Treatment of sporadic inclusion body myositis with bimagrumab.
OBJECTIVE
To study activin signaling and its blockade in sporadic inclusion body myositis (sIBM) through translational studies and a randomized controlled trial.


METHODS
We measured transforming growth factor β signaling by SMAD2/3 phosphorylation in muscle biopsies of 50 patients with neuromuscular disease (17 with sIBM). We tested inhibition of activin receptors IIA and IIB (ActRII) in 14 patients with sIBM using one dose of bimagrumab (n = 11) or placebo (n = 3). The primary outcome was the change in right thigh muscle volume by MRI at 8 weeks. Lean body mass, strength, and function were secondary outcomes. Twelve of the patients (10 bimagrumab, 2 placebo) participated in a subsequent 16-week observation phase.


RESULTS
Muscle SMAD2/3 phosphorylation was higher in sIBM than in other muscle diseases studied (p = 0.003). Eight weeks after dosing, the bimagrumab-treated patients increased thigh muscle volume (right leg +6.5% compared with placebo, p = 0.024; left leg +7.6%, p = 0.009) and lean body mass (+5.7% compared with placebo, p = 0.014). Subsequently, bimagrumab-treated patients had improved 6-minute walking distance, which peaked at 16 weeks (+14.6%, p = 0.008) compared with placebo. There were no serious adverse events; the main adverse events with bimagrumab were mild acne and transient involuntary muscle contractions.


CONCLUSIONS
Transforming growth factor β superfamily signaling, at least through ActRII, is implicated in the pathophysiology of sIBM. Inhibition of ActRII increased muscle mass and function in this pilot trial, offering a potential novel treatment of sIBM.


METHODS
This study provides Class I evidence that for patients with inclusion body myositis, bimagrumab increases thigh muscle volume at 8 weeks.
From Brigham and Women's Hospital and Harvard Medical School (A.A.A., M.S., S.A.G.), Boston; Boston Children's Hospital (S.A.G.); Harvard-Massachusetts Institute of Technology (S.A.G.), Division of Health Sciences and Technology, Cambridge, MA; Barrow Neurological Institute (K.S.), Phoenix AZ; Massachusetts General Hospital (N.G., W.S.D.), Boston; Novartis Institutes for Biomedical Research (E.L.-T., A.-U.T., D.L., D.J.G., R.R., B.S.T.), Cambridge, MA and Basel, Switzerland; and Novartis Pharmaceuticals Corporation (J.P.), East Hanover, NJ.
Anthony A
AA
Amato
From Brigham and Women's Hospital and Harvard Medical School (A.A.A., M.S., S.A.G.), Boston; Boston Children's Hospital (S.A.G.); Harvard-Massachusetts Institute of Technology (S.A.G.), Division of Health Sciences and Technology, Cambridge, MA; Barrow Neurological Institute (K.S.), Phoenix AZ; Massachusetts General Hospital (N.G., W.S.D.), Boston; Novartis Institutes for Biomedical Research (E.L.-T., A.-U.T., D.L., D.J.G., R.R., B.S.T.), Cambridge, MA and Basel, Switzerland; and Novartis Pharmaceuticals Corporation (J.P.), East Hanover, NJ.
Kumaraswamy
K
Sivakumar
From Brigham and Women's Hospital and Harvard Medical School (A.A.A., M.S., S.A.G.), Boston; Boston Children's Hospital (S.A.G.); Harvard-Massachusetts Institute of Technology (S.A.G.), Division of Health Sciences and Technology, Cambridge, MA; Barrow Neurological Institute (K.S.), Phoenix AZ; Massachusetts General Hospital (N.G., W.S.D.), Boston; Novartis Institutes for Biomedical Research (E.L.-T., A.-U.T., D.L., D.J.G., R.R., B.S.T.), Cambridge, MA and Basel, Switzerland; and Novartis Pharmaceuticals Corporation (J.P.), East Hanover, NJ.
Namita
N
Goyal
From Brigham and Women's Hospital and Harvard Medical School (A.A.A., M.S., S.A.G.), Boston; Boston Children's Hospital (S.A.G.); Harvard-Massachusetts Institute of Technology (S.A.G.), Division of Health Sciences and Technology, Cambridge, MA; Barrow Neurological Institute (K.S.), Phoenix AZ; Massachusetts General Hospital (N.G., W.S.D.), Boston; Novartis Institutes for Biomedical Research (E.L.-T., A.-U.T., D.L., D.J.G., R.R., B.S.T.), Cambridge, MA and Basel, Switzerland; and Novartis Pharmaceuticals Corporation (J.P.), East Hanover, NJ.
William S
WS
David
From Brigham and Women's Hospital and Harvard Medical School (A.A.A., M.S., S.A.G.), Boston; Boston Children's Hospital (S.A.G.); Harvard-Massachusetts Institute of Technology (S.A.G.), Division of Health Sciences and Technology, Cambridge, MA; Barrow Neurological Institute (K.S.), Phoenix AZ; Massachusetts General Hospital (N.G., W.S.D.), Boston; Novartis Institutes for Biomedical Research (E.L.-T., A.-U.T., D.L., D.J.G., R.R., B.S.T.), Cambridge, MA and Basel, Switzerland; and Novartis Pharmaceuticals Corporation (J.P.), East Hanover, NJ.
Mohammad
M
Salajegheh
From Brigham and Women's Hospital and Harvard Medical School (A.A.A., M.S., S.A.G.), Boston; Boston Children's Hospital (S.A.G.); Harvard-Massachusetts Institute of Technology (S.A.G.), Division of Health Sciences and Technology, Cambridge, MA; Barrow Neurological Institute (K.S.), Phoenix AZ; Massachusetts General Hospital (N.G., W.S.D.), Boston; Novartis Institutes for Biomedical Research (E.L.-T., A.-U.T., D.L., D.J.G., R.R., B.S.T.), Cambridge, MA and Basel, Switzerland; and Novartis Pharmaceuticals Corporation (J.P.), East Hanover, NJ.
Jens
J
Praestgaard
From Brigham and Women's Hospital and Harvard Medical School (A.A.A., M.S., S.A.G.), Boston; Boston Children's Hospital (S.A.G.); Harvard-Massachusetts Institute of Technology (S.A.G.), Division of Health Sciences and Technology, Cambridge, MA; Barrow Neurological Institute (K.S.), Phoenix AZ; Massachusetts General Hospital (N.G., W.S.D.), Boston; Novartis Institutes for Biomedical Research (E.L.-T., A.-U.T., D.L., D.J.G., R.R., B.S.T.), Cambridge, MA and Basel, Switzerland; and Novartis Pharmaceuticals Corporation (J.P.), East Hanover, NJ.
Estelle
E
Lach-Trifilieff
From Brigham and Women's Hospital and Harvard Medical School (A.A.A., M.S., S.A.G.), Boston; Boston Children's Hospital (S.A.G.); Harvard-Massachusetts Institute of Technology (S.A.G.), Division of Health Sciences and Technology, Cambridge, MA; Barrow Neurological Institute (K.S.), Phoenix AZ; Massachusetts General Hospital (N.G., W.S.D.), Boston; Novartis Institutes for Biomedical Research (E.L.-T., A.-U.T., D.L., D.J.G., R.R., B.S.T.), Cambridge, MA and Basel, Switzerland; and Novartis Pharmaceuticals Corporation (J.P.), East Hanover, NJ.
Anne-Ulrike
AU
Trendelenburg
From Brigham and Women's Hospital and Harvard Medical School (A.A.A., M.S., S.A.G.), Boston; Boston Children's Hospital (S.A.G.); Harvard-Massachusetts Institute of Technology (S.A.G.), Division of Health Sciences and Technology, Cambridge, MA; Barrow Neurological Institute (K.S.), Phoenix AZ; Massachusetts General Hospital (N.G., W.S.D.), Boston; Novartis Institutes for Biomedical Research (E.L.-T., A.-U.T., D.L., D.J.G., R.R., B.S.T.), Cambridge, MA and Basel, Switzerland; and Novartis Pharmaceuticals Corporation (J.P.), East Hanover, NJ.
Didier
D
Laurent
From Brigham and Women's Hospital and Harvard Medical School (A.A.A., M.S., S.A.G.), Boston; Boston Children's Hospital (S.A.G.); Harvard-Massachusetts Institute of Technology (S.A.G.), Division of Health Sciences and Technology, Cambridge, MA; Barrow Neurological Institute (K.S.), Phoenix AZ; Massachusetts General Hospital (N.G., W.S.D.), Boston; Novartis Institutes for Biomedical Research (E.L.-T., A.-U.T., D.L., D.J.G., R.R., B.S.T.), Cambridge, MA and Basel, Switzerland; and Novartis Pharmaceuticals Corporation (J.P.), East Hanover, NJ.
David J
DJ
Glass
From Brigham and Women's Hospital and Harvard Medical School (A.A.A., M.S., S.A.G.), Boston; Boston Children's Hospital (S.A.G.); Harvard-Massachusetts Institute of Technology (S.A.G.), Division of Health Sciences and Technology, Cambridge, MA; Barrow Neurological Institute (K.S.), Phoenix AZ; Massachusetts General Hospital (N.G., W.S.D.), Boston; Novartis Institutes for Biomedical Research (E.L.-T., A.-U.T., D.L., D.J.G., R.R., B.S.T.), Cambridge, MA and Basel, Switzerland; and Novartis Pharmaceuticals Corporation (J.P.), East Hanover, NJ.
Ronenn
R
Roubenoff
From Brigham and Women's Hospital and Harvard Medical School (A.A.A., M.S., S.A.G.), Boston; Boston Children's Hospital (S.A.G.); Harvard-Massachusetts Institute of Technology (S.A.G.), Division of Health Sciences and Technology, Cambridge, MA; Barrow Neurological Institute (K.S.), Phoenix AZ; Massachusetts General Hospital (N.G., W.S.D.), Boston; Novartis Institutes for Biomedical Research (E.L.-T., A.-U.T., D.L., D.J.G., R.R., B.S.T.), Cambridge, MA and Basel, Switzerland; and Novartis Pharmaceuticals Corporation (J.P.), East Hanover, NJ. sagreenberg@partners.org brian.tseng@novartis.com.
Brian S
BS
Tseng
From Brigham and Women's Hospital and Harvard Medical School (A.A.A., M.S., S.A.G.), Boston; Boston Children's Hospital (S.A.G.); Harvard-Massachusetts Institute of Technology (S.A.G.), Division of Health Sciences and Technology, Cambridge, MA; Barrow Neurological Institute (K.S.), Phoenix AZ; Massachusetts General Hospital (N.G., W.S.D.), Boston; Novartis Institutes for Biomedical Research (E.L.-T., A.-U.T., D.L., D.J.G., R.R., B.S.T.), Cambridge, MA and Basel, Switzerland; and Novartis Pharmaceuticals Corporation (J.P.), East Hanover, NJ. sagreenberg@partners.org brian.tseng@novartis.com.
Steven A
SA
Greenberg
D030301:Activin Receptors, Type II / Q000037:antagonists & inhibitors; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D019138:Antibodies, Blocking; D000911:Antibodies, Monoclonal / Q000009:adverse effects / Q000627:therapeutic use*; D061067:Antibodies, Monoclonal, Humanized; D004311:Double-Blind Method; D005080:Exercise Test; D005260:Female; D006801:Humans; D007155:Immunologic Factors / Q000009:adverse effects / Q000627:therapeutic use*; D008279:Magnetic Resonance Imaging; D008297:Male; D008875:Middle Aged; D018482:Muscle, Skeletal / Q000378:metabolism / Q000473:pathology; D018979:Myositis, Inclusion Body / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D009468:Neuromuscular Diseases / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology; D009929:Organ Size; D010766:Phosphorylation; D051899:Smad2 Protein / Q000378:metabolism; D051900:Smad3 Protein / Q000378:metabolism; D013848:Thigh / Q000473:pathology; D016896:Treatment Outcome
D019138:Antibodies, Blocking; D000911:Antibodies, Monoclonal; D061067:Antibodies, Monoclonal, Humanized; D007155:Immunologic Factors; C497782:SMAD2 protein, human; C497790:SMAD3 protein, human; D051899:Smad2 Protein; D051900:Smad3 Protein; D030301:Activin Receptors, Type II; C000596367:bimagrumab