nms

Pipeline

The current portfolio of projects includes a number of anticancer compounds in Phase I-II clinical trials, others in advanced preclinical development, as well as target identification and early discovery activities. The pipeline includes several programs in collaboration with third parties.

pipelined This is a B-Raf inhibitor, a highly relevant molecular target in various solid tumors such as melanoma or colorectal cancer, currently in the late clinical development phase. This is a selective inhibitor of the tyrosine kinases ALK, ROS and TRK, which are expressed in an altered (“rearranged”) and activated form in a fraction of various types of tumors. The drug has already shown significant clinical activity, with objective responses in ROS, TRK or ALK positive lung tumors, in ALK mutated neuroblastoma and in TRK positive colorectal cancer where, for the first time, a response was observed following treatment with a drug targeting TRK kinase. Milciclib (PHA-848125) is a spectrum selective multi-kinase inhibitor, initially identified in a CDK inhibitor project as a potent inhibitor of the CDK2/Cyclin A complex. Orphan designation was granted by the European Commission and by the FDA to Milciclib for the treatment of malignant thymoma/thymic epithelial tumors. This is an inhibitor of TTK/MPS1, a kinase that plays a role in the regulation and control of chromosome segregation during cell division. TTK/MPS1 is an innovative target that is highly expressed in several tumors and the inhibition of which leads to cancer cell death. Clinical evaluation of this compound is ongoing. NMS-P937 is a novel, orally-available, PLK1-specific inhibitor. Polo-like kinase 1 (PLK1) is a serine/threonine protein kinase considered to be the master player of cell cycle regulation during mitosis. NMS-P937 potently causes a mitotic cell cycle arrest followed by apoptosis in cancer cell lines and it inhibits xenograft tumor growth with demonstrated PLK1-related mechanism of action, after oral administration. NMS-P937 also shows potential for combination with approved cytotoxic drugs in various clinical settings, causing tumor regression in xenograft models. Currently NMS-P937 is being evaluated for the treatment of solid tumors. A potent cytotoxic anthracycline derivative to be used to arm antibodies for therapeutic use. Oxford BioTherapeutics (OBT) has licensed Nerviano’s payload technology for an exclusive OBT target for development of an ADC. Mediapharma S.r.l. has licensed Nerviano’s payload technology for an exclusive Mediapharma target for development of an ADC. A chemical series of potent inhibitors of a kinase whose activity is implicated in many solid tumors and leukemias. Danusertib is a potent inhibitor of Aurora kinases and of Abl (including the T315I mutation). The Aurora kinases are serine/threonine protein kinases essential for proliferating cells as key regulators of different steps in mitosis; they are overexpressed in several tumors. Danusertib has already shown signs of clinical activity in both solid and hematologic malignancies, when administered both as monotherapy or in combination with chemotherapeutic drugs. Recent preclinical findings show that danusertib is particularly active against N-Myc amplified neuroblastoma and other neuroendocrine tumors harbouring this genetic alteration (e.g. NEPC, SCLC), suggesting that it may have an especially high clinical potential in these diseases. This is a selective inhibitor of CSF1R, FLT3 and KIT. Activating mutations of these kinases are involved in the pathogenesis of gastrointestinal stromal tumors (GIST), of some leukemias (in particular, AML), and other solid tumors, including certain subtypes of melanoma. CSF1R inhibition is additionally a highly promising approach for targeting tumor-associated macrophages, cells which cooperate with the tumor in the evasion of host immune responses. NMS-088 is planned to initiate clinical studies in 2017. Nerviano is developing a potent and highly selective PARP-1 inhibitor, representing a significant advancement over competitors’ compounds. NMS-P293 is selectively active on tumor cell lines defective in the HR DNA repair pathway, such as BRCA and pTEN mutated lines, while sparing DNA repair proficient cells and normal myelocytes. Its highly favorable preclinical characteristics confirm this compound as a candidate for clinical development in 2017. NMS’ projects portfolio in early preclinical development includes innovative driver oncogenes, cell cycle and DNA repair mechanisms, metabolic and immune-oncology pathways, as well as novel ADC payloads. Nerviano’s novel drug-linker technology of new DNA intercalating agents is based on a proprietary thienoindole scaffold, characterized both by potent antitumor activity and by physicochemical properties that are highly compatible with deployment as antibody payloads. Nerviano’s core technologies in the field further include: medicinal chemistry expertise, know-how for establishing proof of concept, GMP manufacturing of payloads as well as efficacy and safety profiling of ADCs.
 
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