Our mission is to translate complex powerful biology with urgency and rigor to deliver life-changing medicines
Recent advances in immunotherapy, including the introduction of checkpoint inhibition, have ushered in a new era of cancer treatment. However, many patients and/or types of cancer continue to remain unresponsive to currently approved immunotherapies. For example, immune checkpoint inhibitors targeting Programmed Cell Death Protein 1 and Programmed Cell Death Protein Ligand 1, or PD-1 and PD-L1, respectively, have driven significant improvements in clinical outcomes, especially in certain cancer types that are immunogenic, or capable of provoking an immune response. However, the overall response rate to PD-1/PD-L1 inhibitors is typically only 20-30%. Furthermore, given tumor heterogeneity and the complexity of cancer escape mechanisms that are still not fully understood, even cancer patients who experience a full or partial response using checkpoint inhibitors may eventually experience cancer progression. Over the last five years, one of our areas of research has been immune-modulating therapies to enable more patients to experience the benefits of immunotherapy. We are currently developing several molecules that are part of an exciting and still-emerging class of oncology drugs that work to inhibit myeloid and stromal checkpoints of the anti-tumor immune response. By removing supposed “brakes” (i.e., checkpoints) that may be preventing the immune system from launching an effect attack against a tumor, NGM’s oncology drugs may be able to reprogram myeloid cells in the tumor microenvironment from an immune-suppressive to an immune-activating phenotype. This, in turn, may promote an anti-tumor immune response by converting “cold” tumors that are not immunogenic into “hot,” or inflamed tumors.
Myeloid-derived suppressor cells (MDSC) feature heavily in the tumor microenvironment, sometimes making up over 50% of the weight of a tumor in mass. In comparison to T-cell checkpoints, myeloid biology and myeloid checkpoint inhibition is an emerging and yet still largely untapped area of investigation that holds significant promise as a monotherapy option for PD-1/L1 refractory patients or when used in combination with PD-1/L1 for relapsed patients (or for deepening response for PD-1/L1 high / responder patient populations). ILT4 and ILT2 are among the most highly enriched receptors in myeloid cells and are upregulated in non-responders to PD-1 therapy. Today, there are only six disclosed programs targeting ILT4. Merck’s MK4830 program is the furthest along in this class of drugs. In a single arm Phase 1 study of relapsed/refractory PD-1/L1 patients with various solid tumors, Merck reported a 45% overall response rate (ORR) for patients when treated with MK4830 in combination with Merck’s anti-PD1 therapy KEYTRUDA® (pembrolizumab). NGM707 is a dual ILT2/ILT4 antagonist antibody; in addition to inhibiting ILT4, NGM707, also has an anti-ILT2 component. ILT2 is a unique receptor that is present on highly cytolytic T-cells, natural killer (NK) cells and macrophages. Therefore, an anti-ILT2 may have multiple anti-cancer effects that improve on treatment with monospecific anti-ILT4 or PD-1/L1 (current frontline standard of care for many solid tumors). NGM707’s groundbreaking engineering as a dual antagonist versus a bispecific may lead to certain advantages, including higher affinity target binding and less challenging manufacturing.
NGM120, NGM707 and NGM438 were originally discovered by NGM under its collaboration with Merck that was first signed in 2015 and was extended once in its original structure and recently amended and restated. Under the terms of the original collaboration, Merck paid ~$250M in upfront fees and equity to NGM, funded all research and development costs (over $500M through the end of 2020) and obtained an option right for any program discovered by NGM at the end of a human proof-of-concept study (Phase 1 or 2, depending on the indication). NGM would have co-development and co-commercialization rights and up to 50% profit sharing for each program. In turn, NGM was solely responsible for identifying promising targets, conducting preclinical research, and advancing these programs to the clinical stage. The strategic rationale for this collaboration agreement – which was particularly unique given the level of research and development autonomy that NGM held – was aimed at leveraging NGM’s industry-leading biologics expertise. Through the collaboration, Merck aimed to identify novel programs and targets that would lead to the potential deliver of transformative medicines for patients/diseases with significant unmet need. Recently, Merck and NGM agreed to amend their collaboration agreement for focus primarily on advancing novel medicines for retinal and cardiovascular and metabolic diseases. Per the amended and restated agreement, NGM gained worldwide rights to its disclosed oncology portfolio, including NGM120, NGM707 and NGM438 as well as all of its undisclosed preclinical and research assets falling outside the amended collaboration’s narrower scope.