"Our Mission: Restoring Life to Cancer Cachexia Patients"

According to the World Health Organization (WHO) and the International Agency for Research on Cancer (IARC), there are currently approximately 53.5 million cancer patients worldwide, a number driven by factors such as population aging and lifestyle changes. In 2022 alone, approximately 20 million new cancer patients and 9.7 million cancer-related deaths were diagnosed, and according to various estimates, the number of new cancer cases per year is expected to increase significantly in the coming decades and reach 35 million by 2050.

Cachexia, one of the primary causes of death in cancer patients, is a complex, debilitating syndrome seen in advanced cancer patients, characterized by severe weight loss, muscle wasting, fat tissue breakdown, and reduced appetite. It is particularly prevalent in aggressive cancer types, such as pancreatic, esophageal, stomach, lung, liver, and gastric cancers — which are responsible for half of cancer deaths worldwide.

"Studies on cancer cachexia show that about 30% of all cancer patients globally, about 2.9 million people, will die from cachexia. In aggressive cancer types, such as gastric, pancreatic and respiratory tract cancers up to 85% of patients suffer from cachexia", explains Ronen Sarusi, one of MetaboCure's founders. MetaboCure is an Israeli startup that develops a novel drug for cachexia, co-founded by Sarusi with Tarom Innovative, represented by Dr. Dror Melamed, MetaboCure's CEO and Chief Technology Officer, and Prof. Ayelet Erez, the company's Principal Investigator.

Prof. Ayelet Erez is an Associate Professor at the Weizmann Institute of Science, an MD graduate of the Technion, a pediatrician and a clinical geneticist, with a PhD in cancer genetics from Tel Aviv University. She focuses on cachexia research and was awarded the prestigious POC ERC grant from the European Union to lead the scientific discoveries in the current project, on which MetaboCure is based. Prof. Erez is also a consultant at the Onco-Genetic Clinic at Schneider Children's Hospital.

Dr. Dror Melamed holds a PhD in molecular and cellular biology from the Faculty of Virology at the Weizmann Institute of Science and an MBA from Bar-Ilan University. He has over 25 years of experience in senior executive management roles in the biopharmaceutical industry.

Ronen Sarusi, MetaboCure's co-founder and Chairperson, holds a BA in environmental engineering and software engineering from the Technion, as well as a Business Management certificate from Tel Aviv University. He has over 20 years of experience in management positions and entrepreneurship in the pharmaceutical and medical device industries.

The three leaders of MetaboCure emphasize why it is so important that a development proven effective in mice will progress to become a drug that can help patients suffering from cancer cachexia.

A common complication
Cachexia, which can also appear with other diseases, is a common cancer complication, causing dramatic weight loss in patients and may affect their quality of life as well as the effectiveness of cancer treatments. It is considered a terminal condition that ultimately leads to death. Additional symptoms of cancer cachexia include fatigue and weakness, anemia, inflammation, and anorexia.

Cancer cachexia cannot be cured with current treatments, not even by increasing the amount of food consumed by the patient, including foods rich in protein and calories. Dr. Melamed emphasizes that today, the treatments given to those suffering from cachexia address only the symptoms and not the root cause of the condition and, therefore, do not prevent many cases in which patients ultimately succumb to cachexia.

Research Breakthrough
The biopharmaceutical startup MetaboCure, which focuses on developing innovative solutions for metabolic disorders, specifically cancer cachexia, is currently working to provide a solution. MetaboCure develops a breakthrough drug designed to treat the underlying mechanism of cachexia, based on mRNA technology. This mRNA will be translated in the patient's liver cells into a protein called HNF4α. The goal of the drug under development is to restore metabolic balance, thus enhancing cancer patients' response to treatments and increasing survival rates, while simultaneously improving their quality of life.

This approach combines a medical perspective with an understanding of how a patient's quality of life and overall physical condition, particularly liver function, influence survival. Dr. Melamed and Sarusi were introduced to this approach by discovering Prof. Erez's groundbreaking research.

In her research, Prof. Erez found that during cancer progression, cancer-related inflammation leads to the early infiltration of innate immune cells into the liver. This, in turn, suppresses the transcription factor HNF4α, found in hepatocytes - liver cells - which is crucial for regulating liver metabolism. The sharp decrease in the levels of HNF4α leads to tissue breakdown, which increases macromolecule availability that tumors exploit to fuel their growth.

Prof. Erez and her team, led by Dr. Omer Goldman, demonstrated that when the HNF4α protein levels are suppressed in a complex process, the muscle and fat wasting begin and the cachexia manifestations appear, while at the same time, the breakdown products support the tumor growth.

By restoring HNF4α levels in the liver of cancer mouse models, using HNF4α mRNA, cachexia symptoms were reversed. This was evident by reduced weight loss, tumor shrinkage, and improved survival rates. This very important discovery laid the foundations for drug development and has been acknowledged by the scientific community.

"If a major factor like HNF4α is suppressed and leads to the loss of metabolic balance, then we can restore it in liver cells using mRNA technology, similar to what was used to create vaccines against the Covid-19 virus", explains Dr. Melamed. He adds that this method involves introducing messenger RNA (mRNA) encoding the desired protein into cells, where it is translated into the protein of interest, in this case HNF4α.

Prof. Erez highlights that in laboratory experiments on mice conducted by Dr. Goldman, they demonstrated that restoring the protein's expression levels led to significant improvement: sick and emaciated mice gained weight, increased muscle and fat mass, and exhibited reduced tumor size and prolonged survival, compared to untreated mice in the control group. Additional successful animal trials were performed in collaboration with Prof. Avi Schroeder, head of the Laboratory for Targeted Drugs and Personalized Medicine Technologies at the Technion.

A possible solution for a terminal condition
MetaboCure's founders say they decided to establish a startup specifically in the field of cancer cachexia after realizing that many cancer patients deteriorate into this terminal condition, losing physical and mental function, and developing resistance to the various treatments given for cancer. "When it comes to cancer, cachexia affects the entire course of the disease and is identified as a terminal condition, causing enormous frustration among doctors. There is currently no treatment for cachexia, and it leads to a lack of response to cancer treatments. The patients' emaciated appearance and behavior also convey to those around them that the end is near, without any ability to help," Dr. Melamed says with pain. "When we learned about Prof. Erez's research which enables the preservation of HNF4α levels — the natural mechanism responsible for metabolism in the liver and limits cancer growth in mice — we realized that there was something special here on all levels: scientific, technological, humane, and personal. This is especially true when we felt that Prof. Erez's driving force was the patient's well-being and the desire to address the condition at its root, not merely its symptoms."

Cancer Cachexia — A Common and Widespread Threat
Dr. Melamed presents the data that led to MetaboCure's foundation: "Cachexia is responsible for about 30% of all cancer deaths and occurs in high percentage of patients with aggressive cancers. To provide an effective response, we will focus initially on cachexia caused by pancreatic cancer, which affects more than 80% of patients. Studies show that these patients are likely to die from cachexia, thin, emaciated, and without functional independence. Specifically for pancreatic cancer, we do not intend to 'hit our heads against the wall' and treat a cancer that so far has resisted all curative efforts. Instead, we aim to improve the patient's general condition, thereby improving their response to treatments and altering the course of the cancer disease," adds Dr. Melamed.

Prof. Erez emphasizes that the medical community in Israel and the US is looking forward to a drug that, she says, "could provide an effective treatment for a condition that currently lacks efficient solutions".

What is the significance of the research for cancer patients who cope with cachexia?
Dr. Melamed: "Prof. Erez and her team have reached a deep understanding of the mechanisms that contribute to cancer cachexia and have shown that the cancerous tumor triggers an inflammatory response that impairs liver metabolism in the early stages of the disease, by suppressing the expression of HNF4α. As a result, there is an impairment in fatty acid and protein metabolism, which contributes to muscle wasting. This metabolic disruption prioritizes nutrients for the tumor at the expense of the patient's body. It is manifested in body tissue breakdown so that the tumor consumes more nutrients and energy, like a parasite on a host. This ultimately results in body weight loss and eventually the patient's death."

Sarusi: "Getting to the root cause of the problem and understanding the mechanism is more than half way to a solution. This is the significance of the study in which the team not only addressed the phenomenon itself, but also uncovered its causes and demonstrated the solution in cancer cachexia mouse models. We are now developing the drug to prove feasibility. If we treat cachexia as we plan with the drug we are developing, we can achieve a breakthrough, starting with a significant improvement in symptoms, increasing the patients' response to treatment, improving their quality of life and extending their lifespan".

Prof. Erez: "The drug is effective in animal models of pancreatic cancer with cachexia. HNF4a is a protein the body naturally produces, and its function is preserved in humans. This gives doctors and oncologists confidence that there is a high likelihood the drug will be effective for cancer cachexia patients with minimal side effects".

How does the drug you plan to develop prevents the body's depletion and tumor growth?
Prof. Erez: "As mentioned, the goal of the drug is to restore what is missing, namely the HNF4α protein in the liver, which regulates the body's metabolism. We proved the connection between the lack of HNF4α and cachexia in our study. While cancer mouse models with cachexia had a loss of HNF4a, when we treated mice with pancreatic cancer with the HNF4α mRNA, their weight loss decreased and their survival improved, compared to untreated mice".

Sarusi: "Our drug is designed to preserve metabolic balance in the body while halting constant nutrient supply to the tumor, starting from the disease's early stages. Since some of the changes in the liver also affect the immune system, mainly decreasing the number and activity of lymphocytes, the drug may also improve the immune system's ability to fight the tumor and protect the body".

What stage is the company currently in?
Dr. Melamed: "We are in the optimization and final development phase of the molecule, that will treat patients. This stage comprises all the necessary tests, including efficacy and preliminary toxicity evaluation. Later, we will determine the correct dosages, therapeutic regimens, drug safety and other elements being assessed in the preclinical stages. Altogether, this process takes about two to three years. At the end of this process, we will begin the clinical trials, the most advanced stage of drug development".

Sarusi: "We are about to meet with the FDA representatives. The drug falls under several FDA-supported categories: breakthrough technology, prioritized fast-track technology, and orphan drug status. These three elements define the fastest regulatory track, reflecting the immense unmet need that will increase the expected FDA involvement".

Market Potential
"Our market research indicates that the potential is enormous, with revenue expectations in the billions of dollars, supported by regulatory protection", reveals Sarusi. According to him, one of the main distribution channels being considered for the drug is collaboration with one of the large international pharmaceutical chains.

"One of the leading pharmaceutical corporations is currently in clinical trials stages for the treatment of cancer cachexia, which treats the symptoms rather than the root cause of the disease", emphasizes Dr. Melamed, who indicates that the high revenue expectations have increased awareness. Sarusi adds that this will open up a very competitive market, in which MetaboCure will be well positioned and have a significant share.

MetaboCure has recently been awarded a grant from the Israel Innovation Authority and is now seeking additional investments to accelerate and expand its development plans.

MetaboCure
Year of establishment: 2024.
Founders: Tarom Innovative (Dr. Dror Melamed), Prof. Ayelet Erez, Ronen Sarusi.
Field of activity: Development of a drug for the treatment of cancer cachexia, patented in the US, Europe and China.
Leading motto: Restoring life to cancer cachexia patients.

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In collaboration with MetaboCure