Julian Gold1,2,3, Dominic B Rowe4, Matthew C Kiernan5, Steve Vucic6, Susan Mathers7, Ruben P A van Eijk8, Avindra Nath9, Marta Garcia Montojo9, Gina Norato9, Ulisses A Santamaria9, Mary-Louise Rogers10, Andrea Malaspina3, Vittoria Lombardi3, Puja R Mehta2, Henk-Jan Westeneng8, Leonard H van den Berg8, Ammar Al-Chalabi2. 1. Prince of Wales Hospital, The Albion Centre and Faculty of Medicine and Health, The University of Sydney , Australia. 2. King's College London, Maurice Wohl Clinical Neuroscience Institute, Department of Basic and Clinical Neuroscience , London , United Kingdom. 3. Blizard Institute, Queen Mary University of London , London , United Kingdom. 4. Faculty of Medicine and Health Sciences, Macquarie University , Sydney , Australia. 5. Brain and Mind Centre, University of Sydney and Department of Neurology, Royal Prince Alfred Hospital , Sydney , Australia. 6. Department of Neurology, Westmead Hospital , Sydney , Australia. 7. Department of Neurology, Calvary Health Care Bethlehem , Melbourne , Australia. 8. Department of Neurology, University Medical Centre Utrecht , Utrecht , Netherlands. 9. National Institute of Neurological Disorders and Stroke, Section of Infections of the Nervous System , Bethesda , MD , USA. 10. Centre for Neuroscience, Faculty of Medicine and Public Health, Flinders University , Adelaide , Australia.
Abstract
Background: Neuroinflammation and human endogenous retroviruses (HERV) are thought to have a role in the pathophysiology of amyotrophic lateral sclerosis (ALS). Therapy directed against endogenous retroviruses has demonstrated positive effects during in vitro and biomarker studies. Consequently, the present study was undertaken to assess the safety and tolerability of long-term antiretroviral therapy (ART), Triumeq (abacavir, lamivudine, and dolutegravir) exposure in patients with ALS, and efficacy against biomarkers of disease progression. Methods: Patients were observed during a 10-week lead-in period before receiving Triumeq treatment for 24 weeks at four specialist ALS centers. The primary outcomes were safety and tolerability. Secondary outcomes included HERV-K expression levels, urinary p75ECD levels, neurophysiological parameters, and clinical indicators. The ENCALS prediction model was applied to provide an estimate of the cohort survival. The trial was registered (NCT02868580). Findings: 40 patients with ALS received Triumeq and 35 (88%) completed treatment. There were no drug-related serious adverse events; one patient was withdrawn from the study due to a drug-associated increase in liver enzymes. A favorable response on HERV-K expression levels was observed, accompanied by a decline in ALSFRS-R progression rate of 21.8% (95% CI -4.8%-48.6%) and the amount of urinary p75ECD measured. One patient died five months after stopping treatment, while five were expected to have died during the treatment period (interquartile range 2-8). Interpretation: Long-term Triumeq exposure was safe and well tolerated in this cohort. There was suggestive indication for a possible biological response in some pharmacodynamic and clinical biomarkers. A larger international phase 3 trial will be deployed to assess the effect of Triumeq on overall survival and disease progression. Funding: Funding was provided by the FightMND Foundation; MND Research Institute of Australia; MND Association, United Kingdom, and GSK. ViiV Healthcare provided the Triumeq.
Background: Neuroinflammation and human endogenous retroviruses (HERV) are thought to have a role in the pathophysiology of amyotrophic lateral sclerosis (ALS). Therapy directed against endogenous retroviruses has demonstrated positive effects during in vitro and biomarker studies. Consequently, the present study was undertaken to assess the safety and tolerability of long-term antiretroviral therapy (ART), Triumeq (abacavir, lamivudine, and dolutegravir) exposure in patients with ALS, and efficacy against biomarkers of disease progression. Methods: Patients were observed during a 10-week lead-in period before receiving Triumeq treatment for 24 weeks at four specialist ALS centers. The primary outcomes were safety and tolerability. Secondary outcomes included HERV-K expression levels, urinary p75ECD levels, neurophysiological parameters, and clinical indicators. The ENCALS prediction model was applied to provide an estimate of the cohort survival. The trial was registered (NCT02868580). Findings: 40 patients with ALS received Triumeq and 35 (88%) completed treatment. There were no drug-related serious adverse events; one patient was withdrawn from the study due to a drug-associated increase in liver enzymes. A favorable response on HERV-K expression levels was observed, accompanied by a decline in ALSFRS-R progression rate of 21.8% (95% CI -4.8%-48.6%) and the amount of urinary p75ECD measured. One patient died five months after stopping treatment, while five were expected to have died during the treatment period (interquartile range 2-8). Interpretation: Long-term Triumeq exposure was safe and well tolerated in this cohort. There was suggestive indication for a possible biological response in some pharmacodynamic and clinical biomarkers. A larger international phase 3 trial will be deployed to assess the effect of Triumeq on overall survival and disease progression. Funding: Funding was provided by the FightMND Foundation; MND Research Institute of Australia; MND Association, United Kingdom, and GSK. ViiV Healthcare provided the Triumeq.
Entities:
Keywords:
ALS and MND; ENCALS prediction model; Human endogenous retrovirus; Triumeq antiretroviral; p75ECD biomarker
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Authors: M Garcia-Montojo; S Fathi; G Norato; B R Smith; D B Rowe; M C Kiernan; S Vucic; S Mathers; R P A van Eijk; U Santamaria; M-L Rogers; A Malaspina; V Lombardi; P R Mehta; H-J Westeneng; L H van den Berg; A Al-Chalabi; J Gold; A Nath Journal: J Neurol Sci Date: 2021-02-23 Impact factor: 3.181
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