Inhibiting resistance to immunotherapy in Oncology by targeting Netrin-1

Informations projet

ImmunoNet

N° de convention de subvention: 190109071

DOI

10.3030/190109071

Projet clôturé

Date de signature de la CE 31 Août 2022

Date de début 1 Septembre 2022

Date de fin 30 Septembre 2025

Financé au titre de

• The European Innovation Council (EIC)

Coût total

€ 8 327 233,75

Contribution de l’UE

€ 2 500 000,00

Coordonné par

NETRIS PHARMA SAS
France

Periodic Reporting for period 2 - ImmunoNet (Inhibiting resistance to immunotherapy in Oncology by targeting Netrin-1)

Période du rapport: 2023-10-01 au 2025-09-30

Résumé du contexte et des objectifs généraux du projet

Despite efforts to investigate and deploy preventive measures, cancer incidences in Europe remain high and its victims often seem randomly hit. Treatment is therefore at the core of our fight for these patients. Traditionally, universally cytostatic chemotherapies, often based on the infliction of DNA damage in all cells of the body, have been employed. These remain a first-line defense today, but in recent decades, targeted therapies based on detailed molecular analyses of the disease have additionally emerged. Among these, Immune Checkpoint Inhibitors (ICIs) have recently revolutionized the treatment and management of cancer. Yet, progress recorded and impact on long-term survival affect only a limited fraction of patients, as most cancer patients do not or incompletely respond to ICIs thereby leaving an important care gap for patients and clinicians.

NETRIS Pharma is an innovative clinical-stage pharmaceutical company based in Lyon that has developed NP137, a humanized monoclonal antibody targeting netrin-1. This first-in-class therapeutic antibody with a new target has a unique mode-of-action that was published in 2 back-to-back papers in Nature® in August 2023. It was found, that NP137 is able to block epithelial-mesenchymal-transition of tumor cells - a critical process in cancer progression, therapy resistance and metastases development across indications and treatments – including chemotherapy and ICIs.

The objective of the ImmunoNET project is to conduct a proof-of-concept clinical trial that assesses the benefit of NP137 on top of immunotherapy to alleviate resistance to ICIs and increase overall survival, which will have a major impact for these patients that are left with limited treatment options. Based on its universal mode of action, this impact is furthermore extendable to other indications and treatment combinations, two of which are additionally investigated in this project. Overall, the success of NP137 will create significant growth opportunities for the European company NETRIS Pharma and Europe’s technological leadership in the health sector.

Travail effectué depuis le début du projet jusqu’à la fin de la période considérée dans le rapport et principaux résultats atteints jusqu’à présent

The work performed as part of the ImmunoNET project gravitates around 3 clinical trials. The core of the project is the realization of the ImmunoNET clinical trial that includes patients that do not respond to ICIs either as “primary refractory” patients that experienced continued tumor growth in spite of the treatment or patients whose tumors initially shrank under ICI treatment but then regrew again, the so called “secondary refractory” patients. For both groups, NP137 was added to their ICI treatment with the aim to overcome the treatment resistance they were blocked in.

Additionally, two more trials were added to the project scope. Firstly, NP137 was added to standard of care (SoC) ICI treatment for patients with liver cancer as a first-line treatment after diagnosis (trial LiverNET). Secondly, NP137 was added to first-line SoC chemotherapy for patients affected by pancreas cancer (trial LapNET).

Safety of the experimental treatments was confirmed for all indications and drug combinations included. Clinical benefit was confirmed for patients included in both the ImmunoNET and LapNET trial with respect to comparable trials investigating SoC treatment alone. Detailed analysis was able to link this benefit with specific patient subgroups, therefore providing rationale for targeted further development of NP137 for these groups. The analysis of the LiverNET trial results is not yet mature enough to draw binding conclusions, but initial outcomes look promising.

As integral part of all three trials, tumor samples were collected from patients and analyzed molecularly. This important part of ancillary research aims to identify molecular signatures in the tumors at diagnosis that will be predictive of the patient’s clinical outcome under the applied treatment. These molecular markers will then be used to better group patients in future applications and match them with the most effective treatment for each of them individually right at diagnosis. Such an approach protects patients from the strains of ineffective treatments and the deceptions that come with it.

Within this project, researchers from NETRIS Pharma were able to identify a molecular marker in tumors at diagnosis of patients with pancreas cancer that is predictive of a better clinical outcome under treatment with NP137 than the average experienced by patients without the presence of this marker. This result is especially remarkable when considering that patients with marker positive tumors tend to form a group with worse prognosis than average under SoC treatment alone. It can therefore be concluded that NP137 provided these patients with a specific benefit and increased their survival in this trial.

Progrès au-delà de l’état des connaissances et impact potentiel prévu (y compris l’impact socio-économique et les conséquences sociétales plus larges du projet jusqu’à présent)

In this project we work with a first-in-class molecule with an innovative target and a new mode of action (MoA). Achievements and beyond-the-state-of-art impacts of this project are:
Achievement: safety of NP137 for all cancer indications and drug combinations tested in this project
>>> Impact: proof of concept for a first-in-class, new target in oncology with a very positive toxicity profile untypical in the oncology field
Achievement: NP137 provides added clinical benefit to SoC ICI and chemotherapy
>>> Impact: proof-of-concept for a new MoA targeting a universal cross-indication resistance mechanism with potential applicability of NP137 as combination drug for numerous SoCs
Achievement: identification of specific patient target subgroups based on clinical and molecular analyses
>>> Impact: This patient subgroup identification will importantly facilitate recognition by the regulatory authorities as well as the follow-up development until market entry of NP137

As this is a first-in-class completely new target and MoA, key needs now to assure continuous success are solid evidence from Phase2b/3 randomized controlled trials and important commercialization efforts. Both goals will best be achieved through partnering with established pharma companies with international reach and the necessary financial resources to accompany our development from the current level to market.

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