Researchers at OncoArendi study the therapeutic potential of chitinases and chitinase-like-proteins (CLPs) which provide multiple points for therapeutic intervention. OncoArendi currently has a platform of 3 distinct small molecule programs targeting chitinases and CLPs, with potential utility in diverse inflammatory and fibrotic diseases of high unmet medical need.

Further to that, and in close collaboration with several leading academic and clinical institutions and industrial partners, OncoArendi has initiated a program focused on development of small molecule immune-modulators to knock down the ability of tumors to escape immune surveillance.  These unique, proprietary compounds will target a strategic enzyme involved in amino-acid metabolism that allows tumor cells to hamper antitumor immunity and to avoid immune surveillance.

OATD-01 clinical candidate

OATD-01, a novel inhibitor of chitinases was developed by OncoArendi Therapeutics as an innovative and unique therapy for multiple lung diseases including asthma, idiopathic pulmonary fibrosis and sarcoidosis, as well as other fibrotic diseases such as NASH.

Asthma is a chronic inflammatory lung disease which affects more than 300 mln people worldwide. Despite the availability of antiinflammatory steroidal drugs and bronchodilators, asthma remains an unmet medical need as a significant fraction of patients, particularly with severe asthma, exhibits poor response to treatment.

Interstitial lung diseases is a group of over 300 lung disorders which affects lung interstitium: the most common are sarcoidosis and the idiopathic pulmonary fibrosis. These diseases, many with unknown etiology, are characterized by the alveolar damage which often leads to a chronic inflammation and fibrosis resulting in a diminished lung functions.

The growing evidence from preclinical and clinical studies implicated members of the chitinase family, acidic mammalian chitinase (AMCase) and chitotriosidase (CHIT1), in pathology of multiple interstitial lung diseases and asthma providing a rationale for a therapeutic targeting of these enzymes.

Following a rational design and synthesis of over 1000 compounds, OncoArendi has developed a first-in-class therapeutic product for asthma treatment, the clinical candidate OATD-01. This is the first chitinase inhibitor to have entered pre-clinical and clinical development.

OATD-01 has certain unique features:

  • Novel, efficacious and safe, non-steroidal small molecule inhibitor strategy to treat asthma by targeting the key pathways involved in airway inflammation
  • Dual anti-inflammatory and anti-fibrotic activity through inhibiting chitinases with a single NCE in the in vivo model of airway inflammation induced by house dust mite
  • Anti-fibrotic therapeutic efficacy in the bleomycin-induced lung fibrosis model and the STAM model of non-alcoholic steatohepatitis
  • Oral delivery significantly improving patient compliance, once-a-day dosing (supported by animal PK studies in three species)
  • Proprietary IP (two US patents granted, three pending in national validation & PCT phase)

Program is currently in the clinical development.

CHIT-1 selective inhibitor

Based on the crystallographic analysis and biochemical testing, OncoArendi has developed a series of highly potent and selective inhibitors of CHIT1 as a novel therapy for interstitial lung diseases like idiopathic pulmonary fibrosis (IPF) and sarcoidosis. The current work is focused on the lead optimization.

Idiopathic pulmonary fibrosis, is an interstitial lung disease with unknown ethiology and very poor prognosis with life expectancy of 3-5 years. The progressive fibrosis underlies the irreversible decline in lung function. There is no effective treatment for IPF and the two recently approved drugs, nintedanib (Ofev) and pirfenidone (Esbriet), moderately delay disease progression. Therefore there is an urgent need to develop novel therapies for IPF.

Sarcoidosis is a multiorgan systemic disease characterized by a formation of granulomas, a tightly packed clusters of activated immune cells. Granulomas can develop in various organs, but most patients will have a pulmonary presentation. Spontaneous remission occurs in a majority of cases, but up to one-third of patients develop a chronic, progressive or relapsing disease with a concomitant interstitial fibrosis and decline in lung functions. Currently, there is no therapy for an advanced sarcoidosis.

Highly elevated chitotriosidase levels were found in serum and BALf from patients with IPF and sarcoidosis and correlated with the disease stage and progression. Results from preclinical and clinical studies demonstrated a role of CHIT1 in pathology of fibrosis and in formation of granulomas confirming that CHIT1 represents a novel therapeutic target for the interstitial lung diseases.

Program YKL-40

Development of YKL-40 inhibitors represents an innovative therapeutic approach for glioblastoma multiforme (GBM) and other cancers. YKL-40 is one of the most highly induced proteins in GBM and its expression correlates closely with disease progression and clinical prognosis. YKL-40 promotes tumorigenesis of GBM and other cancers by multiple mechanisms including increased angiogenesis and invasiveness of tumor cells. It also contributes to a formation of the immunosuppressive tumor microenvironment.

Although YKL-40 belongs to the chitinase family of hydrolases, it does not have enzymatic activity and instead functions as a growth factor/cytokine which modulates multiple signaling pathways promoting tumorigenesis. Almost all therapies involving small molecules rely on inhibition of the enzymatic activity of proteins implicated in tumor formation, limiting a scope of druggable targets. Successful identification of the YKL-40 inhibitor will confirm a feasibility of targeting a cytokine-like protein and will pave a way for the development of novel small molecule inhibitors for the non-enzymatic targets. Several high affinity inhibitors have been identified and the current work is focused on the lead optimization.

Arginase inhibitor program

Cancer immunotherapy has quickly become a mainstay therapy for many types of cancer, either as a monotherapy or in combinations with other modalities. Inhibitors of immune check points have demonstrated spectacular clinical efficacy, however only about 20% of patients have shown long-term benefits. These findings prompted development of novel modulators targeting anti-tumor immune responses.

The level of arginine in lymph nodes and in the tumor microenvironment represents a metabolic check point which regulates antitumor immunity. Full immune response requires adequate arginine levels and its decreased concentration suppresses activation and proliferation of T and NK cells. Highly elevated levels of arginases, enzymes which hydrolyze arginine, have been found in a majority of patients with various types of cancer resulting in a decreased concentration of arginine. Low levels of arginine contribute the immunosuppression. The aim of the arginase inhibitor program is to develop arginase inhibitors to increase arginine levels and to reactivate antitumor immune response.

OncoArendi has developed highly potent, selective, orally active inhibitors of arginases which restored functional efficacy of T lymphocytes and demonstrated significant antitumor efficacy in multiple models of cancer, either as a monotherapy or in combinations with other immunotherapies. The lead compound, OATD-02, has been nominated for a clinical development. OATD-02 is designed to target a novel immune check point mechanism and represents a promising new immunotherapy for multiple types of cancer, in particular in combination with other immunotherapies and other modalities.

New Exploratory Programs

To ensure a continuous flow of drug candidate molecules into our development pipeline, we regularly initiate new exploratory drug discovery programs based on the existing targets that will complement or reinforce our pipeline and use our in-house expertise. We are looking for first-in-class or best-in-class opportunities that address diseases with unmet medical needs.