Vamorolone
Clinical data
Trade namesAgamree
Other namesVBP; VBP-15; 17α,21-Dihydroxy-16α-methylpregna-1,4,9(11)-triene-3,20-dione
License data
Routes of
administration
By mouth
ATC code
Legal status
Legal status
Identifiers
  • (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
CAS Number
PubChem CID
ChemSpider
UNII
KEGG
ChEBI
ChEMBL
CompTox Dashboard (EPA)
ECHA InfoCard100.032.874
Chemical and physical data
FormulaC22H28O4
Molar mass356.462 g·mol−1
3D model (JSmol)
  • 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
  • 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.[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]

Medical uses

Vamorolone is indicated for the treatment of Duchenne muscular dystrophy.[1]

Available forms

Vamorolone is provided in the form of an oral suspension at a concentration of 40 mg/mL.[1]

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.[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]

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.[9] In contrast to other corticosteroids, vamorolone is a potent antagonist of the mineralocorticoid receptor and hence has antimineralocorticoid activity.[9]

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 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]

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.[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]

Society and culture

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]

Brand names

Vamorolone is the international nonproprietary name.[20]

Vamorolone is sold under the brand name Agamree.[1][2][3]

References

  1. 1 2 3 4 5 6 7 8 9 10 11 "Agamree- vamorolone kit". DailyMed. 26 October 2023. Retrieved 20 November 2023.
  2. 1 2 3 4 5 6 "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. 1 2 3 4 "Agamree Product information". Union Register of medicinal products. 15 December 2023. Retrieved 26 December 2023.
  4. "Vamorolone - ReveraGen Biopharma". AdisInsight. Springer Nature Switzerland AG. Archived from the original on 7 October 2017. Retrieved 2 July 2017.
  5. Reeves EK, Hoffman EP, Nagaraju K, Damsker JM, McCall JM (April 2013). "VBP15: preclinical characterization of a novel anti-inflammatory delta 9,11 steroid". Bioorganic & Medicinal Chemistry. 21 (8): 2241–2249. doi:10.1016/j.bmc.2013.02.009. PMC 4088988. PMID 23498916.
  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.{{cite journal}}: CS1 maint: overridden setting (link)
  7. Dadgar S, Wang Z, Johnston H, Kesari A, Nagaraju K, Chen YW, et al. (October 2014). "Asynchronous remodeling is a driver of failed regeneration in Duchenne muscular dystrophy". The Journal of Cell Biology. 207 (1): 139–158. doi:10.1083/jcb.201402079. PMC 4195829. PMID 25313409.{{cite journal}}: CS1 maint: overridden setting (link)
  8. Damsker JM, Conklin LS, Sadri S, Dillingham BC, Panchapakesan K, Heier CR, et al. (September 2016). "VBP15, a novel dissociative steroid compound, reduces NFκB-induced expression of inflammatory cytokines in vitro and symptoms of murine trinitrobenzene sulfonic acid-induced colitis". Inflammation Research. 65 (9): 737–743. doi:10.1007/s00011-016-0956-8. PMID 27261270. S2CID 18698831.{{cite journal}}: CS1 maint: overridden setting (link)
  9. 1 2 3 4 Heier CR, Yu Q, Fiorillo AA, Tully CB, Tucker A, Mazala DA, et al. (February 2019). "Vamorolone targets dual nuclear receptors to treat inflammation and dystrophic cardiomyopathy". Life Sci Alliance. 2 (1): e201800186. doi:10.26508/lsa.201800186. PMC 6371196. PMID 30745312.
  10. 1 2 3 "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.
  11. Liu X, Wang Y, Gutierrez JS, Damsker JM, Nagaraju K, Hoffman EP, et al. (September 2020). "Disruption of a key ligand-H-bond network drives dissociative properties in vamorolone for Duchenne muscular dystrophy treatment". Proceedings of the National Academy of Sciences of the United States of America. 117 (39): 24285–24293. Bibcode:2020PNAS..11724285L. doi:10.1073/pnas.2006890117. PMC 7533876. PMID 32917814.
  12. 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.{{cite journal}}: CS1 maint: overridden setting (link)
  13. 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.{{cite journal}}: CS1 maint: overridden setting (link)
  14. Hoffman EP, Schwartz BD, Mengle-Gaw LJ, Smith EC, Castro D, Mah JK, et al. (September 2019). "Vamorolone trial in Duchenne muscular dystrophy shows dose-related improvement of muscle function". Neurology. 93 (13): e1312–e1323. doi:10.1212/WNL.0000000000008168. PMC 7011869. PMID 31451516.{{cite journal}}: CS1 maint: overridden setting (link)
  15. Smith EC, Conklin LS, Hoffman EP, Clemens PR, Mah JK, Finkel RS, et al. (September 2020). "Efficacy and safety of vamorolone in Duchenne muscular dystrophy: An 18-month interim analysis of a non-randomized open-label extension study". PLOS Medicine. 17 (9): e1003222. doi:10.1371/journal.pmed.1003222. PMC 7505441. PMID 32956407.{{cite journal}}: CS1 maint: overridden setting (link)
  16. Mavroudis PD, van den Anker J, Conklin LS, Damsker JM, Hoffman EP, Nagaraju K, et al. (July 2019). "Population Pharmacokinetics of Vamorolone (VBP15) in Healthy Men and Boys With Duchenne Muscular Dystrophy". Journal of Clinical Pharmacology. 59 (7): 979–988. doi:10.1002/jcph.1388. PMC 6548694. PMID 30742306.{{cite journal}}: CS1 maint: overridden setting (link)
  17. Li X, Conklin LS, van den Anker J, Hoffman EP, Clemens PR, Jusko WJ (October 2020). "Exposure-Response Analysis of Vamorolone (VBP15) in Boys With Duchenne Muscular Dystrophy". Journal of Clinical Pharmacology. 60 (10): 1385–1396. doi:10.1002/jcph.1632. PMC 7494537. PMID 32434278.
  18. "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.
  19. "Santhera Receives U.S. FDA Approval of Agamree (vamorolone) for the Treatment of Duchenne Muscular Dystrophy" (Press release). Santhera Pharmaceuticals Holding AG. 27 October 2023. Archived from the original on 31 October 2023. Retrieved 13 November 2023 via GlobeNewswire.
  20. World Health Organization (2017). "International nonproprietary names for pharmaceutical substances (INN): recommended INN: list 77". WHO Drug Information. 31 (1). hdl:10665/330984.
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