vamorolone

Vamorolone is indicated for the treatment of Duchenne muscular dystrophy.

Vamorolone is provided in the form of an oral suspension at a concentration of 40{{nbsp}}mg/mL.

Side effects of vamorolone in clinical trials that occurred at a rate of 10% or greater included development of cushingoid features, psychiatric disorders, vomiting, weight gain, vitamin D deficiency, and cough. The psychiatric disorders that occurred more frequently than with placebo included abnormal behavior, aggression, agitation, anxiety, irritability, altered mood, sleep disorder, and stereotypy. In addition to the preceding side effects, vamorolone shows dose-dependent suppression of the hypothalamic–pituitary–adrenal axis (HPA axis) and hence has potential risks of adrenal suppression and adrenal insufficiency with discontinuation. Vamorolone also shows immunosuppression and is expected to increase the risk of infection, among various other potential adverse effects.

Adverse events observed more frequently in the treated cohort in clinical studies included adrenal suppression, cushingoid features, psychiatric disorders, vomiting, weight gain, and vitamin D deficiency, among others.

Vamorolone is a partial agonist of the glucocorticoid receptor with relative loss of transactivation activities, but retention of transrepression activities, compared to other glucocorticoids. As a result, it is described as possessing "dissociative" glucocorticoid properties. In contrast to other corticosteroids, vamorolone is a potent antagonist of the mineralocorticoid receptor and hence has antimineralocorticoid activity.

Vamorolone has anti-inflammatory and immunosuppressive effects as well as other glucocorticoid effects but is thought to lack certain other effects typical of glucocorticoids.

Vamorolone is a synthetic corticosteroid and is also known by the chemical name 17α,21-dihydroxy-16α-methylpregna-1,4,9(11)-triene-3,20-dione or as 16α-methyl-9,11-dehydroprednisolone. It is a derivative of cortisol (hydrocortisone) and prednisolone (1,2-dehydrocortisol).

Anti-inflammatory drugs of the corticosteroid class show a carbonyl (=O) or hydroxyl (-OH) group on the C11 carbon of the steroid backbone. In contrast, vamorolone contains a Δ^9,11 double bond between the C9 and C11 carbons. This change in structure has been shown to remove a molecular contact site with the glucocorticoid receptor, and leads to dissociative properties.{{cite journal | vauthors = Liu X, Wang Y, Gutierrez JS, Damsker JM, Nagaraju K, Hoffman EP, Ortlund EA | title = Disruption of a key ligand-H-bond network drives dissociative properties in vamorolone for Duchenne muscular dystrophy treatment | journal = Proceedings of the National Academy of Sciences of the United States of America | volume = 117 | issue = 39 | pages = 24285–24293 | date = September 2020 | pmid = 32917814 | pmc = 7533876 | doi = 10.1073/pnas.2006890117 | doi-access = free | bibcode = 2020PNAS..11724285L }}

In phase I clinical trials of adult volunteers, vamorolone was shown to be safe and well tolerated, with blood biomarker data suggesting possible loss of safety concerns of the corticosteroid class.{{cite journal | vauthors = Hoffman EP, Riddle V, Siegler MA, Dickerson D, Backonja M, Kramer WG, Nagaraju K, Gordish-Dressman H, Damsker JM, McCall JM | title = Phase 1 trial of vamorolone, a first-in-class steroid, shows improvements in side effects via biomarkers bridged to clinical outcomes | journal = Steroids | volume = 134 | pages = 43–52 | date = June 2018 | pmid = 29524454 | pmc = 6136660 | doi = 10.1016/j.steroids.2018.02.010 }}

In phase IIa dose-ranging clinical trial of 48 children with Duchenne muscular dystrophy (2 weeks on drug, 2 weeks off drug), vamorolone was shown to be safe and well tolerated, and showed blood biomarker data consistent with a myofiber membrane stabilization and anti-inflammatory effects, and possible loss of safety concerns.{{cite journal | vauthors = Conklin LS, Damsker JM, Hoffman EP, Jusko WJ, Mavroudis PD, Schwartz BD, Mengle-Gaw LJ, Smith EC, Mah JK, Guglieri M, Nevo Y, Kuntz N, McDonald CM, Tulinius M, Ryan MM, Webster R, Castro D, Finkel RS, Smith AL, Morgenroth LP, Arrieta A, Shimony M, Jaros M, Shale P, McCall JM, Hathout Y, Nagaraju K, van den Anker J, Ward LM, Ahmet A, Cornish MR, Clemens PR | title = Phase IIa trial in Duchenne muscular dystrophy shows vamorolone is a first-in-class dissociative steroidal anti-inflammatory drug | journal = Pharmacological Research | volume = 136 | pages = 140–150 | date = October 2018 | pmid = 30219580 | pmc = 6218284 | doi = 10.1016/j.phrs.2018.09.007 }} These children continued on to a 24-week open-label extension study at the same doses, and this showed dose-dependent improvement of motor outcomes, with 2.0 and 6.0 mg/kg/day suggesting benefit.{{cite journal | vauthors = Hoffman EP, Schwartz BD, Mengle-Gaw LJ, Smith EC, Castro D, Mah JK, McDonald CM, Kuntz NL, Finkel RS, Guglieri M, Bushby K, Tulinius M, Nevo Y, Ryan MM, Webster R, Smith AL, Morgenroth LP, Arrieta A, Shimony M, Siener C, Jaros M, Shale P, McCall JM, Nagaraju K, van den Anker J, Conklin LS, Cnaan A, Gordish-Dressman H, Damsker JM, Clemens PR | title = Vamorolone trial in Duchenne muscular dystrophy shows dose-related improvement of muscle function | journal = Neurology | volume = 93 | issue = 13 | pages = e1312–e1323 | date = September 2019 | pmid = 31451516 | pmc = 7011869 | doi = 10.1212/WNL.0000000000008168 }} These same children continued on a long-term extension study with dose escalations, and this suggested continued clinical improvement through 18-months treatment.{{cite journal | vauthors = Smith EC, Conklin LS, Hoffman EP, Clemens PR, Mah JK, Finkel RS, Guglieri M, Tulinius M, Nevo Y, Ryan MM, Webster R, Castro D, Kuntz NL, Kerchner L, Morgenroth LP, Arrieta A, Shimony M, Jaros M, Shale P, Gordish-Dressman H, Hagerty L, Dang UJ, Damsker JM, Schwartz BD, Mengle-Gaw LJ, McDonald CM | title = Efficacy and safety of vamorolone in Duchenne muscular dystrophy: An 18-month interim analysis of a non-randomized open-label extension study | journal = PLOS Medicine | volume = 17 | issue = 9 | pages = e1003222 | date = September 2020 | pmid = 32956407 | pmc = 7505441 | doi = 10.1371/journal.pmed.1003222 | doi-access = free }}

Population pharmacokinetics (PK) of vamorolone was shown to fit to a 1-compartment model with zero-order absorption, with both adult men and young boys showing dose-linearity of PK parameters for the doses examined, and no accumulation of the drug during daily dosing. Apparent clearance averaged 2.0 L/h/kg in men and 1.7 L/h/kg in boys. Overall, vamorolone exhibited well-behaved linear PK, with similar profiles in healthy men and boys with DMD, moderate variability in PK parameters, and absorption and disposition profiles similar to those of classical glucocorticoids.{{cite journal | vauthors = Mavroudis PD, van den Anker J, Conklin LS, Damsker JM, Hoffman EP, Nagaraju K, Clemens PR, Jusko WJ | title = Population Pharmacokinetics of Vamorolone (VBP15) in Healthy Men and Boys With Duchenne Muscular Dystrophy | journal = Journal of Clinical Pharmacology | volume = 59 | issue = 7 | pages = 979–988 | date = July 2019 | pmid = 30742306 | pmc = 6548694 | doi = 10.1002/jcph.1388 }} Exposure/response analyses have suggested that the motor outcome of time to stand from supine velocity showed the highest sensitivity to vamorolone, with the lowest AUC value providing 50% of maximum effect (E50 = 186 ng·h/mL), followed by time to climb 4 stairs (E50 = 478 ng·h/mL), time to run/walk 10 m (E50 = 1220 ng·h/mL), and 6-minute walk test (E50 = 1770 ng·h/mL). Week 2 changes of proinflammatory PD biomarkers showed exposure-dependent decreases. The E50 was 260 ng·h/mL for insulin-like growth factor-binding protein 2, 1200 ng·h/mL for matrix metalloproteinase 12, 1260 ng·h/mL for lymphotoxin α1/β2, 1340 ng·h/mL for CD23, 1420 ng·h/mL for interleukin-22-binding protein, and 1600 ng·h/mL for macrophage-derived chemokine/C-C motif chemokine 22.{{cite journal | vauthors = Li X, Conklin LS, van den Anker J, Hoffman EP, Clemens PR, Jusko WJ | title = Exposure-Response Analysis of Vamorolone (VBP15) in Boys With Duchenne Muscular Dystrophy | journal = Journal of Clinical Pharmacology | volume = 60 | issue = 10 | pages = 1385–1396 | date = October 2020 | pmid = 32434278 | pmc = 7494537 | doi = 10.1002/jcph.1632 }}

A trial titled “Efficacy and Safety of Vamorolone Over 48 Weeks in Boys With Duchenne Muscular Dystrophy” published in March 2024 found vamorolone (Agamree) at a dose of 6 mg/kg/d showed maintenance of improvement for all motor outcomes to week 48. There was also significant improvement in linear growth after crossover in the prednisone to vamorolone 6 mg/kg/d group, and quick reversal of prednisone-induced decline in bone turnover biomarkers in each crossover group.{{cite web |title=Efficacy and Safety of Vamorolone Over 48 Weeks in Boys With Duchenne Muscular Dystrophy: A Randomized Controlled Trial |url=https://pubmed.ncbi.nlm.nih.gov/38335499/ |website=PubMed}}

The US Food and Drug Administration (FDA) approved vamorolone based on evidence from a single clinical trial of 121 boys with DMD who were 4 to <7 years of age. The trial (Study 1) was conducted at 33 sites in 11 countries in Australia, Belgium, Canada, the Czech Republic, Spain, the United Kingdom, Greece, Israel, Netherlands, Sweden, and the United States. In addition to Study 1, safety was also evaluated in a separate, open-label study of children with DMD aged 2 to <4 years (N=16) and children with DMD aged 7 to <18 years (N=16).

Santhera Pharmaceuticals signed an agreement with Catalyst Pharmaceuticals for the North American commercialization of vamorolone in July 2023.{{cite web |last1=Deswal |first1=Phalguni |title=Santhera and Catalyst to market DMD drug vamorolone in North America |url=https://www.pharmaceutical-technology.com/news/santhera-and-catalyst-to-market-dmd-drug-vamorolone-in-north-america/ |website=Pharmaceutical Technology}}

In October 2023, the FDA approved vamorolone (Agamree; Catalyst Pharmaceuticals) for the treatment of Duchenne muscular dystrophy.{{cite web | title=Drug Approval Package: Agamree | website=U.S. Food and Drug Administration (FDA) | date=7 November 2023 | url=https://www.accessdata.fda.gov/drugsatfda_docs/nda/2023/215239Orig1s000TOC.cfm | access-date=13 November 2023 | archive-date=13 November 2023 | archive-url=https://web.archive.org/web/20231113073626/https://www.accessdata.fda.gov/drugsatfda_docs/nda/2023/215239Orig1s000TOC.cfm | url-status=live }}{{Cite web|url=https://www.pharmacytimes.com/view/fda-approves-vamorolone-for-treatment-of-duchenne-muscular-dystrophy-in-patients-aged-2-years-and-older|title=FDA Approves Vamorolone for Treatment of Duchenne Muscular Dystrophy in Patients Aged 2 Years and Older|date=26 October 2023|website=Pharmacy Times|access-date=27 October 2023|archive-date=27 October 2023|archive-url=https://web.archive.org/web/20231027040506/https://www.pharmacytimes.com/view/fda-approves-vamorolone-for-treatment-of-duchenne-muscular-dystrophy-in-patients-aged-2-years-and-older|url-status=live}}{{cite press release | publisher=Santhera Pharmaceuticals Holding AG | title=Santhera Receives U.S. FDA Approval of Agamree (vamorolone) for the Treatment of Duchenne Muscular Dystrophy | via=GlobeNewswire | date=27 October 2023 | url=https://www.globenewswire.com/news-release/2023/10/27/2768135/0/en/Santhera-Receives-U-S-FDA-Approval-of-AGAMREE-vamorolone-for-the-Treatment-of-Duchenne-Muscular-Dystrophy.html | access-date=13 November 2023 | archive-date=31 October 2023 | archive-url=https://web.archive.org/web/20231031232903/https://www.globenewswire.com/news-release/2023/10/27/2768135/0/en/Santhera-Receives-U-S-FDA-Approval-of-AGAMREE-vamorolone-for-the-Treatment-of-Duchenne-Muscular-Dystrophy.html | url-status=live }}

In October 2023, the Committee for Medicinal Products for Human Use adopted a positive opinion, recommending the granting of a marketing authorization for the medicinal product Agamree, intended for the treatment of Duchenne muscular dystrophy. The applicant for this medicinal product is Santhera Pharmaceuticals (Deutschland) GmbH.{{cite web | title=Agamree EPAR | website=European Medicines Agency | date=12 October 2023 | url=https://www.ema.europa.eu/en/medicines/human/EPAR/agamree | access-date=27 December 2023}} Text was copied from this source which is copyright European Medicines Agency. Reproduction is authorized provided the source is acknowledged. Vamorolone was approved for medical use in the European Union in December 2023.

Vamorolone is the international nonproprietary name.{{cite journal | vauthors = ((World Health Organization)) | year = 2017 | title = International nonproprietary names for pharmaceutical substances (INN): recommended INN: list 77 | journal = WHO Drug Information | volume = 31 | issue = 1 | hdl = 10665/330984 | hdl-access = free | author-link = World Health Organization }}

Vamorolone is sold under the brand name Agamree. Agamree (vamorolone) is a dissociative steroid that selectively binds to the glucocorticoid receptor to exert anti-inflammatory and immunosuppressive effects. Vamorolone also inhibits mineralocorticoid receptor activation by aldosterone.{{cite web |title=Agamree for the Treatment of Duchenne Muscular Dystrophy, US |url=https://www.clinicaltrialsarena.com/projects/agamree-treatment-dmd-us/ |website=Clinicaltrials Arena |access-date=11 February 2025}}

{{Reflist}}

• {{ClinicalTrialsGov|NCT03439670|A Study to Assess the Efficacy and Safety of Vamorolone in Boys With Duchenne Muscular Dystrophy (DMD)}}

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