Rapamycin for inclusion body myositis: targeting non-inflammatory mechanisms

Rapamycin for inclusion body myositis: targeting non-inflammatory mechanisms Inclusion body myositis (IBM) is an acquired myopathy usually occurring in those aged >50 years and with a prevalence of 33 cases per million. While conventionally grouped with the idiopathic inflammatory myopathies, IBM has several unique clinical and pathological characteristics. Muscle inflammation is a prominent feature, but the disease is resistant to treatment with routine immunosuppressive therapies, none of which have demonstrated sustained therapeutic benefits. Disease progression is characterised by an accumulation of degenerative change in skeletal muscle, including misfolded protein aggregates and rimmed vacuoles. The exact sequence of events that culminate in severely disabling muscle atrophy is the subject of intense debate and the lack of effective treatment represents a significant unmet need for sufferers [1]. There has been a shift away from targeting immunosuppressive and immunomodulatory pathways and towards alternative damage-inducing mechanisms. Encouraging signals have been demonstrated in several small-scale studies, although a robust demonstration of long-term effects modifying the relentless accumulation of disability has not yet been forthcoming. For example, despite promising pilot work [2], a recently completed large phase 2b/3 multicentre study of the activin receptor inhibitor bimagrumab did not meet its primary end point [change in 6-min walking distance (6MWD)] (ClinicalTrials.gov Identifier: NCT01925209). It is postulated that meaningful differences between the groups were not detected due to the primary outcome measure chosen being insensitive to the disability observed in patients with IBM, rather than because of a failure of the treatment per se. In order to avoid similar failures, highly sensitive surrogate outcome measures, such as the rate of accumulation of fatty change on muscle MRI, are likely to be increasingly used in future clinical trials [3]. Such practice may permit conduct of well-powered clinical trials with fewer participants and over shorter duration, although acceptance of such measures by the regulatory authorities is a hurdle not yet overcome. Additionally, if the use of highly targeted therapies is to increase, specific diagnostic criteria for the disease in question are required. While these do exist for IBM, it is noted that such criteria require the demonstration of particular patterns of muscle weakness [4]. Assuming the onset of muscle weakness occurs as the final and irreversible consequence of disease, alternative diagnostic tools might be required to facilitate earlier diagnosis and commencement of treatment prior to onset of significant muscle weakness. Two drugs with novel non-inflammatory mechanisms of action are currently being evaluated for the treatment of IBM. The first, arimoclomol, co-induces the heat shock response by prolonging activation of heat shock factor-1. HSPs act as chaperone molecules in protein homeostasis by promoting normal protein folding. Upregulation of the HSP pathway has the potential to promote normalization of protein handling within muscle and prevent ongoing activation of damage-inducing mechanisms in IBM muscle. In a recent double-blind, placebo-controlled phase 2a study, 24 patients with IBM were randomized to arimoclomol or placebo (2: 1 ratio). Safety and promising therapeutic signals were demonstrated and a larger scale phase 2/3 study has recently started recruitment (ClinicalTrials.gov Identifier: NCT02753530) [5]. The second is rapamycin (sirolimus), which seeks to restore aberrant autophagic (protein degradation) pathways evident in IBM muscle by inhibiting the mechanistic target of rapamycin (mTOR), a protein kinase that regulates several intracellular processes including survival, protein synthesis and autophagy. Rapamycin also has immunosuppressive effects mediated via inhibition of IL-2 signalling and as such is used to prevent rejection after organ transplant. Variable results have been encountered in pre-clinical work using rapamycin in IBM mouse models that overexpress valosin containing protein to induce an IBM-like state [6, 7]. Despite this, a recent study presented at the ACR 2017 meeting has stimulated further interest of use of this compound for the treatment of IBM [8]. In this prospective, randomized, double blind, placebo-controlled phase 2b trial conducted at Pitié-Salpêtrière University Hospital (Paris, France), 22 patients received oral Rapamycin and 22 received placebo over a 12-month period. Quadriceps strength using quantitative muscle testing was chosen as the primary outcome measure, with 6MWD and various other measures being used as secondary outcomes. Interestingly, while no difference in the primary outcome was identified at 12 months (mean relative change: −11.07% vs −12.36%), significantly less fatty replacement of muscle in the quadriceps and hamstrings was observed in the actively treated arm. Additionally, those receiving rapamycin showed less pronounced loss of contractile cross-sectional area in the quadriceps. Quite why these apparent effects did not translate into a significant measurable difference in quadriceps strength remains uncertain, especially as significant beneficial effects were also observed on 6MWD, the IBM weakness composite index and the forced vital capacity in the actively treated group. An open phase continuation of this study is ongoing to further evaluate these findings. These recent results are encouraging and look to usher in a new dawn of IBM treatments focusing on non-immune mechanisms. This alternative approach reflects the culmination of careful translational research endeavours over several decades. While there are several barriers yet to be overcome, there is hope on the horizon for patients with this severely debilitating condition. Funding: No specific funding was received from any bodies in the public, commercial or not-for-profit sectors to carry out the work described in this manuscript. Disclosure statement: M.B. has been sponsored to attend regional, national and international meetings by Union Chimique Belge (UCB) Celltech, Roche/Chugai, Pfizer, AbbVie, Merck, Mennarini, Janssen, Bristol-Myers Squib, Novartis and Eli-lilly and has received honoraria for speaking and attended advisory boards with Bristol-Myers Squib, UCB Celltech, Roche/Chugai, Pfizer, AbbVie, Merck, Mennarini, Sanofi Aventis, Eli-Lilly, Janssen and Novartis. H.C. has received consulting and educational grant from Novartis. The other author has declare no conflicts of interest. References 1 Benveniste O, Stenzel W, Hilton-Jones D et al.   Amyloid deposits and inflammatory infiltrates in sporadic inclusion body myositis: the inflammatory egg comes before the degenerative chicken. Acta Neuropathol  2015; 129: 611– 24. Google Scholar CrossRef Search ADS PubMed  2 Amato A. a, Sivakumar K, Goyal N et al.   Treatment of sporadic inclusion body myositis with bimagrumab. Neurology  2014; 83: 2239– 46. Google Scholar CrossRef Search ADS PubMed  3 Morrow JM, Sinclair CDJ, Fischmann A et al.   MRI biomarker assessment of neuromuscular disease progression: a prospective observational cohort study. Lancet Neurol  2016; 15: 65– 77. Google Scholar CrossRef Search ADS PubMed  4 Lloyd TE, Mammen AL, Amato AA et al.   Evaluation and construction of diagnostic criteria for inclusion body myositis. Neurology  2014; 83: 426– 33. Google Scholar CrossRef Search ADS PubMed  5 Ahmed M, Machado PM, Miller A et al.   Targeting protein homeostasis in sporadic inclusion body myositis. Sci Transl Med  2016; 8: 331ra41. Google Scholar CrossRef Search ADS PubMed  6 Nalbandian A, Llewellyn KJ, Nguyen C et al.   Rapamycin and chloroquine: the in vitro and in vivo effects of autophagy-modifying drugs show promising results in valosin containing protein multisystem proteinopathy. PLoS One  2015; 10: e0122888. Google Scholar CrossRef Search ADS PubMed  7 Ching JK, Elizabeth SV, Ju J-S et al.   mTOR dysfunction contributes to vacuolar pathology and weakness in valosin-containing protein associated inclusion body myopathy. Hum Mol Genet  2013; 22: 1167– 79. Google Scholar CrossRef Search ADS PubMed  8 Benveniste O, Hogrel J, Annoussamy M et al.   Rapamycin vs. placebo for the treatment of inclusion body myositis: improvement of the 6 min walking distance, a functional scale, the FVC and muscle quantitative MRI [abstract]. Arthritis Rheumatol  2017; 69(Suppl S10):5L. © The Author(s) 2018. Published by Oxford University Press on behalf of the British Society for Rheumatology. All rights reserved. For Permissions, please email: journals.permissions@oup.com http://www.deepdyve.com/assets/images/DeepDyve-Logo-lg.png Rheumatology Oxford University Press

Rapamycin for inclusion body myositis: targeting non-inflammatory mechanisms

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Oxford University Press
Copyright
© The Author(s) 2018. Published by Oxford University Press on behalf of the British Society for Rheumatology. All rights reserved. For Permissions, please email: journals.permissions@oup.com
ISSN
1462-0324
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1462-0332
D.O.I.
10.1093/rheumatology/key043
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Abstract

Inclusion body myositis (IBM) is an acquired myopathy usually occurring in those aged >50 years and with a prevalence of 33 cases per million. While conventionally grouped with the idiopathic inflammatory myopathies, IBM has several unique clinical and pathological characteristics. Muscle inflammation is a prominent feature, but the disease is resistant to treatment with routine immunosuppressive therapies, none of which have demonstrated sustained therapeutic benefits. Disease progression is characterised by an accumulation of degenerative change in skeletal muscle, including misfolded protein aggregates and rimmed vacuoles. The exact sequence of events that culminate in severely disabling muscle atrophy is the subject of intense debate and the lack of effective treatment represents a significant unmet need for sufferers [1]. There has been a shift away from targeting immunosuppressive and immunomodulatory pathways and towards alternative damage-inducing mechanisms. Encouraging signals have been demonstrated in several small-scale studies, although a robust demonstration of long-term effects modifying the relentless accumulation of disability has not yet been forthcoming. For example, despite promising pilot work [2], a recently completed large phase 2b/3 multicentre study of the activin receptor inhibitor bimagrumab did not meet its primary end point [change in 6-min walking distance (6MWD)] (ClinicalTrials.gov Identifier: NCT01925209). It is postulated that meaningful differences between the groups were not detected due to the primary outcome measure chosen being insensitive to the disability observed in patients with IBM, rather than because of a failure of the treatment per se. In order to avoid similar failures, highly sensitive surrogate outcome measures, such as the rate of accumulation of fatty change on muscle MRI, are likely to be increasingly used in future clinical trials [3]. Such practice may permit conduct of well-powered clinical trials with fewer participants and over shorter duration, although acceptance of such measures by the regulatory authorities is a hurdle not yet overcome. Additionally, if the use of highly targeted therapies is to increase, specific diagnostic criteria for the disease in question are required. While these do exist for IBM, it is noted that such criteria require the demonstration of particular patterns of muscle weakness [4]. Assuming the onset of muscle weakness occurs as the final and irreversible consequence of disease, alternative diagnostic tools might be required to facilitate earlier diagnosis and commencement of treatment prior to onset of significant muscle weakness. Two drugs with novel non-inflammatory mechanisms of action are currently being evaluated for the treatment of IBM. The first, arimoclomol, co-induces the heat shock response by prolonging activation of heat shock factor-1. HSPs act as chaperone molecules in protein homeostasis by promoting normal protein folding. Upregulation of the HSP pathway has the potential to promote normalization of protein handling within muscle and prevent ongoing activation of damage-inducing mechanisms in IBM muscle. In a recent double-blind, placebo-controlled phase 2a study, 24 patients with IBM were randomized to arimoclomol or placebo (2: 1 ratio). Safety and promising therapeutic signals were demonstrated and a larger scale phase 2/3 study has recently started recruitment (ClinicalTrials.gov Identifier: NCT02753530) [5]. The second is rapamycin (sirolimus), which seeks to restore aberrant autophagic (protein degradation) pathways evident in IBM muscle by inhibiting the mechanistic target of rapamycin (mTOR), a protein kinase that regulates several intracellular processes including survival, protein synthesis and autophagy. Rapamycin also has immunosuppressive effects mediated via inhibition of IL-2 signalling and as such is used to prevent rejection after organ transplant. Variable results have been encountered in pre-clinical work using rapamycin in IBM mouse models that overexpress valosin containing protein to induce an IBM-like state [6, 7]. Despite this, a recent study presented at the ACR 2017 meeting has stimulated further interest of use of this compound for the treatment of IBM [8]. In this prospective, randomized, double blind, placebo-controlled phase 2b trial conducted at Pitié-Salpêtrière University Hospital (Paris, France), 22 patients received oral Rapamycin and 22 received placebo over a 12-month period. Quadriceps strength using quantitative muscle testing was chosen as the primary outcome measure, with 6MWD and various other measures being used as secondary outcomes. Interestingly, while no difference in the primary outcome was identified at 12 months (mean relative change: −11.07% vs −12.36%), significantly less fatty replacement of muscle in the quadriceps and hamstrings was observed in the actively treated arm. Additionally, those receiving rapamycin showed less pronounced loss of contractile cross-sectional area in the quadriceps. Quite why these apparent effects did not translate into a significant measurable difference in quadriceps strength remains uncertain, especially as significant beneficial effects were also observed on 6MWD, the IBM weakness composite index and the forced vital capacity in the actively treated group. An open phase continuation of this study is ongoing to further evaluate these findings. These recent results are encouraging and look to usher in a new dawn of IBM treatments focusing on non-immune mechanisms. This alternative approach reflects the culmination of careful translational research endeavours over several decades. While there are several barriers yet to be overcome, there is hope on the horizon for patients with this severely debilitating condition. Funding: No specific funding was received from any bodies in the public, commercial or not-for-profit sectors to carry out the work described in this manuscript. Disclosure statement: M.B. has been sponsored to attend regional, national and international meetings by Union Chimique Belge (UCB) Celltech, Roche/Chugai, Pfizer, AbbVie, Merck, Mennarini, Janssen, Bristol-Myers Squib, Novartis and Eli-lilly and has received honoraria for speaking and attended advisory boards with Bristol-Myers Squib, UCB Celltech, Roche/Chugai, Pfizer, AbbVie, Merck, Mennarini, Sanofi Aventis, Eli-Lilly, Janssen and Novartis. H.C. has received consulting and educational grant from Novartis. The other author has declare no conflicts of interest. References 1 Benveniste O, Stenzel W, Hilton-Jones D et al.   Amyloid deposits and inflammatory infiltrates in sporadic inclusion body myositis: the inflammatory egg comes before the degenerative chicken. Acta Neuropathol  2015; 129: 611– 24. Google Scholar CrossRef Search ADS PubMed  2 Amato A. a, Sivakumar K, Goyal N et al.   Treatment of sporadic inclusion body myositis with bimagrumab. Neurology  2014; 83: 2239– 46. Google Scholar CrossRef Search ADS PubMed  3 Morrow JM, Sinclair CDJ, Fischmann A et al.   MRI biomarker assessment of neuromuscular disease progression: a prospective observational cohort study. Lancet Neurol  2016; 15: 65– 77. Google Scholar CrossRef Search ADS PubMed  4 Lloyd TE, Mammen AL, Amato AA et al.   Evaluation and construction of diagnostic criteria for inclusion body myositis. Neurology  2014; 83: 426– 33. Google Scholar CrossRef Search ADS PubMed  5 Ahmed M, Machado PM, Miller A et al.   Targeting protein homeostasis in sporadic inclusion body myositis. Sci Transl Med  2016; 8: 331ra41. Google Scholar CrossRef Search ADS PubMed  6 Nalbandian A, Llewellyn KJ, Nguyen C et al.   Rapamycin and chloroquine: the in vitro and in vivo effects of autophagy-modifying drugs show promising results in valosin containing protein multisystem proteinopathy. PLoS One  2015; 10: e0122888. Google Scholar CrossRef Search ADS PubMed  7 Ching JK, Elizabeth SV, Ju J-S et al.   mTOR dysfunction contributes to vacuolar pathology and weakness in valosin-containing protein associated inclusion body myopathy. Hum Mol Genet  2013; 22: 1167– 79. Google Scholar CrossRef Search ADS PubMed  8 Benveniste O, Hogrel J, Annoussamy M et al.   Rapamycin vs. placebo for the treatment of inclusion body myositis: improvement of the 6 min walking distance, a functional scale, the FVC and muscle quantitative MRI [abstract]. Arthritis Rheumatol  2017; 69(Suppl S10):5L. © The Author(s) 2018. Published by Oxford University Press on behalf of the British Society for Rheumatology. All rights reserved. For Permissions, please email: journals.permissions@oup.com

Journal

RheumatologyOxford University Press

Published: Feb 26, 2018

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