Phase III, Double-blind, Randomized Placebo-controlled Study to Evaluate the Effects of Dalcetrapib on Cardiovascular (CV) Risk in a Genetically Defined Population With a Recent Acute Coronary Syndrome (ACS)

This is a placebo-controlled, randomized, double-blind, parallel group, phase 3 multicenter study in subjects recently hospitalized for ACS and with the appropriate genetic profile. Subjects will provide informed consent before any study-specific procedures are performed. A separate informed consent will be allowed for an initial pre-screening genetic testing. Subjects meeting the AA genotype will then consent to the full study and confirmatory genetic testing as required. Subject enrollment may begin in the hospital and will continue following release from the hospital or may begin following release from hospital. Screening procedures may be performed at the time of the index ACS event or anytime thereafter, with the condition that randomization must occur within the mandated window (up to12 weeks after the index event). Subjects will be assessed based on their medical history. Those who are likely to qualify will undergo Genotype Assay testing to evaluate genetic determination for the presence of AA genotype.

Start Date03 Oct 2023

Sponsor / Collaborator

DalCor Pharmaceuticals Canada, Inc.Startup

NCT04676867 / CompletedPhase 2

A Double-blind, Placebo-controlled, Phase 2a Proof-of-concept Trial of Dalcetrapib in Patients With Confirmed Mild to Moderate COVID-19

This study is a placebo-controlled, Phase 2a proof-of-concept clinical study which will evaluate efficacy and safety of dalcetrapib in outpatients patients with mild to moderate, symptomatic, confirmed COVID 19.

Start Date11 Jan 2021

Sponsor / Collaborator

DalCor Pharmaceuticals Canada, Inc.Startup

[+1]

NCT02525939 / CompletedPhase 3

A Phase III, Double-blind, Randomized Placebo-controlled Study to Evaluate the Effects of Dalcetrapib on Cardiovascular (CV) Risk in a Genetically Defined Population With a Recent Acute Coronary Syndrome (ACS): The Dal-GenE Trial

A placebo-controlled, randomized, double-blind, parallel group, phase III multicenter study in subjects recently hospitalized for ACS and with the appropriate genetic profile. Subjects will provide informed consent before any study-specific procedures are performed. Subject enrollment may begin in the hospital and will continue following release from the hospital. Screening procedures may be performed at the time of the index ACS event or anytime thereafter, with the condition that randomization must occur within the mandated window (4-12 weeks after the index event). Subjects will be assessed based on their medical history. Those who are likely to qualify will undergo Genotype Assay testing to evaluate genetic determination for the presence of AA genotype.

Start Date01 Apr 2016

Sponsor / Collaborator

DalCor Pharmaceuticals Canada, Inc.Startup

[+2]

100 Clinical Results associated with DalCor Pharmaceuticals Canada, Inc.

0 Patents (Medical) associated with DalCor Pharmaceuticals Canada, Inc.

Literatures (Medical) associated with DalCor Pharmaceuticals Canada, Inc.

14 Oct 2022·European heart journal

Pharmacogenetics-guided dalcetrapib therapy after an acute coronary syndrome: the dal-GenE trial

Article

Author: Maggioni, Aldo P ; Kouz, Simon ; Tardif, Jean Claude ; Levesque, Sylvie ; Wouter Jukema, J ; Laghrissi-Thode, Fouzia ; Dubé, Marie Pierre ; McMurray, John J V ; Pfeffer, Marc A ; Heinonen, Therese ; Guertin, Marie Claude ; White, Harvey D. ; Koenig, Wolfgang ; Grégoire, Jean C ; Mooser, Vincent ; Waters, David D ; L’Allier, Philippe L ; Black, Donald M

Abstract:

Aims:

In a retrospective analysis of dal-Outcomes, the effect of dalcetrapib on cardiovascular events was influenced by an adenylate cyclase type 9 (ADCY9) gene polymorphism. The dal-GenE study was conducted to test this pharmacogenetic hypothesis.

Methods and results:

dal-GenE was a double-blind trial in patients with an acute coronary syndrome within 1–3 months and the AA genotype at variant rs1967309 in the ADCY9 gene. A total of 6147 patients were randomly assigned to receive dalcetrapib 600 mg or placebo daily. The primary endpoint was the time from randomization to first occurrence of cardiovascular death, resuscitated cardiac arrest, non-fatal myocardial infarction, or non-fatal stroke. After a median follow-up of 39.9 months, the primary endpoint occurred in 292 (9.5%) of 3071 patients in the dalcetrapib group and 327 (10.6%) of 3076 patients in the placebo group [hazard ratio 0.88; 95% confidence interval (CI) 0.75–1.03; P = 0.12]. The hazard ratios for the components of the primary endpoint were 0.79 (95% CI 0.65–0.96) for myocardial infarction, 0.92 (95% CI 0.64–1.33) for stroke, 1.21 (95% CI 0.91–1.60) for death from cardiovascular causes, and 2.33 (95% CI 0.60–9.02) for resuscitated cardiac arrest. In a pre-specified on-treatment sensitivity analysis, the primary endpoint event rate was 7.8% (236/3015) in the dalcetrapib group and 9.3% (282/3031) in the placebo group (hazard ratio 0.83; 95% CI 0.70–0.98).

Conclusion:

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.

Clinical Trial Registration:

Trial registration dal-GenE ClinicalTrials.gov Identifier: NCT02525939

01 Nov 2018·Clinical pharmacokineticsQ2 · MEDICINE

Clinical Pharmacokinetics and Pharmacodynamics of Dalcetrapib

Q2 · MEDICINE

Review

Author: Chapel, Sunny ; Briggs, Emily ; Black, Donald M ; Bentley, Darren ; Heinonen, Therese ; Lee, Jongtae

The cholesterol ester transfer protein (CETP) inhibitor dalcetrapib has been under evaluation for its potential to prevent cardiovascular (CV) events for almost two decades. The current clinical development program, representing new advances in precision medicine and focused on a genetically defined population with acute coronary syndrome (ACS), is supported by a large body of pharmacokinetic and pharmacodynamic data as well as substantial clinical experience in over 13,000 patients and volunteers. Dalcetrapib treatment of 600 mg/day produces significant inhibition of CETP activity, and has been utilized in phase II and III studies, including CV endpoint trials. Numerous studies have investigated the interactions between dalcetrapib and most drugs commonly prescribed to CV patients and have not demonstrated any clinically significant effects. Evaluations in patients with renal and hepatic impairment demonstrate a greater exposure to dalcetrapib than in the non-impaired population, but long-term clinical studies including patients with mild to moderate hepatic and renal dysfunction demonstrate no increase in adverse events. Safety pharmacology and toxicology studies as well as the clinical safety experience support the continuing development of dalcetrapib as an adjunct to 'standard of care' for the ACS population. This article provides a full review of the pharmacokinetics, as well as pharmacodynamics and pharmacology, of dalcetrapib in the context of a large clinical program.

News (Medical) associated with DalCor Pharmaceuticals Canada, Inc.

13 Sep 2023

·www.globenewswire.com

DalCor Pharmaceuticals announces Dal-GenE-2 confirmatory trial and closing of Series D financing round

MONTREAL, Sept. 13, 2023 (GLOBE NEWSWIRE) -- DalCor Pharmaceuticals today announced the closing of the company’s Series D financing round of $80m USD to conduct the Dal-GenE-2 confirmatory trial in North America under a Special Protocol Assessment (SPA) agreement with the U.S. Food and Drug Administration (FDA). 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. “Following the dal-GenE trial results showing a potential benefit in a genetically defined patient population, we are pleased to have reached agreement with the FDA to conduct the Dal-GenE-2 confirmatory trial to support a potential new drug application (NDA) filing,” said Dr. Fouzia Laghrissi Thode, CEO of DalCor Pharmaceuticals. This confirmatory trial follows the results of the dal-GenE trial which showed a 21% relative risk reduction (RRR) in fatal and non-fatal MI in 6,149 patients across 34 countries, and a 45% RRR in 1,200 patients in North America and confirmed the safety profile of dalcetrapib. “The AA genotype frequency is up to 20% in European populations and is higher than 40% in populations of African ancestery,” said Dr Eldrin F. Lewis, Chief of the Division of Cardiovascular Medicine at Stanford University, Professor of Cardiovascular Medicine, and Chair of the Dal-GenE-2 diversity committee. “With the relative risk reduction seen in North American patients in the dal-GenE study and the continued commitment to investigating the first potential pharmacogenetic precision medicine for patients with cardiovascular disease, we are pleased to partner with DalCor Pharmaceuticals in this confirmatory trial.” The Series D financing includes the participation of Fonds de Developpement Économique from the Québec government managed by Investissement Québec and Fonds Propres d’ Investissement Québec as well as current investors including Andes Growth, TB Pharma, Fonds de Solidarité FTQ, and CTI Life Sciences. “Québec’s life-sciences expertise is recognized worldwide. Our government is keen to support projects with the potential to generate meaningful spinoffs, like DalCor’s work on cardiovascular health,” said Pierre Fitzgibbon, Minister of Economy, Innovation and Energy, Minister Responsible for Regional Economic Development and Minister Responsible for the Montréal Region. “We are pleased to support DalCor in this round of financing so they can carry on development in precision medicine for cardiovascular disease,” said Guy LeBlanc, President, and CEO of Investissement Québec. “Their research can ultimately revolutionize their industry and reduce the number of cardiovascular events. Investissement Québec will keep supporting emerging young businesses to position Québec in key sectors of our economy, such as life sciences.”- - Notes: Dal-GenE-2: The primary objective of Dal-GenE-2 is to evaluate the potential of dalcetrapib to reduce the occurrence of fatal and non-fatal myocardial infarction in 2,000 patients with a documented recent ACS and the AA genotype at variant rs1967309 in the ADCY9 gene. The trial is expected to start in Q3 2023 with an interim efficacy analysis in 2026, and completion anticipated in 2027. Dal-GenE: While the trial missed the primary endpoint, most likely due to the impact of the COVID-19 pandemic, the results show a 21% relative risk reduction (RRR) in fatal and non-fatal MI in 6,149 patients across 34 countries, and 45% RRR in 1,200 patients in North America. These data support the further development of dalcetrapib. DalCor Pharmaceuticals: DalCor Pharmaceuticals is pioneering precision medicine for patients with cardiovascular disease. By combining genetic and clinical insights, the company’s development program, dalcetrapib, is intended to reduce fatal and non-fatal myocardial infarction (MI) following a recent acute coronary syndrome and deliver superior cardiovascular outcome in a specific genetic subset of patients. DalCor Pharmaceuticals holds the worldwide exclusive license to develop, manufacture and commercialise dalcetrapib, and holds the right to the genetic marker for use with dalcetrapib in patients with the AA genotype at variant rs1967309 in the ADCY9 gene. A companion diagnostic test, developed in conjunction with Roche Diagnostics, identifies patients with the ADCY9 AA genotype who may potentially benefit from dalcetrapib treatment. For more information, visit www.dalcorpharma.com.

Phase 3License out/in

21 Jul 2022

·www.globenewswire.com

dal-GenE Phase 3 Cardiovascular Precision Medicine Outcomes Trial Results Published in European Heart Journal

Trial was negatively impacted by the COVID-19 pandemic and did not meet the primary endpoint. However, the results validate the interaction between dalcetrapib treatment and AA genotype at variant rs1967309 in the ADCY9 gene.LONDON and MONTREAL, July 21, 2022 (GLOBE NEWSWIRE) -- DalCor Pharmaceuticals announced the results of the dal-GenE Phase 3 cardiovascular precision medicine outcomes trial with publication of ‘Pharmacogenetics-guided dalcetrapib therapy after an acute coronary syndrome: the dal-GenE trial’ in the European Heart Journal.1 The dal-GenE (DAL-301) trial was initiated to determine the ability of dalcetrapib to reduce cardiovascular (CV) morbidity and mortality in a population experiencing an acute coronary syndrome (ACS) within 1-3 months before randomization (N=6147) and identified as carrying the AA genotype at variant rs1967309 in the adenylate cyclase type 9 (ADCY9) gene, as determined by the cobas® ADCY9 genotype test. This AA genotype is carried by approximately 20% of the total population and up to 40% in people of African descent. Eligible patients were optimally treated for CV risk factors. The prespecified primary endpoint was time-to-first event for the composite of CV death, resuscitated cardiac arrest, non-fatal myocardial infarction (MI) or non-fatal stroke. In the dal-GenE trial, treatment with dalcetrapib in the intent-to-treat (ITT) analysis did not demonstrate a statistically significant result, with the composite primary endpoint event occurring in 9.5% of the patients in the dalcetrapib group, as compared with 10.6% in the placebo group (hazard ratio (HR) 0.88; 95% CI 0.75-1.03; p=0.12). However: On fatal and non-fatal MI, the dalcetrapib treatment showed a relative risk reduction of 21% compared to placebo (5.9% vs. 7.3%; HR 0.79; 95% CI 0.65-0.96; p=0.02). Dalcetrapib was safe and well tolerated in the dal-GenE trial.For the seven months prior to the COVID-19 pandemic, the hazard ratio and p-value in the dal- GenE trial were consistently clinically meaningful (HR< 0.85) and statistically significant (p<0.05).Study results censored on January 2020, prior to the COVID-19 pandemic, showed a relative risk reduction of 18% (HR = 0.82, 95% CI, 0.68-0.98; p=0.03) in the occurrence of the primary endpoint in the dalcetrapib treated group compared to placebo indicating that dalcetrapib appeared to be associated with this benefit up to the emergence of COVID-19.COVID-19 occurred as early as January 2020 worldwide and had a global impact on cardiovascular care. In particular, the numbers of patients diagnosed and hospitalized with myocardial infarction decreased steeply, while deaths increased. The dal-GenE study endpoints appear to have been impacted by the last 17 months of follow-up that occurred during COVID- 19 pandemic. The ratio of non-fatal events to death dropped from 1.7 to 0.9 during this period, most likely due to a reduction of reporting in non-fatal events and an increase in CV and non-CV death during the pandemic compared to pre-COVID. This finding is consistent with the published impact of the pandemic on cardiovascular care2.A pre-specified on-treatment sensitivity analysis of the primary endpoint showed a relative risk reduction of 17% with dalcetrapib treatment compared to placebo (7.8% vs. 9.3%; HR 0.83; 95% CI 0.70-0.98, p=0.03).Further pre-specified analyses demonstrated that patients at a higher risk had greater benefits on dalcetrapib treatment. In patients with type 2 diabetes, the observed relative risk reduction with dalcetrapib was 23% versus placebo (HR = 0.77; 95% CI, 0.60-0.99, p=0.04).In North America, where randomized patients were at a higher risk, they had a relative risk reduction of 41% in the primary composite endpoint (HR 0.59; 95% CI, 0.42-0.82, p=0.002). In contrast, countries with low-risk patients representing 20% of randomized patients had no significant benefit. Pre-COVID-19, the clinical efficacy of dalcetrapib seen in the dal-GenE study was also consistent with that of the retrospective analysis conducted in patients with the rs1967309 AA genotype in the dal-OUTCOMES study3. The totality of these data validates the pharmacogenetic hypothesis that dalcetrapib can safely improve, beyond the current standard of care, the prognosis of ACS patients with the rs1967309 AA genotype. DalCor is working closely with Health Authorities to determine the path forward for the approval of dalcetrapib for the treatment of patients with the rs1967309 AA genotype following an ACS event. About DalCorDalCor is a biopharmaceutical company with a focus on addressing cardiovascular disease, the greatest global healthcare burden. Our purpose is to deliver the first pharmacogenomic precision medicine in cardiovascular disease that specifically targets patients with the ADCY9 AA genotype. For more information, please visit dalcorpharma.com. About dal-GenEdal-GenE was a double-blind, parallel-group, placebo-controlled, randomized trial comparing orally administered dalcetrapib 600 mg once daily with placebo in a 1:1 ratio in patients with an acute coronary syndrome within 1 to 3 months and the AA genotype at variant rs1967309 in the ADCY9 gene. A total of 6147 patients were randomly assigned to receive dalcetrapib 600 mg or placebo daily. The primary endpoint was the time from randomization to first occurrence of cardiovascular death, resuscitated cardiac arrest, non-fatal myocardial infarction, or non-fatal stroke. Participants were enrolled across 630 investigational sites located in North America, South America, Europe, Middle East, South Africa, Australia, and New Zealand. Patients were eligible if they were at least 45 years of age, recently hospitalized for an acute coronary syndrome within the previous 1 to 3 months, clinically stable, treated with guidelines-based management of LDL- cholesterol at a minimum to a target level less than 2.6 mmol/L, and confirmed in a central laboratory to have the AA genotype at variant rs1967309 in the ADCY9 gene. About DalcetrapibDalcetrapib is potentially the first pharmacogenomic precision medicine in cardiovascular disease developed for patients with the ADCY9 AA genotype. A companion diagnostic test, developed in conjunction with Roche Molecular Systems, identifies patients with the ADCY9 AA genotype who may potentially benefit from dalcetrapib treatment. DalCor obtained global rights to develop, manufacture and commercialize dalcetrapib under a license and collaboration agreement with Roche. References Tardif JC, Pfeffer MA, Kouz S, et al. Pharmacogenetics-guided dalcetrapib therapy after an acute coronary syndrome: the dal-GenE trial. Eur Heart J 2022. European Heart Journal (2022) 00, 1–10 https://doi-org.libproxy1.nus.edu.sg/10.1093/eurheartj/ehac374Nadarajah R, Wu J, Hurdus B, et al. The collateral damage of COVID-19 to cardiovascular services: a meta-analysis. European Heart Journal (2022) 00, 1–15 https://doi-org.libproxy1.nus.edu.sg/10.1093/eurheartj/ehac227.Schwartz GG, Olsson AG, Abt M, et al. Effects of dalcetrapib in patients with a recent acute coronary syndrome. N Engl J Med. 2012;367(22):2089–2099. Media Contact:Clare EvansIris Communication+1 403 888 6869clare.evans@iriscommunication.net

Collaborate

11 Jan 2021

·www.biospace.com

DalCor Announces Launch of Dalcetrapib Clinical Trial for COVID-19New dal-COVID Phase 2 proof of concept study results anticipated in Q1 2021

LONDON and MONTREAL, Jan. 11, 2021 (GLOBE NEWSWIRE) -- DalCor Pharmaceuticals today announced the initiation of dal-COVID, a Phase 2 proof-of-concept study for dalcetrapib as a potential oral anti-viral treatment for COVID-19. The main protease (3CLMpro) of the SARS-CoV-2 virus is a key enzyme that plays a pivotal role in mediating viral replication and transcription. Dalcetrapib is a potential anti-viral treatment as it binds to the catalytic site of 3CLMpro of SARS-CoV-2 in vitro, thereby inhibiting its activity and viral replication. dal-COVID is a double-blind, placebo-controlled trial in patients with confirmed mild to moderate symptomatic COVID-19. The study will evaluate the efficacy and safety of three different doses of dalcetrapib compared to placebo in approximately 200 adult patients over a 10-day treatment period. “I am delighted that dalcetrapib is being investigated as an oral antiviral treatment for mild to moderate COVID-19,” said Dr. Guy Boivin, Centre Hospitalier Universitaire de Québec, Université Laval, Quebec City, Canada and Chairman of the Executive Committee for dal-COVID. “Effective oral anti-viral treatments for patients with COVID-19 would significantly improve patient symptoms, reduce complications and the burden on healthcare systems while contributing alongside vaccines to mitigate the impact of the pandemic.” dal-COVID will be coordinated by the Montreal Health Innovations Coordinating Center (MHICC). Results are anticipated in Q1 2021. Dalcetrapib is also currently being evaluated in the dal-GenE Phase 3 cardiovascular precision medicine clinical outcomes trial. To date, it has been administered, with a good safety and tolerability profile, for more than two years to over 10,000 patients with cardiovascular diseases and risk factors such as obesity, diabetes, and hypertension. About DalCor DalCor is a biopharmaceutical company with a focus on addressing cardiovascular disease, the greatest global healthcare burden. Our purpose is to deliver the first pharmacogenomic precision medicine in cardiovascular disease that specifically targets patients with the ADCY9 AA genotype. The company has operations in Canada, the UK, Switzerland, and the U.S. For more information, please visit dalcorpharma.com. About Dalcetrapib Dalcetrapib is an investigational therapy that would potentially be the first pharmacogenomic precision medicine in cardiovascular disease developed for patients with the ADCY9 AA genotype. It is currently being evaluated in the dal-GenE Phase 3 cardiovascular clinical outcomes trial aiming to deliver a relative risk reduction of 15% or greater for major adverse cardiovascular events (MACE). dal-GenE passed a futility analysis in January 2020 and trial completion is expected in the first half of 2021. A companion diagnostic test, developed in conjunction with Roche Molecular Systems, identifies patients with the ADCY9 AA genotype who may potentially benefit from dalcetrapib treatment. DalCor obtained global rights to develop, manufacture and commercialize dalcetrapib under a license and collaboration agreement with Roche. Media Contact: Clare Evans Iris Communication +1 403 888 6869 clare.evans@iriscommunication.net

VaccineCollaborate

100 Deals associated with DalCor Pharmaceuticals Canada, Inc.

100 Translational Medicine associated with DalCor Pharmaceuticals Canada, Inc.

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Drug(Targets)	Indications	Global Highest Phase

Dalcetrapib ( CETP )	Acute Coronary Syndrome More	Phase 3

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