Lenzilumab is a Humaneered® recombinant monoclonal antibody that neutralizes soluble granulocyte-macrophage colony-stimulating factor (GM-CSF) a critical cytokine. GM-CSF is an upstream driver in the paths of multiple diseases. Of interest, GM-CSF is a key cytokine in toxicity related to groundbreaking chimeric antigen receptor T-cell (CAR-T) cancer therapy for certain leukemias.

Source: Avci, A.B. et al. Targeting GM-CSF in rheumatoid arthritis. Clin Exp Rheumatol 2016; 34 (Suppl. 98): S39-S44.

Lenzilumab is a highly potent GM-CSF antagonist with a favorable safety profile. It has been tested in more than 90 patients and found to be well tolerated in previous clinical studies in either healthy adults or those with leukemia or autoimmune diseases.

Following up-to-the-minute science, Humanigen has pivoted the prime development focus for lenzilumab to its potential to make CAR-T cancer therapy better.

CAR-T-related Neurotoxicity

CAR-T is emerging as an exciting breakthrough to treat blood cancers, and potentially solid cancers someday. But neurotoxicity related to CAR-T therapy is a key unresolved issue and unmet need. There is a strong scientific rationale building for GM-CSF as a key trigger in CAR-T-related neurotoxicity. Neutralizing GM-CSF could potentially improve the utility of CAR-T therapy including: making it safer by blunting dangerous neurotoxicity and/or other side effects; boosting the CAR-T therapy to be more effective by allowing a higher dose, greater CAR-T expansion and potentially reducing myeloid-derived suppressor cells (MDSC) that inhibit T cell function; enabling CAR-T to be a more routine out-patient procedure; and eventually helping to expand CAR-T into more tumor types. GM-CSF is one of three biomarkers only associated with severe neurotoxicity, and increased levels also have been seen with other CAR-T toxicity.

Source: Zachary J. Roberts, Marc Better, Adrian Bot, Margo R. Roberts & Antoni Ribas (2017): Axicabtagene ciloleucel, a first-in-class CAR T cell therapy for aggressive NHL, Leukemia & Lymphoma, DOI: 10.1080/10428194.2017.1387905 https://doi.org/10.1080/10428194.2017.1387905

Humanigen has pre-clinical animal model work underway for lenzilumab in CAR-T neurotoxicity. Phase 1 study designs have been developed by leading key opinion leaders to explore lenzilumab as a prophylactic treatment to minimize neurotoxicity associated with CAR-T.

CAR-T neurotoxicity is a top priority concern in this cutting-edge treatment field. The side effect is a toxic encephalopathy that ranges from confusion to seizures to cerebral edema and can be fatal. It occurs in up to 66 percent of patients with often scary, intensive-care-unit monitoring needed. There is no effective prophylaxis or treatment for this hurdle to fully reaping the benefits of a new, booming science and innovation.

Please see the References section for lenzilumab for the current body of evidence supporting the scientific rationale to target GM-CSF to improve CAR-T therapy.


Phase I Lenzilumab Study Underway in CMML Patients

GM-CSF also stimulates white blood cell production and is the hallmark of some hematologic malignancies - such as chronic myelomonocytic leukemia (CMML) and juvenile myelomonocytic leukemia (JMML) - and perhaps some solid tumors. In addition, it is tied to inflammation in several significant, chronic autoimmune diseases.

GM-CSF is one of the cytokines involved in the development and maturation of certain types of myeloid blood cells. Earlier data generated by a collaborator confirmed that hypersensitivity to GM-CSF plays an important role in the growth and survival of CMML cells. Such hypersensitivity is also a hallmark of JMML. Inhibition of GM-CSF may affect growth of leukemic cells in patients. CMML is an orphan disease and JMML is a rare pediatric disease.

Humanigen continues to study lenzilumab as a potential treatment for CMML and JMML. A Phase I trial focused on patients with previously treated CMML is underway. The Phase I study is a multi-center, open-label dose escalation trial to evaluate the safety, maximum tolerated dose and preliminary activity of single-agent lenzilumab in CMML patients who are relapsed, refractory to, or intolerant to standard-of-care treatments. The first patient was dosed with lenzilumab in late July 2016.

The study will enroll up to 18 patients and is designed to identify the maximum tolerated dose -and a recommended Phase II dose - of lenzilumab in previously treated CMML patients. It will also assess preliminary efficacy of single-agent lenzilumab and provide additional data on pharmacokinetics, pharmacodynamics - including correlative biomarkers and mutational analysis - and safety.

Currently available treatments in CMML are limited and produce inadequate responses, leaving these patients with high unmet medical need for effective and tolerable therapies.

CMML is a Rare and Aggressive Cancer of the blood.

CMML affects approximately 1,500 - 3,000 new patients per year in the United States. The cancer is considered a clonal disease which begins with one or more mutations to the DNA of bone marrow stem cell that multiplies uncontrollably. The change interferes with normal blood cell production, including red and white blood cells and platelets.

CMML patients often present with anemia, but can also experience low platelet counts leading to bleeding and abnormal white cell counts leading to infections, an enlarged spleen, bone marrow fibrosis and other symptoms. CMML patients have a shortened life expectancy and approximately 15-30 percent of patients progress to develop acute myeloid leukemia (AML).

The World Health Organization (WHO) reclassified CMML in 2008 into a separate disease from a therapeutic perspective. Prior to reclassification, CMML accounted for 10 percent of all myelodysplastic syndrome (MDS) cases for which hypomethylating agents (HMAs) have been approved. Treatment options are limited and include: blood transfusions; HMAs for non-proliferative forms; hydroxyurea for palliating symptoms related to massive splenomegaly and controlling elevated blood counts; and erythropoiesis stimulating agents for anemia.