COVID-19 Infections and COVID-19 pneumonia
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  . 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]  . 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  . 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  .
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  . 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    .
In March 2021, Humanigen announced that, plans to submit conditional approval Marketing 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  .
In March 2021, Humanigen reported that, plans to submit Biologics License Application (BLA) for lenzilumab in COVID-2019 infections to the US FDA  .
As of May 2021, Humanigen is reviewing the possibility of similar regulatory submissions for approval or compassionate use of lenzilumab in other countries worldwide  .
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  .
As of November 2020, lenzilumab was part of Operation Warp Speed  .
In November 2020, Humanigen announced intention to apply for Emergency Use Authorization (EUA) for COVID-2019 pneumonia in the first quarter of 2021  .
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  .
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  .
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 randomized, placebo-controlled, double-blind, single-dose, dose escalation trial of lenzilumab will be conducted by Telcon and KPM Tech in 20 healthy Korean adults. The primary endpoints of the trial will be safety, tolerability, and pharmacokinetics of lenzilumab  .
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  .
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  .
In August 2021, Humanigen reported that the phase III LIVE-AIR trial achieved its primary endpoint of survival without ventilatilation  . 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  . 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                . In September 2021, Humanigen presented updated efficacy results from this study at the IDWeek (2021)  . In October 2021, efficacy data from an exploratory analysis of the phase III LIVE-AIR trial were released by the company  .
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  .
In July 2021, National Institute of Allergy and Infectious Diseases (NIAID), expanded the trial to phase II/III to evaluate lenzilumab in patients with COVID-2019 infections. In March 2021, the NIAID had re-initiated enrolment in the phase II ACTIV-5 / Big Effect Trial (BET-B) trial of putative therapeutics for the treatment of COVID-2019 infections. Earlier in February 2021, enrolment in the trial was suspended in the trial 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 includes 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). As at July 2021, the company enrolled half of the 400 patients in the trial. The double-blind, parallel, prospective, randomised trial initiated in October 2020 and intends to recruit approximately 400 patients in the US and may expand to 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     .
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  .
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    . 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  .
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     
Chimeric antigen receptor T-cell
(CAR-T) neurotoxicity: In November 2021, Humanigen announced that it has scheduled a meeting with the US FDA to discuss a protocol to conduct a phase III randomized, placebo-controlled, open-label trial of lenzilumab to improve the safety and efficacy of CD19 CAR-T therapies in the treatment of non-Hodgkin lymphoma in December 2021  .
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   .
Acute graft-versus-host disease
As of December 2020, Humanigen is in planning stage for initiation of phase II/III 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 expected to be conducted by the IMPACT Partnership in the UK  .
Preclinical development is ongoing in the UK for acute GvHD.
In May 2021, Humanigen initiated a phase II trial (PREACH-M study) 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 is designed to enroll approximately 72 patients in Australia. 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 
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)              .
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)  .
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  .
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  .
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  ..
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  .
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  .
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).
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   .
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    .
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  .
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  .
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   .
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  .
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  .
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   .
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  .
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   .