Inno Biopharma Advances Novel Therapy for Chronic Heart Failure Targeting Pathological Myocardial Hypertrophy and Fibrosis

Chronic Heart Failure (CHF, referred to as “chronic heart failure”) is a disease caused by various etiologies that impair ventricular filling and ejection function, ultimately leading to reduced ventricular pumping capacity. It represents the severe and terminal stage of conditions such as coronary heart disease, hypertension, valvular heart disease, and diabetes. Known as the “final battlefield of heart disease,” CHF is characterized by high incidence and mortality rates, as well as poor prognosis, making it one of the major threats to human health today.

It is estimated that the prevalence of heart failure among adults in China is 0.9%, with more than 10 million patients nationwide. Approximately 50% of patients die within five years of diagnosis, and the mortality rate is two to three times higher than that of cancers such as breast cancer and colorectal cancer. Furthermore, heart failure is the leading cause of hospitalization, with patients being hospitalized an average of 2.4 times per year. Globally, annual expenditure on heart failure amounts to $108 billion, with hospitalization costs accounting for 60%–70% of total treatment expenses.

Because heart failure is a syndrome caused by multiple etiologies, it is extremely difficult to treat. For over a century, various approaches have been attempted to enhance the contractile and relaxant capacity of residual viable myocardial cells, and efforts have also been made to reduce the workload of the diseased heart by promoting diuresis and vasodilation. Although these therapeutic strategies are imperfect, they remain the only beacon of hope for patients with heart failure.

On November 25, 2017, Novartis’ new heart failure medication, Entresto (sacubitril/valsartan sodium tablets), was officially launched in China, following its successive sweeps of the heart failure treatment markets in the United States and Europe. As the world’s first angiotensin receptor-neprilysin inhibitor (ARNI), Entresto provides a novel therapeutic option for patients with chronic heart failure with reduced ejection fraction (LVEF) (New York Heart Association [NYHA] functional class II–IV, LVEF ≤40%).

As the only new drug for systolic heart failure launched in the past decade, Entresto demonstrated its potential as a blockbuster drug immediately upon its market entry. Novartis’ quarterly financial report showed that Entresto’s sales reached $110 million in the second quarter of 2017. Furthermore, sales forecasts by Elevatepharm indicate that Entresto’s sales will reach $4.881 billion in 2022, positioning it to become the top-selling product in the cardiovascular drug market.

In 2019, sacubitril/valsartan received expert consensus from the Heart Failure Association of the European Society of Cardiology (ESC) and was recommended as first-line therapy for patients with newly diagnosed heart failure and those hospitalized for heart failure.

The mechanism of Entresto in the treatment of chronic heart failure primarily involves inhibiting angiotensin II receptors and neprilysin (NEP) within the renin-angiotensin-aldosterone system (RAAS), thereby exerting effects such as vasodilation, prevention and reversal of cardiovascular remodeling, and promotion of natriuresis. While there is no fundamental difference from conventional treatment regimens, its efficacy is significantly more pronounced.

In reality, the traditional "three-pronged" approach to heart failure treatment—using inotropes, diuretics, and vasodilators—does not ameliorate cardiomyocyte necrosis. Patients merely remain in a state of slight physical comfort while awaiting complete cardiac failure, which ultimately precipitates multi-organ failure and death.

In the early 1990s, Professor Yu-Jian Kang, a Fellow of the Academy of Toxicological Sciences (USA), accidentally discovered during the development of an animal model for cardiotoxicity research that several mice, which were expected to die from heart failure according to the experimental design, did not die as anticipated but instead showed a trend toward improved survival. After repeated checks and tests of the experimental design, Professor Kang found that the reason for the mice’s “remarkable turnaround” was their accidental ingestion of feed with high copper content.

Upon further dissection of the experimental mice, Professor Kang Yujian made a startling discovery that fundamentally reshaped his understanding of heart failure treatment and marked the beginning of a new research endeavor spanning three decades. Professor Kang found that necrotic cardiomyocytes in the mice exhibited signs of repair. This finding was undoubtedly groundbreaking. “At the time, we hypothesized that copper ions might be correlated with cardiomyocyte repair.”

In subsequent extensive studies, researchers have gradually elucidated copper metabolism, transmembrane copper transport, and their roles in cellular regulation and expression mechanisms, further clarifying the biological basis underlying the correlation between copper ions and cardiomyocyte repair. Professor Kang Yujian discovered that the correlation between copper ions and cardiomyocyte repair is associated with hypoxia-inducible factor (HIF).

HIF was discovered by scientists in the 1990s, who were subsequently awarded the 2019 Nobel Prize in Physiology or Medicine. HIF is a nuclear protein complex that serves as a cellular sensor for hypoxia regulation. Under normal oxygen conditions, HIF is automatically degraded; however, upon detection of cellular hypoxia, HIF translocates into the nucleus to regulate gene expression in an effort to alleviate the hypoxic state.

However, while studying animal models of ischemic injury, Professor Kang discovered that although the ischemic state led to upregulation of HIF, the expression of its downstream copper-dependent proteins was not upregulated. Most of these copper-dependent proteins are associated with angiogenesis, as well as fibrosis and stem cell homing. Upon supplementation with sufficient copper ions, the levels of copper-dependent proteins were correspondingly upregulated, and researchers observed biological phenomena such as defibrosis, angiogenesis, and stem cell homing in the animal models of ischemic injury.

Professor Kang Yujian decided to extend his research on the correlation between copper ions and cardiomyocyte repair to large animal models. In 2009, Professor Kang returned to China and was appointed as the Director of the Regenerative Medicine Research Center at West China Hospital, where he gradually built a team of nearly 80 members and initiated studies on cellular mechanisms, including the role of copper ions in cardiomyocyte repair.

Translating laboratory research findings into clinical applications is a key objective for Professor Kang Yujian upon his return to China. However, developing a new drug from scratch is even several times more challenging than conventional new drug development within large pharmaceutical companies.

The first challenge encountered by Professor Kang’s team was the construction of an animal model of ischemic myocardial injury that met specific criteria. Unlike traditional myocardial ischemia-reperfusion models, which primarily restrict cardiac blood supply, the ischemic myocardial injury model requires researchers to precisely control the duration of coronary occlusion and select specific vascular branches. This approach aims to induce necrosis in a defined region of the myocardium while ensuring the animal’s stable survival.

“The area of myocardial necrosis cannot be too small, otherwise the body will automatically repair it; nor can it be too large, otherwise the experimental monkeys will die.” With no precedents to reference, constructing such an animal model was extremely difficult, as “a reliable animal model is the foundation for obtaining reliable experimental conclusions.” After three years of effort and trials on more than 70 experimental monkeys, the team finally established the animal model and initiated the intervention procedures. Researchers found that the introduction of copper ions reduced scarring in the damaged areas of the experimental monkeys by approximately 20%.

Professor Kang Yujian’s team has proposed a novel theory in regenerative medicine: all human tissues possess the capacity for self-repair. By reconstructing injury signals, it is possible to reactivate the tissue’s intrinsic self-repair mechanisms, thereby achieving therapeutic effects for degenerative diseases. This approach holds broad application prospects for various age-related conditions and chronic ischemic injuries.

In 2014, Professor Kang Yujian joined forces with Mr. Chen Xiaozhong to establish InnoBio. In 2017, Beijing Cardiorem Biopharmaceutical Co., Ltd. (hereinafter referred to as “InnoBio”) was founded, dedicated to translating the preliminary research conducted by Professor Kang’s team on reconstructing injury signals to reactivate tissue self-repair into practical applications. With many years of experience in clinical medicine and over two decades in the pharmaceutical industry, Mr. Chen Xiaozhong possesses an in-depth understanding of China’s healthcare sector and is well-versed in capital markets.

Cardiorem Co., Ltd. has established a complex patent barrier based on the preliminary research findings of Professor Kang’s team. The theory of copper ion-mediated reactivation of cardiomyocyte repair is only one suitable delivery molecule away from becoming a viable drug. After multiple trials, the team discovered that a small-molecule drug for a rare disease associated with copper metabolism can achieve targeted delivery of copper ions at specific doses. Although this small-molecule compound has not yet been marketed in China, its patent protection period has expired. Cardiorem Co., Ltd. has filed patents for new indications and dosing regimens, while also securing more fundamental protection through strategic patent design covering the underlying mechanism of action.

The team’s time- and labor-intensive preliminary research has paid off. The U.S. FDA has currently granted Inno Biologics permission to proceed with clinical trials for this small-molecule drug. “The FDA spoke highly of our research, acknowledging the regenerative repair mechanism of INL1. In addition to approving a Phase II clinical trial, they have encouraged us to explore the use of this drug in repairing cardiomyocyte injury caused by various etiologies. As a result, they have granted us unprecedented approval to conduct exploratory clinical trials across all heart-related diseases,” Mr. Chen Xiaozhong told VCBeat.

Mr. Chen Xiaozhong pointed out that heart failure is a highly challenging field, with the pharmaceutical industry ranking it alongside Alzheimer’s disease (AZ) as areas of significant difficulty, “Backed by three decades of foundational research, Cardiorem has ventured into this field with considerable confidence and thorough preparation.”

Fortune favors the bold. In July 2019, the FDA revised its guidelines on heart failure endpoints, placing greater emphasis on improving quality of life for patients with this fatal condition. Rather than prioritizing reductions in all-cause mortality, the agency now considers improvement in patient symptoms as the primary basis for product approval, provided that drug safety is ensured.This change has significantly lowered the difficulty, representing a major benefit for Cardiorem Co., Ltd., which is currently conducting clinical trials.“said Mr. Chen Xiaozhong.

Currently, Cardiorem Co., Ltd. is recruiting patients with heart failure with reduced ejection fraction (HFrEF) in the United States to complete the Phase II clinical trial of INL1. “The Phase II clinical trial of INL1 plans to enroll 200 patients and will be completed within two years,” said Mr. Chen Xiaozhong. “According to the new guidelines, if the Phase II clinical data are sufficiently robust, we can directly apply for conditional marketing approval of INL1.”

Meanwhile, Cardiorem has filed for an international multi-center clinical trial of INL1 and expects to conduct a Phase II clinical trial involving 50–100 patients in China in the second quarter of 2020. In addition, Cardiorem plans to launch several exploratory trials in the near future targeting fatal cardiac conditions that remain clinically challenging, such as myocardial fibrosis and pathological cardiac hypertrophy, with partial clinical data expected in the second half of 2020. “If successfully developed into a drug, this would be a groundbreaking product in the field of heart failure treatment,” said a prominent Chinese heart failure expert.We hope that the drugs with truly innovative mechanisms from InnoBio will have smooth clinical trials and benefit patients as soon as possible.”

It was revealed that Inno Biologics has launched an A+ round of financing ranging from RMB 70 million to RMB 120 million. The funds will be primarily used for the Phase II clinical trials of INL1 and the expansion of key personnel within the team.