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Dalcetrapib

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Dalcetrapib
Names
IUPAC name
S-[2-({[1-(2-Ethylbutyl)cyclohexyl]carbonyl}amino)phenyl]-2-methylpropanethioate
Identifiers
3D model (JSmol)
ChEMBL
ChemSpider
ECHA InfoCard 100.250.741 Edit this at Wikidata
KEGG
UNII
  • InChI=1S/C23H35NO2S/c1-5-18(6-2)16-23(14-10-7-11-15-23)22(26)24-19-12-8-9-13-20(19)27-21(25)17(3)4/h8-9,12-13,17-18H,5-7,10-11,14-16H2,1-4H3,(H,24,26)
    Key: YZQLWPMZQVHJED-UHFFFAOYSA-N
  • InChI=1/C23H35NO2S/c1-5-18(6-2)16-23(14-10-7-11-15-23)22(26)24-19-12-8-9-13-20(19)27-21(25)17(3)4/h8-9,12-13,17-18H,5-7,10-11,14-16H2,1-4H3,(H,24,26)
    Key: YZQLWPMZQVHJED-UHFFFAOYAR
  • O=C(Sc1ccccc1NC(=O)C2(CC(CC)CC)CCCCC2)C(C)C
  • CCC(CC)CC1(CCCCC1)C(=O)NC2=CC=CC=C2SC(=O)C(C)C
Properties
C23H35NO2S
Molar mass 389.5945
Except where otherwise noted, data are given for materials in their standard state (at 25 °C [77 °F], 100 kPa).

DalCor is currently conducting the Dal-GenE-2 confirmatory trial with dalcetrapib and placebo in North America under a Special Protocol Assessment (SPA) agreement with the U.S. Food and Drug Administration (FDA).[1]

Dal-GenE-2 (Dal-302), a phase III, double-blind, randomized placebo-controlled study, will evaluate the potential of dalcetrapib to reduce the occurrence of fatal and non-fatal myocardial infarction (MI) in approximately 2,000 patients with a documented recent acute coronary syndrome (ACS) and the AA genotype at variant rs1967309 in the ADCY9 gene.[1]

Based on a genetic discovery from a study called dal-OUTCOMES,[2] that suggested patients with a recent acute coronary syndrome and a specific AA genotype in a gene called ADCY9 may gain a potential benefit for future cardiovascular events such as heart attack and stroke, a study called Dal-GenE[3] trial was performed by DalCor Pharmaceuticals to validate these observations. This specific AA genotype is carried by approximately 20% of the total population and up to 40% in people of African descent.

Dal-GenE[3] was a randomized placebo-controlled study to evaluate the effects of dalcetrapib versus placebo on cardiovascular risk in patients with a recent acute coronary syndrome bearing this potentially protective AA genotype.  Eligible patients were optimally treated for their cardiovascular risk factors such as diabetes, hypertension and elevated LDL cholesterol. The prespecified primary endpoint was time-to-first event for the composite of cardiovascular death, resuscitated cardiac arrest, non- fatal myocardial infarction (MI) or non-fatal stroke.

The results published in 2022 showed that dalcetrapib did not significantly reduce the risk of occurrence of the primary endpoint of ischaemic cardiovascular events at end of study in patients with an acute coronary syndrome within 1–3 months of randomization and the AA genotype at variant rs1967309 in the ADCY9 gene.However, the results of the dal-GenE trial showed a 21% relative risk reduction (RRR) in fatal and non-fatal MI in 6,149 patients across 34 countries, and a 45% RRR for the same endpoint in 1,200 patients in North America and further confirmed the safety profile of dalcetrapib.[3]

Dalcetrapib[4] (INN, codenamed JTT-705) is a CETP inhibitor which was originally being developed by F. Hoffmann–La Roche until May 2012.[5] [6] DalCor Pharmaceuticals licensed dalcetrapib as a potential pioneering precision medicine for patients with cardiovascular disease. By combining genetic and clinical insights into the development program, dalcetrapib is intended to reduce fatal and non-fatal myocardial infarction (MI) following a recent acute coronary syndrome (ACS) and deliver superior cardiovascular outcome in a specific genetic subset of patients. A companion diagnostic test, developed in conjunction with Roche Diagnostics, identifies patients with the specific genotype, AA genotype at variant rs1967309 in the adenylate cyclase type 9 (ADCY9), who may potentially benefit from dalcetrapib treatment.

The drug was initially aimed at raising the blood levels of HDL cholesterol.[7] Prevailing observations indicate that high HDL-C levels correlate with better overall cardiovascular health, though it remains unclear whether pharmacologically raising HDL-C levels consequently leads to a benefit in cardiovascular health.[8]

F. Hoffmann-La Roche conducted the dal-OUTCOMES phase III trial which was halted in 2012 “due to a lack of clinically meaningful efficacy.”[6] The results of dal-OUTCOMES were published in November 2012.Subsequently,  a pharmacogenomic genome-wide association study (GWAS) conducted by the Montreal Heart Institute reported that patients from the dal-OUTCOMES study bearing a protective allele, the AA genotype, at SNP rs1967309 in the ADCY9 gene may have benefited from dalcetrapib therapy.[9] Changes in inflammation and cholesterol efflux capacity observed in these patients may in part explain the benefits associated with the protective genotype. These findings led to DalCor Pharmaceuticals conducting the dal-GenE[3] and Dal-GenE-2[1] trials described above.

See also

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References

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  1. ^ a b c "Effect of Dalcetrapib vs Placebo on CV Risk in a Genetically Defined Population With a Recent ACS (dal-GenE)". ClinicalTrials.gov (Information provided by DalCor Pharmaceuticals). Retrieved 6 October 2024.
  2. ^ Schwartz, Gregory G.; Olsson, Anders G.; Abt, Markus; Ballantyne, Christie M.; Barter, Philip J.; Brumm, Jochen; Chaitman, Bernard R.; Holme, Ingar M.; Kallend, David; Leiter, Lawrence A.; Leitersdorf, Eran; McMurray, John J.V.; Mundl, Hardi; Nicholls, Stephen J.; Shah, Prediman K. (29 November 2012). "Effects of Dalcetrapib in Patients with a Recent Acute Coronary Syndrome" (PDF). New England Journal of Medicine. 367 (22): 2089–2099. doi:10.1056/NEJMoa1206797. ISSN 0028-4793.
  3. ^ a b c d Tardif, Jean Claude; Pfeffer, Marc A.; Kouz, Simon; Koenig, Wolfgang; Maggioni, Aldo P.; McMurray, John J. V.; Mooser, Vincent; Waters, David D.; Grégoire, Jean C.; L'Allier, Philippe L.; Wouter Jukema, J.; White, Harvey D.; Heinonen, Therese; Black, Donald M.; Laghrissi-Thode, Fouzia (14 October 2022). "Pharmacogenetics-guided dalcetrapib therapy after an acute coronary syndrome: the dal-GenE trial". European Heart Journal. 43 (39): 3947–3956. doi:10.1093/eurheartj/ehac374. ISSN 1522-9645. PMC 9565632. PMID 35856777.
  4. ^ "International Nonproprietary Names for Pharmaceutical Substances (INN). Recommended International Nonproprietary Names: List 58" (PDF). World Health Organization. pp. 250–1. Retrieved 3 January 2017.
  5. ^ Huang Z; Inazu A; Nohara A; Higashikata T; Mabuchi H (December 2002). "Cholesteryl ester transfer protein inhibitor (JTT-705) and the development of atherosclerosis in rabbits with severe hypercholesterolaemia". Clin. Sci. 103 (6): 587–594. doi:10.1042/cs1030587. hdl:2297/15762. PMID 12444911. S2CID 22400248.
  6. ^ a b Simeon Bennett & Naomi Kresge. "Roche Drops After Halting Cholesterol Drug Development". Bloomberg.
  7. ^ Michelle Fay Cortez (5 November 2012), "Roche's Good Cholesterol Drug Shows Negative Side Effects", Bloomberg Businessweek, archived from the original on 8 November 2012, retrieved 6 November 2012
  8. ^ "NIH stops clinical trial on combination cholesterol treatment". National Institute of Health. NHLBI. Retrieved 2 June 2011.
  9. ^ Tardif, Jean-Claude; Rhéaume, Eric; Lemieux Perreault, Louis-Philippe; Grégoire, Jean C.; Feroz Zada, Yassamin; Asselin, Géraldine; Provost, Sylvie; Barhdadi, Amina; Rhainds, David (1 April 2015). "Pharmacogenomic determinants of the cardiovascular effects of dalcetrapib". Circulation: Cardiovascular Genetics. 8 (2): 372–382. doi:10.1161/CIRCGENETICS.114.000663. ISSN 1942-3268. PMID 25583994.
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