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Vamorolone

Clinical data
Trade names	Agamree
Other names	VBP; VBP-15; 17α,21-Dihydroxy-16α-methylpregna-1,4,9(11)-triene-3,20-dione
AHFS/Drugs.com	Monograph
MedlinePlus	a624005
License data	US DailyMed: Vamorolone
Routes of administration	By mouth
ATC code	H02AB18 (WHO)
Legal status
Legal status	US: ℞-only EU: Rx-only
Identifiers
IUPAC name (8S,10S,13S,14S,16R,17R)-17-Hydroxy-17-(2-hydroxyacetyl)-10,13,16-trimethyl-7,8,12,14,15,16-hexahydro-6H-cyclopentaphenanthren-3-one
CAS Number	13209-41-1
PubChem CID	3035000
DrugBank	DB15114
ChemSpider	2299335
UNII	8XP29XMB43
KEGG	D11000
ChEBI	CHEBI:228304
ChEMBL	ChEMBL2348780
CompTox Dashboard (EPA)	DTXSID60927527
ECHA InfoCard	100.032.874
Chemical and physical data
Formula	C22H28O4
Molar mass	356.462 g·mol
3D model (JSmol)	Interactive image
SMILES C1C23CCC4=CC(=O)C=C4(C3=CC2(1(C(=O)CO)O)C)C
InChI 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 Key:ZYTXTXAMMDTYDQ-DGEXFFLYSA-N

Vamorolone, sold under the brand name Agamree, is a synthetic corticosteroid, which is used for the treatment of Duchenne muscular dystrophy. It is taken by mouth. It is a dual atypical glucocorticoid and antimineralocorticoid.

The most common adverse reactions include cushingoid features, psychiatric disorders, vomiting, increased weight, and vitamin D deficiency.

Vamorolone was approved for medical use in the United States in October 2023, and in the European Union in December 2023.

Medical uses

Vamorolone is indicated for the treatment of Duchenne muscular dystrophy.

Available forms

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

Side effects

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.

Pharmacology

Pharmacodynamics

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.

Chemistry

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 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.

History

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.

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. 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. These same children continued on a long-term extension study with dose escalations, and this suggested continued clinical improvement through 18-months treatment.

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. 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.

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).

Society and culture

Legal status

In October 2023, the FDA approved vamorolone (Agamree; Santhera Pharmaceuticals) for the treatment of Duchenne muscular dystrophy.

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. Vamorolone was approved for medical use in the European Union in December 2023.

Brand names

Vamorolone is the international nonproprietary name.

Vamorolone is sold under the brand name Agamree.

References

1. ^ "Agamree- vamorolone kit". DailyMed. 26 October 2023. Retrieved 20 November 2023.
2. ^ "Agamree EPAR". European Medicines Agency. 12 October 2023. Retrieved 27 December 2023. Text was copied from this source which is copyright European Medicines Agency. Reproduction is authorized provided the source is acknowledged.
3. ^ "Agamree Product information". Union Register of medicinal products. 15 December 2023. Retrieved 26 December 2023.
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6. Heier CR, Damsker JM, Yu Q, Dillingham BC, Huynh T, Van der Meulen JH, et al. (October 2013). "VBP15, a novel anti-inflammatory and membrane-stabilizer, improves muscular dystrophy without side effects". EMBO Molecular Medicine. 5 (10): 1569–1585. doi:10.1002/emmm.201302621. PMC 3799580. PMID 24014378.
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10. ^ "Drug Trials Snapshots: Agamree". U.S. Food and Drug Administration (FDA). 16 February 2024. Retrieved 14 March 2024. This article incorporates text from this source, which is in the public domain.
11. ^ "Drug Approval Package: Agamree". U.S. Food and Drug Administration (FDA). 7 November 2023. Archived from the original on 13 November 2023. Retrieved 13 November 2023.
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13. Hoffman EP, Riddle V, Siegler MA, Dickerson D, Backonja M, Kramer WG, et al. (June 2018). "Phase 1 trial of vamorolone, a first-in-class steroid, shows improvements in side effects via biomarkers bridged to clinical outcomes". Steroids. 134: 43–52. doi:10.1016/j.steroids.2018.02.010. PMC 6136660. PMID 29524454.
14. Conklin LS, Damsker JM, Hoffman EP, Jusko WJ, Mavroudis PD, Schwartz BD, et al. (October 2018). "Phase IIa trial in Duchenne muscular dystrophy shows vamorolone is a first-in-class dissociative steroidal anti-inflammatory drug". Pharmacological Research. 136: 140–150. doi:10.1016/j.phrs.2018.09.007. PMC 6218284. PMID 30219580.
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19. "FDA Approves Vamorolone for Treatment of Duchenne Muscular Dystrophy in Patients Aged 2 Years and Older". Pharmacy Times. 26 October 2023. Archived from the original on 27 October 2023. Retrieved 27 October 2023.
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External links

• Clinical trial number NCT03439670 for "A Study to Assess the Efficacy and Safety of Vamorolone in Boys With Duchenne Muscular Dystrophy (DMD)" at ClinicalTrials.gov

• Medicine

• Antimineralocorticoids
• Diketones
• Diols
• Glucocorticoids
• Orphan drugs
• Pregnanes
• Muscle stabilizers
• Muscle protectors