R&D

Research Programmes

The proprietary chitinase platform developed by OncoArendi focuses on chitinase and chitinase-like proteins (CLPs) as potential new therapeutic targets. As part of this platform, the Company carries out a number of programs aimed at developing small molecule inhibitors of chitinase and CLPs ligands, which work by inhibiting inflammatory and fibrotic processes.

In addition, as part of the arginase platform, OncoArendi implements programs to develop small-molecule immunomodulators that work by unlocking the immune system to fight cancer.

OncoArendi’s latest research programs include a deubiquitinase platform in which the Company develops small-molecule inhibitors of enzymes from the deubiquitinase group (DUBs), which modulate key proteins involved in immune response to cancer.

OATD-01

OATD-01 is a first-in-class small molecule chitinase inhibitor that successfully completed Phase I clinical trials in healthy volunteers.

OATD-01 inhibits the activity of chitinases (CHIT1 and AMCase), which are enzymes that break down chitin, a component of many organisms, which is not produced by the human body. However, our Company among other academic and clinical research groups has shown that macrophages, or cells that are activated during inflammation, produce an increased amount of chitinases. This often correlates with the course of a number of inflammatory diseases, and the activity of chitinases is closely related to the processes of organ fibrosis, especially in the lungs. Our scientists have shown that removing a gene that encodes one of the chitinases leads to a much milder course of inflammation and fibrosis in preclinical models. We also confirmed that by blocking chitinases with OATD-01, we can significantly reduce the burden of disease in the same animal models. Thanks to this, our compound can find potential use in idiopathic pulmonary fibrosis, sarcoidosis or asthma, diseases that still pose a major therapeutic problem.

OATD-01 has an orphan drug designation (ODD) status for the treatment of idiopathic pulmonary fibrosis and sarcoidosis by the U.S. Food and Drug Administration (FDA).

Idiopathic Pulmonary Fibrosis (IPF) is a disease of the group of interstitial lung diseases, with an undetermined etiology and poor prognosis. It is characterized by progressive pulmonary fibrosis leading to respiratory failure. The average survival of patients from diagnosis is 3 to 5 years. In recent years, two drugs for IPF therapy have been registered – pirfenidone and nintedanib. These drugs limit the decline of lung capacity, that is, slow down the progression of the disease, but they are not fully efficacious, hence IPF still represents an important unmet medical need.

Sarcoidosis is a systemic disease, manifested by the formation of nodules called granulomas composed of inflammatory cells, which can be localized in various organs, most often in the lungs. In most cases, granulomas are eliminated spontaneously or as a result of treatment with oral corticosteoroid anti-inflammatory drugs. In about 30% of patients, however, the disease progresses, there is no response to treatment and pulmonary interstitial fibrosis occurs leading to an impairment of lung performance. There is currently no effective advanced, progressive sarcoidosis therapy.

YKL-40 Program

YKL-40 belongs to the proteins of the chitinase family, however, it has no enzymatic activity and its mechanism of action is similar to cytokines and growth factors, which accelerate the development of tumors by activating various signalling pathways.

As part of the YKL-40 project, OncoArendi continues to work on the synthesis of new ligands of this protein. The therapeutic potential of YKL-40 ligands is being studied in animal models of cancer using human cancer cells naturally producing the YKL-40 protein. Therapeutic efficacy studies of these compounds are also conducted in animal models based on genetically modified cancer lines with YKL-40 overexpression. In addition, these compounds are evaluated in animal models of pulmonary fibrosis (bleomycin-induced model) since the YKL-40 protein has been identified as one of the main markers of profibrotic macrophages present only in patients with idiopathic pulmonary fibrosis (IPF).

If the results of these preclinical studies prove positive, the YKL-40 protein ligands may be developed as future treatments for cancer and fibrosis.

Arginase Inhibitors Program

Cancer immunotherapy, or modulation of the activity of pathways regulating the immune anticancer response, is currently the most promising therapeutic approach in oncology.

Adequate levels of arginine are necessary to induce an optimal immune response to the development of cancerous tumors and low level of arginine blocks the proliferation and activation of certain immune cells. Arginine levels in patients with many types of cancer are significantly reduced due to the strongly induced expression of arginase, an enzyme that hydrolyses arginine. The OncoArendi research programme aims to develop small molecule arginase inhibitors, aiming to increase arginine levels and reactivate the immune response.

The OncoArendi research team has developed a new class of highly active, oral arginase inhibitors that restore immune cell activity in preclinical studies. These compounds showed strong anticancer effects in animal models of different types of cancer as monotherapy and in combination with other immunotherapies. As part of the program, the clinical candidate OATD-02 was selected. The compound represents a new class of checkpoint inhibitors with great therapeutic potential for the treatment of many types of cancer, in particular in combination with other immuno- and classical therapies.

Deubiquitinase Program

Deubiquitinase enzymes (DUBs) modulate the levels of proteins crucial for immune response in cancer, as their activity regulates the process of ubiquitination and subsequent protein degradation. Ubiquitination is a process necessary for “tagging” of proteins that are then destined for cellular “cleaning” system, responsible for regulation of cell function, e.g. multiplication, death, immune response or presentation of antigen. Excessive activity of deubiquitinase enzymes can lead to many diseases, including tumors and neurodegenerative diseases. Inhibition of deubiquitination restores the body’s ability to respond correctly to cancer.

OncoArendi is currently conducting research focused on the selection of lead compounds that inhibit selected enzymes from the DUBs group. Preliminary lead compounds have been already characterised at the level of in vitro studies and pharmacokinetics. Further optimisation is now based on a thorough analysis of the structure activity relationship (SAR). In addition, the first in vivo experiments are in the process of being designed to select the right cancer model, along with a comparison of the in vivo activity of our relationship leading to the literature reference.

New Research Programmes

In order to identify new molecules for the development of further potential drugs, OncoArendi carries preliminary exploratory research based on new biological targets, the role of which in specific disease units has been validated in scientific literature. The new programs are intended to strengthen or extend the experience and know-how of the OncoArendi team. We focus on research projects in which the molecules we develop may be first-in-class or best-in-class in their category and address diseases that are currently unmet medical needs.

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