Cardior Pharmaceuticals: Advanced Treatment for Heart Failure

WHAT HAPPENED

Cardior Pharmaceuticals is a German biotechnology startup developing RNA-based medicines to prevent, repair and reverse diseases of the heart.

Cardior’s primary focus is on a broad spectrum of pathologies related to ischemia-induced heart failure, including post–myocardial infarction heart failure and heart failure with preserved ejection fraction. The focus of activity is also directed toward hypertrophic and dilated cardiomyopathy.

The specificity of Cardio’s approach is that its experimental drugs modulate pathophysiological processes at the cellular level, thereby exerting a concerted therapeutic effect across key cardiac disease hallmarks such as cardiac hypertrophy, fibrosis, impaired contractility, and decreased vascularization.

At the end of March 2024, Novo Nordisk agreed to buy Cardior. The deal, which will close in the second quarter, assumes that the Danish pharmaceutical giant will pay a maximum of €1.025 billion ($1.1 billion), including an upfront payment and milestone payments as projects advance [1].

Cardior, which left the walls of Hannover Medical School at the beginning of July 2016, was previously able to raise €80 million in investment funding [2] [3].

 

WHY IT MATTERS

Despite the proven efficacy of pharmacotherapy, heart failure (HF) remains very prevalent worldwide, with an estimated 64.3 million people suffering from it in 2017 [1] [2]. The essentially pandemic rate of HF carries a serious public health burden and is related, among other things, to the fact that the treatment of this progressive and largely irreversible cardiac disease remains largely symptomatic, focused principally on reducing cardiac load by shielding the heart against secondary neurohormonal overdrive and volume retention [3].

There is a large unmet medical need for new therapies that target the pathophysiology of chronic HF at the organ level and act on its key pathophysiologic processes.

The situation is exacerbated by the fact that patients with acute myocardial infarction (MI) are at high risk of developing early and progressive HF or cardiac death, especially if acute MI is complicated by left ventricular systolic dysfunction [4] [5] [6].

HF that develops after MI is common and is a powerful predictor of death [7] [8]. The incidence of early HF among patients hospitalized for MI ranges between 14% and 36% [6] [9]. According to a retrospective analysis of patients with acute MI, 31% without a history of HF developed it during hospitalization, and the mortality rate within one year after its diagnosis was 11%, whereas the same rate among those who did not develop HF was half as high (5%) [10].

 

HOW IT WORKS

CDR132L is a selective inhibitor of microRNA-132 (miR-132), the overactivation of which in cardiac tissue results in progressive adverse remodeling of the heart (changes in its structure), eventually giving birth to heart failure and fueling its progression.

Therapeutic use of CDR132L halts and partially reverses the pathologic impairment caused by heart failure, improving cardiac function and prolonging life in the long term.

 

MECHANISM OF ACTION

MicroRNA-132 (miR-132) is a non-coding (regulatory) ribonucleic acid (ncRNA) whose levels increase in cardiac tissue in response to cardiomyocyte stress [1] [2].

In cardiomyocytes, miR-132 functions as a central switch affecting the expression of genes that are critically involved in maladaptive cardiac remodeling, transformation and pathological growth of heart muscle (hypertrophy), contributing to adverse cardiac remodeling and the development and progression of heart failure.

According to preclinical studies, miR-132 affects signaling pathways involved in cardiomyocyte growth, autophagy, calcium metabolism, and contractility [1] [3] [4] [5] [6] [7].

Thus, miR-132 overexpression leads to suppression of the antihypertrophic and proautophagic transcription factor FOXO3, which results in hyperactivation of prohypertrophic calcineurin–NFAT signaling and impaired autophagic response. Overexpression of miR-132 is reflected by suppression of ATP2A2 (SERCA2) gene expression involved in calcium handling and contraction kinetics, which contributes to cardiac remodeling.

CDR132L is a synthetic antisense oligonucleotide (ASO) that is a selective inhibitor of miR-132 [5].

In preclinical studies in animal models of subacute and chronic heart failure after myocardial infarction, CDR132L had strong beneficial effects in the form of reversing cardiac remodeling, improving left ventricular ejection fraction, improving systolic and diastolic cardiac function, and reducing NT-proBNP concentration [1] [3] [4] [5].

In summary, through the cardiomyocyte-specific effects of CDR132L, which blocks aberrantly elevated miR-132 expression causally associated with cardiac remodeling and heart failure progression, it appears possible to reverse ischemic and non-ischemic cardiac remodeling and restore normal cellular functions, ultimately improving cardiac function in patients with heart failure.

 

WHAT IT FOUND OUT

In the FiH (NCT04045405) phase 1b clinical trial among adult patients (n=28) with stable heart failure of ischemic origin (NYHA class I–III) and reduced left ventricular ejection fraction (LVEF between ≥ 30% and < 50%), administration of CDR132L, which was given intravenously in two doses at 4-week intervals, was reflected by early signs of improvement in cardiac function.

Thus, the median reduction in the level of N-terminal pro-brain natriuretic peptide (NT-proBNP), a reliable biomarker of heart failure, amounted to 23% — versus its increase by 1% in the placebo group. CDR132L therapy was mirrored by an improvement in LVEF, significant narrowing of the QRS complex, and an encouraging positive trend in biomarkers of cardiac fibrosis such as galectin 3 (LGALS3, MAC-2, GALIG), matrix metallopeptidase 1 (MMP1), lipocalin 2 (LCN2, NGAL), and suppression of tumorigenicity 2 (ST2) [1].

No serious adverse events associated with CDR132L have been identified.

 

WHAT’S NEXT

The HF-REVERT (NCT05350969) phase 2 (randomized, double-blind, placebo-controlled, multicenter, international) clinical trial is ongoing, which is evaluating the efficacy and safety of administering CDR132L to patients (n=294) aged 30–80 years with chronic heart failure (NYHA class I–III) with reduced ejection fraction (LVEF ≤ 45%) after acute ST-elevation myocardial infarction (STEMI) or acute non-ST-elevation myocardial infarction (NSTEMI).

The primary endpoint of treatment efficacy was established by the percent change in left ventricular end-systolic volume index (LVESVI) after 6 months, during which subjects would receive three doses of CDR132L (5 mg/kg or 10 mg/kg) or placebo intravenously [1].

The results of the study are expected to be available by the end of 2024 or the beginning of 2025.

 

THE ESSENCE

Adverse structural remodeling of the left ventricle due to myocardial infarction is a common pathological feature characterized by decreased left ventricular ejection fraction and leading to heart failure [1]. Among patients with myocardial infarction, such patients account for approximately 10%–15% [2].

Therapeutic administration of CDR132L, which selectively inhibits miR-132, which is responsible for deleterious remodeling of cardiac cells after myocardial infarction, results in a reduction of abnormally high systemic levels of miR-132, which should be mirrored by beneficial effects such as antihypertrophic and antifibrotic effects, improved contractility, and restoration of capillary density [3].

 

WHAT’S MORE

The REMOD-REVERT (NCT05953831) phase 2 clinical trial is scheduled for launch and will evaluate the myocardial reverse remodeling effect of CDR132L administered intravenously in six doses of 4.52 mg/kg to patients (n=130) aged 40–85 years with cardiac hypertrophy and heart failure with mildly-reduced ejection fraction (HFmrEF) [LVEF 45–49%] or heart failure with preserved ejection fraction (HFpEF) [LVEF ≥ 50%].

After 6 months, ten primary endpoints of treatment efficacy such as left ventricular mass, left atrial maximum volume, total cardiac extracellular volume, left atrial strain, and maximum left ventricular wall thickness will be analyzed.

The study should be completed by early fall 2025.

 

IN ADDITION

Cardior is preparing for a clinical trial of CDR132L for the treatment of dilated cardiomyopathy.

Two drug candidates targeting the treatment of hypertrophic cardiomyopathy, CDR348T and CDR641L, respectively modulating and interacting with as yet undisclosed non-coding RNAs, are in the preclinical stages of development.

 

THE SYNERGY

Novo Nordisk is riding a wave of success for its diabetes and obesity drugs. While they earned the Danish pharmaceutical giant $19.33 billion and $22.09 billion in 2021 and 2022, in 2023 they already earned $31.22 billion. This drug package includes insulins and a series of semaglutide based drugs such as Ozempic, Rybelsus, and Wegovy. Meanwhile, competition in the weight loss pharma sector is so intense that it is necessary to look ahead to the future of the business.

The Cardior developments, intended to diversify Novo Nordisk’s drug portfolio, will organically join other assets from the gradually advancing cardiovascular business. It is possible that a combination approach, bringing together several drugs with different mechanisms of action, will someday be tested.

Thus, the aforementioned semaglutide has been shown to, first, reduce the risk of adverse cardiovascular outcomes in obesity-associated cardiovascular disease and, second, to be successful in the treatment of heart failure with preserved ejection fraction (HFpEF) among obese patients [1] [2].

In the final stages of clinical validation is ziltivekimab (NN6018, COR-001), a monoclonal antibody against interleukin 6 (IL-6), which is being studied in the treatment of, first, chronic heart failure with mildly-reduced ejection fraction (HFmrEF) or preserved ejection fraction (HFpEF) [LVEF > 40%] and systemic inflammation, and second, atherosclerotic cardiovascular disease (ASCVD) with chronic kidney disease (CKD) and systemic inflammation. Ziltivekimab is also being tested in the task of preventing adverse cardiovascular outcomes after hospitalization for acute myocardial infarction (MI).

Ziltivekimab, obtained through the acquisition of Corvidia Therapeutics in mid-June 2020 for an upfront $725 million with the promise of additional milestone payments of up to $1.375 billion, is administered by subcutaneous injection once a month [3].

Soon-to-be-available ocedurenone (NN6023, KBP-5074), an oral small-molecule non-steroidal mineralocorticoid receptor antagonist (nsMRA), purchased from Singapore’s KBP Biosciences for up to $1.3 billion in mid-October 2023, and is being studied in the treatment of uncontrolled hypertension in patients with moderate-to-severe chronic kidney disease (CKD) [4].

In the early stages of clinical trials for the treatment of cardiovascular diseases are NN6491, a monoclonal antibody against ANGPTL3 for the prevention and treatment of atherosclerosis, and NN9003 (HS-001), a cell therapy being studied with Japan’s Heartseed to restore heart function in heart failure caused by coronary heart disease (CHD) [5] [6].

 

MEANWHILE

While oncology is experiencing a boom in new drugs, cardiology is actually stagnating, having been essentially devoid of any new breakthrough medicines for many decades. However, the situation has changed recently.

Thus, in late 2020, Novartis offered Leqvio (Leqvio, inclisiran), indicated for the potent reduction of low-density lipoprotein (LDL) cholesterol with just two injections per year.

In late April 2022, Bristol-Myers Squibb launched Camzyos (mavacamten), the first drug for the specific treatment of obstructive hypertrophic cardiomyopathy.

In mid-March 2024, Idorsia Pharmaceuticals gave the go-ahead to Tryvio (aprocitentan) to lower blood pressure with an entirely new mechanism of action.

At the end of March 2024, Merck & Co. revealed to the world Winrevair (sotatercept), the first drug that treats pulmonary arterial hypertension (PAH) at the pathophysiologic level, not symptomatic like all other drugs.

Merck & Co. continues to work on enlicitide, which reduces LDL cholesterol no worse than Lequo, but in tablet form and therefore will cost significantly less. The fight against atherosclerosis, which is now being carried out by low-efficiency statins, will reach a decisively new level.

AstraZeneca is developing on baxdrostat, which lowers blood pressure even if it is not pharmacologically manageable due to treatment-resistant or refractory hypertension.

Alnylam Pharmaceuticals and Ionis Pharmaceuticals are innovating the treatment of hypertension with injectable zilebesiran and tonlamarsen, which are administered quarterly or even semi-annually.