COVID-19 Infections and COVID-19 pneumonia
As of November 2020, lenzilumab was part of Operation Warp Speed [6] .
In November 2020, Humanigen announced intention to apply for Emergency Use Authorization (EUA) for COVID-2019 pneumonia in the first quarter of 2021 [19] .
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 [20] .
Prior to October 2020, Humanigen received Emergency Use Authorization as single use IND for lenzilumab in the treatment of COVID-2019 pneumonia and associated acute respiratory distress syndrome in the US [21] .
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 [22] .
In January 2021, Humanigen completed enrolment in a pivotal phase III 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 [23] [13] [24] . As of October 2020, Humanigen has received permission from US FDA, Brazilian regulatory agency and Mexican regulatory agency to initiate the trial [20] [25] [26] . Earlier in March 2020,Humanigen submitted an initial protocol synopsis to the US FDA for the same [27] [2] . In June 2020, Humanigen released clinical and safety data in 12 patients. In September 2020, the company reported that following a planned interim analysis that was conducted after 50% of the expected recovery threshold was reached, an independent Data and Safety Monitoring Board recommended continuation of the phase III study without any modifications [28] [29] [30] . In November 2020, interim analysis for sizing and powering suggests that lenzilumab had a clinically meaningful impact on patient recovery, the HR was calculated to be 1.37, with an approximately 37% more recoveries were observed in the lenzilumab arm. As per the recommendation of the DSMB, the company plans to increase enrollment to achieve 402 events (approximately 515 patients) to maintain the power of the trial at 90%. The next interim analysis for efficacy planned when the trial reaches 75% events (302 events) which will require approximately 390 patients to be enrolled in the trial [31] . As of January 2021, Humanigen is preparing for a potential COVID-19 Emergency Use Authorization (EUA) for lenzilumab [5] .
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 [32] .
In October 2020, National Institute of Allergy and Infectious Diseases (NIAID), in October 2020, initiated and dosed the phase II ACTIV-5 / Big Effect Trial (BET-B) trial of putative therapeutics for the treatment of COVID-19 infections. The primary endpoint of the trial is to evaluate 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 (NCT04583969; 20-0013B). This double-blind randomised trial will recruit approximately 200 participants in the US [33] [34] .
B-cell lymphoma
In April 2020, Kite Pharmaceuticals and Humanigen initiated 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 (KT-US-471-0119; EudraCT 2019-004568-23; NCT04314843). The open label trial intends to enrol 36 patients in US. In July 2020, Humanigen announced that the first patient was infused in the trial [35] [25] [36] .
Chimeric antigen receptor T-cell
(CAR-T) neurotoxicity: 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 [37] [38] .
Haematological malignancies
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 61st Annual Meeting and Exposition of the American Society of Hematology (ASH-Hem-2019) [39] [17] [40] [41] [42] [43] [44] [45] [46] [47] [48] [49] [50] .
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) [51] .
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 [52] .
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 [41] .
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 [53] .
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 [54] [55] [56] [57] [58] .
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 [59] .
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 [60] .
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 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 [61] [62] .
Financing information
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 [63] .
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 [64] [65] .
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 [37] .
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 [66] .
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 [41] [67] .
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 [68] .
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 [69] [70] .
