dalcetrapib (JTT-705) / DalCor - LARVOL DELTA

Molecular genetic basis of the primary emotions in young adults: an exploratory analysis of genetic polymorphisms across dopamine, serotonin, oxytocin, endogenous opioid, and neurotrophic factor pathways. (PubMed, Front Pharmacol) - "Following the survey, participants provided buccal swabs and their DNA was genotyped for 14 single nucleotide polymorphisms across five genes relevant to KEGG pathways, including dopamine (COMT rs4680, rs165815), serotonin (TPH2 rs1843809, rs4290270, rs7305115, rs4570625), oxytocin (OXTR rs53576, rs968389, rs2268498), endogenous opioid (OPRM1 rs1799971, rs677830), and neurotrophic factor (BDNF rs6265, rs28722151, rs11030101)...Overall, the present study identified several novel candidate genes which might be related to primary emotions in a sample of young adults. Although our findings should be considered preliminary, they may have important implications for personality research as well as clinical practice."

Journal • BDNF • COMT • OPRM1

Towards Precision Secondary Prevention: Pharmacogenetic Insights from the Dalcetrapib-ADCY9 Pathway. (PubMed, Eur J Prev Cardiol) - No abstract available

Biomarker • Journal

Future myocardial infarction after an acute coronary syndrome and pharmacogenetic response to dalcetrapib. (PubMed, Eur J Prev Cardiol) - "Despite guideline directed therapy following ACS, history of prior coronary events and on-treatment LDL-C, A1c, hs-CRP and blood pressure remain determinants of future MI. In the Dal-GenE AA genotype patients, dalcetrapib reduced the rate of MI, independently of those variables. The Dal-GenE 2 trial is designed to confirm this pharmacogenetic hypothesis."

Biomarker • Journal • Acute Coronary Syndrome • Cardiovascular • Myocardial Infarction

Comparative Effectiveness of Cholesteryl Ester Transfer Protein (CETP) Inhibitors on Lipid Profiles in Adults With Hyperlipidemia: A Comprehensive Systematic Review and Frequentist Network Meta-Analysis of Randomized Controlled Trials. (PubMed, Clin Cardiol) - "CETP inhibitors, particularly anacetrapib and obicetrapib combined with statins, significantly improve lipid profiles, offering potential therapeutic benefits for hyperlipidemia management and cardiovascular risk reduction."

HEOR • Journal • Retrospective data • Review • Cardiovascular • Dyslipidemia

Low HDL-The Challenge. (PubMed, Clin Med Res) - "Several products were tested in large controlled studies, such as dalcetrapib and evacetrapib; neither resulted in any clinical benefit. Anacetrapib only resulted in very limited benefit and is no longer under active development...There was no benefit in the primary end point of myocardial infarction, stroke, or death. In patients with low HDL, a strategy of having LDL as low as can be possibly achieved may be the most appropriate approach."

Journal • Review • Atherosclerosis • Cardiovascular • Coronary Artery Disease • Dyslipidemia • Metabolic Disorders • Myocardial Infarction • Tobacco Cessation • APOA1

Effect of dalcetrapib, voxelotor and their combination on red blood cell deformability and sickling in sickle cell disease. (PubMed, Clin Hemorheol Microcirc) - "Combining the two molecules caused greater RBC rheological improvement. Our findings suggest that dalcetrapib could block HbS polymerization without affecting HbS oxygen affinity."

Journal • Genetic Disorders • Hematological Disorders • Sickle Cell Disease

RISK SCORE FOR FUTURE MYOCARDIAL INFARCTION AFTER AN ACUTE CORONARY SYNDROME AND PHARMACOGENETIC RESPONSE TO DALCETRAPIB - Jean Claude Tardif (ACC 2025) - "Despite the standard of care for ACS survivors, history of prior coronary events as well as on-treatment values for blood pressure, LDL-C, A1C and hs-CRP remain determinants of future MI. In the Dal-GenE AA genotype patients, dalcetrapib significantly reduced the rate of future fatal and non-fatal MI, independently of a risk score including those variables. The ongoing Dal-GenE-2 trial is designed to confirm this pharmacogenetic hypothesis."

Biomarker • Acute Coronary Syndrome • Cardiovascular • Myocardial Infarction

Occupational noise and genetic variants in stress hormone biosynthesis-based genes and rates of blood lipid changes in China: A five-year longitudinal study. (PubMed, Int J Hyg Environ Health) - "However, these findings were not statistically significant after multiple adjustments. These results indicated that Occupational noise exposure was associated with accelerated age-related decreases in HDL-C levels, and the COMT-rs165815 genotype appeared to modify the effect of noise exposure on HDL-C changes among the occupational population."

Journal • Observational data • Atherosclerosis • Cardiovascular • Dyslipidemia • COMT

Genome-wide association exploratory studies in individuals with ultra-high risk for schizophrenia in Chinese Han nationality in two years follow-up: A subpopulation study. (PubMed, Asian J Psychiatr) - "Further expansion of sample size and validation studies are needed to explore the pathogenesis of these risk loci in UHR conversion into schizophrenia in the future."

Journal • CNS Disorders • Genetic Disorders • Psychiatry • Schizophrenia • CHI3L1 • DRD2 • NRXN1

Cholesteryl Ester Transfer Protein Inhibitors and Cardiovascular Outcomes: A Systematic Review and Meta-Analysis. (PubMed, J Cardiovasc Dev Dis) - "Our meta-analysis shows, for the first time, that CETPis are associated with reduced CVD-related mortality and MI."

Journal • Retrospective data • Review • Acute Coronary Syndrome • Atherosclerosis • Cardiovascular • Dyslipidemia • Myocardial Infarction

CARDIOVASCULAR SAFETY PROFILE OF CHOLESTERYL ESTER TRANSFER PROTEIN INHIBITORS: A SYSTEMATIC REVIEW AND META-ANALYSIS OF 17 RANDOMIZED CONTROLLED TRIALS (ACC 2024) - "Six trials examined dalcetrapib (n=23,057), 7 anacetrapib (n=33,643), two torcetrapib (n=16,255), one obicetrapib (n=66), and one evacetrapib (n=12092). The use of anacetrapib resulted in a lower incidence of MACE and MI events than placebo. Besides its robust effects on LDL and HDL cholesterol, it has an acceptable safety profile."

Retrospective data • Review • Cardiovascular

Interventions to Attenuate Cardiovascular Calcification Progression: A Systematic Review of Randomized Clinical Trials. (PubMed, J Am Heart Assoc) - "Currently, there are insufficient or conflicting data for interventions evaluated in clinical trials for mitigation of cardiovascular calcification. Therapy involving aged garlic extract appears most promising, but evaluable studies were small and of short duration."

Clinical • Journal • Review • Cardiovascular • Chronic Kidney Disease • Diabetes • Metabolic Disorders • Nephrology • Renal Disease

Impact of Additives on Drug Particles during Liquid Antisolvent Crystallization and Subsequent Freeze-Drying. (PubMed, Org Process Res Dev) - "The impact of single or combinations of additives on the generation of nanosuspensions of two poorly water-soluble active pharmaceutical ingredients (APIs), fenofibrate (FF) and dalcetrapib (DCP), and their isolation to the dry state via antisolvent (AS) crystallization followed by freeze-drying was explored in this work. Agglomeration occurred during freeze-drying, resulting in micron-size particles. However, after freeze-drying, powders produced with single or multiple additives showed similar dissolution profiles, irrespective of aging time before drying, thus attenuating the advantage of multiple additives in terms of size observed before the freeze-drying process."

Journal

Photocatalytic Phosphine-Mediated Thioesterification of Carboxylic Acids with Disulfides. (PubMed, Org Lett) - "In addition to batch reactions, a continuous-flow reactor was employed, enabling rapid thioester synthesis on a gram scale. Preliminary experimental mechanistic studies and the rapid synthesis of dalcetrapib are also demonstrated."

Journal

dal-GenE-2: Effect of Dalcetrapib on CV Risk in a Genetically Defined Population With a Recent ACS (clinicaltrials.gov) - P3 | N=2000 | Recruiting | Sponsor: DalCor Pharmaceuticals | Not yet recruiting ➔ Recruiting

Enrollment open • Acute Coronary Syndrome • Cardiovascular

dal-GenE-2: Effect of Dalcetrapib on CV Risk in a Genetically Defined Population With a Recent ACS (clinicaltrials.gov) - P3 | N=2000 | Not yet recruiting | Sponsor: DalCor Pharmaceuticals | Initiation date: Jun 2023 ➔ Sep 2023

Trial initiation date • Acute Coronary Syndrome • Cardiovascular

dal-GenE-2: Effect of Dalcetrapib on CV Risk in a Genetically Defined Population With a Recent ACS (clinicaltrials.gov) - P3 | N=2000 | Not yet recruiting | Sponsor: DalCor Pharmaceuticals

New P3 trial • Acute Coronary Syndrome • Cardiovascular

Adcy9 gene inactivation improves cardiac function after myocardial infarction in mice. (PubMed, Can J Cardiol) - "Adcy9 inactivation reduced infarct size, pathological remodeling and cardiac dysfunction. These changes were accompanied by preserved myocardial capillary density and increased adaptive immune response. Most of the benefits of Adcy9 inactivation were only observed in the absence of CETP."

Journal • Preclinical • Acute Coronary Syndrome • Cardiovascular • Myocardial Infarction

Structure-based mechanism and inhibition of cholesteryl ester transfer protein. (PubMed, Curr Atheroscler Rep) - "CETP inhibitors, including torcetrapib, dalcetrapib, evacetrapib, anacetrapib and obicetrapib, were designed and evaluated in phase III clinical trials for the treatment of ASCVD or dyslipidemia. Insights into the structural-based CETP-lipoprotein interactions can unravel CETP inhibition machinery, which can hopefully guide the design of more effective CETP inhibitors that combat ASCVD. Individual-molecule 3D structures of CETP bound to lipoproteins provide a model for understanding the mechanism by which CETP mediates lipid transfer and which in turn, guide the rational design of new anti-ASCVD therapeutics."

Journal • Review • Atherosclerosis • Cardiovascular • Dyslipidemia • Metabolic Disorders

Dalcetrapib and anacetrapib increase apolipoprotein E-containing HDL in rabbits and humans. (PubMed, J Lipid Res) - "New Zealand White rabbits receiving atorvastatin were treated with dalcetrapib or anacetrapib. Overall, in rabbits and humans, CETPi increase large apo E-containing HDL particle concentration, which can interact with hepatic LDLr. The catabolism of these particles may depend on an adequate level of LDLr to contribute to reverse cholesterol transport."

Journal • Preclinical • Dyslipidemia • APOE

Pharmacogenetics-guided dalcetrapib therapy after an acute coronary syndrome. (PubMed, Eur Heart J) - No abstract available

Biomarker • Journal • Acute Coronary Syndrome • Cardiovascular

dal-GenE: Effect of Dalcetrapib vs Placebo on CV Risk in a Genetically Defined Population With a Recent ACS (clinicaltrials.gov) - P3 | N=6149 | Completed | Sponsor: DalCor Pharmaceuticals | Active, not recruiting ➔ Completed | Trial completion date: May 2021 ➔ Oct 2021 | Trial primary completion date: May 2021 ➔ Oct 2021

Trial completion • Trial completion date • Trial primary completion date • Acute Coronary Syndrome • Cardiovascular

Pharmacogenetics-guided dalcetrapib therapy after an acute coronary syndrome: the dal-GenE trial. (PubMed, Eur Heart J) - P3 | "Dalcetrapib did not significantly reduce the risk of occurrence of the primary endpoint of ischaemic cardiovascular events at end of study. A new trial would be needed to test the pharmacogenetic hypothesis that dalcetrapib improves the prognosis of patients with the AA genotype."

Biomarker • Journal • Acute Coronary Syndrome • Atherosclerosis • Cardiovascular • Dyslipidemia • Myocardial Infarction

Adenylate cyclase type 9 antagonizes cAMP accumulation and regulates endothelial signaling involved in atheroprotection. (PubMed, Cardiovasc Res) - "Adcy9 is expressed in endothelial cells and regulates local cAMP and endothelial functions including permeability relevant to atherogenesis."

Journal • Atherosclerosis • Cardiovascular • Dyslipidemia

CETP-inhibitors: from HDL-C to LDL-C lowering agents? (PubMed, Cardiovasc Res) - "The use of CETP inhibitors is supported by genetic evidence from Mendelian randomization studies, showing that LDL-C lowering by CETP gene variants achieves equal ASCVD risk reduction as LDL-C lowering through gene proxies for statins, ezetimibe and proprotein convertase subtilisin-kexin type 9 (PCSK9) inhibitors. Whereas first-generation CETP inhibitors (torcetrapib, dalcetrapib) were mainly raising HDL-C or had off-target effects, next generation CETP inhibitors (anacetrapib, evacetrapib) were also effective in reducing LDL-C and apoB and have been proven safe...The newest-generation CETP inhibitor obicetrapib, specifically designed to lower LDL-C and apoB, has achieved significant reductions of LDL-C up to 45%. Obicetrapib, about to enter phase III development, could become the first CETP inhibitor as add-on therapy for patients not reaching their guideline LDL-C targets."

Journal • Atherosclerosis • Cardiovascular • Diabetes • Dyslipidemia • Metabolic Disorders • APOB