Humanigen, Inc. (Nasdaq: HGEN) today extended previously reported results by showing additional, statistically significant hematological improvements and reductions in inflammatory markers of its investigational drug lenzilumab, in a Phase 2/3 trial of participants treatment-naïve patients with chronic myelomonocytic leukemia and RAS– pathway mutations.
The additional data demonstrate that in the 10 participants who received at least three months of treatment with lenzilumab and azacitidine, the number of blood monocytes fell fivefold (P=0.03), the percentage of blasts and pro-monocytes more than doubled (P=0.04), and C-reactive protein decreased more than three-fold (P=NS) with improvements noted after 3 months and 6 months of this combination treatment. These results suggest that lenzilumab may normalize hematological and inflammatory aberrations in CMML and improve participants’ condition. All ten evaluable participants had a rapid clinical response.
CMML is a rare and aggressive cancer in which levels of monocytes, blast cells, and pro-monocytes are significantly elevated compared to normal levels. These pathological changes are accompanied by significantly elevated pro-inflammatory markers, including C-reactive protein. Current treatment options for patients with CMML are limited to blood transfusions, hydroxyurea, and supportive care alongside the current standard of care, which includes hypomethylating agents such as azacitidine and decitabine, which have limited response rates of 7% to 18%1, 2, 3 with no proven increase in overall survival.
Over the past 30 years, no new drugs with a new mechanism of action have been approved for patients with CMML who are at high risk of death or disease progression.4 Only about 20% of patients diagnosed with CMML survive for three years.5
Results from the PREACH-M trial to date indicate that lenzilumab may improve treatment response in MMC. These results could pave the way for the development of lenzilumab in myelodysplastic leukaemias. I look forward to sharing the data during the poster presentation at the European Hematology Association Congress 2023 in Frankfurt, Germany. »
Cameron Durrant, MD, MBA, Humanigen Chief Executive Officer
The presentation, titled “Lenzilumab and Azacitidine Improve Hematological Alterations in Chronic Myelomonocytic Leukemia in the PREACH-M Trial,” highlighted new data in poster format (P737) at 6:00 p.m. CEST on June 9. 2023, during the 2023 edition of the European Association of Hematology congress.
“Patients with CMML are normally treated with hypomethylating agents such as azacitidine, with reported response rates of only 7% to 18%, usually of limited duration,” said lead researcher Daniel Thomas, MD, PhD. , head of the blood cancer research program at SAHMRI. and Associate Professor of Medicine at the University of Adelaide. “Treating patients with lenzilumab appears to improve clinical parameters, quality of life, and systemic inflammation in patients studied thus far, and patients appear to tolerate lenzilumab well. Importantly, clinical responses seem to occur early, before the fourth monthly treatment cycle. . No patient has relapsed, and we currently have two patients who have been on treatment for over 18 months. »
Lenzilumab, a granulocyte-macrophage colony-stimulating factor (GM-CSF) neutralizing antibody, prevents GM-CSF from binding to hematological progenitor cell receptors. When GM-CSF binds to these receptors, it triggers the normal proliferation and maturation of myelocytes. In the presence of RAS-pathway mutations, GM-CSF contributes to the hyperproliferation of myelocytes in myelodysplastic leukemias such as CMML, juvenile myelomonocytic leukemia (JMML) and acute myeloid leukemia (AML).6,7,8 Therefore, the ability of lenzilumab to prevent the binding of GM-CSF to its receptor may inhibit hyperproliferation under these conditions.
PREACH-M (PREdecision ANDapproach to CHronic Myelomonocytic leukemia), an open-label, non-randomized trial, is being conducted at multiple sites in Australia. It is sponsored by the South Australian Health and Medical Research Institute (SAHMRI), with a grant from the Australian government and the study drug provided by Humanigen.
As of May 9, 2023, 14 patients with CMML at intermediate or high risk of death or disease progression had received at least one dose of lenzilumab, along with azacitidine. Ten of these participants were evaluable based on at least three months of follow-up, and each experienced rapid clinical benefit. Twenty-one grade 3 or 4 serious adverse events were observed, of which the investigators assessed five as possibly related to lenzilumab.
CMML is an orphan disease with an approximate annual incidence of 1 to 4 cases per million in Western countries and has limited treatment options. CMML is an aggressive and poorly understood cancer with only about 20% of patients surviving to the three-year mark.
The incidence of CMML in the United States, United Kingdom and Australia is approximately 1,700 patients per year. As an orphan disease, lenzilumab may enjoy certain regulatory and commercial advantages that could expedite development and potential approval. Humanigen and the principal investigator are evaluating regulatory pathways that could allow early results to support regulatory submission and possible approval by the Therapeutic Goods Administration in Australia, which could be expanded through the Orbis project from the United States and the United Kingdom (https://www.fda.gov/about-fda/oncology-center-excellence/project-orbis).
About the PREEACH-M trial
PREACH-M (PREcision Approach to CHronic Myelomonocytic Leukemia) is a non-randomized, open-label, phase 2/3 clinical trial of precision medicine for adults with CMML. This trial investigates treatment response rates determined by the Savona criteria for patients with CMML after administration of lenzilumab in combination with azacitidine in patients with CMML. RAS pathway mutations. The study also measures patients’ quality of life using the MPN symptom assessment form: Total Symptom Score.
Fourteen study participants were recruited and treated with lenzilumab and azacitidine as of May 9, 2023, ten of whom were evaluable for hematology and inflammatory parameters based on at least three months of follow-up. Initial data demonstrates that the number of blood monocytes decreased five-fold (p=0.03), the percentage of blast cells and pro-monocytes decreased more than double (p=0.04), the number of platelets and hemoglobin concentration both increased and remained elevated at 12 months (p=0.07 and p=0.02, respectively), and the size of the craniocaudal spleen decreased by nearly 50% at 6 months (p = 0.03). The inflammatory marker, C-reactive protein, decreased more than three-fold (p = NS). All ten evaluable participants had a rapid clinical response.
During the active treatment phase of the study, participants are required to attend clinic visits on Days 1 and 15 of the first cycle, then on Day 1 of each subsequent 28-day cycle to assess how the participant is tolerating therapy and ensure continuity security. In addition to regular safety blood tests throughout each cycle, participants’ disease response assessments are scheduled after 3, 6, 12 and 24 treatment cycles to measure their disease response. These evaluations include blood tests, bone marrow aspiration and trephine, ultrasound of the spleen, physical exam, and assessment of transfusion needs and clinical symptoms.
Participants who complete 24 cycles of active treatment enter the follow-up phase of the study where they are followed every 6 months for 24 months for survival, disease status and other CMML-related treatments. For patients with confirmed disease progression or relapse during the active treatment phase of the study, further study treatment will be discontinued. Patients remain on study and are followed for disease status, survival, and other CMML-related treatments every 6 months through 48 months from Cycle 1, Day 1. During the period follow-up, participants no longer receive investigational drugs but are allowed to receive any CMML treatment at the discretion of the treating clinician.
As part of the screening process, participants must have a bone marrow aspirate and trephine to test for some acquired mutations that may be present in CMML. The study is looking for participants with mutations in the TET2 and/or RAS pathway. Participants with RAS pathway mutations or both TET2 et RAS mutations, receive azacitidine (administered subcutaneously at a dose of 75 mg/m2 days 1-5, 8-9, or days 1-7 for a total of 7 doses per 28-day cycle) in combination with lenzilumab (given intravenously at a dose of 552 mg on days 1 and 15 of the cycle 1. Day 1 only for all subsequent cycles).
The trial is sponsored by the South Australian Health and Medical Research Institute (“SAHMRI”) and funded by a grant from the Australian Government’s National Health and Medical Research Council Medical Research Future Fund to the University of Adelaide. Humanigen is supplying lenzilumab for use in the study through its Australian subsidiary, Humanigen Australia Pty Ltd. Registration is open to patients with newly diagnosed CMML who have not received any treatment.
Anyone wishing to learn more about the study or obtain additional information can consult the Australian and New Zealand Clinical Trials Register (www.anzctr.org.au).
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