On October 26, 2021 Humanigen, Inc. (Nasdaq: HGEN) ("Humanigen"), reported the first patient was dosed with lenzilumab in the Precision Approach to Chronic Myelomonocytic Leukemia (‘PREACH-M’) clinical trial being sponsored by the South Australian Health and Medical Research Institute (SAHMRI) and funded by a Medical Research Future Fund grant from the National Health and Medical Research Council of the Australian government to the University of Adelaide (Press release, Humanigen, OCT 26, 2021, View Source [SID1234591974]). Humanigen is providing lenzilumab for use in the study through its Australian subsidiary, Humanigen Australia Pty Ltd.
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"The prognosis for CMML is poor, with median survival of 30 months, and it has remained essentially unchanged over the past 30 years," said Associate Professor Daniel Thomas, the coordinating investigator for the trial and Associate Professor of Hematology at the University of Adelaide. "The overarching goal of the clinical trial is to improve response rates and survival. If we can improve response rates to 30%-50%, from the current 18% response rate normally seen in CMML patients treated with azacitidine, we think median survival may be increased to more than three years."
The PREACH-M trial is designed to focus on Chronic Myelomonocytic Leukemia (CMML) patients who carry mutations believed to drive the leukemia. One arm of the study (n≈29) will focus on patients with RAS pathway mutations (KRAS, NRAS, or CBL) that appear to be associated with hyper-proliferative features and sensitivity to GM-CSF neutralization. These patients will be treated with high-dose azacitidine and lenzilumab, Humanigen’s proprietary GM-CSF neutralizing antibody. Results will be compared to historical trials of azacitidine alone and with the South Australian MDS Registry data.
"We have been encouraged by our prior Phase 1 results in CMML and are privileged to partner with SAHMRI and the University of Adelaide to further assess the potential of lenzilumab in this rare form of cancer for which there has been so little progress in treatment over the past 30 years," said Dr. Cameron Durrant, CEO of Humanigen, Inc. "Following results from our Phase 3 LIVE-AIR study of lenzilumab in hospitalized patients with COVID-19 and the positive outcome of the Phase 1b portion of the ZUMA-19 study of lenzilumab in CAR-T, we are excited about the opportunity the PREACH-M study affords to validate our expectation that lenzilumab may offer potential benefits across multiple therapeutic indications."
About PREACH-M
The study is a precision medicine approach to treating CMML. Investigators at 5 sites in Australia plan to enroll a total of 72 CMML patients with specific mutations. Patients with RAS pathway mutations such as KRAS, NRAS, or CBL, will be enrolled in the lenzilumab and azacitidine arm. Those who have the TET2 mutation will be enrolled in an arm of the study (n≈40) testing high-dose sodium ascorbate (vitamin C) and azacitidine. Those who have both TET2, and RAS pathway mutations will be allocated to the lenzilumab arm, unless they meet an exclusion criterion for the lenzilumab cohort. Those who do not have mutations in either category will be considered screening failures. However, these patients will still benefit from study because it includes free gene sequencing for all trial participants and gene sequencing is otherwise not a pathology test funded by Medicare, the Australian government funded universal health insurance system. With an incidence rate for CMML of just 0.3 per 100,000 Australians, SAHMRI, expects enrollment may take three years. The primary outcome will be the frequency of complete response (CR) and partial response (PR) at any point during the first 12 months of active therapy. Overall and progression-free survival will each be key secondary endpoints measured during the two-year period following initiation of treatment.
Those who would like to learn more about PREACH-M should refer to the ANZCTR website: View Source
"SAHMRI and South Australia enjoy several natural advantages when it comes to running clinical trials such as PREACH-M," said SAHMRI Executive Director, Professor Steve Wesselingh. "Our size, geography, outstanding centralized public health system and cooperative population mean we have been remarkably resistant to COVID-19 outbreaks. South Australia also has a track record of success specific to phase III kinase inhibitor studies in patients with blood cancers, such as chronic myeloid leukaemia. It is exciting to be able to apply this expertise to CMML."
Evidence of potential for lenzilumab in CMML
The PREACH-M trial was conceived, in part, based on evidence from earlier in-vitro, in-vivo and Phase 1 studies showing the GM-CSF neutralizing ability of lenzilumab and clinical benefits in CMML. An in-vitro study of bone marrow-mononuclear cells (BM-MNC) from 20 patients with CMML showed that patients with signaling mutations (KRAS, NRAS, or CBL) have greater sensitivity to GM-CSF and the level of hypersensitivity was an indicator of disease severity. The in-vitro results also correlated with reduced colony formation by BM-MNC, in a dose-dependent manner, and viability of CMML cells from patients with GM-CSF hypersensitivity.1 A subsequent Phase 1 study of lenzilumab showed a clinical benefit in 33% of the 15 CMML patients dosed and those with an NRAS mutation showed a proportionally higher response (3 of 4). Those responses demonstrated greater clinical benefit and reduction in bone marrow blasts.2