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Lenzilumab Study Published in 'blood', the Official Journal of the American Society of Hematology (ASH), First Edition
[November 30, 2018]

Lenzilumab Study Published in 'blood', the Official Journal of the American Society of Hematology (ASH), First Edition


  • Lenzilumab (an anti-GM-CSF antibody) in combination with CAR-T cell therapy prevents cytokine release syndrome and neuro-inflammation while improving durable control of leukemic disease
  • Exponential increase in T cell proliferation, enhanced anti-tumor activity, and improved overall survival observed with GM-CSF blockade
  • GM-CSF neutralization can be viewed as a potential next generation strategy to enable routine CAR-T cellular immunotherapy

BURLINGAME, Calif., Nov. 30, 2018 (GLOBE NEWSWIRE) -- Humanigen, Inc., (OTCQB: HGEN) (“Humanigen”), a biopharmaceutical company focused on the development of its proprietary Humaneered® monoclonal antibodies to improve the safety and efficacy of chimeric antigen receptor T cell (CAR-T) therapy, announced today that final results from the xenograft study of lenzilumab, a first-in-class anti-GM-CSF monoclonal antibody, have been published as a first edition paper by ‘blood’® in the November 21, 2018 edition and are available online at http://www.bloodjournal.org/content/early/2018/11/21/blood-2018-10-881722. The principal investigator for the study was Saad Kenderian, M.B., Ch.B., Mayo Clinic hematologist.  

The study was designed to closely replicate the findings in clinical trials and utilized human acute lymphoblastic leukemia (ALL), human CD19 targeted CAR-T (CART19), and human peripheral blood mononuclear cells (PBMCs) and conducted in mice. Within 4-6 days after treatment with CART19, animals began to develop a syndrome characterized by motor weakness, hunched bodies, and progressive weight loss in a model which recapitulates symptoms consistent with cytokine release syndrome (CRS) and neuro-inflammation (NI).  This syndrome was associated with elevation of key serum cytokines and chemokines 4-11 days post-CART19 injection, similar to what is seen in human CRS after CAR-T cell therapy (including human GM-CSF, IFN-g, IL-2, IL-3, IP-10, MCP-1, MIP-1, MIP-1, and mouse IL-6, IP-10, MCP-1, MIG).  This syndrome also displays development of NI as indicated by brain MRI analyses revealing abnormal T1 enhancement, suggestive of blood-brain-barrier disruption and possibly brain edema. 

With the addition of prophylactic lenzilumab to the CART19 therapy, the physical symptoms of the syndrome were prevented. Prophylactic lenzilumab also resulted in a 75% reduction in NI by quantitative MRI.  In addition, neutralization of GM-CSF with lenzilumab resulted in a statistically significant reduction in ten other cytokines and chemokines thought to be important in the development of CRS and NI.

These results suggest that GM-CSF is an important regulatory switch that initiates this cascade and plays a central rol in the downstream activity of several cytokines and chemokines that are instrumental in the development of CRS and NI. 



Although the study was designed to test whether GM-CSF neutralization would have any negative effects on CART19 efficacy, there was a surprising result that the prophylactic administration of lenzilumab in combination with CART19 therapy resulted in a significant improvement in leukemic disease control sustained over time for at least 35 days post CART19 administration as compared to CART19 plus isotype control.  “We observed an exponential increase in CART19 cell proliferation, enhanced anti-tumor activity, and improved overall survival with GM-CSF blockade,” said Dr. Saad Kenderian. He continued, “this suggests that GM-CSF neutralization may play a role in reducing relapses and increasing durable complete responses after CART19 cell therapy. This work represents a significant advance in understanding and preventing toxicities after CAR-T cell therapy.  Our results strongly suggest that modulating myeloid cell behavior through GM-CSF blockade helps control CAR-T cell mediated toxicities and reduces their immunosuppressive features to improve leukemic control.”

Toxicities of CART19 therapy, including CRS and NI, are associated with extended hospitalization and ICU admissions, which creates an added pharmaco-economic burden, may lead to unfavorable reimbursement, and limits the utility of CAR-T cell therapy.  Although CART19 therapies are associated with high response rates, 50% of responders are expected to relapse within the first year which is a key consideration in the cost-effectiveness of these therapies.


“With this study, we propose a new paradigm in CAR-T cell therapy via the neutralization of GM-CSF with lenzilumab as a prophylactic strategy to prevent CRS and NI and improve durable responses,” commented Dr. Cameron Durrant, chief executive officer of Humanigen. “Based on these results, GM-CSF neutralization can be viewed as a potential next generation strategy to enable routine CAR-T cellular immunotherapy.”

Company sponsored, multi-center phase I/II clinical trials of lenzilumab in combination with CART19 therapies are expected to be initiated in the coming months.

The abstract entitled “GM-CSF Blockade during Chimeric Antigen Receptor T Cell Therapy Reduces Cytokine Release Syndrome and Neurotoxicity and May Enhance Their Effector Functions” will be presented in the oral plenary session at the 2018 Annual Meeting of the American Society of Hematology, at 4:30pm PT on Monday, December 3rd, 2018 at the Marriott Marquis San Diego Marina, San Diego Ballroom B.  The full abstract with corresponding figures is available for review at:
https://ash.confex.com/ash/2018/webprogram/Paper111766.html.

About Humanigen, Inc. 

Humanigen, Inc. is developing its portfolio of Humaneered® monoclonal antibodies to address cutting-edge CAR-T optimization and oncology treatments advancing safer, better, and more effective cancer therapies.  Derived from the company’s Humaneered® platform, lenzilumab and ifabotuzumab are monoclonal antibodies with first-in-class mechanisms. Lenzilumab, which neutralizes circulating GM-CSF, is in development as a potential biologic to make CAR-T therapy safer and more effective, as well as a potential treatment for rare hematologic cancers such as CMML and JMML. Ifabotuzumab, which targets the Eph type-A receptor 3 (EphA3), is being explored as a potential treatment for glioblastoma multiforme (GBM) and other deadly cancers, as a monoclonal antibody, as part of an antibody-drug conjugate, as a backbone for a novel CAR-T construct and a bispecific antibody platform.  For more information, visit www.humanigen.com

Forward-Looking Statements

This release contains forward-looking statements that are intended to be subject to protection afforded by the safe harbor for forward-looking statements contained in the Private Securities Litigation Reform Act of 1995. Forward-looking statements reflect management's current knowledge, assumptions, judgment and expectations regarding future performance or events. Although management believes that the expectations reflected in such statements are reasonable, they give no assurance that such expectations will prove to be correct and you should be aware that actual events or results may differ materially from those contained in the forward-looking statements. Words such as "will," "expect," "intend," "plan," "potential," "possible," "goals," "accelerate," "continue," and similar expressions identify forward-looking statements, including, without limitation, statements regarding our expectations for future development of lenzilumab to help CAR-T therapy reach its full potential, including in respect of the anticipated nature and timing of our contemplated Phase I/II clinical trials. Forward-looking statements are subject to a number of risks and uncertainties including, but not limited to, the risks inherent in Black Horse Capital and its affiliates owning more than 50% of our outstanding common stock, including their ability to control the company; our lack of profitability and need for additional capital to operate our business as a going concern; the uncertainties inherent in the development and launch of any new pharmaceutical product; the outcome of pending or future litigation; and the various risks and uncertainties described in the "Risk Factors" sections and elsewhere in the Company's periodic and other filings with the Securities and Exchange Commission.

All forward-looking statements are expressly qualified in their entirety by this cautionary notice. You should not place undue reliance on any forward-looking statements, which speak only as of the date of this release. We undertake no obligation to revise or update any forward-looking statements made in this press release to reflect events or circumstances after the date hereof or to reflect new information or the occurrence of unanticipated events, except as required by law.

CONTACT:

Investors:
Al Palombo
650-243-3181
ir@humanigen.com 


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