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Trade names | Agamree |
Other names | VBP; VBP-15; 17α,21-Dihydroxy-16α-methylpregna-1,4,9(11)-triene-3,20-dione |
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Routes of administration | By mouth |
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CompTox Dashboard (EPA) | |
ECHA InfoCard | 100.032.874 |
Chemical and physical data | |
Formula | C22H28O4 |
Molar mass | 356.462 g·mol−1 |
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Vamorolone, sold under the brand name Agamree, is a synthetic corticosteroid, which is used for the treatment of Duchenne muscular dystrophy.[4][5][6][7][8] It is taken by mouth.[1]
Vamorolone has anti-inflammatory and immunosuppressive effects as well as other glucocorticoid effects but is thought to lack certain other effects typical of glucocorticoids.[9][1]
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.[1] It is a dual atypical glucocorticoid and antimineralocorticoid.[9]
Vamorolone was approved for medical use in the United States in October 2023,[10] and in the European Union in December 2023.[2][3]
Vamorolone is indicated for the treatment of Duchenne muscular dystrophy.[1]
Vamorolone is provided in the form of an oral suspension at a concentration of 40 mg/mL.[1]
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.[1] The psychiatric disorders that occurred more frequently than with placebo included abnormal behavior, aggression, agitation, anxiety, irritability, altered mood, sleep disorder, and stereotypy.[1] 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.[1] Vamorolone also shows immunosuppression and is expected to increase the risk of infection, among various other potential adverse effects.[1]
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.[9] In contrast to other corticosteroids, vamorolone is a potent antagonist of the mineralocorticoid receptor and hence has antimineralocorticoid activity.[9]
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 Δ9,11 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.[11]
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.[12]
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.[13] 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.[14] These same children continued on a long-term extension study with dose escalations, and this suggested continued clinical improvement through 18-months treatment.[15]
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.[16] 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.[17]
In October 2023, the US Food and Drug Administration (FDA) approved vamorolone (Agamree; Santhera Pharmaceuticals) for the treatment of Duchenne muscular dystrophy.[10][18][19]
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.[2] The applicant for this medicinal product is Santhera Pharmaceuticals (Deutschland) GmbH.[2]
Vamorolone was approved for medical use in the United States in October 2023,[10] and in the European Union in December 2023.[2][3]
Vamorolone is the international nonproprietary name.[20]