Lenzilumab is a humaneered^® antibody, being developed by Humanigen (formerly KaloBios Pharmaceuticals), for the treatment of various types of cancers, COVID-2019 infections, COVID-2019 pneumonia, cytokine storm associated with COVID-2019 infections (cytokine release syndrome) and drug hypersensitivity. Humaneered^® technology uses bacterial expression systems to convert non-human antibodies (typically mouse) into high affinity humanised antibodies that are close to human germline in sequence. Lenzilumab is a selective antibody targeting circulating granulocyte-macrophage colony-stimulating factor (GM-CSF). GM-CSF is the driver causing CCR2⁺ myeloid cells to traffic to the site of inflammation and initiating a self perpetuating inflammatory cascade within tissues, including in the central nervous system. By neutralising circulating GM-CSF, and upon demonstrating effects on neurotoxicity without affecting the efficacy of CAR-T, lenzilumab has the potential to make CAR-T therapy safer and more effective by allowing higher CAR-T doses, greater CAR-T expansion, and potentially reducing myeloid-derived suppressor cells (MDSC) that inhibit T cell function. Lenzilumab is designed for the prevention and treatment of an immune hyper-response called cytokine storm in COVID-2019 patients. Lenzilumab is under review for cytokine release syndrome associated with COVID-2019 infections in the US and the UK. Clinical development for drug hypersensitivity, cytokine release syndrome, chronic myelomonocytic leukemia and COVID-2019 infections is underway in the US, Australia, South Korea and Brazil. Clinical development for acute graft-versus-host disease and preclinical development for acute lymphoblastic leukaemia (precursor cell lymphoblastic leukaemia lymphoma) is underway in the UK and the US, respectively.

In August 2022, Humanigen and Kite Pharma discontinued the development of lenzilumab in combination with axicabtagene ciloleucel for the treatment of large B-cell lymphoma, as the company discontinued the programme.

Phase I development in chronic myelomonocytic leukaemia was conducted in the US. Early research development in solid tumours was conducted in the US. As at October 2020, no recent reports of development were identified. Phase II development for the treatment of asthma and rheumatoid arthritis was discontinued previously because of programme refocus.

Lenzilumab shares the same epitope and pharmacokinetic properties as KB 002 [see AdisInsight drug profile 800021215], a chimeric mouse precursor and prototype drug candidate that was discontinued in favour of lenzilumab. KaloBios was leveraging data from the phase I/II clinical studies of KB 002 in patients with asthma for the development of lenzilumab.

In August 2017, KaloBios Pharmaceuticals changed its name to Humanigen ^[1] .

As at December 2022, no recent reports of development had been identified for preclinical development in Precursor-cell-lymphoblastic-leukaemia-lymphoma (Combination therapy) in USA (Parenteral).

In January 2024, Humanigen entered into an asset purchase agreement with Taran Therapeutics for the acquisition of certain assets related to the Humanigen's biopharmaceutical business, including its portfolio of proprietary Humaneered^® monoclonal antibodies, lenzilumab, ifabotuzumab and HGEN 005. Humanigen will receive up to $US 20 million, comprised of $US 2 million in cash at closing of the transaction and up to $US 18 million in milestone payments in cash. However, later Humanigen filed for bankruptcy. Upon bankruptcy court approval, Taran is expected to be designated as the “stalking horse” bidder in connection with a sale of the Assets under section 363 of the bankruptcy code. The transaction will be conducted through a bankruptcy court-supervised process pursuant to bankruptcy court-approved bidding procedures and is subject to the receipt of higher or better offers from competing bidders at an auction, approval of the sale by the bankruptcy court, and the satisfaction of certain conditions. ^[2]

In September 2021, Humanigen announced that due to the emergency use authorisation status in the US, the company decided to terminate the initial statement of work related to commercialisation support of lenzilumab for the treatment of COVID-2019 in the US. Eversana is disputing the termination notice and has requested payment of approximately $US4.5 million it has asserted that Humanigen owes for services rendered from April 1, 2021 to September 30, 2021. Humanigen has disputed this assertion and Eversana has filed for arbitration to resolve this dispute. In January 2021, Humanigen and EVERSANA-Life Science entered in an agreement for commercialisation of lenzilumab. According to the terms of the agreement, Humanigen will be granted access to the services of EVERSANA-Life Science, that are not limited to marketing, market access, medical education, health economics and outcomes research, medical information, compliance and medical science liaison teams and predictive analytics. ^{[3] [4]}

In April 2021, Humanigen terminated the clinical collaboration and announced that both parties will collaborate to wind down current study activities. The effective termination date of the collaboration was December 2021. Earlier in June 2019, Kite and Humanigen entered into a clinical collaboration to conduct a phase I/II study, to determine the effect of lenzilumab on the safety of axicabtagene ciloleucel in patients suffering with relapsed or refactory diffuse large B-cell lymphoma (DLBCL). Kite will both, conduct and sponsor the study. No other information was disclosed. ^{[5] [6] [7]}

In October 2021, Humanigen Inc entered into a marketing agreement with Clinigen Group plc, for a Managed Access Program for lenzilumab (LenzMAP™). Under the terms of the agreement, Clinigen will manage key elements of the LenzMAP including regulatory oversight, logistics and access management. LenzMAP will be available in the following 16 European countries, including Austria, Bulgaria, Croatia, Cyprus, Denmark, Estonia, France, Greece, Ireland, Lithuania, Luxembourg, Netherlands, Portugal, Spain, Sweden, and Switzerland. Humanigen will use Clinigen's expertise working with regulatory authorities in the relevant 16 countries to make access to lenzilumab. LenzMAP will enable access to lenzilumab on a case-by-case basis for hospitalised patients with COVID-2019 infections, where the regulations allow. ^[8]

In May 2021, Humanigen entered into manufacturing agreement with Chime Biologics to produce lenzilumab bulk drug substance for commercial sale following receipt of the requisite regulatory authorizations or approvals in regions outside of the United States including Europe, the United Kingdom, India and Brazil. Under the terms of this agreement, Chime will use the state-of-the-art modular single use KuBio (Cytiva) biologics facility in China. Technical transfer work has already begun, and commercial product is planned to be available in 2022.

In July 2004, KaloBios Pharmaceuticals in-licensed an antibody drug candidates for the treatment of autoimmune diseases from the Ludwig Institute for Cancer Research (LICR). The initial clinical trials of this antibody will be in patients with rheumatoid arthritis. KaloBios is responsible for using commercially reasonable efforts to research, develop, and sell lenzilumab. Company paid LICR a quarterly license fee and are obligated to pay to LICR a royalty from 1.5% to 3% of net sales of licensed products, subject to certain potential offsets and deductions. Royalty obligation applies on a country-by-country and licensed product-by-licensed product basis, and will begin on the first commercial sale of a licensed product in a given country and end on the later of the expiration of the last to expire patent covering a licensed product in a given country (which in the US is currently expected in 2029 for the composition of matter and 2038 for methods of use in CAR-T) or 10 years from first commercial sale of such licensed product in the country. In year 2006, KaloBios licensed the intellectual property rights of the ifabotuzumab prototype from the Ludwig Institute for Cancer Research (LICR). Under the terms of the agreement, KaloBios paid LICR an upfront fee of $US50 000 and a further fee of $US50 000, after obtaining the exclusive license to ifabotuzumab. LICR is entitled to receive milestone payments of approximately $US2.5 million and 3% royalties on net sales. LICR is obligated to obtain a percentage of the payments received by KaloBios, if the company exercises the option to sub-license ifabotuzumab. As per the license agreement with LICR pursuant to which LICR granted to us certain exclusive rights to the ifabotuzumab prototype (IIIA4) which targets EphA3 and EphA3-related intellectual property. Under the agreement, KaloBios obtained rights to develop and commercialise products made through use of licensed patents and any improvements thereto, including human antibodies that bind to or modulate EphA3. KaloBios royalty obligation exists on a country-by-country and licensed product-by-licensed product basis, which will begin on the first commercial sale and end on the later of the expiration of the last to expire patent covering such licensed product in such country, which in the US is currently expected in 2031, or 10 years from first commercial sale of such licensed product in such country ^{[10] [11]}

In February 2021, Humanigen Inc entered into a manufacturing services agreement with Avid Bioservices Inc to expand production capacity for lenzilumab^™, designed for the prevention and treatment of immune hyper-response called cytokine storm associated with COVID-2019 infections. Under the terms of the agreement, Avid will initiate technical transfer and analytical validation activities for Humanigen's lenzilumab under the current Good Manufacturing Practice (cGMP) drug substance batches to support the regulatory and potential commercial activities, and for potential filings for emergency use authorisation (EUA) and subsequent biologics license application (BLA) for the drug.
^[12]

In January 2021, Ajinomoto Bio-Pharma Services and Humanigen expanded manufacturing agreement to support fill finish for investigational COVID-19 therapeutic, Lenzilumab. In May 2020, Ajinomoto Bio-Pharma Services and Humanigen entered into a manufacturing agreement for the fill finish supply of lenzilumab. ^{[13] [14]}

In January 2021, Humanigen announced an expansion to the Cooperative Research and Development Agreement (CRADA) that the company had previously entered into with the Department of Defense Joint Program Executive Office for Chemical, Biological, Radiological and Nuclear Defense (JPEO-CBRND), to gain access to manufacturing capacity reserved by the Biomedical Advanced Research and Development Authority (BARDA), part of the Office of the Assistant Secretary for Preparedness and Response (ASPR) at the US Department of Health and Human Services. The agreement supports development of lenzilumab in advance of a potential Emergency Use Authorization (EUA) for COVID-19. The amended CRADA, now co-signed by BARDA, provides Humanigen with access to manufacturing capacity reserved by BARDA for fill-finish product to accelerate the drug product manufacturing of lenzilumab. The initial agreement, originally signed in November 2020, complements Humanigen’s development efforts for lenzilumab by providing access to a full-scale, integrated team of manufacturing and regulatory subject matter experts and statistical support in anticipation of applying for EUA and subsequently a Biologics License Application (BLA) for lenzilumab as a potential treatment for COVID-19. Earlier, in November 2020, Humanigen and the Department of Defense (DoD) JPEO-CBRND or JPEO entered into a CRADA in collaboration with BARDA, in support of Operation Warp Speed (OWS). The CRADA will provide access to OWS manufacturing and regulatory subject matter experts, leading decision makers and statistical support for Emergency Use Authorization (EUA) and subsequently a Biologics License Application for lenzilumab as a treatment for COVID-19. The CRADA also provides that OWS regulatory experts will work with the Humanigen on US FDA communications, meetings and regulatory filings. The CRADA aims to support the ongoing lenzilumab phase III clinical trials. Also, CRADA will ensure lenzilumab receives the benefits provided by Public Law 115-92 ^{[15] [16]}

In November 2020, Humanigen entered into a licensing agreement with Telcon RF Pharmaceutical (affiliate of KPM Tech) for development and commercialisation rights to lenzilumab for COVID-19 in South Korea and the Philippines. The licensing agreement includes payments of up to $US20 million with $US6 million as an upfront payment upon execution of the licensing agreement and the balance of $US14 million in two payments based on achievement of specified milestones in the US by Humanigen. Telcon and KPM Tech will be responsible for gaining regulatory approval and subsequent commercialisation of lenzilumab in its territories. Humanigen will earn double-digit royalties following receipt of those approvals on net sales subsequent to commercialisation. Further details were not disclosed. ^[17]

In September 2020, Humanigen entered into collaboration with Thermo Fisher Scientific for lenzilumab, currently in a phase III registration study in patients with COVID-19, to support a potential Emergency Use Authorization (EUA). Thermo Fisher will begin the technical transfer of the lenzilumab bulk drug substance process and commercial scale production could begin before the end of this year
^[18]

In September 2020, Humanigen entered into a manufacturing agreement with Lonza to expand manufacturing of lenzilumab in advance of potential Emergency Use Authorization in 2020 and subsequent commercialisation. Under the agreement, Humanigen will leverage Lonza's monoclonal antibody manufacturing and regulatory expertise. The collaboration also provides Humanigen with additional capacity for cGMP production of the candidate with operations intended to start in 2021. Production of will begin at Lonza's 2,000L manufacturing facilities at Hayward (CA), USA and technology transfer is expected to begin in Q3 2020. Other financial details of the agreement were not disclosed. ^[19]

In July 2020, Humanigen entered into a research and development agreement with National Institute of Allergy and Infectious Diseases (NIAID) to evaluate lenzilumab in an NIAID-sponsored Big Effect Trial (BET) in hospitalised patients with COVID 2019 infections. As per agreement terms, BET will help advance NIAID’s strategic plan for COVID 2019 research, including studies to advance high-priority therapeutic candidates. Identification of agents with mechanisms of action for therapy is a strategic priority. ^[20]

In July 2020, Humanigen expanded previously signed supply agreement. Under the terms of expanded partnership, Catalent will provide development, manufacturing and commercialisation services for lenzilumab. Earlier, in May 2020, Humanigen entered into an agreement with Catalent for clinical supply support. Under the terms of agreement, Catalent will provide clinical supply support to Humanigen and its partners to accelerate the investigation of phase III study for lenzilumab in COVID patients from its Philadelphia facility. ^{[21] [22]}

In July 2019, Humanigen signed an exclusive worldwide licensing agreement with the University of Zurich (UZH), licensing from the latter, technology used to prevent graft versus host disease (GvHD), through GM-CSF neutralisation. The license provides coverage for multiple patent applications filed by UZH. ^[23]

In April 2018, Humanigen entered into a research agreement with the University of Texas M. D. Anderson Cancer Center to begin investigator-led research on lenzilumab and its potential to support chimeric antigen receptor T cell (CAR-T) therapy ^[24]

KaloBios was granted a non-exclusive licence to the Potelligent^® technology of BioWa, which is used to enhance antibody-dependent cellular cytotoxicity (ADCC). The agreement was announced in October 2008. The technology is being used to improve the ADCC of select therapeutic antibodies of KaloBios. KaloBios will be able to research, develop and commercialise therapeutic antibodies by use of Potelligent^® for an undisclosed number of targets. The application of Potelligent^® reduces the quantity of fucose in the carbohydrate structure of an antibody, thereby improving ADCC. The mechanism behind the enhanced ADCC of a low/no-fucose antibody is its increased affinity to FcγRIIIa (CD16), the major Fc receptor for ADCC in humans. An upfront payment to BioWa by KaloBios was included in the agreement, along with development milestone payments and royalty payments to BioWa ^[25] .

COVID-19 infections and COVID-19 pneumonia

As of December 2022, Humanigen is executing the strategic realignment plan to deemphasize the deployment of certain resources for the development of lenzilumab for COVID-2019 and currently do not plan to pursue regulatory pathways unless further data from ACTIV-5/BET-B (see below) or a future large-scale study merit such an approach ^[4] . Previously, Humanigen held a productive Type B pre-EUA meeting with FDA where company gained alignment on the data and statistical analysis plan to be included as part of the amendment to EUA for lenzilumab in COVID-19 patients ^[26] . Earlier in September 2021, the US FDA declined the emergency use authorisation request of lenzilumab to treat newly hospitalised COVID-19 patients and requested Humanigen to submit additional data as it becomes available. The US FDA further stated that it was unable to conclude that the known and potential benefits of lenzilumab outweigh the known and potential risks of its use as a treatment for COVID-19 ^[27] . In May 2021, Humanigen had submitted application to the US FDA requesting Emergency Use Authorization (EUA) for lenzilumab for the treatment of patients hospitalized with COVID-19. The EUA application follows positive results from the LIVE-AIR Phase III clinical trial evaluating the ability of lenzilumab to improve the likelihood of survival without ventilation (SWOV) in newly hospitalised COVID-19 patients [see below] ^[28] . As of May 2021, Humanigen held a meeting with the FDA to discuss the filing of an EUA for lenzilumab for hospitalised, hypoxic COVID-19 patients ^[29] . In March 2021, Humanigen had announced intension to file Emergency Use Authorization (EUA) to the US FDA for lenzilumab in the treatment for hospitalized and hypoxic patients with COVID-2019 infections. Company have plans to begin the distribution of lenzilumab if the drug is approved under EUA ^[30] .

In October 2021, Humanigen submitted all the planned modules, a risk management plan and pediatric investigation plan for the conditional marketing authorisation (CMA) of lenzilumab in hospitalised COVID-2019 patients to the UK's Medicines and Healthcare Products Regulatory Agency (MHRA). The LIVE-AIR study results will also support this application ^[31] . In July 2021, Humanigen submitted a marketing authorisation application for lenzilumab with the MHRA for expedited COVID-related rolling review. Earlier, in June 2021, Humanigen had initiated a rolling review submission for CMA with the MHRA for use of lenzilumab in addition to current standard of care to alleviate the immune-mediated cytokine release syndrome in patients with COVID-2019. The submission is supported by data from the phase III LIVE-AIR trial [see below]. As of May 2021, Humanigen was in discussion with the Medicines and Healthcare Products Regulatory Agency (MHRA) for the use of lenzilumab in COVID-2019 patients in the UK ^{[32] [33] [29]} .

As of March 2021, Humanigen plans to submit conditional approval Maketing Authorization Application (MAA) for lenzilumab in COVID-2019 infections to the European Medicines Agency for use in Europe and to the Medicines and Healthcare Products Regulatory Agency for use in the United Kingdom ^[30] .

As of March 2021, Humanigen plans to submit Biologics License Application (BLA) for lenzilumab in COVID-2019 infections to the US FDA ^[30] .

As of May 2021, Humanigen was reviewing the possibility of similar regulatory submissions for approval or compassionate use of lenzilumab in other countries worldwide ^[29] .

As of May 2021, Humanigen announced intention to submit regulatory filings for the approval of lenzilumab for COVID-2019 infections in India, UK, Europe and Brazil ^[9] .

As of November 2020, lenzilumab was part of Operation Warp Speed ^[15] .

In November 2020, Humanigen announced intention to apply for Emergency Use Authorization (EUA) for COVID-2019 pneumonia ^[34] .

As of October 2020, Humanigen received written guidance from the US FDA following type B meeting to obtain feedback on Emergency Use Authorization of lenzilumab for the treatment ofCOVID-2019 pneumonia ^[35] .

Prior to October 2020, Humanigen received Emergency Use Authorization as single use IND (often referred to as compassionate use) for lenzilumab in the treatment of COVID-2019 pneumonia and associated acute respiratory distress syndrome in the US ^[36] .

In February 2022, Humanigen initiated a managed access program for lenzilumab (LenzMAP™) to be available for certain hospitalized COVID-19 patients through Humanigen initiated a managed access program. LenzMAP will enable access to lenzilumab on a case-by-case basis for hospitalized patients with COVID-19 for whom the treating physician deems there are no suitable alternatives. Lenzilumab is available via LenzMAP in 17 countries, including Austria, Bulgaria, Croatia, Cyprus, Denmark, Estonia, France, Greece, Ireland, Lithuania, Luxembourg, the Netherlands, Portugal, Spain, Sweden, Switzerland and the UK ^[37] .

As of March 2024, Humanigen completed a phase I bridging study that evaluated the safety, tolerability and pharmacokinetics of lenzilumab. The trial was initiated prior to March 2022 and enrolled 20 participants in South Korea. Earlier in July 2021, Humanigen announced that its development and commercialisation partners Telcon RF Pharmaceutical and KPM Tech received approval from South Korea’s Ministry of Food and Drug Safety (MFDS) to conduct a phase I clinical trial of lenzilumab in the treatment of hospitalised COVID-19 infection patients. The randomised, placebo-controlled, double-blind, single-dose, dose escalation trial was initiated prior to March 2022. The primary endpoints of the trial will be safety, tolerability, and pharmacokinetics of lenzilumab ^{[7] [38] [39]} . In March 2024, clinical data was presented at the 125th Annual Meeting of the American Society for Clinical Pharmacology and Therapeutics (ASCPT-2024) ^[40] .

In July 2021, Humanigen reported that Telcon and KPM Tech plans to apply for emergency use authorization from the Ministry of Food and Drug Safety (MFDS) for lenzilumab in the treatment of hospitalised COVID-19 patients in South Korea. The support for conditional approval would be based on data from the planned phase I trial and the existing data from phase III LIVE-AIR trial ^[38] .

A case control study was conducted to evaluate effects of lenzilumab in patients with COVID-2019 infections. A total of 39 patients were included, including 12 who received lenzilumab, and 27 who received standard of care treatment. Data from the study were released in September 2020 ^[41] .

In August 2021, Humanigen reported that the phase III LIVE-AIR trial achieved its primary endpoint of survival without ventilatilation ^[42] . Earlier, in March 2021, Humanigen completed the pivotal phase III LIVE-AIR trial in hospitalised patients with pneumonia associated with SARS-CoV-2 infection in COVID-19 patients (HGEN003-06; NCT04351152). The trial is designed to evaluate whether the use of lenzilumab in addition to current standard of care can alleviate the immune-mediated cytokine release syndrome and prevent progression to respiratory failure and/or death in high risk patients. The randomised, double blind, placebo-controlled trial initiated in May 2020 enrolled 520 patients in the US and Brazil ^[43] . The trial enrolment was completed in January 2021. As of October 2020, Humanigen has received permission from US FDA, Brazilian regulatory agency and Mexican regulatory agency to initiate the trial. Earlier in March 2020, Humanigen submitted an initial protocol synopsis to the US FDA for the same. In June 2020, Humanigen released clinical and safety data in 12 patients. In March 2021, updated data from the trial were released by the company. In May 2021, Humanigen announced online publication of the results from the phase III study ^{[44] [6] [14] [45] [46] [47] [48] [49] [50] [51] [35] [52] [53] [21] [54]} . In September 2021, Humanigen presented updated efficacy results from this study at the Conference on Infectious Diseases (IDWeek-2021) ^{[55] [56]} . In October 2021, efficacy data from an exploratory analysis of the phase III LIVE-AIR trial were released by the company ^[57] . In September 2021, Humanigen presented updated efficacy results from this study at the British Thoracic Society Winter Meeting (2021) ^[58] . In January 2021, company released data from the trial ^[59] . In October 2022, pharmacodynamics data was presented at the IDWeek 2022 ^[60] .

In December 2020, Peter MacCallum Cancer Centre initiated the phase III C-SMART trial to evaluate prophylactic effect of interferon-alpha in cancer patients with no COVID-2019 infection or positive contact (arm 1), as post exposure prophylactic in cancer patients with confirmed exposure (arm 2), effect of selinexor [see ADIS Insight Drug profile800036503] for treatment of patients with moderate COVID-2019 infections (arm 3) and effect of lenzilumab for the treatment of cancer patients with severe COVID-2019 infections (arm 4) (NCT04534725; Peter Mac ID 20/135; ACTRN12620000844943). The sequential multiple assignment randomized, placebo-controlled trial intends to enrol approximately 2 282 participants in Australia. The trial is being funded by a grant from the Australian Government's Medical Research Future Fund ^{[7] [61]} .

In April 2022, National Institute of Allergy and Infectious Diseases (NIAID) completed a phase II/III trial that evaluated lenzilumab plus remdesivir, in patients with COVID-2019 infections (NCT04583969; 20-0013B). Earlier, in July 2021, NIAID expanded the trial to phase II/III. In March 2021, the NIAID had re-initiated enrolment in the phase II ACTIV-5 / Big Effect Trial (BET-B) trial of putative therapeutics. Earlier, in February 2021, enrolment in the trial was suspended, due to decision of Institutional Review Boars (IRB). The company amended the primary endpoint to survival without ventilation. The primary endpoint of the trial also included to evaluate the clinical efficacy of different investigational therapeutics relative to the control arm in adults hospitalised with COVID-19 according to clinical status (8-point ordinal scale) at day 8. The double-blind, parallel, prospective, randomised trial was initiated in October 2020, and enrolled 473 patients in the US and South Korea. In August 2021, the National Institutes of Health (NIH) reported the expansion of the Accelerating COVID-19 Therapeutic Interventions and Vaccines (ACTIV-5) and Big Effect Trial, in the B arm of the trial (BET-B), referred to as ACTIV-5/BET-B. Following feedback from and consultation with the company, the NIH advanced the study to a phase II/III study with target enrolment of at least 400 patients and amended the protocol for ACTIV-5/BET-B in a manner that aligns with the design of the company’s LIVE-AIR trial. As a result of the advancement to a phase II/III and amended protocol, the company anticipates that ACTIV-5/BET-B will serve as a second confirmatory study required for submission to FDA as part of a Biologics License Application (BLA) that the company would submit if the ACTIV-5/BET-B data further validate the benefits of lenzilumab in COVID-19 patients. In July 2022, results from this trial were released by National Institute of Allergy and Infectious Diseases (NIAID) ^{[62] [63] [64] [65] [59] [66]} .

B-cell lymphoma

As of April 2021, Humanigen intends to initiate a randomized, multicenter, potentially registrational, phase II clinical trial to evaluate the efficacy and safety of lenzilumab in combination with all commercially available CD19 CAR-T therapies in DLBCL. The study is estimated to enroll approximately 150 patients in the US. Humanigen also announced that the protocol is being submitted to the US FDA ^[6] .

In August 2022, Kite Pharmaceuticals and Humanigen terminated the phase I/II ZUMA-19 trial of lenzilumab and axicabtagene ciloleucel [see Adis Insight Drug profile 800039436], in patients with relapsed or refractory large B-cell Lymphoma because development programme was terminated by the companies (KT-US-471-0119; EudraCT 2019-004568-23; NCT04314843). The open label trial was initiated in April 2020 and enrolled six patients in US ^{[67] [52] [68]} . In April 2021, Humanigen announced positive efficacy and safety data from the Ib part of the trial, and also announced the recommended phase II dose. In December 2022, results from this trial were presented at the 64th American Society of Hematology Annual Meeting and Exposition (ASH-Hem-2022) ^{[69] [6]} .

Asthma

KaloBios Pharmaceuticals completed a 24-week proof-of-concept phase II efficacy and safety trial of lenzilumab in January 2014, in patients with moderate-to-severe asthma that is inadequately controlled with corticosteroids (KB003-04; NCT01603277). This randomised, double-blind, placebo-controlled study assessed the change in percent predicted FEV1 after 400mg single doses, which were intravenously administered every four weeks with one additional dose at week 2. Patient enrolment was completed ahead of schedule in June 2013. The trial enrolled 160 patients in the US, Australia, France, Poland, and the United Kingdom. Top-line data were announced in January 2014. The trial did not meet its primary clinical endpoint of improvement in FEV1 compared with placebo in the overall study participants. Based on these data, KaloBios decided to discontinue development of lenzilumab in severe asthma ^{[70] [71] [72] [73] [74]}

Chimeric antigen receptor T-cell

(CAR-T) neurotoxicity: In December 2022, Humanigen announced that the previously planned Company sponsored study of lenzilumab with certain CAR-T therapies, known as SHIELD, has been terminated, in pursuit of the strategic realignment plan (see above) ^[4] . Earlier, in January 2022, Humanigen reported the US FDA type C meeting and advice created alignment on registration pathway and design for the phase III SHIELD trial of lenzilumab for the prevention of CAR-T therapy related toxicities including immune effector cell-associated neurotoxicity (ICANS) and cytokine release syndrome (CRS) ^[75] . In November 2021, Humanigen had scheduled a meeting with the US FDA to discuss a protocol to conduct the trial of lenzilumab to improve the safety and efficacy of CD19 CAR-T therapies in the treatment of non-Hodgkin lymphoma ^[76] .

Humanigen is conducting a phase Ib/II trial of lenzilumab for the prevention of CAR-T induced neurotoxicity (Humanigen pipeline, May 2018). The company believes that lenzilumab has the potential to make CAR-T therapy more effective by reducing neurotoxicity, allowing higher CAR-T doses, greater CAR-T expansion, and potentially reducing myeloid-derived suppressor cells (MDSC) that inhibit T-cell function ^{[77] [78]} .

Graft-versus-host disease

In January 2022, Humanigen initiated a phase II/III RATinG trial with lenzilumab in high risk graft versus host disease patients (21EM028042585840; CPMS51332; IRAS286785; EudraCT2021-001193-29; IRAS286785). The double-blind, randomised trial intends to enrol 590 participants in the UK ^[79] . As of December 2020, Humanigen was in planning stage for initiation of phase II/III RATinG trial of lenzilumab in treat patients who have undergone allogeneic hematopoietic stem cell therapy who are at high and intermediate risk for acute GvHD. The trial is in the IMPACT Partnership in the UK ^{[11] [80]} . As of May 2022, University of Birmingham notified that the amended Investigational Medicinal Product Dossier has been accepted by Medicines & Healthcare products Regulatory Agency for the RATinG study ^[26]

Preclinical development is ongoing in the UK for acute GvHD (Humanigen website, December 2020).

Haematological malignancies

In May 2021, Humanigen initiated a phase II/III PREACH-M trial to investigate the efficacy of lenzilumab in patients with Chronic Myelomonocytic Leukaemia (CMML) based on their individual molecular profile (lenzilumab plus azacitidine versus sodium ascorbate plus azacitidine) (ACTRN12621000223831p; U1111-1261-2350). The primary outcome of the study was evaluating frequency of complete response (CR) and partial response (PR) at any point during the first 12 months of active therapy. The non-randomized trial intends to enrol approximately 72 patients in Australia ^[81] . The first patient of the trial was dosed in October 2021. The PREACH-M trial was conceived based on evidence from earlier in vitro, in vivo studies and phase 1 study (see below) which demonstrated 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. In addition, 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 ^[82] . In April 2023, the company presented efficacy and safety data at the 114^th Annual Meeting of the American Association for Cancer Research (AACR-2023) ^[83] . In June 2023, efficacy and adverse events data from the trial were released by the company at the 28th Congress of the European Haematology Association (EHA-2023) ^[84] . In December 2023, updated efficacy and adverse events data from an interim analysis in the trial were presented at the 65th American Society of Hematology Annual Meeting and Exposition (ASH-Hem-2023) ^{[85] [86]} . In December 2024, results from the trial were presented at the 66th American Society of Hematology Annual Meeting and Exposition (ASH-Hem-2024) ^[87]

In February 2020, Humanigen completed a phase I trial that evaluated the safety, pharmacokinetics and efficacy of lenzilumab in previously-treated patients with chronic myelomonocytic leukaemia (CMML) (NCT02546284; HGEN003-05; KB003-05). The open label trial was initiated in July 2016, and enrolled 15 patients in the US. The trial was previously suspended in early November 2015 by the company further to its decision to wind down operations. The US FDA cleared the IND application for this trial in July 2015. In December 2019, Humanigen presented safety and efficacy data from the study at the 61^st Annual Meeting and Exposition of the American Society of Hematology (ASH-Hem-2019) ^{[88] [24] [89] [90] [91] [92] [93] [94] [95] [96] [97] [98] [99]} .

In July 2017, KaloBios announced that it plans to submit an application for rare paediatric designation and orphan drug designation for lenzilumab in myeloid leukaemia (juvenile myelomonocytic leukaemia) ^[100] .

Humanigen intends to initiate a phase I trial of lenzilumab in juvenile myelomonocytic leukaemia (JMML). Data from the phase I/II trial in CMML will determine the feasibility of the trial in JMML ^[101] .

In November 2015, KaloBios reported preclinical results demonstrating the potential of lenzilumab to cause apoptosis in CMML cells by antagonising granulocyte macrophage colony stimulating factor ^[90] .

In preclinical studies, lenzilumab, along with CD19 targeted chimeric antigen receptor T-cell therapy (CART19), was shown to reduce neurotoxicity (NT) and cytokine release syndrome (CRS) and enhance CART19 proliferation and effector functions ^[102] ..

Rheumatoid arthritis

In September 2011, due to a programme refocus, KaloBios Pharmaceuticals terminated the phase II trial of intravenous lenzilumab in patients with rheumatoid arthritis who had an inadequate response to biologics (NCT00995449). Lenzilumab was dosed five times over 14 weeks, and the primary endpoint was ACR20 response. The randomised, double-blind, placebo-controlled, dose-ranging trial was to enrol 208 patients, but only recruited total of eight patients ^[103] .

Patient dosing in a phase I dose-escalation trial of lenzilumab was completed by KaloBios in April 2008. The placebo-controlled, single-dose study aimed to evaluate safety and immunogenicity of the agent among healthy volunteers ^[104] .

Solid tumours

Lenzilumab has the potential to reduce tumour viability and allow immune cell killing for the treatment of solid tumours, including prostate, renal, and breast cancer that express the functional receptor for granulocyte macrophage-colony stimulating factor (GM-CSF) (KaloBios website, November 2015).

Preclinical

In April 2022, preclinical data from a GM-CSF knock-out CAR-T study was released by Humanigen ^[105] .

In November 2018, Humanigen released final results from the xenograft study of lenzilumab which demonstrated that lenzilumab in combination with CAR-T cell therapy prevents cytokine release syndrome and neuro-inflammation and improved durable control of acute lymphoblastic leukemia ^{[106] [107]} .

Financing information

In April 2021, Humanigen completed its underwritten public offering of common stock, resulting in gross proceeds to Humanigen of approximately $US92.5 million. Humanigen intends to use the net proceeds from the offering for manufacturing and commercial preparation in the event of receipt of an Emergency Use Authorization from the Food and Drug Administration for lenzilumab™ in hospitalised COVID-19 patients, as well as for working capital and other general corporate purposes ^{[108] [109] [110]} .

In March 2021, Humanigen obtained a term loan facility from Hercules Capital of up to $US80 million of secured debt financing. The funds will be utilised to support the production of lenzilumab ^[111] .

In September 2020, Humanigen announced that it has completed its previously announced underwritten public offering of common stock. Humanigen raised net proceeds of approximately $US72.8 million from the sale of 9 200 000 shares in the offering. Humanigen intends to use the net proceeds from the offering to support its manufacturing, production and commercial preparation activities relating to lenzilumab as a potential therapy for COVID-19 patients and for general corporate purposes ^[112] .

In September 2020, Humanigen announced that it has commenced an underwritten public offering of 8,000,000 shares of common stock, that are expected to generate gross proceeds of approximately $US68 million. Humanigen also announced its intention to grant the underwriters a 30-day option to purchase up to an additional 1,200,000 shares. The company intends to use the net proceeds from the offering to support its manufacturing, production and commercial preparation activities of lenzilumab as a potential therapy for COVID-2019 infections and for general corporate purposes ^{[113] [114]} .

In December 2017, Humanigen reported that it will receive a $US3 million investment from an affiliate of Black Horse Capital to fund the further development of lenzilumab ^[77] .

In March 2017, KaloBios Pharmaceuticals received additional funding of approximately $US5.5 million from its existing investors, through an amendment to its term loan facility. The proceeds will used to support the ongoing development of lenzilumab for treatment of chronic myelomonocytic leukemia ^[115] .

In November 2015, KaloBios reported that the development of lenzilumab has been resumed after acquisition of 70% of its outstanding shares by an investor group. KaloBios will receive an equity investment of at least $US3 million plus a $US10 million equity financing facility from the group of investors, subject to applicable shareholder approval. The company has approximately $US5 million in cash as at November 2015 ^{[90] [116]} .

KaloBios completed a long-term debt financing deal worth up to $US15 million in September 2012. This deal followed the closing of Series E Preferred Stock financing, which raised $US20.25 million. The funds were to be used to support clinical development of the company's lead candidates, including phase II trials for lenzilumab ^[117] .

In September 2008, KaloBios raised $US20 million in the first closing of its Series D venture financing. In December 2008, the company raised an additional $US12 million in the second closing of its Series D financing. The funds, amongst other things, enabled the company to complete the current trials for lenzilumab and to prepare for phase IIb trials ^{[118] [119]} .

In September 2021, United States Patent and Trademark Office (USPTO) issued a patent titled "Method of treating CAR-T cell therapy-induced neurotoxicity using a GM-CSF inhibitor" (Patent No. US 11 130 805). It has an expected patent term through October 2, 2038 ^[76] .

In February 2021, United States Patent and Trademark Office (USPTO) issued a patent titled "Method of reducing tumour relapse rate in immunotherapy by administration of lenzilumab" (Patent No US 10 927 168 B2). The patent covers the use of lenzilumab for reducing relapse rate or preventing occurrence of tumour relapse during immunotherapy, as well as treating or preventing immunotherapy-related toxicity associated with adoptive cell transfer, including chimeric antigen receptor-expressing T-cells (CAR-T cells), T-cell receptor (TCR) modified T-cells, tumour-infiltrating lymphocytes (TILs), chimeric antigen receptor (CAR)-modified natural killer cells, or combination thereof; administration of monoclonal antibodies; administration of cytokines; administration of a cancer vaccine; T-cell-engaging therapies; or any combination thereof ^[120] .

The United States Patent and Trademark Office (USPTO) in January 2021 issued a patent titled "Method of reducing the level of non-GM-CSF cytokines/chemokines in immunotherapy related toxicity" (Patent No. US 10 899 831 B2). The patent covers the use of lenzilumab for reducing relapse rate or preventing occurrence of tumour relapse during immunotherapy in the presence or absence of immunotherapy-related toxicity; reducing cytokine or chemokine levels other than GM-CSF during immunotherapy-related toxicity and treating or preventing immunotherapy-related toxicity associated with adoptive cell transfer, including chimeric antigen receptor-expressing T-cells (CAR T-cells), T-cell receptor (TCR) modified T-cells, tumour-infiltrating lymphocytes, chimeric antigen receptor (CAR)-modified natural killer cells, or combination thereof; administration of monoclonal antibodies; administration of cytokines; administration of a cancer vaccine; T-cell engaging therapies; or any combination thereof ^[120] .

In December 2020, Humanigen announced that the United States Patent and Trademark Office issued a patent titled “Methods of Treating Immunotherapy-Related Toxicity using a GM-CSF Antagonist,” (Patent No. 10,870,703). The patent covers the use of lenzilumab in prevention or treatment of cytokine storm and neurotoxicity in patients undergoing chimeric antigen receptor T (CAR-T) cell therapy ^[121]

According to KaloBios Pharmaceuticals form 10-K filed in March 2015, the company has developed and own a composition of matter patent covering lenzilumab and related Humaneered^® anti-GM-CSF antibodies which provides patent protection through April 2029. The company have additional pending patents covering various methods of treatment in the US and a number of other countries.