On October 26, 2021 Gamida Cell Ltd. (Nasdaq: GMDA), an advanced cell therapy company committed to cures for cancer and other serious diseases, reported that it will be hosting a virtual R&D Day event detailing the company’s proprietary NAM-enabled natural killer (NK) cell therapy pipeline today, Tuesday, October 26, at 8:00 a.m. ET (Press release, Gamida Cell, OCT 26, 2021, View Source [SID1234591977]). During the event, the company will highlight Gamida Cell’s new programs leveraging next-generation, NAM-enabled, genetically modified NK cells in development for solid tumors and hematological cancers, as well as provide an update on the clinical development of GDA-201, its lead cryopreserved, off-the-shelf cell therapy candidate for the treatment of patients with follicular and diffuse large B cell lymphomas, including an update on the status of its Phase 1/2 Investigational New Drug (IND) application with the U.S. Food and Drug Administration (FDA).

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Update Regarding IND Application for GDA-201:

The company recently submitted an IND application to FDA for a Phase 1/2 trial with a cryopreserved formulation of GDA-201 in patients with diffuse large B cell lymphoma and follicular lymphoma and was notified that the IND application has been placed on Clinical Hold prior to the initiation of patient dosing. The FDA has requested modifications in donor eligibility procedures and sterility assay qualification. Gamida Cell is in active communication with the FDA with the objective to promptly address these requests to potentially enable the requirements for IND acceptance and study initiation. The initiation of the planned Phase 1/2 trial of GDA-201 may be delayed beyond the end of 2021, pending the outcome of FDA interactions.

"While we work to resolve outstanding issues with our IND, we are pleased to be able to share updates regarding our NAM-enabled NK cell programs," said Julian Adams, Ph.D., Chief Executive Officer of Gamida Cell. "We believe that the issues raised by FDA are addressable and can hopefully be resolved in an expeditious manner. In the meantime, we are pleased to elaborate on the power of NAM combined with the genomic tools that we have harnessed to enable us to create potentially transformative immuno-oncological therapies that may move beyond what is currently possible with existing approaches. These advances in our NK cell pipeline will help to further our mission to bring cancer patients potentially curative cell therapies."

Update Regarding NK Cell Therapy Programs:

During today’s virtual event, Gamida Cell management and partners will provide an overview of the company’s NK cell programs, including:

Objective to improve treatment of both hematological cancers and solid tumors in which genetic modifications to allogeneic NK cells may overcome immunosuppressive microenvironments.
Review of Gamida Cell’s proprietary NAM expansion process, which enhances the potency, function and persistence of NK cells while improving homing to and retention in lymphoid tissues.
Descriptions of Gamida Cell’s genetically modified NK cell immunotherapy programs (GDA-301, GDA-401, GDA-501 and GDA-601), which utilize CAR- and CRISPR-mediated strategies to increase targeting, potency and persistence against hematologic malignancies and solid-tumors.
Discuss a research collaboration with the Dana-Farber Cancer Institute studying the in vitro natural killer (NK) cell killing activity of GDA-601, Gamida Cell’s nicotinamide (NAM)-enabled genetically modified NK cell therapy in multiple myeloma. GDA-601 is a CD38 CRISPR knockout combined with a CD38 CAR NK cell construct that has demonstrated promising preclinical results, including reduced fratricide and increased cytotoxicity against a multiple myeloma cell line.
Phase 1 data on the safety and efficacy of GDA-201, a NAM-enabled, unmodified allogeneic NK cell therapy that has produced positive clinical results in the treatment of diffuse large B cell lymphoma and follicular lymphoma, both of which have significant unmet need.
"This is an exciting time for Gamida Cell as we have expanded R&D activities to augment our NK cell pipeline," said Ronit Simantov, M.D., Chief Medical Officer of Gamida Cell. "During today’s event, we will share our plans to advance the clinical development of GDA-201 based on highly encouraging clinical data in patients with lymphoma that have arisen from a physician sponsored study. We also plan to illustrate how our proprietary NAM expansion process, combined with our advanced genetic modifications, differentiate our NK cell programs as may meaningfully help patients with solid tumors and hematologic malignancies."

A replay of the webcast will be available on the "Investors & Media" section of Gamida Cell’s website at www.gamida-cell.com, and will be available for at least 14 days following the event.

About GDA-201

Gamida Cell applied the capabilities of its nicotinamide (NAM)-enabled cell expansion technology to develop GDA-201, an innate NK cell immunotherapy for the treatment of hematologic and solid tumors in combination with standard of care antibody therapies. GDA-201, the lead candidate in the NAM-enabled NK cell pipeline, has demonstrated promising initial clinical trial results, as reported at the 2020 American Society of Hematology (ASH) (Free ASH Whitepaper) Annual Meeting & Exposition1. GDA-201 addresses key limitations of NK cells by increasing the cytotoxicity and in vivo retention and proliferation in the bone marrow and lymphoid organs. Furthermore, GDA-201 improves antibody-dependent cellular cytotoxicity (ADCC) and tumor targeting of NK cells. For more information about GDA-201, please visit View Source

GDA-201 is an investigational therapy, and its safety and efficacy have not been established by the FDA or any other health authority.

On October 26, 2021 SQZ Biotechnologies (NYSE: SQZ), focused on unlocking the full potential of cell therapies for multiple therapeutic areas, reported that the independent Data and Safety Monitoring Board (DSMB) for the Phase 1/2 clinical trial SQZ-PBMC-HPV-101 has recommended that the trial advance into the combination stage with checkpoint inhibitors. In June, the company presented initial results from the first three monotherapy cohorts at the American Society of Clinical Oncology (ASCO) (Free ASCO Whitepaper) annual meeting demonstrating that the investigational cell therapy is safe and well-tolerated and can stimulate immune responses in certain patients with advanced or metastatic human papillomavirus positive (HPV16+) tumors (Press release, SQZ Biotech, OCT 26, 2021, View Source [SID1234591976]). Data from the highest dose monotherapy cohort has been accepted for oral presentation at the European Society for Medical Oncology Immuno-Oncology (ESMO-IO) Congress being held December 8-11, 2021.

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"We are encouraged by our initial SQZ-PBMC-HPV-101 Phase 1/2 trial data and pleased to advance the highest dose of our SQZ APC clinical candidate into the combination stage of the trial," said Armon Sharei, Ph.D., Chief Executive Officer and Founder of SQZ Biotechnologies. "Based on our preclinical studies and available clinical trial data, we believe SQZ APCs could work synergistically with checkpoint inhibitors to provide additional clinical benefit to patients. Our clinical team and trial sites are ready to begin this important phase of the study."

The combination stage of the trial is now open for enrollment and will include checkpoint inhibitors targeting the PD-(L)1 and CTLA-4 pathways. In parallel, the company plans to continue to enroll in the highest dose monotherapy cohort.

The DSMB recommendation and initiation of the combination cohorts will trigger a Roche collaboration agreement milestone payment. The company’s most recently reported cash runway projections anticipated these proceeds.

New data from the monotherapy portion of the SQZ-PBMC-HPV-101 trial will be part of an oral presentation at ESMO (Free ESMO Whitepaper)-IO on December 9 in Geneva, Switzerland. Full presentation details can be found below.

ESMO-IO Presentation Details

Oral Presentation: Thursday, December 9 at 12:10 pm CET
Presentation Number: 48MO
Abstract Title: SQZ-PBMC-HPV-101: Preliminary results of a first-in-human, dose-escalation study of a cell-based vaccine in HLA-A*02+ patients with recurrent, locally advanced, or metastatic HPV16+ solid tumors

Lead Author: Jong Chul Park, MD, Massachusetts General Hospital; Developmental Therapeutics Member, Dana-Farber/Harvard Cancer Center

ESMO-IO will publish full abstracts on their website on Thursday, December 2 at 12:00 pm CET. SQZ will post its oral presentation on the company website on December 9 at 11:00 am CET.

SQZ-PBMC-HPV-101 Trial Design

SQZ-PBMC-HPV is being evaluated in a Phase 1/2 clinical trial for the treatment of HPV16+ advanced or metastatic solid tumors. Patients must be positive for the human leukocyte antigen serotype HLA-A*02. The investigational candidate, which targets E6 and E7 oncoproteins, is being studied as a monotherapy and in combination with immuno-oncology agents. The study’s primary outcome measures in the monotherapy and combination phases of the trial include safety and tolerability. Antitumor activity is a secondary outcome measure in both the monotherapy and combination stages of the trial, and manufacturing feasibility is a secondary outcome measure in the monotherapy phase of the trial. The monotherapy phase of the study includes escalating dose cohorts with a dose-limiting toxicity (DLT) window of 28 days and the definition of a recommended phase 2 dose. The planned combination phase of the study will include SQZ-PBMC-HPV and checkpoint inhibitors. DLT will be measured over 42 days.

About Human Papillomavirus Positive Cancers

Human papillomavirus (HPV) is one of the most common viruses worldwide and certain strains persist for many years leading to cancer. According to the Centers for Disease Control (CDC), in the United States HPV+ tumors represent 3% of all cancers in women and 2% of all cancers in men, resulting in over 39,000 new cases of HPV+ tumors every year. HPV infection is larger outside of the U.S., and according to the International Journal of Cancer HPV+ tumors account for 4.5% of all cancers worldwide, resulting in approximately 630,000 new cases every year. According to the CDC, HPV infection plays a significant role in the formation of more than 90% of anal and cervical cancers, and most cases of vaginal (75%), oropharyngeal (70%), vulval (70%) and penile (60%) cancers.

On October 26, 2021 Diverse Biotech, Inc., View Source, reported that its DBT-12733 molecule was more effective in killing glioblastoma tumor cells than temozolomide (Temodar), outperforming all expectations in early testing (Press release, Diverse Biotech, OCT 26, 2021, View Source [SID1234591975]). In fact, DBT-12733 maintained its efficacy against the temozolomide-resistant glioblastoma cancer cell line T98G, with an 8,000-fold higher effect.

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"T98G cells are actually resistant to temozolomide, due to a cellular change that results in limited treatment options for patients. DBT-12733 has shown to be most effective at killing cells with this particular alteration."

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25 times (25x) more effective on A172 cells
50 times (50x) more effective on U87-MG cells
8,000 times (8,000x) more effective on T98G cells
Chief Science Officer, Philip Arlen, PhD, adds, "T98G cells are actually resistant to temozolomide, due to a cellular change that results in limited treatment options for patients. DBT-12733 has shown to be most effective at killing cells with this particular alteration."

Glioblastoma is very hard to treat. On May 4th, 2020, the FDA granted Diverse Biotech "Orphan Drug Status" for this investigational drug for the treatment of glioblastoma, and it continues to show significant promise against the disease.

Board Chairman William Fisher said, "I was pleasantly surprised with the results against T98G cells. We are increasingly having a better idea of the capabilities of what’s coming through our pipeline and the data is extraordinary. We are excited to get this new molecule over to our collaborators at The Preston Robert Tisch Brain Tumor Center at Duke University for further studies."

On October 26, 2021 Humanigen, Inc. (Nasdaq: HGEN) ("Humanigen"), reported the first patient was dosed with lenzilumab in the Precision Approach to Chronic Myelomonocytic Leukemia (‘PREACH-M’) clinical trial being sponsored by the South Australian Health and Medical Research Institute (SAHMRI) and funded by a Medical Research Future Fund grant from the National Health and Medical Research Council of the Australian government to the University of Adelaide (Press release, Humanigen, OCT 26, 2021, View Source [SID1234591974]). Humanigen is providing lenzilumab for use in the study through its Australian subsidiary, Humanigen Australia Pty Ltd.

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"The prognosis for CMML is poor, with median survival of 30 months, and it has remained essentially unchanged over the past 30 years," said Associate Professor Daniel Thomas, the coordinating investigator for the trial and Associate Professor of Hematology at the University of Adelaide. "The overarching goal of the clinical trial is to improve response rates and survival. If we can improve response rates to 30%-50%, from the current 18% response rate normally seen in CMML patients treated with azacitidine, we think median survival may be increased to more than three years."

The PREACH-M trial is designed to focus on Chronic Myelomonocytic Leukemia (CMML) patients who carry mutations believed to drive the leukemia. One arm of the study (n≈29) will focus on patients with RAS pathway mutations (KRAS, NRAS, or CBL) that appear to be associated with hyper-proliferative features and sensitivity to GM-CSF neutralization. These patients will be treated with high-dose azacitidine and lenzilumab, Humanigen’s proprietary GM-CSF neutralizing antibody. Results will be compared to historical trials of azacitidine alone and with the South Australian MDS Registry data.

"We have been encouraged by our prior Phase 1 results in CMML and are privileged to partner with SAHMRI and the University of Adelaide to further assess the potential of lenzilumab in this rare form of cancer for which there has been so little progress in treatment over the past 30 years," said Dr. Cameron Durrant, CEO of Humanigen, Inc. "Following results from our Phase 3 LIVE-AIR study of lenzilumab in hospitalized patients with COVID-19 and the positive outcome of the Phase 1b portion of the ZUMA-19 study of lenzilumab in CAR-T, we are excited about the opportunity the PREACH-M study affords to validate our expectation that lenzilumab may offer potential benefits across multiple therapeutic indications."

About PREACH-M

The study is a precision medicine approach to treating CMML. Investigators at 5 sites in Australia plan to enroll a total of 72 CMML patients with specific mutations. Patients with RAS pathway mutations such as KRAS, NRAS, or CBL, will be enrolled in the lenzilumab and azacitidine arm. Those who have the TET2 mutation will be enrolled in an arm of the study (n≈40) testing high-dose sodium ascorbate (vitamin C) and azacitidine. Those who have both TET2, and RAS pathway mutations will be allocated to the lenzilumab arm, unless they meet an exclusion criterion for the lenzilumab cohort. Those who do not have mutations in either category will be considered screening failures. However, these patients will still benefit from study because it includes free gene sequencing for all trial participants and gene sequencing is otherwise not a pathology test funded by Medicare, the Australian government funded universal health insurance system. With an incidence rate for CMML of just 0.3 per 100,000 Australians, SAHMRI, expects enrollment may take three years. The primary outcome will be the frequency of complete response (CR) and partial response (PR) at any point during the first 12 months of active therapy. Overall and progression-free survival will each be key secondary endpoints measured during the two-year period following initiation of treatment.

Those who would like to learn more about PREACH-M should refer to the ANZCTR website: View Source

"SAHMRI and South Australia enjoy several natural advantages when it comes to running clinical trials such as PREACH-M," said SAHMRI Executive Director, Professor Steve Wesselingh. "Our size, geography, outstanding centralized public health system and cooperative population mean we have been remarkably resistant to COVID-19 outbreaks. South Australia also has a track record of success specific to phase III kinase inhibitor studies in patients with blood cancers, such as chronic myeloid leukaemia. It is exciting to be able to apply this expertise to CMML."

Evidence of potential for lenzilumab in CMML

The PREACH-M trial was conceived, in part, based on evidence from earlier in-vitro, in-vivo and Phase 1 studies showing the 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. 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.1 A subsequent Phase 1 study of lenzilumab showed a clinical benefit in 33% of the 15 CMML patients dosed and those with an NRAS mutation showed a proportionally higher response (3 of 4). Those responses demonstrated greater clinical benefit and reduction in bone marrow blasts.2

On October 26, 2021 Vertex Pharmaceuticals Incorporated (Nasdaq: VRTX) and Mammoth Biosciences, a biotech company building the next generation of CRISPR products to cure and detect disease, reported a new partnership to develop in vivo gene-editing therapies for two genetic diseases using Mammoth’s next-generation CRISPR systems (Press release, Vertex Pharmaceuticals, OCT 26, 2021, View Source [SID1234591973]).

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"We believe our novel ultra-small CRISPR systems have the potential to be game changers when it comes to systemic and targeted delivery of in vivo gene-editing therapies," said Peter Nell, Chief Business Officer and Head of Therapeutic Strategy at Mammoth Biosciences. "The combination of Mammoth’s unique technology with Vertex’s unmatched experience in serious disease research and development will only accelerate programs with the goal of reaching patients with high unmet medical need."

Driven by its unique protein discovery engine, Mammoth’s CRISPR platform consists of a proprietary toolbox of novel, ultracompact Cas enzymes, including Cas14 and Casɸ. The small size of these Mammoth systems, together with further optimized parameters, have the potential to facilitate advanced delivery, which may increase the scope of in vivo gene-editing for genetic diseases.

"Vertex and Mammoth share the same commitment to developing therapies that have the potential to be transformative for people with serious diseases," said David Altshuler, M.D., Ph.D., Chief Scientific Officer of Vertex Pharmaceuticals. "We look forward to expanding our cell and genetic therapies capabilities with the addition of Mammoth’s ultra-small CRISPR systems for in vivo genome editing, which will provide us with another set of tools to tackle many of the diseases we’re interested in."

About the Collaboration

Under the terms of the agreement, Mammoth Biosciences will receive upfront payments of $41 million, including an investment in the form of a convertible note, and is eligible to receive up to $650 million in potential future payments based upon the successful achievement of prespecified research, development and commercial milestones across two potential programs. In addition, Vertex will pay tiered royalties on future net sales on any products that may result from this collaboration.