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 – 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.

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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. For more information, please visit dalcorpharma.com.

About dal-GenE
dal-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 Dalcetrapib
Dalcetrapib 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

1. 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/10.1093/eurheartj/ehac374
2. Nadarajah 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/10.1093/eurheartj/ehac227.
3. 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.

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