On December 7, 2020 Boehringer Ingelheim and Proxygen reported they have entered into a collaboration and license agreement to enable the identification of molecular glue degraders against various oncogenic targets (Press release, Proxygen, DEC 7, 2020, View Source [SID1234574446]). The collaboration combines Proxygen’s unique molecular glue degrader discovery platform and its expertise in targeted protein degradation with Boehringer Ingelheim’s long-term strategy to provide first-in-class, breakthrough therapies for cancer patients.

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Molecular glue degraders and PROTACs harness the power of the cell’s recycling machinery to selectively eliminate disease-causing proteins. Molecular glue degraders achieve this by specifically bridging the distance between target proteins and ubiquitin ligases, which consequently flag the target proteins for rapid degradation. Molecular glues orchestrate this protein-protein proximity through highly cooperative binding. They circumvent the need for a defined binding pocket on the surface of the target protein, a requirement for conventional small molecule drugs, allowing pharmaceutical intervention on proteins that were previously considered undruggable.

"Proxygen’s molecular glue degrader platform has the potential to become a valuable component of Boehringer Ingelheim’s cancer research strategy to treat tumors driven by the most frequently mutated cancer-causing proteins that were previously considered undruggable and to further expand our efforts in the area of targeted protein degradation," says Norbert Kraut, Global Head of Cancer Research at Boehringer Ingelheim. "We are very pleased to partner with Proxygen, complementing our efforts in taking difficult-to-treat cancers on."

The identification of molecular glue degraders has been serendipitous up to this point. Proxygen’s highly scalable and broadly applicable molecular glue discovery platform promises a goal-oriented and comprehensive avenue towards an improved identification of molecular glue degrader candidates.

"We are very excited to join forces with Boehringer Ingelheim," says Bernhard Boidol, Chief Executive Officer of Proxygen. "Working together with a leader in innovative oncological research and development not only validates the broad applicability of our molecular glue degrader platform but also allows us to rapidly develop new therapies for the high unmet medical need of many patients with lung and colorectal cancers."

Proxygen’s new method has recently been recognized by Boehringer Ingelheim through its Grass Roots ‘Innovation Prize’ in Vienna, Austria. The ‘Innovation Prize’ recognizes the innovation power of young life-science companies and bio-entrepreneurs to create and sustain pipelines for the next generation of medicines. Launched in 2015, the Grass Roots programs comprise of ‘Office Hours,’ ‘Academy’ and the ‘Innovation Prize.’ As a company dedicated to improving health and quality of life, these programs give Boehringer Ingelheim the opportunity to lend expertise to the early-stage innovation community and offer guidance around the science to help enable ideas to deliver the next breakthroughs.

Proxygen is entitled to receive up-front payments, research and development support and milestone gated development payments, as well as tiered royalties based on future commercial sales of developed products.

On December 7, 2020 Bayer AG and Atara Biotherapeutics reported an exclusive worldwide license agreement for next-generation, mesothelin-directed CAR-T cell therapies for the treatment of solid tumors (Press release, Bayer, DEC 7, 2020, View Source [SID1234573600]). The agreement includes the development candidate ATA3271, an armored next generation allogeneic T-cell immunotherapy, and an autologous version, ATA2271, for the treatment of high mesothelin-expressing tumors such as malignant pleural mesothelioma and non-small-cell lung cancer.

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Atara is a pioneer in allogeneic T-cell immunotherapy with industry-leading allogeneic cell manufacturing processes and next-generation CAR-T technologies. The licensed technology leverages Atara´s novel, proprietary Epstein-Barr Virus (EBV) T-cell platform combined with next generation CAR-T technologies targeting mesothelin to improve efficacy, persistence, safety, and durability of response.

"This transaction is a fundamental element of Bayer’s new Cell & Gene Therapy strategy. It strengthens our development portfolio through allogeneic cell therapies and consolidates our emerging leadership in the field," said Wolfram Carius, Head of Bayer’s Cell & Gene Therapy Platform. "We look forward to partnering with Atara to develop next-generation off-the-shelf CAR-T cell therapies for patients with difficult-to-treat cancers."

"This exciting partnership between Atara and Bayer will accelerate the development of next-generation mesothelin-targeted CAR-T cell therapies for the treatment of multiple solid tumors and helps us bring the power of our allogeneic cell therapy platform to patients as quickly as possible," said Pascal Touchon, President and CEO Atara. "Bayer’s proven track record in oncology global development and commercialization, and growing presence in cell and gene therapy, enhances Atara’s capabilities and complements our leading allogeneic T-cell platform."

Under the terms of the agreement, Atara will lead IND (Investigational New Drug)-enabling studies and process development for ATA3271 while Bayer will be responsible for submitting the IND and subsequent clinical development and commercialization. Atara will continue to be responsible for the ongoing ATA2271 phase 1 study, for which an IND filing has been accepted and the clinical trial has been initiated. Atara will receive an upfront payment of USD 60 million and is eligible to receive payments from Bayer upon achievement of certain development, regulatory and commercialization milestones totaling USD 610 million, as well as tiered royalties up to low double-digit percentage of net sales.

As part of the transaction, Atara will also provide translational and clinical manufacturing services to be reimbursed by Bayer. In addition, for a limited period of time, Bayer has a non-exclusive right to negotiate a license for additional Atara CAR-T product candidates.

About CAR-T cell therapy
T cells are a type of white blood cell that are critical in eliminating the body of abnormal and cancerous cells in healthy individuals. In cancer patients, these T cells frequently fail to either recognize or effectively engage cancer cells. CAR-T cell therapies involve engineering a human T cell to express a chimeric antigen receptor (CAR) that increases its ability to recognize cancer cells. These therapies use the immune system to fight cancer and have the potential to disrupt cancer care and potentially even provide a cure. Mesothelin is a tumor-specific antigen that is commonly expressed at high levels on the cell surface in many aggressive solid tumors and is an attractive target for immune-based therapies, including CAR-T therapy.

About Bayer’s new Cell & Gene Therapy (C&GT) Platform
In order to build up its presence in C&GT, Bayer is strengthening its internal C&GT capabilities. At the same time, the company is pursuing external strategic collaborations, technology acquisitions and licensing. The goal is to build robust platforms with broad application across different therapeutic areas. Strategically, Bayer focuses on selected areas of C&GT, such as stem cell therapies (with focus on induced pluripotent cells or iPSCs), gene augmentation, gene editing and allogeneic cell therapies in different indications. Leveraging external innovation together with the expertise of the teams at Bayer represents a key value-driver, especially in the highly dynamic and competitive field of C&GT. Bayer’s operating model for C&GT, where partners operate autonomously and are fully accountable to develop and progress their portfolio and technology, is essential for preserving their entrepreneurial culture and positions Bayer as a partner of choice. The role of Bayer’s C&GT Platform is to steer strategically, ensuring the different parts of the organization complement each other and combining the best in Biotech and Pharma know-how. As part of the Pharmaceuticals Division, the C&GT Platform will combine multiple backbone functions providing support across the entire value chain for the research and development of cell and gene therapies. This includes expertise in Research and Preclinical Development, CMC (Chemistry, Manufacturing and Controls), Clinical Development, Commercial, Strategy Implementation and Project Management. With a high level of flexibility, it will orchestrate operations from science to launch in order to generate and maintain a sustainable pipeline, with the goal to bring breakthrough science to market as fast as possible.

About Atara’s Mesothelin CAR-T Franchise
Two of Atara’s next generation CAR T immunotherapy programs target mesothelin – the autologous ATA2271 program and allogeneic ATA3271 program. Mesothelin is a tumor-specific antigen that is commonly expressed at high levels on the cell surface in many aggressive solid tumors including mesothelioma, non-small cell lung cancer, ovarian cancer and pancreatic cancer.

Both ATA2271 and ATA3271 are engineered for use in solid tumors as they incorporate Atara’s novel inclusion of both a PD-1 DNR construct to overcome checkpoint inhibition and a 1XX costimulatory domain on the CAR (chimeric antigen receptor) to enhance expansion and functional persistence of the CAR T cells. ATA3271, the allogeneic version of this CAR T, leverages Atara’s EBV T-cell platform and is currently in IND-enabling studies. ATA2271, the autologous version has enrolled the first patient in an an open-label, single-arm Phase 1 clinical study in November 2020.

On December 7, 2020 Bristol Myers Squibb (NYSE: BMY) reported data from multiple studies evaluating lisocabtagene maraleucel (liso-cel), an investigational CD19-directed chimeric antigen receptor (CAR) T cell therapy, in relapsed or refractory chronic lymphocytic leukemia (CLL) and small lymphocytic lymphoma (SLL), in relapsed or refractory mantle cell lymphoma (MCL), and in relapsed or refractory large B-cell lymphoma (LBCL) were presented at the 62nd American Society of Hematology (ASH) (Free ASH Whitepaper) Annual Meeting and Exposition (Press release, Bristol-Myers Squibb, DEC 7, 2020, View Source [SID1234573350]). The data include longer-term follow-up from the Phase 1 TRANSCEND CLL 004 study in a cohort of patients with relapsed or refractory CLL and SLL treated with liso-cel as monotherapy and initial results from the combination cohort with ibrutinib, and safety and preliminary efficacy results from TRANSCEND NHL 001 in the cohort of patients with relapsed or refractory MCL treated with liso-cel. Additionally, initial results from the OUTREACH study evaluating outcomes of treatment with liso-cel for patients with relapsed or refractory LBCL across inpatient and outpatient settings were presented.

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"In our mission to transform patients’ lives through science, we have established a diverse and comprehensive development program to understand the potential of liso-cel across both aggressive and indolent hematologic malignancies and sites of care," said Noah Berkowitz, M.D., Ph.D., senior vice president, Global Clinical Development, Hematology, Bristol Myers Squibb. "In addition, we continue to advance our cell therapy research to inform potential combination strategies with our CAR T cell therapies to optimize treatment outcomes for patients in need."

Liso-cel in Combination with Ibrutinib and as Monotherapy in CLL/SLL: TRANSCEND CLL 004

In the Phase 1/2 TRANSCEND CLL 004 study, patients with relapsed or refractory CLL and SLL were enrolled in a cohort receiving liso-cel in combination with ibrutinib (Presentation #544). Nineteen patients started or continued ibrutinib treatment for >90 days at enrollment and were evaluated for safety and efficacy following liso-cel treatment.

Seventy-four percent of patients experienced any grade cytokine release syndrome (CRS) with one Grade 3 event. Median time to onset of CRS was 6.5 days (1-13) and median duration of CRS was 6 days (3-13). Any grade neurologic events (NEs) occurred in 32% of patients with three Grade 3 events. Median time to onset of NEs was 8 days (5-12) and median duration of NEs was 6.5 days (1-8).1

With median follow-up of 10 months, liso-cel in combination with ibrutinib demonstrated high rates of response with 18 patients (95%) deriving an overall response, and 12 (63%) achieving a complete response. All responses were achieved by Day 30 following liso-cel treatment and among 18 patients with >6 months of follow-up, 89% maintained or improved their response from Day 30. Of 19 patients evaluable for minimal residual disease (MRD), 17 (89%) achieved undetectable MRD (uMRD) in blood by flow cytometry and 15 (79%) in bone marrow by next-generation sequencing (both with sensitivity 104).1

In a separate cohort of the Phase 1/2 TRANSCEND CLL 004 study, patients with relapsed or refractory CLL, including 83% of patients with high-risk disease, and patients who had progressed on prior therapy with ibrutinib, were enrolled to receive liso-cel as a monotherapy (Presentation #546). At median follow-up of 24 months, 23 patients were evaluable for safety and 22 patients were evaluable for efficacy.

In the 23 patients evaluated for safety, the safety profile for liso-cel was consistent with the known safety profile of liso-cel with no new late or delayed adverse events of concern emerging with longer follow-up. Seventy-four percent of patients experienced any grade CRS, with Grade >3 CRS occurring in 9% of patients. Median time to onset of CRS was three days (1-10) and median duration of CRS was 12 days (2-50). Any grade NEs occurred in 39% of patients, with 22% of patients experiencing Grade >3 NEs. Median time to onset of NEs was four days (2-21) and median duration of NEs was 20.5 days (6-50).2

Among the 22 patients evaluable for efficacy, the overall response rate was 82% (18/22). Complete responses were seen in 46% (10/22) of patients. By Day 30, 68% of patients (n=15) responded to therapy, and 27% had a deepening of response. At 12 months, 50% of patients remained in response and all seven patients who completed the 24-month follow-up maintained their response. The median duration of response was not reached (95% CI: 4.8 – NR) at median follow-up of 24 months and median progression-free survival was 18 months (95% CI: 3.0 – NR).2

"Patients with relapsed or refractory chronic lymphocytic leukemia and small lymphocytic lymphoma are often faced with a difficult treatment journey and many changes in therapy due to relapse," said William G. Wierda, M.D., Ph.D., executive medical director and professor, Department of Leukemia, Division of Cancer Medicine at the University of Texas MD Anderson Cancer Center. "Results from TRANSCEND CLL 004 underscore the potential of liso-cel to deliver rapid, deep and durable responses as a monotherapy in heavily pretreated patients with difficult-to-treat disease and the potential of using liso-cel in combination with ibrutinib to provide high rates of overall response with a very manageable safety profile to address a significant unmet need for this disease."

Safety and Efficacy of Liso-cel in Relapsed or Refractory MCL: TRANSCEND NHL 001

In the TRANSCEND NHL 001 study cohort of patients with relapsed or refractory MCL, including many with highly proliferative disease, 32 patients received liso-cel across dose levels of 50 x 106 CAR positive T cells and 100 x 106 CAR positive T cells (Presentation #118).

Sixteen patients (50%) experienced any grade CRS, including one Grade >3 event. Median time to CRS onset and resolution was six days (2‒10) and four days (2-9), respectively. Eleven patients (34%) experienced any grade NEs, all of which occurred in those who received the higher dose level, including four Grade >3 NEs. Median time to NE onset and resolution was eight days (2-25) and four days (1-27), respectively.3

Preliminary efficacy results showed that treatment with liso-cel resulted in high response rates with 84% of patients responding to treatment and 66% of patients achieving a complete response (CR). Overall, the median time to first complete or partial response was less than one month (0.95; range 0.9-2.0). Median duration of response was not reached with a median follow-up of 3.9 months (0.0-21.3).3

"Mantle cell lymphoma is an aggressive type of non-Hodgkin lymphoma and many patients relapse after initial therapies with limited remaining treatment options," said M. Lia Palomba, M.D., Lymphoma Service and Center for Cellular Therapeutics, Memorial Sloan Kettering Cancer Center. "Initial results of liso-cel in MCL from TRANSCEND NHL 001 demonstrate the potential of this CAR T cell therapy to provide patients with high rates of response, representing a potentially important treatment option for these patients."

Initial Results from the OUTREACH Study of Liso-cel in Relapsed or Refractory Large B-Cell Lymphoma (LBCL) Across Sites of Care

In the Phase 2 OUTREACH study, adults with relapsed or refractory LBCL were treated with liso-cel in the inpatient and outpatient settings at nonuniversity centers (Presentation #1196). The primary endpoint was incidence of Grade >3 CRS based on the Lee grading system, NEs, prolonged cytopenias through day 29 and infections. Secondary endpoints included safety and overall response rate (ORR).

Based on initial results from 46 patients treated with liso-cel (inpatient n=16; outpatient n=30) at data cutoff, patients were successfully treated and monitored in the inpatient and outpatient settings. Any grade CRS was reported in six (37.5%) patients treated in the inpatient setting and 13 (43%) patients treated in the outpatient setting, with no Grade >3 events reported. NEs were reported in five (31%) inpatients and nine (30%) outpatients, with one Grade >3 event in the inpatient group and two in the outpatient group. Median time to onset of CRS and NEs, respectively, was 2.5 (1–3) and 10 (3–16) days for inpatients and five (2–9) and nine (6–14) days for outpatients.4

Among efficacy-evaluable patients (n=44), 75% of inpatients achieved an overall response with 50% of patients achieving a complete response (CR), and 79% of outpatients achieved an overall response with 61% achieving a CR.4

Bristol Myers Squibb: Creating a Better Future for People with Cancer

Bristol Myers Squibb is inspired by a single vision—transforming people’s lives through science. The goal of the company’s cancer research is to deliver medicines that offer each patient a better, healthier life and to make cure a possibility. Building on a legacy across a broad range of cancers that have changed survival expectations for many, Bristol Myers Squibb researchers are exploring new frontiers in personalized medicine, and through innovative digital platforms, are turning data into insights that sharpen their focus. Deep scientific expertise, cutting-edge capabilities and discovery platforms enable the company to look at cancer from every angle. Cancer can have a relentless grasp on many parts of a patient’s life, and Bristol Myers Squibb is committed to taking actions to address all aspects of care, from diagnosis to survivorship. Because as a leader in cancer care, Bristol Myers Squibb is working to empower all people with cancer to have a better future.

On December 7, 2020 Allogene Therapeutics, Inc. (Nasdaq: ALLO), a clinical-stage biotechnology company pioneering the development of allogeneic CAR T (AlloCAR T) therapies for cancer, reported preclinical findings of ALLO-605, the Company’s first TurboCAR clinical candidate and next-generation AlloCAR T therapy for relapsed or refractory multiple myeloma, will be presented in a poster session today at the 62nd Annual Meeting of the American Society of Hematology (ASH) (Free ASH Whitepaper) (Press release, Allogene, DEC 7, 2020, View Source [SID1234572474]).

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Allogene developed the TurboCAR technology to further enhance the potency of cell therapies. This technology allows ligand independent, cytokine signaling to be engineered selectively into CAR T cells. TurboCARs have the potential to enhance AlloCAR T cell proliferation and overcome T cell exhaustion. The technology is being deployed initially as part of the Company’s three-pronged approach to targeting BCMA in patients with multiple myeloma. Results from the preclinical studies demonstrated that ALLO-605 showed enhanced cytokine secretion, polyfunctionality, improved serial killing activity in vitro, and enhanced eradication of tumors in animal models of myeloma.

"Allogene continues to innovate across our AlloCAR T platform with next generation technologies that can be applied to multiple programs," said Rafael Amado, M.D., Executive Vice President of Research & Development and Chief Medical Officer of Allogene. "The advances with TurboCAR not only support our approach to targeting BCMA, but also allow us to potentially enhance the activity of other AlloCAR T candidates. We are eager to bring ALLO-605 into the clinic and anticipate filing our first IND utilizing this novel technology in the first half of 2021."

In a highly aggressive orthotopic mouse model of multiple myeloma, ALLO-605 demonstrated an increase in peak expansion and persistence compared to standard BCMA CAR T cells, resulting in rapid and durable antitumor responses. No bone marrow or extramedullary relapses were seen in mice treated with ALLO-605 which resulted in increased survival. The expansion and persistence of ALLO-605 was dependent upon BCMA expression on the target cells and there was no evidence of TurboCAR T cell expansion in the absence of target engagement.

On December 7, 2020 OncoMyx Therapeutics, a privately-held oncolytic immunotherapy company, reported that The University of Western Ontario (Western) has assigned to OncoMyx the technology and patent rights associated with pioneering research on the use of myxoma virus in the treatment of cancer (Press release, OncoMyx Therapeutics, DEC 7, 2020, View Source [SID1234572370]). This research was led by OncoMyx cofounder Grant McFadden, Ph.D., when he was a Professor at Western and the Robarts Research Institute.

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Lisa Cechetto, the Executive Director of WORLDiscoveriesTM, the technology transfer office for Western, Robarts Research Institute, and Lawson Research Institute, said, "We are pleased to assign these patents to OncoMyx, as it is important that the outputs of pioneering research, such as Dr. McFadden’s use of myxoma virus to create novel oncolytic therapies, be further developed to improve the lives of cancer patients or others who may benefit."

"The assignment of this technology and intellectual property to OncoMyx further reinforces our IP portfolio protecting our use of myxoma virus and our pipeline of myxoma virotherapies for the treatment of cancer," said Steve Potts, Ph.D., MBA, cofounder and chief executive officer of OncoMyx. "The myxoma virus has a number of important attributes that we are leveraging to develop potentially impactful oncolytic immunotherapies with the goal of increasing the number of cancer patients who could benefit from immunotherapies."

"Oncolytic viruses are emerging as a new pillar of cancer care with the potential to expand the effectiveness of immunotherapies, such as immune checkpoint inhibitors," said Dr. McFadden. "I am pleased that OncoMyx has been assigned the patent rights associated with the pioneering myxoma research that was done at Western, as the myxoma virus is unique as a technology platform to build oncolytic immunotherapies."

About Myxoma Virotherapy for the Treatment of Cancer

The myxoma virus is highly immuno-interactive and can selectively infect and kill a broad range of cancer cell types. Because myxoma virus is not pathogenic to humans, myxoma virotherapy does not have to overcome pre-existing immunity. As a large dsDNA poxvirus, myxoma is engineerable to express multiple transgenic payloads, such as immunomodulatory proteins, to target multiple points in the cancer immunity cycle. The company’s preclinical data demonstrates efficacy of multi-armed myxoma virotherapies via intravenous (IV) and intratumoral (IT) delivery in a number of tumor models across multiple cancer indications and supports a pan-tumor approach to expand the therapeutic effectiveness of immunotherapies.