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Background: Amyotrophic lateral sclerosis is a progressive neurodegenerative disorder leading to muscle weakness and respiratory failure. Arimoclomol, a heat-shock protein-70 (HSP70) co-inducer, is neuroprotective in animal models of amyotrophic lateral sclerosis, with multiple mechanisms of action, including clearance of protein aggregates, a pathological hallmark of sporadic and familial amyotrophic lateral sclerosis. We aimed to evaluate the safety and efficacy of arimoclomol in patients with amyotrophic lateral sclerosis., Methods: ORARIALS-01 was a multinational, randomised, double-blind, placebo-controlled, parallel-group trial done at 29 centres in 12 countries in Europe and North America. Patients were eligible if they were aged 18 years or older and met El Escorial criteria for clinically possible, probable, probable laboratory-supported, definite, or familial amyotrophic lateral sclerosis; had an ALS Functional Rating Scale-Revised score of 35 or more; and had slow vital capacity at 70% or more of the value predicted on the basis of the participant's age, height, and sex. Patients were randomly assigned (2:1) in blocks of 6, stratified by use of a stable dose of riluzole or no riluzole use, to receive oral arimoclomol citrate 1200 mg/day (400 mg three times per day) or placebo. The Randomisation sequence was computer generated centrally. Investigators, study personnel, and study participants were masked to treatment allocation. The primary outcome was the Combined Assessment of Function and Survival (CAFS) rank score over 76 weeks of treatment. The primary outcome and safety were analysed in the modified intention-to-treat population. This trial is registered with ClinicalTrials.gov, NCT03491462, and is completed., Findings: Between July 31, 2018, and July 17, 2019, 287 patients were screened, 245 of whom were enrolled in the trial and randomly assigned. The modified intention-to-treat population comprised 239 patients (160 in the arimoclomol group and 79 in the placebo group): 151 (63%) were male and 88 (37%) were female; mean age was 57·6 years (SD 10·9). CAFS score over 76 weeks did not differ between groups (mean 0·51 [SD 0·29] in the arimoclomol group vs 0·49 [0·28] in the placebo group; p=0·62). Cliff's delta comparing the two groups was 0·039 (95% CI -0·116 to 0·194). Proportions of participants who died were similar between the treatment groups: 29 (18%) of 160 patients in the arimoclomol group and 18 (23%) of 79 patients in the placebo group. Most deaths were due to disease progression. The most common adverse events were gastrointestinal. Adverse events were more often deemed treatment-related in the arimoclomol group (104 [65%]) than in the placebo group (41 [52%]) and more often led to treatment discontinuation in the arimoclomol group (26 [16%]) than in the placebo group (four [5%])., Interpretation: Arimoclomol did not improve efficacy outcomes compared with placebo. Although available biomarker data are insufficient to preclude future strategies that target the HSP response, safety data suggest that a higher dose of arimoclomol would not have been tolerated., Funding: Orphazyme., Competing Interests: Declaration of interests MB reports grants from the National Institutes of Health, the Muscular Dystrophy Association, and the ALS Association; as well as consulting fees from Alector, Alexion, Annexon, Arrowhead, Biogen, Cartesian, Denali, Eli Lilly, Horizon, Immunovant, Novartis, Roche, Sanofi, Takeda, UCB, and UniQure. The University of Miami licensed some of MB's research data to Biogen to aid in the design of the ATLAS trial; MB receives a royalty payment received by the University of Miami as part of this licensing agreement. DR received consulting fees from Orphazyme for biostatistical consulting services for the ORARIALS-01 protocol. LHvdB reports consulting fees from Amylyx, Biogen, Ferrer, Corcept, Orion, and Orphazyme, as well as payment for scientific advisory board activities from Takeda. AC reports grants from the Italian Ministry of Health, the Italian Ministry of University and Research, the European Commission, Biogen, and the ALS Association; as well as consulting fees from Mitsubishi Tanabe, Biogen, Roche, Sanofi, Denali Pharma, Cytokinetics, Eli Lilly, and Amylyx Pharmaceuticals; he has received a research grant from Biogen. PMA report grants from the Swedish Research Council, the Knut and Alice Wallenberg Foundation, the Ulla-Carin Lindquist Foundation, NEURO, the Brain Foundation, and the European Commission; as well as consulting fees from Biogen, Avrion, Arrowhead, Regeneron, uniQure, Orphazyme, and Roche. P-FP reports meeting and travel support from Orphazyme. PVD reports grant from CSL Behring; speakers fees from Biogen and Amylyx; and participation in advisory boards for Biogen, CSL Behring, Alexion Pharmaceuticals, Ferrer, QurAlis, Cytokinetics, Argenx, UCB, Muna Therapeutics, Alector, Augustine Therapeutics, and VectorY. SP reports grants from Cytokinetics, Biogen, and Roche; consulting fees from Cytokinetics, Amylyx, Biogen, Roche, and Zambon; payment or honoraria from Biogen, Zambon, Roche, Amylyx, Italfarmaco, and Desitin; meeting and travel support from Biogen, Desitin, Zambon, Amylyx, Italfarmaco, PTC Therapeutics, and Ferrer; and participation in data safety monitoring boards or advisory boards for ORION Pharma, Amylyx, Biogen, Roche, and Zambon. SL reports consulting fees from Biogen and Amylyx; and participation in a data safety monitoring board (chair) for Neurosense Therapeutics. NAG reports grants from Abcuro, Amylyx, Alexion, Annelixis, Annexon, Brainstorm Cell Therapeutics, Calico, Cytokinetics, Fulcrum, Healey, Janssen, Kezar, Medicinova, MT Pharma, Octapharma, PTC, Sanofi, and Transposon; consulting fees from Abcuro, Alexion, Amylyx, Annexon, Argenx, Astrazeneca, CSL Behring, Fulcrum, Kezar, MT Pharma, Sanofi Genzyme, Sarepta, and UCB; and speakers fees from Argenx and CSL. CQ reports grants from Sanofi, Biogen, and Amylyx; consultant fees from Amylyx and Biogen; and honoraria from Seattle Science Foundation. AG reports consulting fees from Medtronic, Atlantic Research Group, Calico, Apellis, Anexon, ALS Pharmaceuticals, QurAlis, Orion, Sanofi Genzyme, Ionis, Wave Life Therapies, Anelixis, Roche, Cytokinetics, Mitsubishi Tanabe Pharma, Amylyx, Alexion, UCB, Ra Pharmaceuticals (now UCB Biosciences), Biogen, Eli Lilly, and Amicus Therapeutics; support for attending meetings and travel from Amylyx, Mitsubishi Tanabe Pharma, QurAlis, Alexion, and ALS Pharmaceuticals; has a leadership role in ALS Canada; has stock or stock options in QurAlis; and has received equipment, materials, drugs, medical writing, gifts or other services from Amylyx. LZ reports grants from ALS Canada, Amylyx, Biogen, and Mitsubishi Tanabe Pharma; consulting fees from Amylyx, Cytokinetics, Mitsubishi Tanabe Pharma, Neurosense, and Biogen; and participation in a data safety monitoring board (chair) for Amylyx. CS reports speakers fees from Mitsubishi Tanabe Pharma Canada; participation in an advisory board for Biogen; and unpaid roles in Canadian ALS Research Consortium and Scientific Medical Advisory Board for ALS Canada. CN received compensation for consultant fees and training activities by Biogen, Roche, Genzyme, and Mitsubishi Tanabe. JMS reports grants from NINDS, ALS Association, AB Sciences, Acorda Therapeutics, Alector, Amylyx, Biogen, Cytokinetics Incorporated, Ionis, Mitsubishi Tanabe Pharma America, Quralis, PTC, Sanofi, Wave, and Myolex; consulting fees from Amylyx, Cytokinetics, Denali, GSK, Mitsubishi Tanabe Pharma America, Neurosense, Orthogonal, Pinteon, RRD, Acurastem, Revalasio, Apellis, Novartis, Sanofi, and Immunity Pharma; participation in data safety monitoring boards or advisory boards for Swanbio and Braingate; and stock or stock options in Aural Analytics. MRT reports salary support from the Motor Neurone Disease Association; royalties or licences from Oxford University Press, Oneworld, and Karger; speakers' honoraria from University of Miami; and participation in advisory board for Biogen and Novartis. JW reports grants from the National Institutes of Health, the Muscular Dystrophy Association, and the ALS Association. TH, MAG, TB, RB, HD, and CS are previous employees of Orphazyme. MK-K reports research support from the JPND by the National Center for Research and Development, and from E-Rare by the National Science Center of Poland. MK-K also reports paid consulting fees from Amylyx, Ferrer, and Cytokinetics. All other authors declare no competing interests., (Copyright © 2024 Elsevier Ltd. All rights reserved, including those for text and data mining, AI training, and similar technologies.)

Background: Inclusion body myositis is the most common progressive muscle wasting disease in people older than 50 years, with no effective drug treatment. Arimoclomol is an oral co-inducer of the cellular heat shock response that was safe and well-tolerated in a pilot study of inclusion body myositis, reduced key pathological markers of inclusion body myositis in two in-vitro models representing degenerative and inflammatory components of this disease, and improved disease pathology and muscle function in mutant valosin-containing protein mice. In the current study, we aimed to assess the safety, tolerability, and efficacy of arimoclomol in people with inclusion body myositis., Methods: This multicentre, randomised, double-blind, placebo-controlled study enrolled adults in specialist neuromuscular centres in the USA (11 centres) and UK (one centre). Eligible participants had a diagnosis of inclusion body myositis fulfilling the European Neuromuscular Centre research diagnostic criteria 2011. Participants were randomised (1:1) to receive either oral arimoclomol 400 mg or matching placebo three times daily (1200 mg/day) for 20 months. The randomisation sequence was computer generated centrally using a permuted block algorithm with randomisation numbers masked to participants and trial staff, including those assessing outcomes. The primary endpoint was the change from baseline to month 20 in the Inclusion Body Myositis Functional Rating Scale (IBMFRS) total score, assessed in all randomly assigned participants, except for those who were randomised in error and did not receive any study medication, and those who did not meet inclusion criteria. Safety analyses included all randomly assigned participants who received at least one dose of study medication. This trial is registered with ClinicalTrials.gov, number NCT02753530, and is completed., Findings: Between Aug 16, 2017 and May 22, 2019, 152 participants with inclusion body myositis were randomly assigned to arimoclomol (n=74) or placebo (n=78). One participant was randomised in error (to arimoclomol) but not treated, and another (assigned to placebo) did not meet inclusion criteria. 150 participants (114 [76%] male and 36 [24%] female) were included in the efficacy analyses, 73 in the arimoclomol group and 77 in the placebo group. 126 completed the trial on treatment (56 [77%] and 70 [90%], respectively) and the most common reason for treatment discontinuation was adverse events. At month 20, mean IBMFRS change from baseline was not statistically significantly different between arimoclomol and placebo (-3·26, 95% CI -4·15 to -2·36 in the arimoclomol group vs -2·26, -3·11 to -1·41 in the placebo group; mean difference -0·99 [95% CI -2·23 to 0·24]; p=0·12). Adverse events leading to discontinuation occurred in 13 (18%) of 73 participants in the arimoclomol group and four (5%) of 78 participants in the placebo group. Serious adverse events occurred in 11 (15%) participants in the arimoclomol group and 18 (23%) in the placebo group. Elevated transaminases three times or more of the upper limit of normal occurred in five (7%) participants in the arimoclomol group and one (1%) in the placebo group. Tubulointerstitial nephritis was observed in one (1%) participant in the arimoclomol group and none in the placebo group., Interpretation: Arimoclomol did not improve efficacy outcomes, relative to placebo, but had an acceptable safety profile in individuals with inclusion body myositis. This is one of the largest trials done in people with inclusion body myositis, providing data on disease progression that might be used for subsequent clinical trial design., Funding: US Food and Drug Administration Office of Orphan Products Development and Orphazyme., Competing Interests: Declaration of interests PMM has received consulting fees and funding support from Orphazyme, paid to his academic institution (University College London) for the oversight and conduct of this study, and has also received honoraria from Abbvie, Bristol Myers Squibb, Celgene, Eli Lilly, Galapagos, Janssen, MSD, Novartis, Pfizer, Roche, and UCB. MPM has received research funding from the US National Institutes of Health (NIH), the US Food and Drug Administration, Cure SMA, and PTC Therapeutics; received consulting fees from NeuroDerm and Fulcrum Therapeutics; and served on data and safety monitoring boards for NIH, Eli Lilly and Company, Catabasis Pharmaceuticals, Vaccinex, Neurocrine Biosciences, Voyager Therapeutics, Prilenia Therapeutics Development, ReveraGen BioPharma, and NS Pharma. TB, CS, AR, TDC, KB, ANJ, and KP are previous employees of Orphazyme. MF has received consulting fees from UCB, Argenx, Alexion, and CSL Behring; and research support paid to her institution (Ohio State University) from UCB, Argenx, Alexion, Fulcrum, Avidity, Pharnext, Janssen, and Roche. TEL has served as a consultant for Aavogen, Abata Therapeutics, Abcuro, Acceleron, DrenBio, EMD Serano, Kezar Life Sciences, Ono Pharma, Orphazyme, Regenacy, Sarepta, and Takeda; DSMB was Chair of the data and safety monitoring board for a Pharnext-sponsored clinical trial; and received research support from the National Institute of Arthritis and Musculoskeletal and Skin Diseases of the NIH (R01 AR076390), the Muscular Dystrophy Association (MDA630399), Horizon Therapeutics, and The Peter and Carmen Lucia Buck Foundation. TM has served as an advisor to Alexion (AstraZeneca), Amicus, AnnJi, Argenx, Arvinas, Ask-Bio, Audentes (now Astellas Gene Therapy), Horizon Therapeutics, Maze Therapeutics, Momenta (now Janssen), Sanofi, Sarepta, Spark Therapeutics, UCB/Ra Pharmaceuticals, and Modis/Zogenix (now UCB); has served on the speaker's bureau for Sanofi-Genzyme, Alexion, and Argenx; has served on the medical advisory board for the Myositis Association, Neuromuscular Disease Foundation, Myasthenia Gravis Foundation of California, and Myasthenia Gravis Foundation of America; has received research funding from the Myositis Association, the Muscular Dystrophy Association, NIH, and from the following commercial sponsors: Alexion, Amicus, AnnJi, Argenx, Audentes/Astellas Gene Therapy, Bristol Myers Squibb, Cartesian Therapeutics, Grifols, ML-Bio, Momenta, Ra Pharmaceuticals, Sanofi, Spark Therapeutics, UCB, and Valerion; and he serves on the data safety monitoring boards for Acceleron, Avexis, Sarepta, and NIH. RJB has received funding from the FDA Office Orphan Products Development grant for his role in this study. MGH receives research funding from the Medical Research Council UK and has previously acted as a consultant for Novartis and Orphazyme. MMD is a consultant for Orphazyme and received funding support, paid to his academic institution (University of Kansas Medical Center, Research Institute), from Orphazyme for the oversight and conduct of this study. He also serves or recently served as a consultant for Abcuro, Amazentis, ArgenX, Astellas, Catalyst, Cello, Covance/Labcorp, CSL-Behring, EcoR1, Janssen, Kezar, MDA, Medlink, Momenta, NuFactor, Octapharma, Priovant, RaPharma/UCB, Roivant Sciences, Sanofi Genzyme, Shire Takeda, Scholar Rock, Spark Therapeutics, Abata/Third Rock, UCB Biopharma and received research grants or contracts or educational grants from Alexion, Alnylam Pharmaceuticals, Amicus, Biomarin, Bristol Myers Squibb, Catalyst, Corbus, CSL-Behring, FDA Office of Orphan Products Development, GlaxoSmithKline, Genentech, Grifols, Kezar, Mitsubishi Tanabe Pharma, Muscular Dystrophy Association, NIH, Novartis, Octapharma, Orphazyme, Ra Pharma/UCB, Sanofi Genzyme, Sarepta Therapeutics, Shire Takeda, Spark Therapeutics, The Myositis Association, Ra Pharma/UCB, Viromed/Healixmith, and The Myositis Association. All other authors declare no competing interests., (Copyright © 2023 The Author(s). Published by Elsevier Ltd. This is an Open Access article under the CC BY 4.0 license. Published by Elsevier Ltd.. All rights reserved.)

Background: Lipoprotein lipase (LPL) deficiency is a serious lipid disorder of severe hypertriglyceridemia (SHTG) with chylomicronemia. A large number of variants in the LPL gene have been reported but their influence on LPL activity and SHTG has not been completely analyzed. Gaining insight into the deleterious effect of the mutations is clinically essential., Methods: We used gene sequencing followed by in-vivo/in-vitro and in-silico tools for classification. We classified 125 rare LPL mutations in 33 subjects thought to have LPL deficiency and in 314 subjects selected for very SHTG., Results: Of the 33 patients thought to have LPL deficiency, only 13 were homozygous or compound heterozygous for deleterious mutations in the LPL gene. Among the 314 very SHTG patients, 3 were compound heterozygous for pathogenic mutants. In a third group of 51,467 subjects, from a general population, carriers of common variants, Asp9Asn and Asn291Ser, were associated with mild increase in triglyceride levels (11%-35%)., Conclusion: In total, 39% of patients clinically diagnosed as LPL deficient had 2 deleterious variants. Three patients selected for very SHTG had LPL deficiency. The deleterious mutations associated with LPL deficiency will assist in the diagnosis and selection of patients as candidates for the presently approved LPL gene therapy., (Copyright © 2016 National Lipid Association. Published by Elsevier Inc. All rights reserved.)

Objective: Tesofensine is a novel triple monoamine reuptake inhibitor which is in development for the treatment of obesity. Preclinical and clinical data suggest that appetite suppression is an important mechanism by which tesofensine exerts its robust weight reducing effect. Notably, the strong hypophagic response to tesofensine treatment is demonstrated to be linked to central stimulation of noradrenergic and dopaminergic neurotransmission. The sympathomimetic mode of action of tesofensine may also associate with the elevated heart rate and blood pressure observed in clinical settings, and we therefore sought experimentally to address this issue., Design and Methods: The anorexigenic and cardiovascular effects of tesofensine were studied simultaneously in telemetrized conscious rats in a combined real-time food intake and cardiovascular telemetry monitoring system., Results: Acute administration of tesofensine caused a dose-dependent hypophagic effect as well as increased heart rate and blood pressure. Interestingly, combined treatment with metoprolol (b1 adrenoceptor blocker, 10-20 mg/kg, p.o.) fully prevented the cardiovascular sympathetic effects of tesofensine while leaving the robust inhibitory efficacy on food intake unaffected. Similarly, the angiotensin AT1 receptor antagonist telmisartan (1.0-3.0 mg/kg, p.o.) did not interfere with the anti-obesity effects of tesofensine, however, telmisartan only partially reversed the increase in systolic blood pressure and had no effect on the elevated heart rate induced by tesofensine., Conclusion: These data suggests that tesofensine causes elevations in heart rate and blood pressure by increasing sympathetic activity, and that different adrenoceptor subtypes may be responsible for the anti-obesity and cardiovascular effects of tesofensine., (Copyright © 2012 The Obesity Society.)