Safety, tolerability, and preliminary efficacy of an IGF-1 mimetic in patients with spinal and bulbar muscular atrophy: a randomised, placebo-controlled trial

Christopher Grunseich; Ram Miller; Therese Swan; David J. Glass; Mohamed El Mouelhi; Mara Fornaro; Olivier Petricoul; Igor Vostiar; Ronenn Roubenoff; Matthew N. Meriggioli; Angela Kokkinis; Robert D. Guber; Maher S. Budron; John Vissing; Gianni Soraru; Tahseen Mozaffar; Albert Ludolph; John T. Kissel; Kenneth H. Fischbeck; Christopher Grunseich; Ram Miller; Therese Swan; David J. Glass; Mohamed El Mouelhi; Mara Fornaro; Olivier Petricoul; Igor Vostiar; Ronenn Roubenoff; Matthew N. Meriggioli; Julia Dahlqvist; Nanna Witting; John Vissing; Ilaria Martinelli; Giorgia Querin; Gianni Soraru; Namita A. Goyal; Tiyonnoh M. Cash; Brian Minton; Tahseen Mozaffar; Angela Rosenbohm; Ulrike Weiland; Patrick Weydt; Albert Ludolph; Sharon Chelnick; Stanley Iyadurai; Wendy King; John T. Kissel; Maher S. Budron; Robert D. Guber; Angela Kokkinis

doi:10.1016/S1474-4422(18)30320-X

Safety, tolerability, and preliminary efficacy of an IGF-1 mimetic in patients with spinal and bulbar muscular atrophy: a randomised, placebo-controlled trial

Christopher Grunseich, Ram Miller, Therese Swan, David J. Glass, Mohamed El Mouelhi, Mara Fornaro, Olivier Petricoul, Igor Vostiar, Ronenn Roubenoff, Matthew N. Meriggioli, Angela Kokkinis, Robert D. Guber, Maher S. Budron, John Vissing, Gianni Soraru, Tahseen Mozaffar, Albert Ludolph, John T. Kissel, Kenneth H. Fischbeck, Christopher GrunseichRam Miller, Therese Swan, David J. Glass, Mohamed El Mouelhi, Mara Fornaro, Olivier Petricoul, Igor Vostiar, Ronenn Roubenoff, Matthew N. Meriggioli, Julia Dahlqvist, Nanna Witting, John Vissing, Ilaria Martinelli, Giorgia Querin, Gianni Soraru, Namita A. Goyal, Tiyonnoh M. Cash, Brian Minton, Tahseen Mozaffar, Angela Rosenbohm, Ulrike Weiland, Patrick Weydt, Albert Ludolph, Sharon Chelnick, Stanley Iyadurai, Wendy King, John T. Kissel, Maher S. Budron, Robert D. Guber, Angela Kokkinis

Department of Clinical Medicine

12 Citations (Scopus)

Abstract

Background: Spinal and bulbar muscular atrophy is an X-linked neuromuscular disease caused by CAG repeat expansion in the androgen receptor gene. Patients with this disease have low concentrations of insulin-like growth factor-1 (IGF-1), and studies of overexpression and administration of IGF-1 showed benefit in a transgenic model; thus the IGF-1 pathway presents as a potential treatment target. We assessed safety, tolerability, and preliminary efficacy of BVS857, an IGF-1 mimetic, in patients with spinal and bulbar muscular atrophy. Methods: In this randomised, double-blind, placebo-controlled trial, we recruited patients from neuromuscular centres in Denmark (Copenhagen), Germany (Ulm), Italy (Padova), and three sites within the USA (Bethesda, MD; Irvine, CA; and Columbus, OH). Eligible patients were 18 years or older with a confirmed genetic diagnosis of spinal and bulbar muscular atrophy, were ambulatory, had symptomatic weakness, and had serum IGF-1 concentrations of 170 ng/mL or lower. Patients were randomly assigned (2:1) to study drug or placebo by a number scheme. Patients, investigators, and study personnel were masked to treatment assignment. After a safety and tolerability assessment with eight patients, BVS857 was administered once a week (0·06 mg/kg intravenously) for 12 weeks. Primary outcome measures were safety, tolerability, and the effects of BVS857 on thigh muscle volume (TMV) measured by MRI. The ratio of TMV at day 85 to baseline was analysed with ANCOVA per protocol. Secondary outcomes of muscle strength and function were measured with the Adult Myopathy Assessment Tool, lean body mass through dual energy x-ray absorptiometry, and BVS857 pharmacokinetics. This trial was registered with ClinicalTrials.gov, NCT02024932. Findings: 31 patients were assessed for eligibility, 27 of whom were randomly assigned to either BVS857 treatment (n=18) or placebo (n=9), and 24 were included in the preliminary efficacy analysis (BVS857 group, n=15; placebo group, n=9). BVS857 was generally safe with no serious adverse events. No significant differences were found in adverse events between the BVS857 and placebo groups. Immunogenicity was detected in 13 (72%) of 18 patients in the BVS857 group, including crossreacting antibodies with neutralising capacity to endogenous IGF-1 in five patients. TMV decreased from baseline to day 85 in the placebo group (–3·4% [–110 cm³]) but not in the BVS857 group (0% [2 cm³]). A significant difference in change in TMV was observed in the BVS857 group versus the placebo group (geometric-mean ratio 1·04 [90% CI 1·01–1·07]; p=0·02). There were no differences between groups in measures of muscle strength and function. Interpretation: TMV remained stable in patients with spinal and bulbar muscular atrophy after being given BVS857 for 12 weeks. The intervention was associated with high incidence of immunogenicity and did not improve muscle strength or function. Additional studies might be needed to assess the efficacy of activating the IGF-1 pathway in this disease. Funding: Novartis Pharmaceuticals and the US National Institutes of Health.

Original language	English
Journal	The Lancet Neurology
Volume	17
Issue number	12
Pages (from-to)	1043-1052
Number of pages	10
ISSN	1474-4422
DOIs	https://doi.org/10.1016/S1474-4422(18)30320-X
Publication status	Published - 2018

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10.1016/S1474-4422(18)30320-X

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Grunseich, C., Miller, R., Swan, T., Glass, D. J., El Mouelhi, M., Fornaro, M., Petricoul, O., Vostiar, I., Roubenoff, R., Meriggioli, M. N., Kokkinis, A., Guber, R. D., Budron, M. S., Vissing, J., Soraru, G., Mozaffar, T., Ludolph, A., Kissel, J. T., Fischbeck, K. H., ... Kokkinis, A. (2018). Safety, tolerability, and preliminary efficacy of an IGF-1 mimetic in patients with spinal and bulbar muscular atrophy: a randomised, placebo-controlled trial. The Lancet Neurology, 17(12), 1043-1052. https://doi.org/10.1016/S1474-4422(18)30320-X

Safety, tolerability, and preliminary efficacy of an IGF-1 mimetic in patients with spinal and bulbar muscular atrophy: a randomised, placebo-controlled trial. / Grunseich, Christopher; Miller, Ram; Swan, Therese et al.
In: The Lancet Neurology, Vol. 17, No. 12, 2018, p. 1043-1052.

Research output: Contribution to journal › Journal article › Research › peer-review

Grunseich, C, Miller, R, Swan, T, Glass, DJ, El Mouelhi, M, Fornaro, M, Petricoul, O, Vostiar, I, Roubenoff, R, Meriggioli, MN, Kokkinis, A, Guber, RD, Budron, MS, Vissing, J, Soraru, G, Mozaffar, T, Ludolph, A, Kissel, JT, Fischbeck, KH, Grunseich, C, Miller, R, Swan, T, Glass, DJ, Mouelhi, ME, Fornaro, M, Petricoul, O, Vostiar, I, Roubenoff, R, Meriggioli, MN, Dahlqvist, J, Witting, N, Vissing, J, Martinelli, I, Querin, G, Soraru, G, Goyal, NA, Cash, TM, Minton, B, Mozaffar, T, Rosenbohm, A, Weiland, U, Weydt, P, Ludolph, A, Chelnick, S, Iyadurai, S, King, W, Kissel, JT, Budron, MS, Guber, RD & Kokkinis, A 2018, 'Safety, tolerability, and preliminary efficacy of an IGF-1 mimetic in patients with spinal and bulbar muscular atrophy: a randomised, placebo-controlled trial', The Lancet Neurology, vol. 17, no. 12, pp. 1043-1052. https://doi.org/10.1016/S1474-4422(18)30320-X

@article{2c6b6c3436f14735946c1f7030ca4fff,

title = "Safety, tolerability, and preliminary efficacy of an IGF-1 mimetic in patients with spinal and bulbar muscular atrophy: a randomised, placebo-controlled trial",

abstract = "Background: Spinal and bulbar muscular atrophy is an X-linked neuromuscular disease caused by CAG repeat expansion in the androgen receptor gene. Patients with this disease have low concentrations of insulin-like growth factor-1 (IGF-1), and studies of overexpression and administration of IGF-1 showed benefit in a transgenic model; thus the IGF-1 pathway presents as a potential treatment target. We assessed safety, tolerability, and preliminary efficacy of BVS857, an IGF-1 mimetic, in patients with spinal and bulbar muscular atrophy. Methods: In this randomised, double-blind, placebo-controlled trial, we recruited patients from neuromuscular centres in Denmark (Copenhagen), Germany (Ulm), Italy (Padova), and three sites within the USA (Bethesda, MD; Irvine, CA; and Columbus, OH). Eligible patients were 18 years or older with a confirmed genetic diagnosis of spinal and bulbar muscular atrophy, were ambulatory, had symptomatic weakness, and had serum IGF-1 concentrations of 170 ng/mL or lower. Patients were randomly assigned (2:1) to study drug or placebo by a number scheme. Patients, investigators, and study personnel were masked to treatment assignment. After a safety and tolerability assessment with eight patients, BVS857 was administered once a week (0·06 mg/kg intravenously) for 12 weeks. Primary outcome measures were safety, tolerability, and the effects of BVS857 on thigh muscle volume (TMV) measured by MRI. The ratio of TMV at day 85 to baseline was analysed with ANCOVA per protocol. Secondary outcomes of muscle strength and function were measured with the Adult Myopathy Assessment Tool, lean body mass through dual energy x-ray absorptiometry, and BVS857 pharmacokinetics. This trial was registered with ClinicalTrials.gov, NCT02024932. Findings: 31 patients were assessed for eligibility, 27 of whom were randomly assigned to either BVS857 treatment (n=18) or placebo (n=9), and 24 were included in the preliminary efficacy analysis (BVS857 group, n=15; placebo group, n=9). BVS857 was generally safe with no serious adverse events. No significant differences were found in adverse events between the BVS857 and placebo groups. Immunogenicity was detected in 13 (72%) of 18 patients in the BVS857 group, including crossreacting antibodies with neutralising capacity to endogenous IGF-1 in five patients. TMV decreased from baseline to day 85 in the placebo group (–3·4% [–110 cm3]) but not in the BVS857 group (0% [2 cm3]). A significant difference in change in TMV was observed in the BVS857 group versus the placebo group (geometric-mean ratio 1·04 [90% CI 1·01–1·07]; p=0·02). There were no differences between groups in measures of muscle strength and function. Interpretation: TMV remained stable in patients with spinal and bulbar muscular atrophy after being given BVS857 for 12 weeks. The intervention was associated with high incidence of immunogenicity and did not improve muscle strength or function. Additional studies might be needed to assess the efficacy of activating the IGF-1 pathway in this disease. Funding: Novartis Pharmaceuticals and the US National Institutes of Health.",

author = "Christopher Grunseich and Ram Miller and Therese Swan and Glass, {David J.} and {El Mouelhi}, Mohamed and Mara Fornaro and Olivier Petricoul and Igor Vostiar and Ronenn Roubenoff and Meriggioli, {Matthew N.} and Angela Kokkinis and Guber, {Robert D.} and Budron, {Maher S.} and John Vissing and Gianni Soraru and Tahseen Mozaffar and Albert Ludolph and Kissel, {John T.} and Fischbeck, {Kenneth H.} and Christopher Grunseich and Ram Miller and Therese Swan and Glass, {David J.} and Mouelhi, {Mohamed El} and Mara Fornaro and Olivier Petricoul and Igor Vostiar and Ronenn Roubenoff and Meriggioli, {Matthew N.} and Julia Dahlqvist and Nanna Witting and John Vissing and Ilaria Martinelli and Giorgia Querin and Gianni Soraru and Goyal, {Namita A.} and Cash, {Tiyonnoh M.} and Brian Minton and Tahseen Mozaffar and Angela Rosenbohm and Ulrike Weiland and Patrick Weydt and Albert Ludolph and Sharon Chelnick and Stanley Iyadurai and Wendy King and Kissel, {John T.} and Budron, {Maher S.} and Guber, {Robert D.} and Angela Kokkinis",

year = "2018",

doi = "10.1016/S1474-4422(18)30320-X",

language = "English",

volume = "17",

pages = "1043--1052",

journal = "The Lancet Neurology",

issn = "1474-4422",

publisher = "TheLancet Publishing Group",

number = "12",

}

TY - JOUR

T1 - Safety, tolerability, and preliminary efficacy of an IGF-1 mimetic in patients with spinal and bulbar muscular atrophy

T2 - a randomised, placebo-controlled trial

AU - Grunseich, Christopher

AU - Miller, Ram

AU - Swan, Therese

AU - Glass, David J.

AU - El Mouelhi, Mohamed

AU - Fornaro, Mara

AU - Petricoul, Olivier

AU - Vostiar, Igor

AU - Roubenoff, Ronenn

AU - Meriggioli, Matthew N.

AU - Kokkinis, Angela

AU - Guber, Robert D.

AU - Budron, Maher S.

AU - Vissing, John

AU - Soraru, Gianni

AU - Mozaffar, Tahseen

AU - Ludolph, Albert

AU - Kissel, John T.

AU - Fischbeck, Kenneth H.

AU - Grunseich, Christopher

AU - Miller, Ram

AU - Swan, Therese

AU - Glass, David J.

AU - Mouelhi, Mohamed El

AU - Fornaro, Mara

AU - Petricoul, Olivier

AU - Vostiar, Igor

AU - Roubenoff, Ronenn

AU - Meriggioli, Matthew N.

AU - Dahlqvist, Julia

AU - Witting, Nanna

AU - Vissing, John

AU - Martinelli, Ilaria

AU - Querin, Giorgia

AU - Soraru, Gianni

AU - Goyal, Namita A.

AU - Cash, Tiyonnoh M.

AU - Minton, Brian

AU - Mozaffar, Tahseen

AU - Rosenbohm, Angela

AU - Weiland, Ulrike

AU - Weydt, Patrick

AU - Ludolph, Albert

AU - Chelnick, Sharon

AU - Iyadurai, Stanley

AU - King, Wendy

AU - Kissel, John T.

AU - Budron, Maher S.

AU - Guber, Robert D.

AU - Kokkinis, Angela

PY - 2018

Y1 - 2018

N2 - Background: Spinal and bulbar muscular atrophy is an X-linked neuromuscular disease caused by CAG repeat expansion in the androgen receptor gene. Patients with this disease have low concentrations of insulin-like growth factor-1 (IGF-1), and studies of overexpression and administration of IGF-1 showed benefit in a transgenic model; thus the IGF-1 pathway presents as a potential treatment target. We assessed safety, tolerability, and preliminary efficacy of BVS857, an IGF-1 mimetic, in patients with spinal and bulbar muscular atrophy. Methods: In this randomised, double-blind, placebo-controlled trial, we recruited patients from neuromuscular centres in Denmark (Copenhagen), Germany (Ulm), Italy (Padova), and three sites within the USA (Bethesda, MD; Irvine, CA; and Columbus, OH). Eligible patients were 18 years or older with a confirmed genetic diagnosis of spinal and bulbar muscular atrophy, were ambulatory, had symptomatic weakness, and had serum IGF-1 concentrations of 170 ng/mL or lower. Patients were randomly assigned (2:1) to study drug or placebo by a number scheme. Patients, investigators, and study personnel were masked to treatment assignment. After a safety and tolerability assessment with eight patients, BVS857 was administered once a week (0·06 mg/kg intravenously) for 12 weeks. Primary outcome measures were safety, tolerability, and the effects of BVS857 on thigh muscle volume (TMV) measured by MRI. The ratio of TMV at day 85 to baseline was analysed with ANCOVA per protocol. Secondary outcomes of muscle strength and function were measured with the Adult Myopathy Assessment Tool, lean body mass through dual energy x-ray absorptiometry, and BVS857 pharmacokinetics. This trial was registered with ClinicalTrials.gov, NCT02024932. Findings: 31 patients were assessed for eligibility, 27 of whom were randomly assigned to either BVS857 treatment (n=18) or placebo (n=9), and 24 were included in the preliminary efficacy analysis (BVS857 group, n=15; placebo group, n=9). BVS857 was generally safe with no serious adverse events. No significant differences were found in adverse events between the BVS857 and placebo groups. Immunogenicity was detected in 13 (72%) of 18 patients in the BVS857 group, including crossreacting antibodies with neutralising capacity to endogenous IGF-1 in five patients. TMV decreased from baseline to day 85 in the placebo group (–3·4% [–110 cm3]) but not in the BVS857 group (0% [2 cm3]). A significant difference in change in TMV was observed in the BVS857 group versus the placebo group (geometric-mean ratio 1·04 [90% CI 1·01–1·07]; p=0·02). There were no differences between groups in measures of muscle strength and function. Interpretation: TMV remained stable in patients with spinal and bulbar muscular atrophy after being given BVS857 for 12 weeks. The intervention was associated with high incidence of immunogenicity and did not improve muscle strength or function. Additional studies might be needed to assess the efficacy of activating the IGF-1 pathway in this disease. Funding: Novartis Pharmaceuticals and the US National Institutes of Health.

AB - Background: Spinal and bulbar muscular atrophy is an X-linked neuromuscular disease caused by CAG repeat expansion in the androgen receptor gene. Patients with this disease have low concentrations of insulin-like growth factor-1 (IGF-1), and studies of overexpression and administration of IGF-1 showed benefit in a transgenic model; thus the IGF-1 pathway presents as a potential treatment target. We assessed safety, tolerability, and preliminary efficacy of BVS857, an IGF-1 mimetic, in patients with spinal and bulbar muscular atrophy. Methods: In this randomised, double-blind, placebo-controlled trial, we recruited patients from neuromuscular centres in Denmark (Copenhagen), Germany (Ulm), Italy (Padova), and three sites within the USA (Bethesda, MD; Irvine, CA; and Columbus, OH). Eligible patients were 18 years or older with a confirmed genetic diagnosis of spinal and bulbar muscular atrophy, were ambulatory, had symptomatic weakness, and had serum IGF-1 concentrations of 170 ng/mL or lower. Patients were randomly assigned (2:1) to study drug or placebo by a number scheme. Patients, investigators, and study personnel were masked to treatment assignment. After a safety and tolerability assessment with eight patients, BVS857 was administered once a week (0·06 mg/kg intravenously) for 12 weeks. Primary outcome measures were safety, tolerability, and the effects of BVS857 on thigh muscle volume (TMV) measured by MRI. The ratio of TMV at day 85 to baseline was analysed with ANCOVA per protocol. Secondary outcomes of muscle strength and function were measured with the Adult Myopathy Assessment Tool, lean body mass through dual energy x-ray absorptiometry, and BVS857 pharmacokinetics. This trial was registered with ClinicalTrials.gov, NCT02024932. Findings: 31 patients were assessed for eligibility, 27 of whom were randomly assigned to either BVS857 treatment (n=18) or placebo (n=9), and 24 were included in the preliminary efficacy analysis (BVS857 group, n=15; placebo group, n=9). BVS857 was generally safe with no serious adverse events. No significant differences were found in adverse events between the BVS857 and placebo groups. Immunogenicity was detected in 13 (72%) of 18 patients in the BVS857 group, including crossreacting antibodies with neutralising capacity to endogenous IGF-1 in five patients. TMV decreased from baseline to day 85 in the placebo group (–3·4% [–110 cm3]) but not in the BVS857 group (0% [2 cm3]). A significant difference in change in TMV was observed in the BVS857 group versus the placebo group (geometric-mean ratio 1·04 [90% CI 1·01–1·07]; p=0·02). There were no differences between groups in measures of muscle strength and function. Interpretation: TMV remained stable in patients with spinal and bulbar muscular atrophy after being given BVS857 for 12 weeks. The intervention was associated with high incidence of immunogenicity and did not improve muscle strength or function. Additional studies might be needed to assess the efficacy of activating the IGF-1 pathway in this disease. Funding: Novartis Pharmaceuticals and the US National Institutes of Health.

U2 - 10.1016/S1474-4422(18)30320-X

DO - 10.1016/S1474-4422(18)30320-X

M3 - Journal article

AN - SCOPUS:85057145749

SN - 1474-4422

VL - 17

SP - 1043

EP - 1052

JO - The Lancet Neurology

JF - The Lancet Neurology

IS - 12

ER -

Safety, tolerability, and preliminary efficacy of an IGF-1 mimetic in patients with spinal and bulbar muscular atrophy: a randomised, placebo-controlled trial

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