Randomized phase 2 trial and open-label extension of domagrozumab in Duchenne muscular dystrophy

Kathryn R. Wagner; Hoda Z. Abdel-Hamid; Jean K. Mah; Craig Campbell; Michela Guglieri; Francesco Muntoni; Yasuhiro Takeshima; Craig M. McDonald; Anna Kostera-Pruszczyk; Peter Karachunski; Russell J. Butterfield; Eugenio Mercuri; Chiara Fiorillo; Enrico S. Bertini; Cuixia Tian; Jeffery Statland; Alesia B. Sadosky; Vivek S. Purohit; Sarah P. Sherlock; Jeffrey P. Palmer; Michael Binks; Lawrence Charnas; Shannon Marraffino; Brenda L. Wong

doi:10.1016/j.nmd.2020.05.002

Randomized phase 2 trial and open-label extension of domagrozumab in Duchenne muscular dystrophy

Kathryn R. Wagner, Hoda Z. Abdel-Hamid, Jean K. Mah, Craig Campbell, Michela Guglieri, Francesco Muntoni, Yasuhiro Takeshima, Craig M. McDonald, Anna Kostera-Pruszczyk, Peter Karachunski, Russell J. Butterfield, Eugenio Mercuri, Chiara Fiorillo, Enrico S. Bertini, Cuixia Tian, Jeffery Statland, Alesia B. Sadosky, Vivek S. Purohit, Sarah P. Sherlock, Jeffrey P. PalmerMichael Binks, Lawrence Charnas, Shannon Marraffino, Brenda L. Wong

Neurology

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

49 Scopus citations

Abstract

We report results from a phase 2, randomized, double-blind, 2-period trial (48 weeks each) of domagrozumab and its open-label extension in patients with Duchenne muscular dystrophy (DMD). Of 120 ambulatory boys (aged 6 to <16 years) with DMD, 80 were treated with multiple ascending doses (5, 20, and 40 mg/kg) of domagrozumab and 40 treated with placebo. The primary endpoints were safety and mean change in 4-stair climb (4SC) time at week 49. Secondary endpoints included other functional tests, pharmacokinetics, and pharmacodynamics. Mean (SD) age was 8.4 (1.7) and 9.3 (2.3) years in domagrozumab- and placebo-treated patients, respectively. Difference in mean (95% CI) change from baseline in 4SC at week 49 for domagrozumab vs placebo was 0.27 (–7.4 to 7.9) seconds (p = 0.94). There were no significant between-group differences in any secondary clinical endpoints. Most patients had ≥1 adverse event in the first 48 weeks; most were mild and not treatment-related. Median serum concentrations of domagrozumab increased with administered dose within each dose level. Non-significant increases in muscle volume were observed in domagrozumab- vs placebo-treated patients. Domagrozumab was generally safe and well tolerated in patients with DMD. Efficacy measures did not support a significant treatment effect. Clinicaltrials.gov

Original language	English (US)
Pages (from-to)	492-502
Number of pages	11
Journal	Neuromuscular Disorders
Volume	30
Issue number	6
DOIs	https://doi.org/10.1016/j.nmd.2020.05.002
State	Published - Jun 2020

Bibliographical note

Funding Information:
We thank the participating patients and their families and the site investigators and their staff for their commitment to this trial. We thank the Cooperative International Neuromuscular Research Group (CINRG) Duchenne Natural History Study Investigators for contributing historical control data. Medical writing support was provided by Vardit Dror, PhD, of Engage Scientific Solutions, and funded by Pfizer. Upon request, and subject to certain criteria, conditions, and exceptions (see https://www.pfizer.com/science/clinical-trials/trial-data-and-results for more information), Pfizer will provide access to individual de-identified participant data from Pfizer-sponsored global interventional clinical studies conducted for medicines, vaccines and medical devices (1) for indications that have been approved in the US and/or EU or (2) in programs that have been terminated (i.e. development for all indications has been discontinued). Pfizer will also consider requests for the protocol, data dictionary, and statistical analysis plan. Data may be requested from Pfizer trials 24 months after study completion. The de-identified participant data will be made available to researchers whose proposals meet the research criteria and other conditions, and for which an exception does not apply, via a secure portal. To gain access, data requestors must enter into a data access agreement with Pfizer.

Funding Information:
We thank the participating patients and their families and the site investigators and their staff for their commitment to this trial. We thank the Cooperative International Neuromuscular Research Group (CINRG) Duchenne Natural History Study Investigators for contributing historical control data. Medical writing support was provided by Vardit Dror, PhD, of Engage Scientific Solutions, and funded by Pfizer.

Publisher Copyright:
© 2020 Elsevier B.V.

Keywords

4-stair climb
Duchenne muscular dystrophy
domagrozumab
myostatin inhibitor

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10.1016/j.nmd.2020.05.002

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Wagner, K. R., Abdel-Hamid, H. Z., Mah, J. K., Campbell, C., Guglieri, M., Muntoni, F., Takeshima, Y., McDonald, C. M., Kostera-Pruszczyk, A., Karachunski, P., Butterfield, R. J., Mercuri, E., Fiorillo, C., Bertini, E. S., Tian, C., Statland, J., Sadosky, A. B., Purohit, V. S., Sherlock, S. P., ... Wong, B. L. (2020). Randomized phase 2 trial and open-label extension of domagrozumab in Duchenne muscular dystrophy. Neuromuscular Disorders, 30(6), 492-502. https://doi.org/10.1016/j.nmd.2020.05.002

Wagner, KR, Abdel-Hamid, HZ, Mah, JK, Campbell, C, Guglieri, M, Muntoni, F, Takeshima, Y, McDonald, CM, Kostera-Pruszczyk, A, Karachunski, P, Butterfield, RJ, Mercuri, E, Fiorillo, C, Bertini, ES, Tian, C, Statland, J, Sadosky, AB, Purohit, VS, Sherlock, SP, Palmer, JP, Binks, M, Charnas, L, Marraffino, S & Wong, BL 2020, 'Randomized phase 2 trial and open-label extension of domagrozumab in Duchenne muscular dystrophy', Neuromuscular Disorders, vol. 30, no. 6, pp. 492-502. https://doi.org/10.1016/j.nmd.2020.05.002

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title = "Randomized phase 2 trial and open-label extension of domagrozumab in Duchenne muscular dystrophy",

abstract = "We report results from a phase 2, randomized, double-blind, 2-period trial (48 weeks each) of domagrozumab and its open-label extension in patients with Duchenne muscular dystrophy (DMD). Of 120 ambulatory boys (aged 6 to <16 years) with DMD, 80 were treated with multiple ascending doses (5, 20, and 40 mg/kg) of domagrozumab and 40 treated with placebo. The primary endpoints were safety and mean change in 4-stair climb (4SC) time at week 49. Secondary endpoints included other functional tests, pharmacokinetics, and pharmacodynamics. Mean (SD) age was 8.4 (1.7) and 9.3 (2.3) years in domagrozumab- and placebo-treated patients, respectively. Difference in mean (95% CI) change from baseline in 4SC at week 49 for domagrozumab vs placebo was 0.27 (–7.4 to 7.9) seconds (p = 0.94). There were no significant between-group differences in any secondary clinical endpoints. Most patients had ≥1 adverse event in the first 48 weeks; most were mild and not treatment-related. Median serum concentrations of domagrozumab increased with administered dose within each dose level. Non-significant increases in muscle volume were observed in domagrozumab- vs placebo-treated patients. Domagrozumab was generally safe and well tolerated in patients with DMD. Efficacy measures did not support a significant treatment effect. Clinicaltrials.gov",

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author = "Wagner, {Kathryn R.} and Abdel-Hamid, {Hoda Z.} and Mah, {Jean K.} and Craig Campbell and Michela Guglieri and Francesco Muntoni and Yasuhiro Takeshima and McDonald, {Craig M.} and Anna Kostera-Pruszczyk and Peter Karachunski and Butterfield, {Russell J.} and Eugenio Mercuri and Chiara Fiorillo and Bertini, {Enrico S.} and Cuixia Tian and Jeffery Statland and Sadosky, {Alesia B.} and Purohit, {Vivek S.} and Sherlock, {Sarah P.} and Palmer, {Jeffrey P.} and Michael Binks and Lawrence Charnas and Shannon Marraffino and Wong, {Brenda L.}",

note = "Funding Information: We thank the participating patients and their families and the site investigators and their staff for their commitment to this trial. We thank the Cooperative International Neuromuscular Research Group (CINRG) Duchenne Natural History Study Investigators for contributing historical control data. Medical writing support was provided by Vardit Dror, PhD, of Engage Scientific Solutions, and funded by Pfizer. Upon request, and subject to certain criteria, conditions, and exceptions (see https://www.pfizer.com/science/clinical-trials/trial-data-and-results for more information), Pfizer will provide access to individual de-identified participant data from Pfizer-sponsored global interventional clinical studies conducted for medicines, vaccines and medical devices (1) for indications that have been approved in the US and/or EU or (2) in programs that have been terminated (i.e. development for all indications has been discontinued). Pfizer will also consider requests for the protocol, data dictionary, and statistical analysis plan. Data may be requested from Pfizer trials 24 months after study completion. The de-identified participant data will be made available to researchers whose proposals meet the research criteria and other conditions, and for which an exception does not apply, via a secure portal. To gain access, data requestors must enter into a data access agreement with Pfizer. Funding Information: We thank the participating patients and their families and the site investigators and their staff for their commitment to this trial. We thank the Cooperative International Neuromuscular Research Group (CINRG) Duchenne Natural History Study Investigators for contributing historical control data. Medical writing support was provided by Vardit Dror, PhD, of Engage Scientific Solutions, and funded by Pfizer. Publisher Copyright: {\textcopyright} 2020 Elsevier B.V.",

year = "2020",

month = jun,

doi = "10.1016/j.nmd.2020.05.002",

language = "English (US)",

volume = "30",

pages = "492--502",

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AU - Wagner, Kathryn R.

AU - Abdel-Hamid, Hoda Z.

AU - Mah, Jean K.

AU - Campbell, Craig

AU - Guglieri, Michela

AU - Muntoni, Francesco

AU - Takeshima, Yasuhiro

AU - McDonald, Craig M.

AU - Kostera-Pruszczyk, Anna

AU - Karachunski, Peter

AU - Butterfield, Russell J.

AU - Mercuri, Eugenio

AU - Fiorillo, Chiara

AU - Bertini, Enrico S.

AU - Tian, Cuixia

AU - Statland, Jeffery

AU - Sadosky, Alesia B.

AU - Purohit, Vivek S.

AU - Sherlock, Sarah P.

AU - Palmer, Jeffrey P.

AU - Binks, Michael

AU - Charnas, Lawrence

AU - Marraffino, Shannon

AU - Wong, Brenda L.

N1 - Funding Information: We thank the participating patients and their families and the site investigators and their staff for their commitment to this trial. We thank the Cooperative International Neuromuscular Research Group (CINRG) Duchenne Natural History Study Investigators for contributing historical control data. Medical writing support was provided by Vardit Dror, PhD, of Engage Scientific Solutions, and funded by Pfizer. Upon request, and subject to certain criteria, conditions, and exceptions (see https://www.pfizer.com/science/clinical-trials/trial-data-and-results for more information), Pfizer will provide access to individual de-identified participant data from Pfizer-sponsored global interventional clinical studies conducted for medicines, vaccines and medical devices (1) for indications that have been approved in the US and/or EU or (2) in programs that have been terminated (i.e. development for all indications has been discontinued). Pfizer will also consider requests for the protocol, data dictionary, and statistical analysis plan. Data may be requested from Pfizer trials 24 months after study completion. The de-identified participant data will be made available to researchers whose proposals meet the research criteria and other conditions, and for which an exception does not apply, via a secure portal. To gain access, data requestors must enter into a data access agreement with Pfizer. Funding Information: We thank the participating patients and their families and the site investigators and their staff for their commitment to this trial. We thank the Cooperative International Neuromuscular Research Group (CINRG) Duchenne Natural History Study Investigators for contributing historical control data. Medical writing support was provided by Vardit Dror, PhD, of Engage Scientific Solutions, and funded by Pfizer. Publisher Copyright: © 2020 Elsevier B.V.

PY - 2020/6

Y1 - 2020/6

N2 - We report results from a phase 2, randomized, double-blind, 2-period trial (48 weeks each) of domagrozumab and its open-label extension in patients with Duchenne muscular dystrophy (DMD). Of 120 ambulatory boys (aged 6 to <16 years) with DMD, 80 were treated with multiple ascending doses (5, 20, and 40 mg/kg) of domagrozumab and 40 treated with placebo. The primary endpoints were safety and mean change in 4-stair climb (4SC) time at week 49. Secondary endpoints included other functional tests, pharmacokinetics, and pharmacodynamics. Mean (SD) age was 8.4 (1.7) and 9.3 (2.3) years in domagrozumab- and placebo-treated patients, respectively. Difference in mean (95% CI) change from baseline in 4SC at week 49 for domagrozumab vs placebo was 0.27 (–7.4 to 7.9) seconds (p = 0.94). There were no significant between-group differences in any secondary clinical endpoints. Most patients had ≥1 adverse event in the first 48 weeks; most were mild and not treatment-related. Median serum concentrations of domagrozumab increased with administered dose within each dose level. Non-significant increases in muscle volume were observed in domagrozumab- vs placebo-treated patients. Domagrozumab was generally safe and well tolerated in patients with DMD. Efficacy measures did not support a significant treatment effect. Clinicaltrials.gov

AB - We report results from a phase 2, randomized, double-blind, 2-period trial (48 weeks each) of domagrozumab and its open-label extension in patients with Duchenne muscular dystrophy (DMD). Of 120 ambulatory boys (aged 6 to <16 years) with DMD, 80 were treated with multiple ascending doses (5, 20, and 40 mg/kg) of domagrozumab and 40 treated with placebo. The primary endpoints were safety and mean change in 4-stair climb (4SC) time at week 49. Secondary endpoints included other functional tests, pharmacokinetics, and pharmacodynamics. Mean (SD) age was 8.4 (1.7) and 9.3 (2.3) years in domagrozumab- and placebo-treated patients, respectively. Difference in mean (95% CI) change from baseline in 4SC at week 49 for domagrozumab vs placebo was 0.27 (–7.4 to 7.9) seconds (p = 0.94). There were no significant between-group differences in any secondary clinical endpoints. Most patients had ≥1 adverse event in the first 48 weeks; most were mild and not treatment-related. Median serum concentrations of domagrozumab increased with administered dose within each dose level. Non-significant increases in muscle volume were observed in domagrozumab- vs placebo-treated patients. Domagrozumab was generally safe and well tolerated in patients with DMD. Efficacy measures did not support a significant treatment effect. Clinicaltrials.gov

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KW - Duchenne muscular dystrophy

KW - domagrozumab

KW - myostatin inhibitor

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Randomized phase 2 trial and open-label extension of domagrozumab in Duchenne muscular dystrophy

Abstract

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