Corticosteroid Hormone Receptor

At dosages of 1 nM or greater, vamorolone (VBP15) suppresses TNFα-induced pro-inflammatory NF-κB activation in C2C12 ablated cells. Human macrophages that are exposed to vamorolone (0.1, 1 μM) for 30 minutes produce less IL1β and CCL5 mediators in their main tissue [2]. Today's dissociative glucose requirement (GR) ligand and mineralocorticoid receptor (MR)-restricted antagonist is vamorolone [3].

When compared to pharmaceutical glucocorticoids, vamolodone (5–30 mg/kg; Cherry) has been demonstrated to cause more substantial side effects in MDX [1]. In mice with experimental autoimmune encephalitis, vamolodone (30 mg/kg; lateral; once daily for 20 days) decreases inflammation of the central nervous system [2].

Animal/Disease Models: C57BL/6 mice (experimental autoimmune encephalomyelitis) [2]
Doses: 30 mg/kg one time/day for 20 days (starting the day before MOG 33-55 peptide immunization and continuing)
Experimental Results: Small diminished central nervous system inflammation in murine experimental autoimmune encephalomyelitis.

Absorption, Distribution and Excretion
When taken with food, the median Tmax of vamorolone is approximately 2 hours. Taking vamorolone with a high-fat, high-calorie diet decreases Cmax by 18%, increases AUC by 13%, and delays Tmax by 1 hour. Taking vamorolone with a low-fat, low-calorie meal decreases Cmax by 4%, increases AUC by 14%, and delays Tmax by 1 hour. Approximately 30% of the vamorolone dose is excreted in feces (15.4% unchanged) and 48% in urine (<1% unchanged). Based on population pharmacokinetic analysis, the apparent volume of distribution of vamorolone taken with food is 162 L for a 20 kg DMD patient. Based on population pharmacokinetic analysis, the clearance of vamorolone taken with food is 58 L/h for a 20 kg DMD patient.
Metabolism/Metabolites
Vamorolone can be metabolized through multiple pathways, including glucuronidation, hydroxylation, and reduction. Its metabolism is primarily mediated by CYP3A4, CYP3A5, CYP2C8, UGT1A3, UGT2B7, and UGT2B17. Glucuronide—formed through direct glucuronidation and hydrogenation followed by re-glucuronidation—is the main metabolite in plasma and urine.

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Biological Half-Life
The terminal elimination half-life of vamorolone is approximately 2 hours.

Protein Binding
vamorolone exhibits an in vitro protein binding rate of 88.1%.

[1]. VBP15, a novel anti-inflammatory and membrane-stabilizer, improves muscular dystrophy without side effects. EMBO Mol Med. 2013 Oct;5(10):1569-85.

[2]. VBP15, a novel anti-inflammatory, is effective at reducing the severity of murine experimental autoimmune encephalomyelitis. Cell Mol Neurobiol. 2015 Apr;35(3):377-387.

[3]. Vamorolone targets dual nuclear receptors to treat inflammation and dystrophic cardiomyopathy. Life Sci Alliance. 2019 Feb 11;2(1). pii: e201800186.

Vamorolone is a 3-oxo-Δ(1),Δ(4)-steroid with the structure pregnath-1,4,9(11)-trien-17-ol, substituted at positions 3, 20, and 21 with oxo, hydroxyl, and hydroxyl groups, respectively. It has been approved by the U.S. Food and Drug Administration (FDA) for the treatment of patients aged 2 years and older with Duchenne muscular dystrophy. Vamorolone has anti-inflammatory, immunosuppressive, and glucocorticoid receptor agonist effects. It is a corticosteroid, a 3-oxo-Δ(1),Δ(4)-steroid, a 20-oxosteroid, a 17α-hydroxysteroid, a 21-hydroxysteroid, a primary α-hydroxy ketone, and a tertiary α-hydroxy ketone. Vamorolone is a novel, fully synthetic glucocorticoid developed by Santhera Pharmaceuticals. It is used to treat inflammation and immune dysregulation in patients with Duchenne muscular dystrophy (DMD). Duchenne muscular dystrophy (DMD) is a neuromuscular disease characterized by progressive neuromuscular degeneration and is the most common type of muscular dystrophy in the United States. Despite a relatively high incidence of adverse reactions, corticosteroid therapy remains the standard treatment for DMD. Due to its unique receptor-binding properties, Vamorolone has a more tolerable spectrum of adverse reactions compared to other corticosteroids, thus providing a new treatment option for patients who cannot tolerate or accept the adverse effects of corticosteroids. Vamorolone was approved by the US FDA in October 2023 for the treatment of Duchenne muscular dystrophy (DMD) in patients aged 2 years and older. In December 2023, it was approved in the European Union for the treatment of patients aged 4 years and older. Vamorolone is a corticosteroid. Its mechanism of action is as a corticosteroid hormone receptor agonist. Vamorolone is indicated for the treatment of Duchenne muscular dystrophy (DMD) in patients aged 2 years and older in the United States and in patients aged 4 years and older in the European Union.
Treatment of Duchenne Muscular Dystrophy

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Mechanism of Action
Vamorolone is a synthetic corticosteroid that acts as a glucocorticoid receptor agonist, exerting anti-inflammatory and immunosuppressive effects. It is also a mineralocorticoid receptor antagonist. The exact mechanism by which vamorolone exerts its therapeutic effect in patients with DMD is unclear.

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Pharmacodynamics
In clinical studies, vamorolone treatment resulted in a dose-dependent decrease in morning cortisol levels and a dose-dependent increase in white blood cell and lymphocyte counts.

C22H28O4

356.45532

356.199

C, 74.13; H, 7.92; O, 17.95

13209-41-1

13209-41-1; 10106-41-9 (acetate)

3035000

White to yellow solid powder

1.24g/cm3

548.3ºC at 760 mmHg

299.4ºC

2.63E-14mmHg at 25°C

1.603

2.752

2

4

2

26

775

6

C[C@@H]1C[C@H]2[C@@H]3CCC4=CC(=O)C=C[C@@]4(C3=CC[C@@]2([C@]1(C(=O)CO)O)C)C

ZYTXTXAMMDTYDQ-DGEXFFLYSA-N

InChI=1S/C22H28O4/c1-13-10-18-16-5-4-14-11-15(24)6-8-20(14,2)17(16)7-9-21(18,3)22(13,26)19(25)12-23/h6-8,11,13,16,18,23,26H,4-5,9-10,12H2,1-3H3/t13-,16-,18+,20+,21+,22+/m1/s1

(8S,10S,13S,14S,16R,17R)-17-hydroxy-17-(2-hydroxyacetyl)-10,13,16-trimethyl-7,8,12,14,15,16-hexahydro-6H-cyclopenta[a]phenanthren-3-one

Agamree; vamorolone; 13209-41-1; 17,21-Dihydroxy-16alpha-methylpregna-1,4,9(11)-triene-3,20-dione; VBP-15 free alcohol;

2934.99.9001

Powder      -20°C    3 years

                     4°C     2 years

In solvent   -80°C    6 months

                  -20°C    1 month

Room temperature (This product is stable at ambient temperature for a few days during ordinary shipping and time spent in Customs)

DMSO : ~62.5 mg/mL (~175.34 mM)

Solubility in Formulation 1: ≥ 2.08 mg/mL (5.84 mM) (saturation unknown) in 10% DMSO + 40% PEG300 + 5% Tween80 + 45% Saline (add these co-solvents sequentially from left to right, and one by one), clear solution.
For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 20.8 mg/mL clear DMSO stock solution to 400 μL PEG300 and mix evenly; then add 50 μL Tween-80 to the above solution and mix evenly; then add 450 μL normal saline to adjust the volume to 1 mL.
Preparation of saline: Dissolve 0.9 g of sodium chloride in 100 mL ddH₂ O to obtain a clear solution.

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Solubility in Formulation 2: ≥ 2.08 mg/mL (5.84 mM) (saturation unknown) in 10% DMSO + 90% (20% SBE-β-CD in Saline) (add these co-solvents sequentially from left to right, and one by one), clear solution.
For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 20.8 mg/mL clear DMSO stock solution to 900 μL of 20% SBE-β-CD physiological saline solution and mix evenly.
Preparation of 20% SBE-β-CD in Saline (4°C，1 week): Dissolve 2 g SBE-β-CD in 10 mL saline to obtain a clear solution.

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Solubility in Formulation 3: ≥ 2.08 mg/mL (5.84 mM) (saturation unknown) in 10% DMSO + 90% Corn Oil (add these co-solvents sequentially from left to right, and one by one), clear solution.
For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 20.8 mg/mL clear DMSO stock solution to 900 μL of corn oil and mix evenly.

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 (Please use freshly prepared in vivo formulations for optimal results.)