Blank Family Foundation, I AM ALS, Tambourine ALS Collaborative, and other community fundraising initiatives and donors. Study drug and partial regimen-related funding was provided by Seelos.

There is an urgent unmet need for new therapies in amyotrophic lateral sclerosis. In a clinical study with healthy volunteers, levosimendan, a calcium sensitiser, was shown to improve neuromechanical efficiency and contractile function of the human diaphragm. We aimed to evaluate the safety and efficacy of oral levosimendan in people with amyotrophic lateral sclerosis, with a focus on respiratory function. The REFALS study is a randomised, double-blind, placebo-controlled phase 3 trial at 99 amyotrophic lateral sclerosis specialist centres in 14 countries worldwide. People with amyotrophic lateral sclerosis were eligible for participation if they were at least 18 years of age and had a sitting slow vital capacity (SVC) of 60–90% predicted. Participants were randomly assigned (2:1) by interactive web-response system to receive either levosimendan or placebo. The capsules for oral administration were identical in appearance to maintain blinding of participants and investigators. The primary endpoint was the change from baseline in supine SVC at 12 weeks, assessed as the percentage of predicted normal sitting SVC. The key secondary endpoint was the combined assessment of function and survival (CAFS) up to 48 weeks. Analyses were done in the intention-to-treat population, comprising all participants who were randomly assigned. This trial is registered at ClinicalTrials.gov (NCT03505021) and has been completed. An extension study (REFALS-ES; NCT03948178) has also been completed, but will be reported separately. Between June 21, 2018, and June 28, 2019, 871 people were screened for the study, of whom 496 were randomly assigned either levosimendan (n=329) or placebo (n=167). Participants were followed up between June 27, 2018 and June 26, 2020, for a median duration of 50·1 (IQR 37·5–51·1) weeks. The median duration of treatment was 47·9 (IQR 26·4–48·1) weeks. Change from baseline in supine SVC at 12 weeks was –6·73% with levosimendan and –6·99% with placebo, with no significant difference between the treatments (estimated treatment difference 0·26%, 95% CI –2·03 to 2·55, p=0·83). Similarly, at week 48, CAFS did not differ between treatment groups (least squares mean change from baseline 10·69, 95% CI –15·74 to 37·12; nominal p value=0·43). The most frequent adverse events were increased heart rate (106 [33%] of 326 receiving levosimendan vs 12 [7%] of 166 receiving placebo), fall (85 [26%] vs 48 [29%]), headache (93 [29%] vs 36 [22%]), and dyspnoea (59 [18%] vs 32 [19%]). 33 (10%) participants allocated levosimendan and 20 (12%) assigned placebo died during the trial, mainly due to respiratory failure or progression of amyotrophic lateral sclerosis. Levosimendan was not superior to placebo in maintaining respiratory function in a broad population with amyotrophic lateral sclerosis. Although levosimendan was generally well tolerated, increased heart rate and headache occurred more frequently with levosimendan than with placebo. The possibility of a clinically relevant subgroup of responsive individuals requires further evaluation. Orion Corporation.

Although genetic testing for amyotrophic lateral sclerosis (ALS) is widely available, it is unknown what proportion of patients with ALS have access to genetic counseling and testing, and patient attitudes towards ALS genetic testing have not been studied. We conducted a national survey of ALS patients enrolled in the Agency for Toxic Substances and Disease Registry, which consisted of multiple choice questions and two 12 item Likert scale series assessing respondents’ experience with and attitude toward genetic testing. The survey had an 8 % response rate, with 449 completed responses. Genetic testing was offered to 33.4 % and completed by 67.1 % of those offered. A minority of respondents (12.5 %) saw a genetic counselor, and were much more likely to be offered genetic testing ( p  = 0.0001). Respondents with a family history of ALS (8.4 %) were more likely to be offered testing ( p  = 0.0001) and complete testing ( p  = 0.05). Respondents with a family history of ALS were more likely to report a favorable attitude towards genetic testing ( p  = 0.0003), as were respondents who saw a genetic counselor ( p  = 0.02). The majority of respondents (82.7 %) felt that genetic testing should be offered to all patients with ALS. Our results indicate that ALS patients may have limited access to genetic testing, but perceive benefit from this service. Development of practice guidelines for genetic testing in ALS, to include the routine offer of genetic counseling, may result in broader and more consistent access to these services.

Background Amyotrophic lateral sclerosis (ALS) is increasingly recognized as a genetic disease. There is no consensus, however, as to the role of genetic testing in the care of the ALS patient. Methods We conducted a survey to study patient access, attitudes, and experience with ALS genetic testing among patients enrolled in a US ALS registry. Results Among 449 survey respondents, 156 (34.7%) were offered testing and 105 of 156 (67.3%) completed testing. The majority of respondents with familial ALS (fALS) (31/45, 68.9%) were offered testing, while a minority of respondents with sporadic ALS (sALS) (111/404, 27.5%) were offered testing (p = .00001). Comparison of mean test experience scores between groups revealed that respondents with fALS were no more likely to report a favorable experience with genetic testing than those with sALS (p = .51). Respondents who saw a genetic counselor did not have significantly different test experience scores, compared to those who did not (p = .14). In addition, no differences in test experience scores were observed between those who received positive or negative genetic test results (p = .98). Conclusion These data indicate that patients with ALS found value in clinical genetic testing. Patients with ALS have found value in clinical genetic testing.