Vamorolone

Vamorolone (developmental code names VBP-15) is a synthetic steroid, which is under development for the treatment of Duchenne muscular dystrophy.[1][2][3][4][5]

vamorolone
Clinical data
Other namesVBP; VBP-15; 17α,21-Dihydroxy-16α-methylpregna-1,4,9(11)-triene-3,20-dione
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-cyclopenta[a]phenanthren-3-one
CAS Number
PubChem CID
ChemSpider
UNII
KEGG
ChEMBL
CompTox Dashboard (EPA)
ECHA InfoCard100.032.874
Chemical and physical data
FormulaC22H28O4
Molar mass356.462 g·mol−1
3D model (JSmol)
SMILES
  • 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
  • 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

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 delta9,11 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 lead to dissociative properties.[6] Vamorolone is a partial agonist of the glucocorticoid receptor (NR3C1) with relative loss of transactivation activities, but retention of transrepression activities, compared to corticosteroidal drugs. In contrast to drugs of the corticosteroid class, vamorolone is a potent antagonist of the mineralocorticoid receptor (NR3C2).[7]

In Phase 1 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[8]

In Phase 2a 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.[9] 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.[10] These same children continued on a long-term extension study with dose escalations, and this suggested continued clinical improvement through 18-months treatment.[11]

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.[12] 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.[13]

References
  1. "Vamorolone - ReveraGen Biopharma". AdisInsight.
  2. 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.
  3. Heier CR, Damsker JM, Yu Q, Dillingham BC, Huynh T, Van der Meulen JH, Sali A, Miller BK, Phadke A, Scheffer L, Quinn J, Tatem K, Jordan S, Dadgar S, Rodriguez OC, Albanese C, Calhoun M, Gordish-Dressman H, Jaiswal JK, Connor EM, McCall JM, Hoffman EP, Reeves EK, Nagaraju K (October 2013). "VBP15, a novel anti-inflammatory and membrane-stabilizer, improves muscular dystrophy without side effects". EMBO Molecular Medicine. 5 (10): 1569–85. doi:10.1002/emmm.201302621. PMC 3799580. PMID 24014378.
  4. Dadgar S, Wang Z, Johnston H, Kesari A, Nagaraju K, Chen YW, Hill DA, Partridge TA, Giri M, Freishtat RJ, Nazarian J, Xuan J, Wang Y, Hoffman EP (October 2014). "Asynchronous remodeling is a driver of failed regeneration in Duchenne muscular dystrophy". The Journal of Cell Biology. 207 (1): 139–58. doi:10.1083/jcb.201402079. PMC 4195829. PMID 25313409.
  5. Damsker JM, Conklin LS, Sadri S, Dillingham BC, Panchapakesan K, Heier CR, McCall JM, Sandler AD (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): 737–43. doi:10.1007/s00011-016-0956-8. PMID 27261270. S2CID 18698831.
  6. Liu, Xu; Wang, Yashuo; Gutierrez, Jennifer S.; Damsker, Jesse M.; Nagaraju, Kanneboyina; Hoffman, Eric P.; Ortlund, Eric A. (29 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. doi:10.1073/pnas.2006890117. ISSN 1091-6490. PMC 7533876. PMID 32917814.
  7. Heier, Christopher R.; Yu, Qing; Fiorillo, Alyson A.; Tully, Christopher B.; Tucker, Asya; Mazala, Davi A.; Uaesoontrachoon, Kitipong; Srinivassane, Sadish; Damsker, Jesse M.; Hoffman, Eric P.; Nagaraju, Kanneboyina (February 2019). "Vamorolone targets dual nuclear receptors to treat inflammation and dystrophic cardiomyopathy". Life Science Alliance. 2 (1): e201800186. doi:10.26508/lsa.201800186. ISSN 2575-1077. PMC 6371196. PMID 30745312.
  8. Hoffman EP, Riddle V, Siegler MA, Dickerson D, Backonja M, Kramer WG, Nagaraju K, Gordish-Dressman H, Damsker JM, McCall JM (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.
  9. 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 (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.
  10. Hoffman, Eric P.; Schwartz, Benjamin D.; Mengle-Gaw, Laurel J.; Smith, Edward C.; Castro, Diana; Mah, Jean K.; McDonald, Craig M.; Kuntz, Nancy L.; Finkel, Richard S.; Guglieri, Michela; Bushby, Katharine (24 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. ISSN 1526-632X. PMC 7011869. PMID 31451516.
  11. Smith, Edward C.; Conklin, Laurie S.; Hoffman, Eric P.; Clemens, Paula R.; Mah, Jean K.; Finkel, Richard S.; Guglieri, Michela; Tulinius, Mar; Nevo, Yoram; Ryan, Monique M.; Webster, Richard (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. ISSN 1549-1676. PMC 7505441. PMID 32956407.
  12. Mavroudis, Panteleimon D.; van den Anker, John; Conklin, Laurie S.; Damsker, Jesse M.; Hoffman, Eric P.; Nagaraju, Kanneboyina; Clemens, Paula R.; Jusko, William J. (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. ISSN 1552-4604. PMC 6548694. PMID 30742306.
  13. Li, Xiaonan; Conklin, Laurie S.; van den Anker, John; Hoffman, Eric P.; Clemens, Paula R.; Jusko, William J. (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. ISSN 1552-4604. PMC 7494537. PMID 32434278.
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