A pilot randomized trial of oxandrolone in inclusion body myositis

Rutkove, Seward B.; Parker, R.; Nardin, Rachel; Connolly, C. E.; Felice, Kevin J.; Raynor, Elizabeth M.

doi:10.1212/wnl.58.7.1081

Cited by 88 publications

(54 citation statements)

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“…Timed Up and Go, which is the time it takes a patient to stand up from a chair without armrests, walk 3 m, turn around, return to the chair, and sit down, was measured as previously described. 13 The quicker of 2 trials (in seconds) was recorded. In addition, 6MWD was also measured as previously described.…”

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confidence: 99%

“…In addition, 6MWD was also measured as previously described. 13 Statistical analysis. All outcomes were analyzed by analysis of covariance with the pretreatment baseline as a covariate and treatment as a fixed effect.…”

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“…In contrast, all previous sIBM randomized trials have not resulted in statistically significant improvements in their primary outcome measures. 13,[17][18][19][20][21][22] With a single dose of 30 mg/kg, bimagrumab exposure is thought to have been above the therapeutic target of saturating ActRII for approximately 2 months. During this time, muscle mass, measured by MRI of the thigh and by DXA of the whole body, increased substantially from baseline, by approximately 5% more than placebo ( figure 3, A and B).…”

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Treatment of sporadic inclusion body myositis with bimagrumab

et al. 2014

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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 b 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 5 11) or placebo (n 5 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 5 0.003). Eight weeks after dosing, the bimagrumab-treated patients increased thigh muscle volume (right leg 16.5% compared with placebo, p 5 0.024; left leg 17.6%, p 5 0.009) and lean body mass (15.7% compared with placebo, p 5 0.014). Subsequently, bimagrumabtreated patients had improved 6-minute walking distance, which peaked at 16 weeks (114.6%, p 5 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 b 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. Classification of evidence:This study provides Class I evidence that for patients with inclusion body myositis, bimagrumab increases thigh muscle volume at 8 weeks. Neurology ® 2014;83:2239-2246 GLOSSARY ActRII 5 activin receptors IIA and IIB; DXA 5 dual-energy x-ray absorptiometry; LBM 5 lean body mass; pSMAD2/3 5 phosphorylated SMAD2/3; QMT 5 quantitative muscle testing; sIBM 5 sporadic inclusion body myositis; 6MWD 5 6-minute walking distance; TGFb 5 transforming growth factor b; TMV 5 thigh muscle volume.Sporadic inclusion body myositis (sIBM) is a slowly progressive degenerative and inflammatory skeletal muscle disease beginning in middle or later life.1 Its clinical features include a specific pattern of muscle involvement (preferential weakness of finger flexors and knee extensors) accompanied by progressive muscle atrophy, distinctive microscopic pathology including endomysial inflammation and rimmed vacuoles, and a recently identified serum autoantibody (against cytosolic 59-nucleotidase 1A) biomarker.2-4 Despite a prominent adaptive immune response characterized by antigen-stimulated B-and T-cell maturation and prominent infiltration into muscle of immune system cells, sIBM is highly refractory to immunosuppressive therapies studied to date. 2Members of the transforming growth factor b (TGFb) superfamily of ligands signal through a heterodimeric receptor system.5 They first bind a type II receptor, such as the TGFb...

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Treatment of sporadic inclusion body myositis with bimagrumab

et al. 2014

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“…Moreover, the use of T to enhance strength and muscle mass has been considered not only in hypogonadal [28] and aging men [29] but also in glucocorticoid induced myopathy [30,31] and in HIV and cancer-related skeletal muscle loss and wasting [32,33]. Lastly, the effect of oxandrolone, a synthetic dehydroepiandrosterone derivative, has been investigated in dystrophynopathies and inclusion body myositis [34,35]. More recently, the use of T supplementation was proposed in a clinical study in which a high incidence of hypogonadism was observed in men with various types of myopathies, such as facioscapulohumeral dystrophy, inclusion body myositis, dystrophynopathy, and metabolic myopathy, as well as DM1 [36].…”

Section: Discussionmentioning

confidence: 99%

Hypogonadism in DM1 and its relationship to erectile dysfunction

et al. 2011

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Myotonic dystrophy type 1 (DM1) is characterized by both a premature appearance of age-related phenotypes and multiple organ involvement, which affects skeletal and smooth muscle as well as the eye, heart, central nervous system, and endocrine system. Although erectile dysfunction (ED) is a frequent complaint in patients with DM1, it has not been investigated in great depth. Hypogonadism, which is reported to be one of the physical causes of ED in the general population, frequently occurs in DM1. We planned this case-control study to evaluate the relationship between hypogonadism, as defined by the sexual hormone profile (FSH, LH, testosterone (T) and prolactin) and ED, as assessed by means of an internationally validated self-administered questionnaire (IIEF). DM1 patients had significantly increased mean levels of both gonadotropins (FSH and LH) (p < 0.0001) and a reduced mean level of T (p < 0.0001) when compared to controls. Twelve patients were eugonadic (normal LH, T, and FSH), while 18 displayed hormonal evidence of hypogonadism, characterized by tubular failure (increased FSH) in all the subjects and associated with interstitial failure in 14 subjects: seven with primary hypogonadism (increased LH and reduced T) and seven with compensated hypogonadism (increased LH and normal T). Patients with hormonal evidence of interstitial failure had a larger CTG expansion (p = 0.008), longer disease duration (p = 0.013), higher grade of disease (p = 0.004) and lower erectile function score (p = 0.02) than eugonadic patients. Impotence occurred in 13/14 hypogonadic patients with interstitial failure and in 5/12 eugonadic patients (p = 0.017, OR = 18.2).

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“…38 Alemtuzumab (Campath-1), a monoclonal antibody, is directed against CD52, a cell surface molecule present on various immune cells (particularly T cells, B cells, and dendritic cells) and inducing selective immune depletion after intravenous application. Alemtuzumab was used in a controlled study in patients with sIBM.…”

Section: Therapy Of Sporadic Ibmmentioning

confidence: 99%

Idiopathic Inflammatory Myopathies: Current and Future Therapeutic Options

Wiendl

2008

Neurotherapeutics

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Summary:Idiopathic inflammatory myopathies (notably polymyositis and dermatomyositis) are relatively uncommon diseases with a heterogeneous clinical presentation. Only a few randomized, double-blind, placebo-controlled trials have been performed, measures to assess outcome and response to treatment have to be validated. Initial treatment options of first choice are corticosteroids, although rarely tested in randomized, controlled trials. Unfortunately, not all patients respond to them and many develop undesirable side effects. Thus, second line agents or immunosuppressants given in combination with corticosteroids are used. For dermatomyositis/polymyositis, combination with azathioprine is most common. In case this combination is not sufficient or applicable, intravenous immunoglobulins are justified. Alternative or stronger immunosuppressants, such as cyclosporine A, cyclophosphamide, methotrexate, or mycophenolate are also used. There are no defined guidelines or best treatment protocols agreed on internationally; therefore, the medical approach must be individualized based on the severity of clinical presentation, disease duration, presence of extramuscular features, and prior therapy and contraindications to particular agents. Approximately 25% of patients are nonresponders and continue to experience clinical relapses. Those are candidates for alternative treatment options and experimental therapies.New immunoselective therapies directed toward cytokine modulation, immune cell migration, or modification of certain immune subsets (B-and T-cells) are a promising avenue of research and clinical application. Possible future therapeutic options are presented and discussed.

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A pilot randomized trial of oxandrolone in inclusion body myositis

Abstract: Oxandrolone had a borderline significant effect in improving whole-body strength and a significant effect in improving upper-extremity strength as measured by MVICT. Given these findings, further study of this drug, possibly in combination with an immunomodulating agent, is warranted.

Cited by 88 publications

References 22 publications

Treatment of sporadic inclusion body myositis with bimagrumab

Treatment of sporadic inclusion body myositis with bimagrumab

Hypogonadism in DM1 and its relationship to erectile dysfunction

Idiopathic Inflammatory Myopathies: Current and Future Therapeutic Options

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