VBP15, a novel dissociative steroid compound, reduces NFκB-induced expression of inflammatory cytokines in vitro and symptoms of murine trinitrobenzene sulfonic acid-induced colitis

Damsker, Jesse M.; Conklin, Laurie S.; Sadri, Soheil; Dillingham, Blythe C.; Panchapakesan, Karuna; Heier, Christopher R.; McCall, John M.; Sandler, Anthony D.

doi:10.1007/s00011-016-0956-8

Cited by 16 publications

(15 citation statements)

References 37 publications

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“…[8][9][10][11][12][13] Studies of vamorolone in animal models of chronic inflammatory states, including DMD mouse models, have shown retention of antiinflammatory efficacy and loss of adverse effects compared to prednisolone. 10,12,[14][15][16] The retention of antiinflammatory efficacy and loss of side effects in preclinical models are consistent with vamorolone blocking NF-κBassociated proinflammatory signals as a ligand/receptor monomeric state instead of the traditional molecular models of ligand/receptor dimeric complexes. 17 A phase 1 study of vamorolone in healthy adult men 18 and a 2-week treatment, 2-week washout, 4-week phase 2a study in patients with DMD 19 showed an improved profile of typical glucocorticoid-like safety concerns as measured by serum biomarkers after 2 weeks of treatment.…”

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confidence: 56%

Vamorolone trial in Duchenne muscular dystrophy shows dose-related improvement of muscle function

et al. 2019

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ObjectiveTo study vamorolone, a first-in-class steroidal anti-inflammatory drug, in Duchenne muscular dystrophy (DMD). MethodsAn open-label, multiple-ascending-dose study of vamorolone was conducted in 48 boys with DMD (age 4-<7 years, steroid-naive). Dose levels were 0.25, 0.75, 2.0, and 6.0 mg/kg/d in an oral suspension formulation (12 boys per dose level; one-third to 10 times the glucocorticoid dose in DMD). The primary goal was to define optimal doses of vamorolone. The primary outcome for clinical efficacy was time to stand from supine velocity. ResultsOral administration of vamorolone at all doses tested was safe and well tolerated over the 24-week treatment period. The 2.0-mg/kg/d dose group met the primary efficacy outcome of improved muscle function (time to stand; 24 weeks of vamorolone treatment vs natural history controls), without evidence of most adverse effects of glucocorticoids. A biomarker of bone formation, osteocalcin, increased in vamorolone-treated boys, suggesting possible loss of bone morbidities seen with glucocorticoids. Biomarker outcomes for adrenal suppression and insulin resistance were also lower in vamorolone-treated patients with DMD relative to published studies of glucocorticoid therapy. ConclusionsDaily vamorolone treatment suggested efficacy at doses of 2.0 and 6.0 mg/kg/d in an exploratory 24-week open-label study. Classification of evidenceThis study provides Class IV evidence that for boys with DMD, vamorolone demonstrated possible efficacy compared to a natural history cohort of glucocorticoid-naive patients and appeared to be tolerated.

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confidence: 56%

Vamorolone trial in Duchenne muscular dystrophy shows dose-related improvement of muscle function

et al. 2019

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“…Vamorolone has shown efficacy similar or superior to prednisone in mouse models of muscular dystrophy [15,23], lung disease [16,19,24], inflammatory bowel disease [18], and multiple sclerosis [17]. These in vivo pre-clinical studies also showed improvement of bone safety profiles of vamorolone when benchmarked against prednisone tested in parallel, including loss of stunting of growth and osteopenia [15,17,18]. Measures of immune suppression were studied both in vitro and in vivo , where CD4 cells declined with prednisone, but not vamorolone [15].…”

Section: Discussionmentioning

confidence: 99%

Phase 1 trial of vamorolone, a first-in-class steroid, shows improvements in side effects via biomarkers bridged to clinical outcomes

Hoffman

Riddle²,

Siegler

et al. 2018

Steroids

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Background Glucocorticoid drugs are highly effective anti-inflammatory agents, but chronic use is associated with extensive pharmacodynamic safety concerns that have a considerable negative impact on patient quality of life. Purpose Vamorolone (VBP15) is a first-in-class steroidal multi-functional drug that shows potent inhibition of pro-inflammatory NFkB pathways via high-affinity binding to the glucocorticoid receptor, high affinity antagonism for the mineralocorticoid receptor, and membrane stabilization properties. Pre-clinical data in multiple mouse models of inflammation showed retention of anti-inflammatory efficacy, but loss of most or all side effects. Experimental approach We report first-in-human Phase 1 clinical trials (86 healthy adult males), with single ascending doses (0.1–20.0 mg/kg), and multiple ascending doses (1.0–20 mg/kg/day; 14 days treatment). Key results Vamorolone was well-tolerated at all dose levels. Vamorolone showed pharmacokinetic and metabolism profiles similar to prednisone. Biomarker studies showed loss of side effects of traditional glucocorticoid drugs (bone fragility, metabolic disturbance, immune suppression). Suppression of the adrenal axis was 10-fold less than prednisone. The crystallographic structure of vamorolone was solved, and compared to prednisone and dexamethasone. There was overlap in structure, but differences in conformation at the C-ring where glucocorticoids interact with Asn564 of the glucocorticoid receptor. The predicted loss of Asn564 binding to vamorolone may underlie the loss of gene transcriptional activity. Conclusions and interpretations Vamorolone is a dissociative steroid that retains high affinity binding and nuclear translocation of both glucocorticoid (agonist) and mineralocorticoid (antagonist) receptors, but does not show pharmacodynamic safety concerns of existing glucocorticoid drugs at up to 20 mg/kg/day.

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“…Further, the fact that SCD patients treated with corticosteroids typically suffer adverse events related to vaso-occlusion (increase hospitalization for pain, acute chest syndrome, strokes) might suggest that corticosteroids may alter blood rheology, a hypothesis, which is worthy of testing in future studies. Further, while this preclinical study examined only one level of equipotent doses for prednisolone and vamorolone, which have been shown to be beneficial in mouse models of brain tumor and of inflammatory bowel disease 23 , 26 , it is possible that different doses could have yielded different results. In fact, vamorolone was shown to be well tolerated in healthy adults at doses of up to 20 mg/kg/day in completed phase 1 clinical trials and is in phase 2 clinical trials in patients with Duchenne muscular dystrophy (NCT02760264).…”

Section: Discussionmentioning

confidence: 99%

The corticosteroid compounds prednisolone and vamorolone do not alter the nociception phenotype and exacerbate liver injury in sickle cell mice

Almeida

Damsker

Albani

et al. 2018

Sci Rep

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Clinicians often hesitate prescribing corticosteroids to treat corticosteroid-responsive conditions in sickle cell disease (SCD) patients because their use can be associated with complications (increased hospital readmission, rebound pain, strokes, avascular necrosis, acute chest syndrome). Consequently, SCD patients may receive suboptimal treatment for corticosteroid-responsive conditions. We conducted a preclinical trial of dissociative (vamorolone) and conventional (prednisolone) corticosteroid compounds to evaluate their effects on nociception phenotype, inflammation, and organ dysfunction in SCD mice. Prednisolone and vamorolone had no significant effects on nociception phenotype or anemia in homozygous mice. Conversely, prednisolone and vamorolone significantly decreased white blood cell counts and hepatic inflammation. Interestingly, the effects of vamorolone were milder than those of prednisolone, as vamorolone yielded less attenuation of hepatic inflammation compared to prednisolone. Compared to controls and heterozygotes, homozygotes had significant liver necrosis, which was significantly exacerbated by prednisolone and vamorolone despite decreased hepatic inflammation. These hepatic histopathologic changes were associated with increases in transaminases and alkaline phosphatase. Together, these results suggest that, even in the setting of decreasing hepatic inflammation, prednisolone and vamorolone were associated with significant hepatic toxicity in SCD mice. These findings raise the possibility that hepatic function deterioration could occur with the use of corticosteroids (conventional and dissociative) in SCD.

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VBP15, a novel dissociative steroid compound, reduces NFκB-induced expression of inflammatory cytokines in vitro and symptoms of murine trinitrobenzene sulfonic acid-induced colitis

Abstract: VBP15 may reduce symptoms of IBD, while decreasing or avoiding detrimental side effects.

Cited by 16 publications

References 37 publications

Vamorolone trial in Duchenne muscular dystrophy shows dose-related improvement of muscle function

Vamorolone trial in Duchenne muscular dystrophy shows dose-related improvement of muscle function

Phase 1 trial of vamorolone, a first-in-class steroid, shows improvements in side effects via biomarkers bridged to clinical outcomes

The corticosteroid compounds prednisolone and vamorolone do not alter the nociception phenotype and exacerbate liver injury in sickle cell mice

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