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RATinG: Risk Adapted Therapy in Acute GvHD; investigating the use of Lenzilumab for treating high-risk acute graft versus host disease following allogenic stem cell transplantation.
https://www.impactpartnership.org.uk/the-trials/rating/
Study design/summary: A multicentre, phase II/III, randomised (1:1) clinical trial of Lenzulimab compared to placebo in patients with acute GvHD following allogenic stem cell transplantation. Potentially eligible patients will be screened for expression of ST2 and REG3a using a validated assay and assigned a risk score. High-risk patients (interventional cohort) will be eligible for study entry and randomisation between Lenzulimab and placebo (1:1); low-risk patients will form an observational cohort and be treated as per standard of care.
Objectives:
Primary objective will be to study non-relapse mortality (NRM) at 6 months post-transplant.
Secondary objectives will be to determine biomarker risk score at D28 of treatment; response (complete remission + partial remission) at D28 of treatment; cumulative corticosteroid exposure at 6 months; time to treatment failure (increased dose of corticosteroids or starting additional systemic GvHD treatment); cumulative incidence and severity of chronic GvHD (cGvHD); overall survival (OS) at 1 year; GvHD- and relapse free survival at 1 year (GRFS); toxicity including adverse events of special interest; patient-reported outcomes; Lenzulimab immunogenicity, PK and PD. Samples will also be collected for translational research projects in a subset of patients.
Centres: 22 IMPACT centres & additional non-IMPACT centres
Target Number of patients: 220 patients will be randomised to receive either Lenzulimab or placebo (1:1); up to 370 patients will be recruited to the observational cohort.
Patient population: Adults with acute GvHD following allogenic stem cell transplantation will be recruited to this trial.
Sponsorship/Funding: RATinG is sponsored by the University of Birmingham. The trial will be delivered by IMPACT-funded Research Nurses at 9 IMPACT centres. The facilitatory hub, located at the CRCTU at the University of Birmingham, is funded by IMPACT.
Trial Status: In set-up
Trial contacts: RATING@trials.bham.ac.uk
Duration: Patients will be recruited over 3 years and will be followed up for 6 months. Long-term follow up will capture data regarding GvHD treatments as a surrogate for GvHD progression, relapse of underlying disease and survival.
If you are a patient and interested in taking part in a clinical trial, please speak with your consultant who will be able to offer you further information and discuss whether it is suitable for you. A referral from your medical team would be required in order to consider you for treatment on a clinical trial.
IMPACT Partnership
@impactstemcell
We're delighted to announce that RATinG has now been submitted to REC/@HRA_Latest & @MHRAgovuk and we hope to receive approvals around the end of this year!#GvHD #Lenzilumab @humanigen @AnthonyNolan @NHSBT @LeukUK @Becky_Bishop14 https://t.co/YAhNmfSfT8
— ASCENT - Accelerated Stem CEll traNsplant Trials (@crctuASCENTteam) November 16, 2021
IMPACT Partnership
@impactstemcell
We're thrilled to be working with @humanigen to deliver this trial of #lenzilumab for treating high-risk acute graft versus host disease following allogeneic stem cell transplantation, led by Professor Adrian Bloor of @TheChristieNHS #GvHD #ASCT @AnthonyNolan @NHSBT @LeukUK https://t.co/2R9sbNP7gK
— ASCENT - Accelerated Stem CEll traNsplant Trials (@crctuASCENTteam) November 15, 2021
So they had $76.5 million in cash as of Sept 30th and have raised $24.5 million since Sept 30th. So they currently have $101 million in cash minus what has been spent since Sept 30th.
Humanigen Reports Third Quarter and Nine Months Ending September 30, 2021 Financial Results and Provides Corporate Update
https://ir.humanigen.com/English/news/news-details/2021/Humanigen-Reports-Third-Quarter-and-Nine-Months-Ending-September-30-2021-Financial-Results-and-Provides-Corporate-Update/default.aspx
UK is back on the upswing...........
UK COVID update: Daily cases rise for 2nd day in a row
— BNO News (@BNOFeed) November 12, 2021
- New cases: 40,375
- Average: 35,507 (+907)
- In hospital: 8,547 (-124)
- In ICU: 994 (-18)
- New deaths: 145
- Average: 156 (-7)
Covid cases are surging in Europe. America is in denial about what lies in store for it
Eric Topol
https://www.theguardian.com/commentisfree/2021/nov/12/covid-cases-surging-europe-america-denial
It’s deja vu, yet again. The pandemic first hit Europe in March 2020, and Americans were in denial, thinking it wouldn’t happen here. Then, later in the year, the Alpha variant wave took hold in the United Kingdom and the United States was unprepared. This recurred with Delta in the summer of 2021. Now, in the fall of 2021, Europe is the outlier continent on the rise with Covid, with approximately 350 cases per 100,000 people and many countries are soaring to new records. This not only involves eastern and central Europe, where there are some countries with low vaccination rates (such as Georgia, only 24% fully vaccinated) and caseloads as high as 160/100,000 (Slovenia), but also western Europe, such as Austria, Belgium, Ireland and several others. Indeed, in Germany, leading virologist Christian Drosten recently warned their death toll could be doubled if more aggressive mitigation and vaccination strategies were not quickly adopted.
Why is this happening again in Europe after the Delta wave passed through and high rates of vaccination were achieved? There are a few important reasons. First, there are a large proportion of unvaccinated individuals in each country, and only countries such as Spain at 80% and Portugal at 88% that fully vaccinated their total populations have set a high bar and have thus far withstood the continental trend of rise in cases. Noteworthy is Belgium with 74% fully vaccinated and one of the hardest-hit countries in the world, now at 79/100,000, currently 10th highest caseload globally. That alone tells us 74% isn’t enough, and that prior Covid (without vaccination, what some refer to as “natural immunity”) is unreliable for representing a solid immunity wall against the Delta variant. In fact, it has been projected for Delta that any country needs to achieve 90-95% of its total population fully vaccinated (or with recent Covid) in order to have population-level immunity that covers, providing relative protection, for the others.
Key among the unvaccinated are teenagers and children. For European countries, the UK was slower in starting their vaccination program for teens and that has been suggested as one of the reasons their cases started rising again. There is compelling data from both the UK and United States that children and teens have been a key driver of spread in recent months.
It is noteworthy that we are not dealing with just cases or a “casedemic”. For example, Greece’s cases have now quickly soared to 650/100,000 people and so has their death rate increased. While many countries have “uncoupled” their rise in cases from hospitalizations and deaths, that is incomplete at best, and many infected individuals are getting seriously ill, no less the risk of long Covid which remains under-recognized as to its importance and potential of durable disabling effects.
Second, there is evidence of waning of immunity on top of the hyper-contagious Delta strain. Even though much of Europe got a later start in vaccination, a recent study showed that with the Astra Zeneca vaccine the decline in anti-spike antibody occurred quite early and there was a clear relationship between antibody levels and breakthrough infections. Decline below the anti-spike antibody threshold of 500 U/ml was reached at 96 days for AstraZeneca’s vaccine compared with 257 days for Pfizer’s. The impact of waning, and the opportunity to restore very high (~95%) effectiveness of mRNA vaccines (specifically Pfizer/BioNtech) with booster (third) shots has been unequivocally proven from the Israeli data. Yet the adoption of boosters, even in the highest-risk groups such as age 60 plus, has been very slow.
Third, there has been relaxation or abandonment of mitigation measures. Countries such as Denmark and Norway completely reopened and have seen resurgence of cases since that occurred. Throughout the world, the profound pandemic fatigue has led to the irresistible notion that the pandemic end is nigh, that masks, distancing, and other measures have run their course, essentially that enough is enough. It is hard to imagine fighting a foe as formidable as Delta that a vaccine-only strategy can be effective. We’ve seen a dramatic improvement in Japan, with full return to baseline after their worst outbreak, by the combination of high level of vaccination and the continued use of masks and mitigation measures.
That brings us to the United States, sitting in the zone of denial for the fourth time during the pandemic, thinking that in some way we will be “immune” to what is happening in Europe. That somehow the magical combination of mRNA vaccines with only 58% of the population fully vaccinated, a relatively low proportion of booster shot uptake, a start to vaccinating teens and children, and a lot of prior Covid, and little in the way of mitigation, will spare us. That’s no magic. Add to that the complete lack of availability of cheap, rapid home tests to screen for infectiousness. Unlike Europe, the US was not capable of uncoupling cases from hospitalizations and deaths during its initial Delta wave – fully 75% of hospitalizations and 66% of deaths occurred compared to its third wave peak before vaccinations were available.
We are already seeing signs that the US is destined to succumb to more Covid spread, with more than three weeks sitting at a plateau of ~75,000 new cases per day, now there’s been a 10% rise in the past week. We are miles from any semblance of Covid containment, facing winter and the increased reliance of being indoors with inadequate ventilation and air filtration, along with the imminent holiday gatherings.
Now is the time for the US to heed the European signal for the first time, to pull out all the stops. Promote primary vaccination and boosters like there’s no tomorrow. Aggressively counter the pervasive misinformation and disinformation. Accelerate and expand the vaccine mandates that unfortunately became necessary and have been proven effective, and mass distribute medical quality masks and rapid home testing kits at no cost. Soon enough potent pills (Molnupiravar and Paxlovid) that take down the Sars-CoV-2 virus will get authorized and should also be made widely available to help prevent hospitalizations and deaths. Otherwise, we will probably face a fifth wave. Now is not the time for happy talk, but to instead show we can persevere, run this marathon, make it to the finish line. We can acknowledge and accept endemicity – that a low level of Covid will remain in the background, but that is not >75,000 new cases a day. Instead of succumbing to yet another major rise in cases and their sequelae, this is a chance for America to finally rise to the occasion, showing an ability to lead and execute.
After a couple weeks of falling cases, the UK's cases rose today:
@BNODesk
·
42m
UK COVID update: More than 42,000 new cases, highest since October 29
- New cases: 42,408
- Average: 34,600 (+734)
- In hospital: 8,671 (-126)
- In ICU: 1,012 (-4)
- New deaths: 195
- Average: 163 (-2)
@BNODesk
U.S. COVID update: Daily cases rise for fourth day in a row
- New cases: 99,450
- Average: 76,996 (+1,007)
- In hospital: 45,756 (+714)
- In ICU: 11,701 (+71)
- New deaths: 1,749
- Average: 1,253 (+8)
Humanigen Announces Clinical Trial Collaboration to Evaluate Lenzilumab in Acute Graft Versus Host Disease
https://ir.humanigen.com/English/news/news-details/2021/Humanigen-Announces-Clinical-Trial-Collaboration-to-Evaluate-Lenzilumab-in-Acute-Graft-Versus-Host-Disease/default.aspx
-Humanigen is supporting the University of Birmingham to conduct a Phase 2/3, potentially registrational, clinical trial at IMPACT stem cell transplant centers across the United Kingdom
-The “Risk Adapted Therapy in Acute GvHD”, or “RATinG”, study is expected to begin enrolling in 1H22
BURLINGAME, Calif.--(BUSINESS WIRE)-- Humanigen, Inc. (Nasdaq: HGEN), a clinical-stage biopharmaceutical company focused on preventing and treating an immune hyper-response called ‘cytokine storm’ with its lead drug candidate, lenzilumab, today announced it plans to support a Phase 2/3 study to evaluate lenzilumab for the early treatment of acute graft versus host disease (aGvHD) following allogeneic hematopoietic stem cell transplantation (HSCT) in collaboration with IMPACT, a world class accelerated trial network delivering innovative research for stem cell transplant patients in the UK. IMPACT delivers innovative research in partnership with the British Society of Blood and Marrow Transplantation and the University of Birmingham’s Cancer Research UK Clinical Trials Unit. The safety run-in component of the RATinG study is anticipated to be completed in 2022. The study is partially funded by IMPACT with Humanigen providing lenzilumab and the remaining funding for the study.
“The IMPACT partnership is committed to improving the outcomes of stem cell transplant patients. Management of aGvHD disease is an area of significant unmet need in stem cell transplantation and I am really excited to collaborate with Humanigen and IMPACT to deliver on the promise of this therapeutic approach for patients with high risk aGvHD,” said Professor Adrian Bloor MA, MB BChir, PhD, FRCP, FRCPath, Director of Stem Cell Transplantation, The Christie NHS Foundation Trust.
Lenzilumab neutralizes the immune signalling protein granulocyte-macrophage colony-stimulating factor (GM-CSF), which has been shown to initiate the inflammatory cascade that drives aGvHD, a serious condition with significant unmet needs that affects 30%-50% of all patients who undergo HSCT.1, 2
“We are pleased to be supporting the RATinG study in collaboration with IMPACT, the UK’s stem cell transplant clinical trials partnership, to evaluate lenzilumab, which represents a potential way to spare patients from the devastating effects of steroid refractory aGvHD after undergoing allogeneic HSCT,” said Cameron Durrant, Chairman and CEO, Humanigen.
About the Risk Adapted Therapy in Acute Graft versus Host Disease (RATinG) study
The RATinG study will evaluate lenzilumab in patients who have undergone allogeneic hematopoietic stem cell transplantation and been diagnosed with high-risk aGvHD. The trial will be conducted at up to 22 sites across the UK transplant network in two stages. The first stage of the study will treat 20 patients with lenzilumab before halting for an interim assessment of safety, efficacy, and futility. If an independent data monitoring committee deem the second stage to be feasible, then the trial will progress to its double-blind, randomized (1:1), second stage, which will enroll a minimum of 220 patients. A second interim analysis is planned to assess futility based upon the 28-day response rate to the first infusion in the first 150 evaluable patients.
Within seven days following clinical diagnosis of aGvHD, investigators will assess patients’ risk for steroid refractory aGvHD as measured by the Mount Sinai Acute GvHD International Consortium (MAGIC) biomarkers. Intermediate and high-risk groups will be treated with lenzilumab plus steroids in stage 1 and randomized to receive lenzilumab plus steroids or placebo plus steroids in stage 2. The stage 2 primary endpoint, non-relapse mortality, will be assessed once all patients have completed at least 6 months follow up.
About Lenzilumab
Lenzilumab is a proprietary Humaneered® first-in-class monoclonal antibody that has been proven to neutralize GM-CSF, a cytokine of critical importance in the hyperinflammatory cascade, sometimes referred to as cytokine release syndrome, or cytokine storm, associated with COVID-19 and other indications. Lenzilumab binds to and neutralizes GM-CSF, consequently improving outcomes for patients hospitalized with COVID-19. Humanigen believes that its GM-CSF neutralization has the potential to reduce the hyper-inflammatory cascade known as cytokine release syndrome common to chimeric antigen receptor T-cell (CAR-T) therapy and aGvHD.
In CAR-T, lenzilumab successfully achieved the pre-specified primary endpoint at the recommended dose in a Phase 1b study with Yescarta® in which the overall response rate was 100% and no patient experienced severe cytokine release syndrome or severe neurotoxicity. Based on these results, Humanigen plans to test lenzilumab in a randomized, multicenter, potentially registrational, Phase 2 study to evaluate its efficacy and safety when combined with other commercially available CD19 CAR-T therapies in non-Hodgkin lymphoma. Lenzilumab will also be tested to assess its ability to prevent and/or treat aGvHD in patients undergoing allogeneic hematopoietic stem cell transplantation.
A study of lenzilumab is also underway for patients with chronic myelomonocytic leukemia (CMML) exhibiting RAS pathway mutations. This study will build on evidence from a Phase 1 study, conducted by Humanigen, that showed RAS mutations are associated with hyper-proliferative features, which may be sensitive to GM-CSF neutralization.
EVIDENCE OF ELEVATED GM-CSF IN COVID-19 PATIENTS
https://www.cytokinestorm.humanigen.com/clinical-evidence
Europe is getting slammed. It is a preview of where the US will be in a couple of weeks. All of the quotes below are from today from @BNODesk.
https://twitter.com/BNODesk
Germany reports more than 44,000 new coronavirus cases, by far the biggest one-day increase on record, with 18 districts yet to report
Czech Republic reports 14,539 new coronavirus cases, the biggest one-day increase since March
Netherlands reports 12,713 new coronavirus cases, the biggest one-day increase since December and the third-highest on record
Denmark reports 3,017 new coronavirus cases, the biggest one-day increase since December
Austria reports 11,398 new coronavirus cases, the biggest one-day increase on record
Slovakia reports 7,055 new coronavirus cases, the biggest one-day increase on record
Russia reports 1,239 new coronavirus deaths, the biggest one-day increase on record, and 38,058 new cases
@humanigen
#Humanigen updated presentation filed with 8-K. Key messages:
— Humanigen, Inc. (@humanigen) November 9, 2021
NIH ACTIV-5/BET-B enrollment 75%+
FDA granted our meeting request regarding EUA
Awaiting MHRA decision on CMA
Prelim. top-line data from P3 SHIELD study in CAR-T possible for ASH 2022https://t.co/A0CVzYaDym
@BNODesk
U.S. COVID update: Daily cases rise for third day in a row
— BNO News (@BNOFeed) November 10, 2021
- New cases: 81,636
- Average: 75,989 (+1,709)
- In hospital: 45,042 (+991)
- In ICU: 11,630 (+125)
- New deaths: 1,724
- Average: 1,245 (+23)
More data: https://t.co/YDZSbYO7l7
Today's presentation said that the 60 day data and CRP data have already been submitted to the FDA and that the FDA has already granted a meeting to discuss getting the EUA. The FDA granting an EUA this month is not out of the question.
Today's share price drop is entirely due to XBI. We should easily get back to today's opening price of $6.72.
Credit Suisse Healthcare Conference Presentation
https://www.sec.gov/Archives/edgar/data/1293310/000121465921011324/ex99_1.htm
@BNODesk
·
2h
U.S. COVID update: Daily cases rise for second day in a row
— BNO News (@BNOFeed) November 6, 2021
- New cases: 92,359
- Average: 72,191 (+295)
- In hospital: 45,566 (-738)
- In ICU: 11,929 (-239)
- New deaths: 2,326
- Average: 1,197 (+38)
More data: https://t.co/YDZSbYO7l7
Humanigen Announces Release of Abstracts at ASH
https://ir.humanigen.com/English/news/news-details/2021/Humanigen-Announces-Release-of-Abstracts-at-ASH/default.aspx
-Abstract #2777 describes preclinical models that demonstrate GM-CSF neutralization with lenzilumab improves CAR-T cell proliferation, but blocking the GM-CSFa receptor may inhibit CAR-T cell proliferation
-Abstract #1758 describes the Phase 3 SHIELD study, which is planned to confirm whether lenzilumab can break the efficacy/toxicity link thereby improving the toxicity profile of commercially available CAR-T therapies for non-Hodgkin lymphoma while maintaining or improving efficacy
BURLINGAME, Calif.--(BUSINESS WIRE)-- Humanigen, Inc. (Nasdaq: HGEN) (“Humanigen”), a clinical-stage biopharmaceutical company focused on preventing and treating an immune hyper-response called ‘cytokine storm’ with its lead drug candidate, lenzilumab, today announced two abstracts pertaining to the potential use of lenzilumab in CAR-T will be presented at the 63rd Annual Meeting of the American Society of Hematology (ASH) taking place December 11-14, 2021. The society counts more than 18,000 hematologists among its membership from more than 100 countries, and its annual meeting attracts over 30,000 professional attendees.
“After completing a Phase 3 trial of lenzilumab, in 2021, for the treatment of patients hospitalized with COVID-19 pneumonia, we look forward to advancing our efforts to develop lenzilumab as a complementary therapy to potentially reduce CAR-T associated toxicities and to potentially improve outcomes for non-Hodgkin lymphoma patients,” said Adrian Kilcoyne, Chief Medical Officer, Humanigen. “My experience working in the development of CAR-T therapies, which are now currently commercially available, suggests preventing toxicity and optimizing durable response rates remain challenges. Our plans include initiating the Phase 3 SHIELD study of lenzilumab in the first half of 2022 and we may be able to announce interim data at ASH 2022.”
Abstract #2777
Optimized Inhibition of GM-CSF in Preclinical Models of Anti-CD19 Chimeric Antigen Receptor T Cell Therapy
Summary: The abstract describes the evaluation of differential targeting of the GM-CSF ligand using lenzilumab compared to targeting the GM-CSFa receptor using a different antibody in pre-clinical models. The research demonstrated significant differences on CAR-T cell functions and CAR-T cell-monocyte interactions when GM-CSF is neutralized with lenzilumab compared to blocking its receptor with other agents. A key finding is that lenzilumab neutralization of GM-CSF improved CAR-T cell proliferation, but the GM-CSFRa receptor blocking antibody may significantly inhibit CAR-T cell proliferation in a dose-dependent manner. This may have efficacy implications.
Presenter: Evandro Bezerra, MD, Mayo Clinic in Rochester, MN.
Session: 703. Cellular Immunotherapies: Basic and Translational: Poster II
Date: December 12, 2021; 6:00-8:00 PM EST
Abstract #175
A Phase 3 Randomized, Placebo-Controlled, Open-Label, Multi-Center Trial of Lenzilumab to Improve the Safety and Efficacy of CAR-T Cell Therapy in Adults with Relapsed or Refractory Large B-Cell Lymphoma* (The SHIELD Study)
Summary: The abstract describes a planned Phase 3 study of prophylactic lenzilumab administration in sequenced therapy with commercially available CAR-Ts to treat non-Hodgkin lymphoma. The study aim is to determine if lenzilumab can break the efficacy/toxicity linkage associated with CAR-T therapy thereby improving the toxicity and tolerance of CAR-T while maintaining or improving efficacy by neutralizing GM-CSF.
Presenter: Saad Kenderian, MD, principal investigator in the T Cell Engineering Lab at Mayo Clinic in Rochester, MN.
Session: 704. Cellular Immunotherapies: Clinical: Poster I
Date: December 11, 2021; 5:30 PM-7:30 PM EST
* The SHIELD study protocol has been adapted since submission of the abstract to include a broader patient population
That was quite the bounce. We are already $1 above today's low.
The winter wave is already in full swing in Europe and it looks like the US is also now entering it.
Below is a study that found that lenzilumab not only solved toxicity issues in CAR-T but lenz also improved the efficacy of the CAR-T therapy itself. So it has a dual Mechanism of Action. Toxicity issues have been the main impediment preventing the widespread use of CAR-T therapy. These toxicity issues have been dangerous and even deadly. Lenzilumab solves these toxicity issues by inhibiting GM-CSF which might literally be the key to making CAR-T a viable treatment. The extra increase CAR-T efficacy is a nice bonus.
Optimized Inhibition of GM-CSF in Preclinical Models of Anti-CD19 Chimeric Antigen Receptor T Cell Therapy
https://ash.confex.com/ash/2021/webprogram/Paper149859.html
Anti-CD19 chimeric antigen receptor T (CART19) cell therapy has resulted in unprecedented outcomes in patients with relapsed/refractory B-cell malignancies, which led to the FDA approval for several indications. However, CART19 cell therapy is limited by the development of severe life-threatening toxicities, as well as by the limited rates of durable response. It has become apparent that myeloid cells contribute to the development of both CART cell toxicity and also to the inhibitory tumor microenvironment. We and others have identified that granulocyte-monocyte-colony-stimulating factor (GM-CSF) depletion results in decreased myeloid activation, reduced toxicities, and enhancement of CART19 cell therapy efficacy in pre-clinical models. Furthermore, we observed that GM-CSF knockout (GM-CSFk/o) in CART19 cells resulted in the improvement of their functions (in vitro and in vivo). These findings suggest that there is also a direct effect of GM-CSF on CART19 cells, which is independent of the GM-CSF impact on myeloid cell activation.
To further evaluate this, we first examined GM-CSF receptor alpha (GM-CSFRa) expression by flow cytometry on resting and activated CART19 cells (using FMC63-41BB?). When CART19 cells were stimulated with either anti-CD3/CD28 beads or lethally irradiated (120 Gy) CD19+ Nalm6 cells (B cell acute lymphoblastic leukemia cancer cell line), GM-CSFRa expression was upregulated upon both T cell receptor (TCR) (data not shown) and CAR stimulation (Figure 1A).
Having demonstrated that GM-CSFRa is significantly upregulated on stimulated CART19 cells, we aimed to determine the impact of GM-CSF neutralization (clinical-grade anti-GM-CSF antibody, lenzilumab, 10 µg/mL) versus GM-CSFRa blockade (research-grade antibody, 10 µg/mL) on CART19 cell function and CART cell-monocyte interactions. An IgG isotype antibody was used as a control antibody. Neither the GM-CSF neutralizing antibody, nor GM-CSFRa blocking antibody, had any impact on CART19 cell antigen-specific killing against the CD19+ JeKo-1 cells (mantle cell lymphoma cancer cell line), in the presence or absence of CD14+ monocytes (ratio 1:1:1) isolated by magnetic beads from healthy donors (Figures 1B-C).
Next, we compared the effects of GM-CSF neutralization versus GM-CSFRa blockade on CART19 cell antigen-specific proliferation. Here, CART19 cells were co-cultured with lethally irradiated CD19+ cell line JeKo-1 at 1:1 ratio in the presence of 10 µg/mL of the GM-CSF neutralizing antibody, increasing doses of the GM-CSFRa blocking antibody (10-100 µg/mL), or an IgG control. The absolute number of CART cells was measured by flow cytometry on day 5. GM-CSF neutralization did not affect CART19 cell proliferation, but GM-CSFRa blocking antibody significantly inhibited CART19 cell proliferation in a dose-dependent manner. Then, we assessed the effects of GM-CSF neutralizing antibody (20 µg/mL) versus GM-CSFRa blocking antibody (20 µg/mL) on CART19 cell antigen-specific proliferation in the presence of healthy donor monocytes (ratio 1:1:0.5) on day 3. Flow cytometric analysis revealed that GM-CSF neutralization, but not GM-CSFRa blockade, mitigated monocyte-suppression of CART19 antigen-specific proliferation (Figure 1E).
In summary, our findings indicate significant differences on CART cell functions and CART cell-monocyte interactions when a specific cytokine, GM-CSF, is neutralized compared to blocking its receptor. Further mechanistic studies are ongoing to assess the functions of GM-CSFRak/o and GM-CSFk/o CART cells.
$HGEN new ASH abstract shows that GM-CSF receptor blocking (i.e mavrilimumab) BUT not gm-csf neutralization (Lenzilumab) significantly inhibited CART19 cell proliferation
— Jerry Q*👁️🗨️ (@swandivr) November 5, 2021
Lenz > Mav (and others targeting gm-csf receptor) https://t.co/JKoTgtOBx3 pic.twitter.com/e0pow4Wtbf
Anyone who owns NRXP can sell it right now in afterhours trading. With RLFTF, you'll have to wait until tomorrow if you're planning on selling.
RLFTF/NRXP's aviptadil/Zyesami/RLF-100 got the decline from the FDA:
US Food and Drug Administration Declines Emergency Use Authorization for ZYESAMI® (aviptadil) for Patients with Critical COVID-19 with Respiratory Failure
https://www.nrxpharma.com/us-food-and-drug-administration-declines-emergency-use-authorization-for-zyesami-aviptadil-for-patients-with-critical-covid-19-with-respiratory-failure/
-NRx Pharmaceuticals Has Requested a Type A Meeting with US Food and Drug Administration (FDA) to Include Treating Physicians and Patients
-FDA Commits to Working with NRx to Develop ZYESAMI®
-ZYESAMI Clinical Trials Funded by the US National Institutes of Health and BARDA Continue and Advance Towards Enrollment in Brazil and Europe
RADNOR, Pa., Nov. 4, 2021 /PRNewswire/ — NRx Pharmaceuticals (NASDAQ: NRXP), a clinical-stage biopharmaceutical company (NRx), today announced that the US Food and Drug Administration (FDA) has declined to issue an Emergency Use Authorization (EUA) for ZYESAMI® (aviptadil). The FDA stated that it was unable to issue the EUA at this time due to insufficient data regarding the known and potential benefits of the medicine and the known and potential risks of ZYESAMI in patients suffering from Critical COVID-19 with respiratory failure. In its letter, the FDA noted that so far, it has reviewed safety in only 131 randomized patients treated with ZYESAMI. NRx will attempt to coordinate a review by the FDA of the 150 or more additional patients already treated with ZYESAMI in the NIH ACTIV-3b trial. Last week, the study’s Data Safety and Monitoring Board reviewed the ongoing NIH ACTIV-3b trial and found no new safety issues.
“Yesterday, more than 1,500 Americans and many more around the world died lonely deaths from COVID-19, isolated from their loved ones in ICUs despite widespread vaccination and currently-available approved treatments,” said Jonathan Javitt, MD, MPH, Chief Executive Officer and Chairman of the Board of NRx. “We believe that ZYESAMI has demonstrated a high degree of safety and a two-fold increase in the odds of surviving the ICU. Patients treated at the nation’s top hospitals with ZYESAMI had a four-fold increase in odds of survival. We will work actively with the FDA to deliver the data it has requested so that we may offer those patients another chance at life, and have asked the FDA for a Type A meeting that will include the experience of physicians who have witnessed the effects of our medicine firsthand and the experience of patients who are alive today because they were given one last chance at life. In the meantime, we are actively engaged with regulators and potential partners on multiple continents to advance ZYESAMI towards regulatory approval. Now that we have completed the Chemical and Manufacturing Controls (CMC) required for traditional approval pathways, we will move towards filing for accelerated approval based on the unexpectedly strong biomarker results seen in our two clinical trials.”
Last week, NRx requested a Type A meeting with FDA officials, a request endorsed by key study investigators, to discuss the development of ZYESAMI. In the meantime, ZYESAMI remains available upon a physician’s request under Federal and state Right to Try laws for those patients who meet the legal criteria for Right to Try.
The US National Institutes of Health has enrolled more than 300 patients in the ACTIV-3b trial. a confirmatory study that randomizes patients with COVID-19 respiratory failure to ZYESAMI® vs. Veklury® (remdesivir) and placebo in a factorial design trial (NCT04843761). A second nationwide trial to determine if similar benefits may be achieved in critically ill patients with inhaled ZYESAMI is being conducted on the I-SPY platform, maintained by the Quantum Leap Healthcare Collaborative. This week, the Data Safety Monitoring Board of the NIH ACTIV-3b trial reported that no new drug-related Serious Adverse Events were seen and approved the trial for continued enrollment. NRx also continues to study the effect of inhaled ZYESAMI in patients with severe but not critical COVID-19 in a placebo-controlled trial that aims to demonstrate the ability of ZYESAMI to keep patients from requiring intensive care.
US Food and Drug Administration Declines Emergency Use Authorization for ZYESAMI® (aviptadil) for Patients with Critical COVID-19 with Respiratory Failure
https://www.nrxpharma.com/us-food-and-drug-administration-declines-emergency-use-authorization-for-zyesami-aviptadil-for-patients-with-critical-covid-19-with-respiratory-failure/
-NRx Pharmaceuticals Has Requested a Type A Meeting with US Food and Drug Administration (FDA) to Include Treating Physicians and Patients
-FDA Commits to Working with NRx to Develop ZYESAMI®
-ZYESAMI Clinical Trials Funded by the US National Institutes of Health and BARDA Continue and Advance Towards Enrollment in Brazil and Europe
RADNOR, Pa., Nov. 4, 2021 /PRNewswire/ — NRx Pharmaceuticals (NASDAQ: NRXP), a clinical-stage biopharmaceutical company (NRx), today announced that the US Food and Drug Administration (FDA) has declined to issue an Emergency Use Authorization (EUA) for ZYESAMI® (aviptadil). The FDA stated that it was unable to issue the EUA at this time due to insufficient data regarding the known and potential benefits of the medicine and the known and potential risks of ZYESAMI in patients suffering from Critical COVID-19 with respiratory failure. In its letter, the FDA noted that so far, it has reviewed safety in only 131 randomized patients treated with ZYESAMI. NRx will attempt to coordinate a review by the FDA of the 150 or more additional patients already treated with ZYESAMI in the NIH ACTIV-3b trial. Last week, the study’s Data Safety and Monitoring Board reviewed the ongoing NIH ACTIV-3b trial and found no new safety issues.
“Yesterday, more than 1,500 Americans and many more around the world died lonely deaths from COVID-19, isolated from their loved ones in ICUs despite widespread vaccination and currently-available approved treatments,” said Jonathan Javitt, MD, MPH, Chief Executive Officer and Chairman of the Board of NRx. “We believe that ZYESAMI has demonstrated a high degree of safety and a two-fold increase in the odds of surviving the ICU. Patients treated at the nation’s top hospitals with ZYESAMI had a four-fold increase in odds of survival. We will work actively with the FDA to deliver the data it has requested so that we may offer those patients another chance at life, and have asked the FDA for a Type A meeting that will include the experience of physicians who have witnessed the effects of our medicine firsthand and the experience of patients who are alive today because they were given one last chance at life. In the meantime, we are actively engaged with regulators and potential partners on multiple continents to advance ZYESAMI towards regulatory approval. Now that we have completed the Chemical and Manufacturing Controls (CMC) required for traditional approval pathways, we will move towards filing for accelerated approval based on the unexpectedly strong biomarker results seen in our two clinical trials.”
Last week, NRx requested a Type A meeting with FDA officials, a request endorsed by key study investigators, to discuss the development of ZYESAMI. In the meantime, ZYESAMI remains available upon a physician’s request under Federal and state Right to Try laws for those patients who meet the legal criteria for Right to Try.
The US National Institutes of Health has enrolled more than 300 patients in the ACTIV-3b trial. a confirmatory study that randomizes patients with COVID-19 respiratory failure to ZYESAMI® vs. Veklury® (remdesivir) and placebo in a factorial design trial (NCT04843761). A second nationwide trial to determine if similar benefits may be achieved in critically ill patients with inhaled ZYESAMI is being conducted on the I-SPY platform, maintained by the Quantum Leap Healthcare Collaborative. This week, the Data Safety Monitoring Board of the NIH ACTIV-3b trial reported that no new drug-related Serious Adverse Events were seen and approved the trial for continued enrollment. NRx also continues to study the effect of inhaled ZYESAMI in patients with severe but not critical COVID-19 in a placebo-controlled trial that aims to demonstrate the ability of ZYESAMI to keep patients from requiring intensive care.
Below is an abstract that Humanigen just posted on Twitter. The abstract is for a talk that will be given on December 11th. It seems like it is an announcement for their upcoming CAR-T trial where lenz will be paired with all 3 currently available CAR-T therapies.
A Phase 2/3 Randomized, Placebo-Controlled, Open-Label, Multi-Center Trial of Lenzilumab to Improve the Safety and Efficacy of CAR-T Cell Therapy in Adults with Relapsed or Refractory Large B-Cell Lymphoma (The SHIELD Study)
https://ash.confex.com/ash/2021/webprogram/Paper153987.html
Background: Diffuse large B-cell lymphoma (DLBCL) is the most common aggressive sub-type of non-Hodgkin’s lymphoma (Liu, et al. Am J Hematol 2019). All three approved CD19-directed CAR-T therapies (axicabtagene ciloleucel, tisagenlecleucel, lisocabtagene maraleucel) are associated with toxicities, including cytokine release syndrome (CRS) and immune effector cell-associated neurotoxicity syndrome (ICANS) that can be severe, resulting in non-relapse mortality, ICU admission, and significant non-drug related health resource utilization which represent barriers to access and adoption (Nabhan, et al. J Clin. Pathway 2017). Studies have shown that early elevation of granulocyte-macrophage colony-stimulating factor (GM-CSF) levels 1-day post CAR-T infusion correlates with severe ICANS (Rossi, et al. EMA Workshop 2016), which is a negative prognostic factor for overall survival (Karschnia, et al. Blood 2019). It has been proposed that upon contact with the tumor, CAR-Ts produce GM-CSF, which serves as a communication conduit between the specific immune response of CAR-T and the off-target inflammatory cascade produced by myeloid lineage cells, causing myeloid cells to expand and promote the production of other downstream proinflammatory chemokines (MCP-1, IL-8, IP-10), cytokines (IL-1, IL-6), and other markers of systemic inflammation (CRP, Ferritin) (Sterner, et al. Blood 2019). Moreover, IL-6 is predominately released by tumor cells in a contact-independent manner (Barrett et al. Blood 2016), which helps explain why the prophylactic administration of tocilizumab is not effective in reducing the overall incidence of CRS or ICANS, as this cytokine is downstream in the inflammatory cascade. Further, the prophylactic use of tocilizumab has been shown to increase the incidence of all-grades and grade >3 ICANS (Locke, et al. Blood 2017). Lenzilumab is a novel Humaneered® monoclonal antibody that neutralizes GM-CSF and has demonstrated potential to reduce the hyper-immune mediated cytokine storm induced by SARS-CoV-2 infection and significantly improve the likelihood of survival without ventilation in hospitalized COVID-19 patients, as reported in the LIVE-AIR phase 3 study (Temesgen, et al. medRxiv 2021). Methods: Eligible patients are adults (≥ 18 y) with relapsed or refractory DLBCL or are chemorefractory. Prior therapy must have included an anti-CD20 monoclonal antibody and an anthracycline-containing regimen. Patients will undergo leukapheresis and may receive optional corticosteroid bridging therapy. Patients will then receive lymphodepleting chemotherapy on Days ?3 to ?5 followed by infusion of lenzilumab on Day 0, 6-hrs prior to CAR-T infusion. Approximately 40 accredited sites across the U.S. certified to administer the three commercially available CAR-Ts have been engaged to participate in this 2-part study. In Part 1, all patients will receive lenzilumab 1800mg via a single 2-hour infusion prior to CAR-T administration. The objective of Part 1 is to evaluate the optimal regimen and assess whether a second dose of lenzilumab post-CAR-T infusion is required. A translational assessment of GM-CSF axis suppression, levels of CAR-T cells in blood, other inflammatory markers and lenzilumab PK/PD will be evaluated, along with the incidence and severity of CRS and ICANS, objective response rates (ORR) and rates of complete response (CR) by Day 28 to select the optimal regimen to carry forward into Part 2. The objective of Part 2 is to confirm whether lenzilumab can improve the toxicity and tolerance of CAR-T while maintaining or improving efficacy and durability of response. Up to 250 patients will be randomized 1:1 to receive lenzilumab or placebo with CAR-T per standard of care. The primary endpoint of the study is incidence of grade >2 CRS and/or ICANS by Day 28, with a key secondary endpoint of CR at 6-months in patients without grade ≥ 2 CRS and/or ICANS at Day 28 (Toxicity-free CR). This design and sample size yields 90% power to detect a 50% reduction in the primary outcome measure. Secondary endpoints include incidence of all grades and grade >3 CRS and/or ICANS, respectively; ORR and CR at 1, 3, 6, 12 months; durability of CR; progression-free survival, overall survival and health related quality of life using validated patient reported outcome measures. In addition, the study will explore the CRS and ICANS grading criteria that have been utilized with each of the approved CAR-Ts.
@EricTopol
New @NEJM
— Eric Topol (@EricTopol) November 3, 2021
The impact of waning immunity in the Moderna COVE vaccine trial over time and with 97% Delta variant https://t.co/q2vhymCvEr pic.twitter.com/EpPp49PEMx
An ex-RLFTF board member wrote an article to the FDA questioning why lenzilumab, leronlimab, and aviptidil haven't received EUAs.
Warning: article is very low quality. Leronlimab is misspelled Leronlizumab.
DEATH BY FDA
https://investorsprism.com/death-by-fda/
By Thomaz Burckhardt
On October 29, 2021, 2025 Americans died from COVID-19. Although the worst times of the pandemic seem to be over, still too many people are dying and many more linger in ICUs on ventilators, on their way to a lonely death by suffocation. Today, the FDA advises there is limited availability of ventilators, and there are US cities that have run out of morgue space. Tragically, half of these lives, perhaps even more could be saved by investigational drugs currently before the FDA, were those drugs to be granted Emergency Use Authorization (EUA). Congress enacted the EUA law specifically so that FDA would immediately deploy drugs that are safe and “may be effective” in the face of a public health emergency. The COVID-19 public health emergency was declared by the Secretary of Health and Human Service in March 2020 and has been unrelenting since that time.
The concept of EUA has been proven to be highly efficient and successful with the development of vaccine compounds, where in record time several vaccine candidates have been developed, tested, authorized, and eventually distributed across the globe to fight the pandemic through mass-immunization. The question remains to me, why this powerful tool has not been applied to the same extent with highly promising therapeutic cure candidates? National Institutes of Health (NIH) Director Dr. Francis Collins confirmed in a public forum that three such drugs from small, innovative biotech companies, Leronlizumab, Lenzilumab, and Aviptadil are among the few viable candidates for treating COVID-19 of the more than 750 compounds screened by the National Institutes of Health. Yet, inexplicably, despite clear early evidence of efficacy Leronlizumab and Lenzilumab have been denied EUA and Aviptadil has been awaiting an EUA decision already for 150 days.
For the FDA to deny EUA to drugs that show any reasonable promise of saving life is highly questionable in a time of widespread loss of life. The FDA has a legal and moral obligation to weigh benefits and risks according to society’s tolerance for such risks. However, the refusal to grant EUA to these innovative drugs from small companies is wholly out of sync with FDA’s grant of EUA to minimally effective drugs from Big Pharma. Remdesivir has been deemed ineffective for all but the earliest COVID cases by the World Health Organization and other regulators, yet it was approved by the FDA. Tocilizumab has shown only a four percentage point mortality benefit at best. Yet, highly innovative drugs with no reported Serious Adverse Events, that have shown 2, 3, and even 4-fold advantages in survival languish at the FDA with endless demands for more data.
A petition was launched on change.org to demand the FDA grant EUA to Aviptadil and it has received nearly 5,000 signatures: https://chng.it/4jRjfq6MYV People worldwide are threatened by an enemy far more dangerous than any faced on the battlefield while the world looks to the US and the FDA for leadership thru this crisis. More Americans have been killed by COVID than by all of America’s foreign wars.
Every American should be writing their elected representatives and demanding that FDA make available all emergency use medicines that have shown a statistically-significant 50% or greater survival benefit in at least one clinical trial. Congress should threaten to bypass the FDA and legislatively approve EUA for drugs that demonstrate a 100% or greater survival benefit, such as Aviptadil, which it has, according to a medical paper published in the Journal of Infectitious Diseases and Treatment led by Dr. J. Georges Youseff. The question must be answered by the FDA as to why it is simply unwilling to act in a manner that saves the lives of Americans? As every pharmaceutical TV commercial advertising cures for common diseases reminds us, many of these drugs come with serious safety risks and side effects; but we choose to take these drugs to improve our quality of life. I imagine few Americans would turn down the chance to live, even if the drug in question might show some unknown safety risk when used more broadly.
Until February this year, I was a member of the Board of Directors of Swiss based Relief Therapeutics SA (symbol: RLFTF and RLF.SW) which owns the IP for the formulation of Aviptadil. For disclosure purposes I remain an insignificant shareholder of Relief. Relief has been collaborating on the development of Aviptadil with NRX Pharmaceuticals, Inc. (symbol: NRXP), a company which I have no affiliation. NRX Pharmaceuticals has been mandated to manage the submission to the FDA and the ensuing review process. I am writing this article to bring awareness to the availability of a drug which can save lives and to make elected officials as well as patients and their relatives aware of a potential solution for the most serious of Covid cases.
Disclaimer:
This article was prepared by Thomaz Burckhardt in his personal capacity. Mr. Burckhardt is not an affiliate of InvestorsPrism or any related entities, and the opinions and assertions expressed in this article are the author’s own and do not necessarily reflect those of InvestorsPrism or any related people or entities. Neither InvestorsPrism or any related people or entities were compensated in any way for publication of this article.
Here are some lenzilumab science-related articles for those wanting to do some due diligence. Lenzilumab is a GM-CSF inhibitor. The "M" in GM-CSF is macrophage.
Covid
https://www.bbc.com/news/health-56352128
https://immunology.sciencemag.org/content/6/57/eabg9873
https://directorsblog.nih.gov/2021/04/13/mapping-severe-covid-19-in-the-lungs-at-single-cell-resolution/
https://www.thelancet.com/journals/lanres/article/PIIS2213-2600(20)30267-8/fulltext
https://www.nature.com/articles/s41586-021-03569-1
https://www.pharmaceutical-technology.com/news/humanigen-lenzilumab-improves-survival/
CAR-T
https://www.nature.com/articles/s41408-021-00459-7
https://www.nature.com/articles/s41421-021-00255-4
https://www.targetedonc.com/view/lenzilumab-plus-axi-cel-achieves-responses-in-100-of-patients-with-dlbcl-with-limited-toxicity-in-small-study
https://www.healio.com/news/hematology-oncology/20210422/lenzilumab-before-cart-induces-high-response-rates-without-severe-toxicities
HGEN's share price is going to skyrocket when the next catalyst arrives. Hopefully, peer review comes out this week. I wouldn't be surprised is the MHRA is waiting for the peer review before making a decision.
Humanigen Announces Participation and Presentation at Multiple Conferences in November
https://ir.humanigen.com/English/news/news-details/2021/Humanigen-Announces-Participation-and-Presentation-at-Multiple-Conferences-in-November/default.aspx
BURLINGAME, Calif.--(BUSINESS WIRE)-- Humanigen, Inc. (Nasdaq: HGEN) (“Humanigen”), a clinical-stage biopharmaceutical company focused on preventing and treating an immune hyper-response called ‘cytokine storm,’ announced that management will present and participate at multiple investors conferences in November 2021. Details of the conferences are as follows:
Credit Suisse 30th Annual Healthcare Conference
Cameron Durrant, Chairman & CEO, will provide a corporate presentation at 8:00am EST on November 9, 2021. A livestream will be available via the link below and a webcast link to a recording of the event will be posted to the “Events and Presentations” section of Humanigen’s investor relations website after the event.
Webcast: https://kvgo.com/cs-2021-healthcare-conf/humanigen-inc-november
The webcast will be archived for up to one year under the Investor Relations section of the company’s website at www.ir.humanigen.com
Jefferies London Healthcare Conference
Timothy Morris, COO and CFO, will make a corporate presentation at 12:40pm EST on November 17, 2021. A livestream will be accessible via the link below and a webcast link to a recording of the event will be posted to the “Events and Presentations” section of Humanigen’s investor relations website after the event.
Webcast: https://wsw.com/webcast/jeff201/hgen/1823004
The webcast will be available for 90 days under the Investor Relations section of the company’s website at www.ir.humanigen.com
Reuters Total Health Virtual Global Conference
Cameron Durrant, Chairman & CEO, will participate in the Breakthrough Medical Innovation portion of the Reuters Total Health Global Conference on November 18, 2021. For more information, please access the event agenda at https://reutersevents.com/events/healthcare/conference-agenda.php