On March 14, 2022 NETRIS Pharma, a pioneer in the development of dependence receptor targeted cancer medicines, reported the start of enrollment of patients with advanced/metastatic solid tumors in its Phase I clinical study of NP137, a humanized monoclonal antibody targeting Netrin-1 (NCT02977195) (Press release, Netris Pharma, MAR 14, 2022, View Source [SID1234611179]). The study represents the first time a drug candidate targeting dependence receptors has been evaluated in humans. Dependence receptors are tumor suppressors that trigger cell death unless engaged by a ligand, in this case Netrin-1. Blocking Netrin-1 could re-introduce the natural tumor cell death pathway.
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"The launch of this first of its kind clinical trial represents a key milestone in the dependence receptor field as well as for NETRIS Pharma in our commitment to find new therapeutic solutions for cancer patients," said Patrick Mehlen, CEO and co-founder of NETRIS Pharma. "We see in this study the confirmation of the ability to translate the potential of our innovative approach on dependence receptors to a first application of a drug candidate in patients."
This open-label study includes a first phase of dose escalation, followed by an extension phase. The main objective of the dose escalation phase is to determine the maximum tolerated dose (MTD) of NP137 and the recommended Phase II (RP2D) dose. The main objective of the extension phase is to confirm the safety and tolerance of NP137 and collect preliminary clinical activity data.
The study will recruit a maximum of 44 patients in three French centers, the Centre Léon Bérard in Lyon (Prof. Philippe Cassier – principal investigator of the study), the Institut Claudius Régaud in Toulouse and the Institut Gustave Roussy in Villejuif.
"The new therapeutic approach developed by NETRIS Pharma explores a so far non-druggable pathway in oncology. It offers another avenue of research to help us achieve the precision medicine needed in treating cancer. If the Phase I safety profile, which is expected in 2017, is positive, NP137 may represent a major therapeutic advance in the management of cancer patients," said Prof. Jean-Yves Blay, Director General of the Centre Léon Bérard, Lyon.
About Dependence Receptors Concept
Cells depend on external signals for their survival. These signals are mediated by various transmembrane receptors and sensors, such as soluble trophic factors, cytokines, hormones. For any given required stimulus, withdrawal leads to programmed cell death (apoptosis). Data obtained over the past 15 years, pioneered by Prof Patrick Mehlen and his research team at the Cancer Research Center of Lyon – Centre Léon Bérard, argue for a novel form of signal transduction that actively induces cell death following stimulus withdrawal.
This "negative signal transduction" leading to cell death is mediated by specific dependence receptors that induce apoptosis in the absence of the required stimulus, but block apoptosis in its presence. The expression of various dependence receptors at the surface of the cells seems to create a state of dependence (or addiction) to their respective ligands. To date, more than twenty of such receptors have been identified.
About NP137
Most types of tumors have been shown to produce an abnormal amount of dependence receptors’ ligands, thus preventing cells from dying. For instance, the Netrin-1 ligand has been shown to be overexpressed in 60% of metastatic breast cancers, in more than 70% of ovarian cancers, 50% of lung cancers or 80% of melanoma. Its expression often correlates with disease severity and no therapy has ever been tested on this new pathway.
NP137, a humanized monoclonal antibody of isotype IgG1 directed against the ligand Netrin-1, is the first drug candidate developed by NETRIS Pharma. NP137 prevents the binding of Netrin-1 on its dependence receptors, thus re-inducing cell death and leading to tumor growth regression.
Pre-clinical studies show an anti-cancer effect of NP137 in mice, in monotherapy but also in combination with demethylating agents and chemotherapy agents. In addition, remarkable effects are observed on tumor relapse. A synergistic effect of NP137 with immune-checkpoint inhibitors has also been observed, opening novel strategies for clinical investigation.