A portfolio of first-in-class and best-in-class products found thanks to Nanocyclix^® technology

Our chemical diversity has led us to identify Nanocyclix® probes with high potency, selectivity and specificity against the epidermal growth factor receptor kinase (EGFR).

EGFR is an established target for the treatment of advanced non-small cell lung cancer (NSCLC). EGFR kinase inhibitors are a standard treatment for tumors with an EGFR mutation (e.g., an L858R mutation). The majority of patients develop resistance to EGFR inhibitors within one year, which is mostly (> 50%) linked to an acquired EGFR T790M mutation. There is therefore a need to develop a diagnostic tool to determine and predict EGFR activity (wild and mutated) as well as the sensitivity of EGFR inhibitors to adapt treatments and monitor patient response.

We took advantage of our pharmaco-imaging platform to optimize our probe and labeled our drug candidate with ¹⁸F. In preclinical imaging tests, our radiolabeled drug candidate (Florepizol) showed a major signal in xenografted mice that had tumor cells with activated forms of EGFR (L858R and T790M mutations), whereas no signal was observed in xenografted mice that had tumor cells with wild-type EGFR.

Florepizol was evaluated in a phase I clinical trial (NCT02847377) in 13 patients with either wild-type EGFR or mutated EGFR to determine the ratio of the standardized uptake value (SUV). Florepizol allowed primary tumors and metastases (including brain metastases) to be detected with a significant SUV ratio in patients with activated forms of EGFR.

The Florepizol program is available for licensing and/or partnership to move forward to a phase 3 trial.

The RIPK2 program was initiated following the identification, through our chemical-based approach, of Nanocyclix® probes targeting the receptor-interacting serine/threonine-protein kinase 2 (RIPK2).

RIPK2 is a key component of signaling complexes for innate immune receptors and contributes to NF-kB-induced inflammatory signaling pathways. RIPK2 is recruited by NOD1/2 following stimulation by bacterial components, thus promoting inflammatory signaling pathways. NOD2 gene variants and mutations are involved in inflammatory diseases such as Crohn’s disease, ulcerative colitis, Blau syndrome and early sarcoidosis.

A strategic effort was made to optimize the initial probe, which led us to identify ODS-101, our current candidate. ODS-101 has significant preclinical activity in humanized colitis and immunotherapy-induced colitis models. In the PK/PD (pharmacokinetic/pharmacodynamic) and DRF (dose range finding) tests in monkeys, we observed full target engagement at doses with a significant therapeutic margin compatible with oral administration in humans.

We are currently conducting GLP toxicity studies and expect the first-in-man administration in 2022.

Because ODS-101 acts as an immunomodulator rather than an immunosuppressant, this program represents a prime opportunity to treat acute and chronic inflammatory diseases with less toxicity than current treatments.

Our RIPK2 program, which includes fast-followers and a back-up series, is available for licensing.

Through our chemical diversity approach, we identified leucine-rich repeat kinase 2 (LRRK2)-targeting probes with potency, selectivity and a development potential for the drug.

LRRK2 mutations are associated with Parkinson’s disease (PD). Activating mutations are observed in familial and sporadic forms of PD. LRRK2 inhibition therefore represents an opportunity to treat patients with PD.

Our chemical-based approach using our Nanocyclix® technology has led us to identify probes targeting MAP (mitogen-activated protein) kinase-interacting serine/threonine-protein kinases 1 and 2 (MNK1/2).

MNK1/2 regulate translational machinery by activating eIF4E, an effector downstream of the PI3K/Akt/mTor pathway, which is frequently activated in human cancers. The MNK1/2 pathway is activated under stressful conditions and is associated with resistance to rapamycin derivatives. MNK1/2 are also involved in immunomodulation, suggesting that MNK1/2 inhibition could have an impact on tumor progression across a wide range of cancers through direct anti-tumor activity and immunostimulation.

We are currently developing the series through a lead optimization phase. Our main compound has been tested in preclinical models. A dose-dependent response was observed in a PK/PD mouse model, in line with the predicted eIF4E inhibition. In xenografted mice with CT26 syngeneic tumor cells, we observed a significant decrease in tumor growth following oral administration of our primary compound alone and an additive effect when combined with an anti-PD1 agent.

We are currently continuing our efforts to identify a preclinical drug candidate in 2021.

The MNK1/2 program is available for licensing and/or a partnership.

A medicinal chemistry platform containing over 11,000 different nanocyclic kinase inhibitors.

Mapping of probe / target to therapeutic indication based on kinase activity and selectivity data.

Oncodesign/SEngine have identified a series of Nanocyclix® compounds against an undisclosed target that kill organoid systems based on biopsies from cancer patients with no remaining solutions

Compounds active against the target show strong effects in organoids from highly resistant patients in multiple cancer types. The series is being optimized to candidate status.