A Phase 1 safety and imaging trial of radio-labeled ifabotuzumab in recurrent glioblastoma multiforme, a particularly aggressive and deadly form of brain cancer, has fully enrolled at two centers in Australia, the Olivia Newton-John Cancer Research Institute (“ONJCRI”) in Melbourne and the Queensland Institute for Medical Research in Brisbane and interim data have been presented at both American Association for Cancer Research (“AACR”) and Society for Neuro-Oncology (“SNO”) in 2019, with final data expected to be presented in 2021. The lead investigators at the ONJCRI, are also evaluating an antibody-drug conjugate (“ADC” or “ADCs”) based on ifabotuzumab in solid tumor models. The Phase 1 clinical trial has enrolled all 12 patients. Preliminary imaging data reported at AACR and at SNO demonstrated that administration of ifabotuzumab resulted in rapid, specific targeting of GBM tumors in all patients. Whole body bio-distribution imaging demonstrated no normal tissue uptake of the antibody. Post-treatment MRI scans showed predominant T2/Flair changes which were consistent with treatment effect on tumor vasculature. We continue to explore partnering opportunities and seek governmental and institutional grants to facilitate the further development of ifabotuzumab in a range of cancer types.



We are in discussions with separate and various parties and may initiate partnerships to pursue some of the following activities:



· Complete the on-going clinical study and preclinical studies with various ADCs that are based on ifabotuzumab (in partnership with leading centers in Australia); and
· Develop bi-specific antibodies based on ifabotuzumab.


Centers in Australia have worked independently on IIIA4, the murine antibody parent of ifabotuzumab, as an ADC in mice and a December 2018 publication in the journal ‘Cancers’ showed that in mice engrafted with GBM, treatment with an ADC based on IIIA4 showed significantly improved survival.

Gene-edited CAR-T Therapies using GM-CSF Gene Knockout



We believe that our GM-CSF knockout gene-editing CAR-T platform has the potential to create next-generation CAR-T therapies that improve the efficacy and safety profile of CAR-T therapy via gene-edited CAR-T cells which can be engineered to lack the ability to produce GM-CSF, thereby avoiding any efficacy/toxicity linkage and potentially preserving and improving upon the benefits of the CAR-T therapy while altogether avoiding its serious and potentially life-threatening side-effects.



We are advancing our GM-CSF knockout gene-editing CAR-T platform through the Mayo Agreement that we entered into in June 2019 with the Mayo Foundation. Under the Mayo Agreement, we have in-licensed certain technologies that we believe may be used to create CAR-T cells lacking GM-CSF expression through various gene-editing tools including CRISPR-Cas9. The Mayo Agreement broadened our leadership position in the GM-CSF neutralization space and expanded our discovery platform aimed at improving CAR-T therapy to include gene-edited CAR-T cells.



Preclinical data indicates that GM-CSF gene knockout CAR-T cells show improved overall survival compared to GM-CSF-expressing CAR-T cells in addition to the expected benefits of reduced serious side-effects associated with CAR-T therapy. We are establishing a platform of next-generation combinatorial gene knockout CAR-T cells that have potential to be applied across both autologous and allogeneic approaches and we are also investigating multiple CAR-T cell designs using precise dual and triple gene editing to significantly enhance the anti-tumor activity while simultaneously preventing CAR-T therapy induced toxicities. Through targeted gene expression and modulating cytokine activation signaling, we may be able to increase the proportion of fitter T-cells produced during expansion, increase the proliferative potential, and inhibit activation induced cell death, thereby improving the cancer killing activity of our engineered CAR-T cells thereby making them more effective and safer in the treatment of cancers. Preclinical data indicates that CAR-T cells express GM-CSF and signal through GM-CSF receptors upon activation in an autocrine fashion. GM-CSF knockout CAR-T cells are not able to signal through this pathway which results in a gene expression profile distinct from GM-CSF-expressing CAR-T cells after in vitro expansion. This includes lower levels of Fas expression which may indicate a less differentiated state of the CAR-T cells. These data were presented at the 2019 ASH annual meeting and the abstract was the recipient of an Abstract Achievement Award. We continue to explore the phenotypic pattern of GM-CSF knockout CAR-T cells relative to GM-CSF-expressing CAR-T cells and possible implications for improved safety and efficacy. We plan to continue development of this technology in combination approaches that could add to the observed efficacy benefits of current generation CAR-T products.

We plan to continue development of this technology in combination approaches that could add to the observed efficacy benefits of current generation CAR-T products. In addition, we anticipate that our GM-CSF knockout gene-editing CAR-T platform may be a future backbone for controlling the serious side-effects that hamper CAR-T therapy that lead to serious and sometimes fatal outcomes for patients as a result of the CAR-T therapy itself.



CAR-T Overview



As of the date of this filing, four CAR-T therapies that have been approved by the FDA, Gilead/Kite’s Yescarta, and Tecartus, Novartis’s Kymriah and Bristol Myers Squibb’s Breyanzi (lisocabtagene maraleucel; liso-cel), seek to treat forms of B-cell cancers such as various types of Non-Hodgkin Lymphoma (“NHL”), including DLBCL and acute lymphoblastic leukemia (“ALL”) and Mantle Cell Lymphoma (“MCL”) that are refractory or in second or later stage relapse. Although patients suffering from these aggressive cancers frequently undergo multiple treatments, including chemotherapy, radiation and targeted therapy including stem cell transplants, the five-year survival rate has been severely limited and patients who do not respond to, or have relapsed following at least two courses of standard treatment, have no other treatment options and a very poor outcome. According to the Surveillance, Epidemiology, and End Results (“SEER”) program of the National Cancer Institute, which is a source of epidemiologic information on the incidence and survival rates of cancer in the U.S., it is estimated that up to 10,000 patients per year in the U.S. with relapsed or refractory (r/r) B-cell NHL and ALL who have failed at least two prior systemic therapies may be eligible for CAR-T therapy. In addition, if CAR-T therapy is approved as an earlier second line option versus stem cell transplantation, an additional 10,000 to 12,000 patients may be eligible for treatment. However, this is predicated on improving the benefit-to-risk profile of CAR-T therapy, addressing the severe life-threatening adverse events currently associated with these agents and breaking the efficacy/toxicity linkage.



The FDA-approved CAR-T therapies have demonstrated the effectiveness of using targeted immuno-cellular engineering to cause a patient’s own T-cells to fight certain cancers that have not responded to standard therapies. T-cells are often called the “workhorses” of the immune system because of their role in coordinating the immune response and killing cells infected by pathogens and cancer cells. As depicted below, each of the FDA-approved CAR-T therapies is currently a one-time treatment that involves multiple steps:



· Harvesting white blood cells from the patient’s blood, also known as apheresis;
· Engineering T-cells within this population to express cancer-specific receptors;
· Increasing and purifying the number of genetically re-engineered T-cells; and
· Infusing the functional cancer-specific T-cells back into the patient to allow for expansion and targeting the cancer cells.


Kymriah, Yescarta and Tecartus each received FDA approval for adults with r/r DLBCL on the basis of one pivotal, single-arm Phase 2 study (ZUMA-1, in the case of Yescarta, and ZUMA-2, in the case of Tecartus) which served as the pivotal registration trial for each product in this indication, a markedly accelerated process that indicates the FDA’s view of the strong potential of these novel CAR-T therapy treatments to address an unmet need and improve patient outcomes. The number of evaluable patients in the studies that led to FDA approval for Kymriah, Yescarta and Tecartus in large B-cell lymphoma was 68, 101 and 68 respectively. Moreover, Kymriah also received FDA approval for the treatment of pediatrics and adolescents with relapsed refractory (“r/r”) acute lymphoblastic leukemia (“ALL”) based on a single phase 2 study. In the Kymriah registration study in the DLBCL population, 160 patients were enrolled and 68 were evaluable.



ZUMA-1, the single Phase 2 study that led to the FDA approval of Yescarta in r/r DLBCL, showed similarly positive results. The study enrolled 111 patients (101 were evaluable) with large B-cell lymphoma at advanced stages despite having undergone at least two previous treatments, with approximately 20% of patients already having undergone a stem cell transplant. The CR rate within three months of CAR-T treatment, given as a single infusion, was 58%, which dropped to 46% after six months. The CR rate after two years of CAR-T treatment, given as a single infusion, has been reported as 37%.



ZUMA-2, a single-arm, open-label Phase 2 study that led to the FDA approval of Tecartus for treatment of adult patients with relapsed or refractory mantle cell lymphoma (MCL), enrolled a total of 74 patients (68 were evaluable) that had received BTK inhibitor therapy previously. In an intention-to-treat analysis of all 74 patients enrolled, 85% of patients were reported to have had an objective response, and 59% had a complete response (https://www.nejm.org/doi/10.1056/NEJMoa1914347)

This lecture will focus on two areas: the first, on the regulatory context of Operation Warp Speed and a corresponding "snapshot" of the COVID-19 therapeutic clinical trials from the Clinical Research Organizations (CRO's) that run them. COVID-19 vaccines have been developed in record time. Despite this, the process has ensured that they meet the quality, safety, and efficacy standards that the public have come to expect from prophylactic vaccines given to healthy people. Two mRNA vaccines received Emergency Use Authorization in December 2020, and more are on the horizon.

The second part of this lecture will bring into context the pivotal strategic thinking of C-level executives in the biotechnology and the CRO industry when faced with a global pandemic and the decision-making process considering the critical need of FDA expedited timelines, potential need for expanded access for emergency use, and clinical site expansion to meet the endpoints of the registered clinical study. This analysis will incorporate two commercial case studies in the public domain, Humanigen (NASDAQ: HGEN) based in Burlingame, California, USA as well as DURECT (NASDAQ: DRRX) in Cupertino, California, USA. Current research being conducted at Humanigen has a focus on acute respiratory distress syndrome (ARDS) while DURECT seeks to understand multi-organ failure resulting from COVID-19.

Nate Hughes, MPH ‘12, MPP, M.Phil, has been working in the life science industry for almost two decades, and is a writer and public speaker. From 2015-2016, he served as a board member on the Corporate Governance Roundtable for the American College of Preventive Medicine. In 2018, he facilitated the instalment of Real-Time Scheduling for Kymriah for NOVARTIS in Morris Plains, NJ site, the very first US approved CAR-T therapy, among other global deals. In March, 2020, Hughes facilitated the Humanigen Covid-19 mAb Phase 3 study (including site expansion to LATAM), and facilitated the BD side of several deals in the CRO space, including in cell & gene therapy, rare renal, and rare liver disease. He received his Bachelor’s degree from The University of California at Berkeley, his M. Phil degree from Trinity College, Dublin, a MPP from The UCLA Luskin School, and a MPH from The Johns Hopkins Bloomberg School of Public Health.

Peter Marks received his graduate degree in cell and molecular biology and his medical degree at New York University and completed Internal Medicine residency and Hematology/Medical Oncology training at Brigham and Women’s Hospital in Boston. He has worked in academic settings teaching and caring for patients and in industry on drug development. He joined the FDA in 2012 as Deputy Center Director for CBER and became Center Director in January 2016.

Three key considerations will make achieving herd immunity against COVID-19 challenging. First, vaccines will have a reduced effect on preventing infection from the B.1.351 variant. Moderna and Pfizer vaccines have an overall effectiveness against symptomatic disease of approximately 95% for wild-type variants, whereas adenovirus vector vaccines, such as the Janssen/Johnson & Johnson vaccine, have effectiveness closer to 70%. Evidence on vaccine efficacy for preventing infection, however, comes only from 1 group in the AstraZeneca trial that showed 55% protection against infection as measured through weekly nasal swabs vs 70% protection for symptomatic disease.2 Furthermore, for the 3 vaccines tested against the B.1.351 variant, Janssen, Novavax, and AstraZeneca reported effectiveness estimates for symptomatic disease of 57%,3 49%,4 and a statistically nonsignificant percentage, respectively. If the B.1.351 variant becomes dominant, a simple calculation suggests that the aggregate effectiveness of vaccines for preventing B.1.351 transmission in the US could be only 50% (ie, based on current effectiveness of 90% to prevent symptomatic disease × 20% reduction of efficacy for preventing infection compared with symptomatic disease and assuming an average reduction in efficacy for B.1.351 of 33% [excluding the statistically insignificant protection from the AstraZeneca vaccine]).

It is not clear whether COVID-19 will become a chronic seasonal disease. There is too much uncertainty about the probability and frequency of emergence of new variants, the reduction in vaccine efficacy for each variant, the critical question of cross-variant immunity, and the consistency of safe human behavior. However, the prospect of persistent and seasonal COVID-19 is real. If immunity from infection for the same SARS-CoV-2 variant or vaccine-derived immunity wanes, the prospect would increase further. There is much to learn in the coming months about variants, vaccines, and immunity. Recurrent seasonal COVID-19 could require both health system change and profound cultural adjustment for the life of high-risk individuals in the winter months. There is an urgent need to prepare for such a scenario by aligning surveillance, medical response, public health response, and socioeconomic programs.

Dr. Pantginis is a Managing Director of Equity Research at H.C. Wainwright whose research focuses on the healthcare sector. Dr. Pantginis conducted more than seventeen years of healthcare equity research.
Prior to joining H.C. Wainwright, Dr. Pantginis worked as a Senior Research Analyst and Head of Biotechnology Research at ROTH Capital Partners. Dr. Pantginis also held senior positions at Merriman, Canaccord Adams, Commerce Capital Markets, JBHanauer and Ladenburg. Prior to his equity research career, Dr. Pantginis worked at Regeneron Pharmaceuticals, where he founded the Retroviral Core Facility.
Dr. Pantginis’ educational background includes both a Ph.D. and an M.S. in molecular genetics from the Albert Einstein College of Medicine as well as an MBA from Pace University.

Factors driving usage
It would be significant if the Phase III results match the interim lenzilumab results, said Badley, adding it would see wide uptake if approved. The lenzilumab study specifically allows SOC. According to interim Phase III results, which were released on 6 November 2020, 78% of trial participants were on Veklury or dexamethasone. The SOC in the mavrilimumab study is not defined on ClincalTrials.gov.

Despite standard treatments like Veklury and dexamethasone, the greatest efficacy gain may be seen in patients who require oxygen and are progressing rapidly, but are not yet intubated, as well as those who may have been intubated within the last 48 hours, said Abbate. Veklury and dexamethasone are now considered part of SOC, which means it would be difficult to study any drug without those as well, said Gotur. While dexamethasone is a broad immunosuppressant, anti-GM-CSF antibodies provide a more targeted approach, Gotur added.

Continued hyperinflammation indicated by persistent fever and failure to improve under oxygenation would also indicate the potential for treatment with anti-GM-CSF antibodies, said Abbate. Biomarkers like C-reactive protein and ferritin give a snapshot of CRS but do not specify when it started, so a combination of clinical status and a biomarker study is essential to understand CRS in Covid-19, said Gotur. Badley noted a combination of clinical indicators like fevers, reduced blood pressure, shortness of breath and the biomarkers as being indicative of when treatment should begin.

While there has been mixed data on other immunomodulators like anti-interleukin-6 (anti-IL-6) antibodies, including Roche’s Actemra (tocilizumab), one of the potential side effects of anti-IL-6 antibodies is neutropenia and potential suppression of T cell response, leading to opportunistic infections, said Abbate. This is also observed with their chronic use in conditions other than Covid-19. While anti-GM-CSF antibodies have not been studied as much, early data has indicated they are safe, he added. Mavrilimumab was found to be well tolerated with no infusion reactions, and no treatment-emergent adverse events were attributed to lenzilumab, as noted in previous data. There is a theoretical risk of secondary infections, but more data beyond what is currently available is needed to draw conclusions, said Hudock. Additionally, anti-GM-CSF antibodies are not associated with any liver or renal toxicity because they do not affect monocytes or neutrophils, which cause those toxicities, said Hudock. If both drug classes are authorised, their adverse event profile, cost and ease of use may drive therapy choice, said Abbate.

Manasi Vaidya and Sean Rai-Roche are Senior Reporter and Reporter for Clinical Trials Arena parent company GlobalData’s investigative journalism team. A version of this article originally appeared on the Insights module of GlobalData’s Pharmaceutical Intelligence Center. To access more articles like this, visit GlobalData.

Humanigen’s and Kiniksa’s anti-GM-CSF antibodies likely to garner a place for nonventilated Covid-19 patients; mixed views on ideal timepoint to measure clinical improvements

The coronavirus crisis was a huge catalyst for biotech companies, as the world struggled to find a cure for the disease and investors flocked to promising biotech companies working on COVID-19 vaccines. Famous biotech players like Moderna and Novavax Inc. soared to new highs as their vaccines started to show solid results. But relatively unknown biotech stocks like CytoDyn, Equillium Inc. and Humanigen Inc. also received a lot of attention as the world suddenly realized that its apparent progress in healthcare is not enough, and that we still have major existential problems to resolve.

FDA tells Merck to show more data for its OncoImmune COVID-19 drug as EUA pushed back
by Ben Adams | Feb 26, 2021 3:55am

Merck will no longer be able to supply an experimental COVID-19 drug from its $425 million buyout of OncoImmune to the U.S. government under a $356 million contract as the FDA has demanded more data, delaying its supply.

The U.S. Big Pharma, which has already ditched a vaccine program for COVID-19 from a recent buyout, has now run into trouble with a COVID drug from its November acquisition of OncoImmune.

This med, now known as MK-7110 (formerly CD24Fc) was initially used in allogeneic hematopoietic stem-cell transplant patients. But the biotech believed it could be used to help certain COVID-19 patients, and, as evidence of the effect of SARS-CoV-2 accrued, OncoImmune spied an opportunity to use CD24Fc to treat the sickest COVID-19 patients.


OncoImmune began a clinical trial in April to test the theory that CD24Fc fortifies an innate immune checkpoint against excessive inflammation.

This was enough to grab the attention of Merck, which spent $425 million to buy the company and the drug late last year, with OncoImmune later reporting top-line findings from an interim efficacy analysis of a phase 3 study of 203 participants (75% of the planned enrollment) showing that selected hospitalized patients with COVID-19 treated with a single dose of MK-7110 showed a 60% higher probability of improvement in clinical status compared with placebo, as defined by the protocol.

The risk of death or respiratory failure was reduced by more than 50%. Merck says full results from this phase 3 study, “which were consistent with the topline results,” were seen by the company this month.


Merck also signed an agreement with the U.S. government in December last year worth $356 million for a manufacturing and supply deal of around 60,000 to 100,000 doses of MK-7110 by the end of June.

But, now, there’s a major snag. In a 10-k filing with the Securities and Exchange Commission on Thursday, Feb. 25 (and not via a press release), the Big Pharma said: “Merck received feedback from the FDA that additional data, beyond the study conducted by OncoImmune, would be needed to support a potential EUA application. Based on this FDA feedback, Merck no longer expects to supply the U.S. government with MK-7110 in the first half of 2021.”

Merck said it is “actively working with FDA to address the agency’s comments.” It did not give an updated timeline for the supply deal nor the emergency use authorization process.