Safety and tolerability of Triumeq in amyotrophic lateral sclerosis: the Lighthouse trial

Julian Gold; Dominic B. Rowe; Matthew C. Kiernan; Steve Vucic; Susan Mathers; Ruben P.A. van Eijk; Avindra Nath; Marta Garcia Montojo; Gina Norato; Ulisses A. Santamaria; Mary Louise Rogers; Andrea Malaspina; Vittoria Lombardi; Puja R. Mehta; Henk Jan Westeneng; Leonard H. van den Berg; Ammar Al-Chalabi

doi:10.1080/21678421.2019.1632899

Safety and tolerability of Triumeq in amyotrophic lateral sclerosis: the Lighthouse trial

Julian Gold, Dominic B. Rowe, Matthew C. Kiernan, Steve Vucic, Susan Mathers, Ruben P.A. van Eijk, Avindra Nath, Marta Garcia Montojo, Gina Norato, Ulisses A. Santamaria, Mary Louise Rogers, Andrea Malaspina, Vittoria Lombardi, Puja R. Mehta, Henk Jan Westeneng, Leonard H. van den Berg, Ammar Al-Chalabi

Flinders University

Research output: Contribution to journal › Article › peer-review

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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 p75^ECD 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 There were no drug-related serious adverse events; one patient was withdrawn from the study due to a drug-associated increase in liver enzymes.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 p75^ECD 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.

Original language	English
Pages (from-to)	595-604
Number of pages	10
Journal	Amyotrophic Lateral Sclerosis and Frontotemporal Degeneration
Volume	20
Issue number	7-8
Early online date	1 Jul 2019
DOIs	https://doi.org/10.1080/21678421.2019.1632899
Publication status	Published - 2 Oct 2019

Bibliographical note

© 2019 The Author(s). Published by Informa UK Limited, trading as Taylor & Francis Group.
This is an Open Access article distributed under the terms of the Creative Commons Attribution-NonCommercial-NoDerivatives License (http://creativecommons.org/licenses/by-nc-nd/4.0/), which permits non-commercial re-use, distribution, and reproduction in any medium, provided the original work is properly cited, and is not altered, transformed, or built upon in any way.

Keywords

ENCALS prediction model
Human endogenous retrovirus
p75ECD biomarker
Triumeq antiretroviral
ALS and MND

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

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Gold_Safety_P2019Final published version, 909 KBLicence: CC BY-NC-ND

Cite this

Gold, J., Rowe, D. B., Kiernan, M. C., Vucic, S., Mathers, S., van Eijk, R. P. A., Nath, A., Garcia Montojo, M., Norato, G., Santamaria, U. A., Rogers, M. L., Malaspina, A., Lombardi, V., Mehta, P. R., Westeneng, H. J., van den Berg, L. H., & Al-Chalabi, A. (2019). Safety and tolerability of Triumeq in amyotrophic lateral sclerosis: the Lighthouse trial. Amyotrophic Lateral Sclerosis and Frontotemporal Degeneration, 20(7-8), 595-604. https://doi.org/10.1080/21678421.2019.1632899

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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.",

keywords = "ENCALS prediction model, Human endogenous retrovirus, p75ECD biomarker, Triumeq antiretroviral, ALS and MND",

author = "Julian Gold and Rowe, {Dominic B.} and Kiernan, {Matthew C.} and Steve Vucic and Susan Mathers and {van Eijk}, {Ruben P.A.} and Avindra Nath and {Garcia Montojo}, Marta and Gina Norato and Santamaria, {Ulisses A.} and Rogers, {Mary Louise} and Andrea Malaspina and Vittoria Lombardi and Mehta, {Puja R.} and Westeneng, {Henk Jan} and {van den Berg}, {Leonard H.} and Ammar Al-Chalabi",

note = "{\textcopyright} 2019 The Author(s). Published by Informa UK Limited, trading as Taylor & Francis Group. This is an Open Access article distributed under the terms of the Creative Commons Attribution-NonCommercial-NoDerivatives License (http://creativecommons.org/licenses/by-nc-nd/4.0/), which permits non-commercial re-use, distribution, and reproduction in any medium, provided the original work is properly cited, and is not altered, transformed, or built upon in any way. ",

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Gold, J, Rowe, DB, Kiernan, MC, Vucic, S, Mathers, S, van Eijk, RPA, Nath, A, Garcia Montojo, M, Norato, G, Santamaria, UA, Rogers, ML, Malaspina, A, Lombardi, V, Mehta, PR, Westeneng, HJ, van den Berg, LH & Al-Chalabi, A 2019, 'Safety and tolerability of Triumeq in amyotrophic lateral sclerosis: the Lighthouse trial', Amyotrophic Lateral Sclerosis and Frontotemporal Degeneration, vol. 20, no. 7-8, pp. 595-604. https://doi.org/10.1080/21678421.2019.1632899

TY - JOUR

T1 - Safety and tolerability of Triumeq in amyotrophic lateral sclerosis

T2 - the Lighthouse trial

AU - Gold, Julian

AU - Rowe, Dominic B.

AU - Kiernan, Matthew C.

AU - Vucic, Steve

AU - Mathers, Susan

AU - van Eijk, Ruben P.A.

AU - Nath, Avindra

AU - Garcia Montojo, Marta

AU - Norato, Gina

AU - Santamaria, Ulisses A.

AU - Rogers, Mary Louise

AU - Malaspina, Andrea

AU - Lombardi, Vittoria

AU - Mehta, Puja R.

AU - Westeneng, Henk Jan

AU - van den Berg, Leonard H.

AU - Al-Chalabi, Ammar

N1 - © 2019 The Author(s). Published by Informa UK Limited, trading as Taylor & Francis Group. This is an Open Access article distributed under the terms of the Creative Commons Attribution-NonCommercial-NoDerivatives License (http://creativecommons.org/licenses/by-nc-nd/4.0/), which permits non-commercial re-use, distribution, and reproduction in any medium, provided the original work is properly cited, and is not altered, transformed, or built upon in any way.

PY - 2019/10/2

Y1 - 2019/10/2

N2 - 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.

AB - 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.

KW - ENCALS prediction model

KW - Human endogenous retrovirus

KW - p75ECD biomarker

KW - Triumeq antiretroviral

KW - ALS and MND

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ER -

Safety and tolerability of Triumeq in amyotrophic lateral sclerosis: the Lighthouse trial

Abstract

Bibliographical note

Keywords

UN SDGs

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