On December 12, 2019 Oncternal Therapeutics, Inc. (Nasdaq: ONCT), a clinical-stage biopharmaceutical company focused on the development of novel oncology therapies, reported the presentation of interim data from the ongoing, investigator-sponsored Phase 1b clinical study of cirmtuzumab, its investigational anti-ROR1 monoclonal antibody, in combination with paclitaxel in patients with HER2-negative, metastatic or locally-advanced unresectable breast cancer (Press release, Oncternal Therapeutics, DEC 12, 2019, View Source [SID1234552329]). The results were presented at the San Antonio Breast Cancer Symposium (SABCS) in San Antonio, TX. A copy of the poster presentation is available online at www.oncternal.com.

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As of the data cut-off date of November 27, 2019, a total of eight patients with HER2-negative, metastatic or locally-advanced unresectable breast cancer were enrolled in the study. Seven of the eight patients were evaluable for safety and efficacy. Four of the patients had triple negative breast cancer (TNBC) at study enrollment.

Four of the seven evaluable patients achieved a partial response, for an objective response rate of 57%, including one partial response that continued on cirmtuzumab alone for 30 weeks after discontinuing paclitaxel.

The combination of cirmtuzumab and paclitaxel has been well tolerated in this trial, with no study discontinuations for toxicity and no dose-limiting toxicities observed to date. Adverse events have been consistent with the known safety profile of paclitaxel alone.

Pharmacokinetic analysis of serial plasma samples for free unbound antibody from two patients provided results similar to those observed in previous studies of chronic lymphocytic leukemia patients, consistent with a projected half-life of 30 days. No decline in antibody concentration over time was observed, consistent with the absence of neutralizing antibodies.

"It is encouraging to see that cirmtuzumab in combination with paclitaxel has been well tolerated and is active. Future studies will determine whether cirmtuzumab is contributing to the known activity of paclitaxel. Advanced breast cancer patients are in need of improved treatment options with acceptable side effects. We look forward to completing enrollment and treating additional patients in this study," said Rebecca Shatsky, M.D., Assistant Clinical Professor, Medicine at University of California San Diego School of Medicine, lead investigator who presented the poster.

Funding for this trial was provided by Oncternal Therapeutics, California Institute for Regenerative Medicine, UC San Diego Alpha Stem Cell Clinic and Sanford Stem Cell Clinical Center, UC San Diego Moores Cancer Center, Padres Pedal the Cause Grant, and Gonick Breast Cancer Research Funds.

"The early activity signals for cirmtuzumab in combination with paclitaxel for patients with breast cancer seen in this study are encouraging. We believe these data, taken together with the previously updated clinical data in chronic lymphocytic leukemia (CLL) and mantle cell lymphoma (MCL) from the CIRLL study presented at the annual ASH (Free ASH Whitepaper) meeting, reinforce the encouraging safety data and provide evidence of clinical activity of cirmtuzumab and its potential for the treatment of patients with breast cancer and other ROR1-expressing solid tumors and hematological malignancies," said James Breitmeyer, M.D., Ph.D., Oncternal’s President and CEO.

About the Clinical Trial

This clinical trial is an investigator-sponsored Phase 1b Pilot Clinical Trial of Cirmtuzumab, an Anti-ROR1 Monoclonal Antibody, in Combination with Paclitaxel for the Treatment of Patients with Metastatic, or Locally Advanced, Unresectable Breast Cancer. The objectives of the trial include the evaluation of safety, tolerability, pharmacokinetics, and clinical activity. Eligible patients are those with locally-advanced, unresectable or metastatic HER2-negative breast cancer who had not received paclitaxel in the metastatic setting. Study treatment included a fixed dose of 600 mg cirmtuzumab given on days 1 and 15 of cycle 1, and then on day 1 of each subsequent 28-day cycle. Paclitaxel was given weekly at a dose of 80 mg/m2. Additional information about the clinical trial may be accessed at ClinicalTrials.gov (NCT02776917).

About Cirmtuzumab

Cirmtuzumab is an investigational, potentially first-in-class monoclonal antibody targeting ROR1, or Receptor tyrosine kinase-like Orphan Receptor 1. Cirmtuzumab is currently being evaluated in a Phase 1/2 clinical trial in combination with ibrutinib for the treatment of CLL or MCL, in a collaboration with the UC San Diego School of Medicine and the California Institute for Regenerative Medicine (CIRM). In addition, an investigator-initiated Phase 1 clinical trial of cirmtuzumab in combination with paclitaxel for women with metastatic breast cancer is being conducted at the UC San Diego School of Medicine. CIRM has also provided funding to support development programs for cirmtuzumab and a CAR-T therapy that targets ROR1, which is currently in preclinical development as a potential treatment for hematologic cancers and solid tumors.

ROR1 is a potentially attractive target for cancer therapy because it is an oncofetal antigen – a protein that confers a survival and fitness advantage when reactivated and expressed by tumor cells. When expressed by hematologic malignancies such as CLL and MCL, ROR1 acts as a receptor for the tumor growth factor Wnt5a. Researchers at the UC San Diego School of Medicine discovered that targeting a critical epitope on ROR1 was key to inhibiting Wnt5a activation, specifically targeting ROR1 expressing tumors. This led to the development of cirmtuzumab that binds this critical epitope of ROR1, which is highly expressed on many different cancers but not on normal tissues. Preclinical data showed that when cirmtuzumab bound to ROR1, it blocked Wnt5a signaling, inhibited tumor cell proliferation, migration and survival, and induced differentiation of the tumor cells. Cirmtuzumab is in clinical development and has not been approved by the U.S. Food and Drug Administration for any indication.

On December 12, 2019 Physicians’ Education Resource (PER), the nation’s leading resource for oncology and hematology continuing medical education (CME), reported that it will host the 17th Annual Winter Lung Cancer Conference, Feb. 7-9, 2020, at Eden Roc Miami Beach in Miami Beach, Florida (Press release, Physicians’ Education Resource, DEC 12, 2019, View Source [SID1234552328]).

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"We know this one-of-a-kind meeting will be one of the premier educational events to learn state-of-the-art care for patients with lung cancers," said Phil Talamo, president of PER. "Our world-class CME conference not only allows our participants to learn, but to share their personal experiences and best practices in lung cancer management."

The historic Winter Lung Cancer Conference will be co-chaired by Rogerio C. Lilenbaum, M.D., professor of medicine in medical oncology and chief medical officer of Smilow Cancer Hospital, Yale New Haven Health; Mark A. Socinski, M.D., executive medical director at Florida Hospital Cancer Institute and AdventHealth Cancer Institute; Heather A. Wakelee, M.D., professor of medicine (oncology) at Stanford University Medical Center; and Julie R. Brahmer, M.D., M.Sc., FASCO, co-director, upper aerodigestive department, Bloomberg-Kimmel Institute for Cancer Immunotherapy; director, thoracic oncology program, professor of oncology, Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins University.

For 17 years, the Winter Lung Cancer Conference has brought together world-class thoracic oncologists to share the best practices in the treatment of lung cancers. During this two-day program, attendees will have the chance to learn from and interact with international experts in several therapeutic areas, including immunotherapy, targeted agents, and multidisciplinary approaches. This conference provides the most cutting-edge research and practical information for the care of their patients, as well as offer a preview of new agents and techniques that will inform the future of lung cancer treatment. Throughout the program, question-and-answer sessions will also provide attendees with the opportunity to consult with faculty and their community-based peers.

On December 12, 2019 Fuzionaire Radioisotope Technologies K.K. ("FRIT"), a Japanese affiliate of radiopharmaceutical company Fuzionaire Diagnostics, Inc. ("Fuzionaire Dx"), reported a collaborative research agreement with the Department of Nuclear Medicine and Tracer Kinetics at Osaka University Graduate School of Medicine (Press release, Osaka University, DEC 12, 2019, View Source [SID1234552327]). The collaboration will use Fuzionaire Dx’s proprietary chemistry and Osaka’s unique clinical and radiochemistry capabilities to accelerate the discovery of novel anti-cancer radiotherapeutic agents.

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The joint research effort aims to produce therapeutic molecules that contain astatine-211, a radioactive isotope, as the tumor-destroying payload. Astatine-211 emits alpha particles, which have enough energy to destroy cells. Unlike available treatments that emit beta particles, alpha particles penetrate a very limited distance, typically a depth of only a few cells. This makes it possible for alpha particles to treat isolated cancer cells, disseminated tumors, micrometastases, and supplement conventional therapies that may leave undetectable tumors that could lead to a recurrence. The initial research collaboration aims to identify clinical candidates for different oncology indications.

The collaboration will also further explore Fuzionaire Dx’s fluorine-18 radiochemistry platform, which can produce radiopharmaceuticals that identify and localize cancerous tissue in positron emission tomography (PET) scans prior to radiotherapeutic intervention, enabling better treatment stratification and monitoring of patient response.

"The Department of Nuclear Medicine and Tracer Kinetics at Osaka University Graduate School of Medicine is one of Japan’s leading nuclear medicine departments, with particular expertise in alpha nuclides for cancer therapy," said FRIT CEO Hiroshi Nakashita, MD. "We look forward to collaborating with leaders in the field on work that could greatly improve outcomes for patients with cancers that are difficult to treat using existing methods."

Primary leadership for the scientific collaboration includes Tadashi Watabe, MD, PhD, Assistant Professor in the Department of Nuclear Medicine and Tracer Kinetics at Osaka University Graduate School of Medicine, and Anton Toutov, PhD, Chief Science Officer of Fuzionaire Dx.

"We are very pleased to be working with the Fuzionaire team," said Professor Tadashi Watabe, project research lead at Osaka. "This collaborative research agreement is consistent with our department’s vision to become a pipeline of drug development, moving our research from the laboratory into clinical trials."

Anton Toutov, PhD, Chief Science Officer of Fuzionaire Dx, added, "There are unique chemistry challenges associated with the synthesis of astatine-211 and fluorine-18 radiopharmaceuticals, and our insights in this area are among the technological foundations of our company. We are excited to combine Osaka’s clinical capabilities and infrastructure with our expertise and technology to develop treatments and diagnostics to impact cancer care."

About Nuclear Medicine at Osaka University

The Integrated Radiation Laboratory at Osaka University Graduate School of Medicine is an interdisciplinary environment combining the use of diagnostic imaging techniques (PET and SPECT) as well as new application areas in therapeutic radiation oncology and radioactive isotopes. The team has the resources and personnel to explore novel radiopharmaceuticals from pre-clinical models to application in clinical practice. The laboratory was led by Professor Jun Hatazawa, one of Japan’s leading nuclear medicine physicians and current President of Asia Oceania Federation of Nuclear Medicine and Biology.

On December 12, 2019 Rheos Medicines, a biopharmaceutical company harnessing insights in immunometabolism to create a new class of therapeutics for patients with severe autoimmune disorders, inflammatory diseases and cancer, reported the online publication of a perspective in Cell Metabolism that highlights the rationale and potential of employing principles of immunometabolism to discover and develop novel medicines (Press release, Rheos Medicines, DEC 12, 2019, View Source [SID1234552326]). The article, entitled The Untapped Opportunity and Challenge of Immunometabolism: A New Paradigm for Drug Discovery, was published online today in Cell Metabolism (DOI: 10.1016/j.cmet.2019.11.014).

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Immune cells modulate their energy requirements in response to changes in their environment, which include interactions with pathogens, tumor cells, other immune system cells and molecules such as growth factors and antibodies. The metabolic programs that are induced or inhibited as immune cells respond to such stimuli can drive immune cell activation, differentiation, or suppression. Understanding the mechanisms through which metabolism can dictate the function or fate of immune cells is a new platform for target and biomarker discovery with a goal of identifying new medicines with potential to selectively tune the immune system to amplify or dampen its response. The perspective reviewed the underlying biology of immunometabolism and the new tools to discover and develop novel therapeutics based on this paradigm.

"To exploit this new field of immunometabolism, we have developed and industrialized a platform that comprehensively elucidates the metabolic pathways and targets with potential to control immune cell fate or function, as well as their associated metabolite biomarkers," said Laurence Turka, M.D., Chief Scientific Officer and co-founder of Rheos. "Our approach employs a proprietary integration of metabolomic, transcriptomic, and other data to generate immunometabolism network maps (imMAPs) that characterize immune cell activation and differentiation through a metabolic lens. Our imMAPs have potential to tap currently undiscovered or poorly understood biology and enable development of new therapeutics for a wide range of diseases including autoimmunity and cancer."

Barbara Fox, Ph.D., Chief Executive Officer of Rheos, added, "Immunometabolism has the potential to be the next frontier in drug discovery. Our pioneering product engine has the breadth and power to identify novel metabolic targets across a diverse set of pathways, better understand the metabolic impact of existing therapies and bring the benefits of personalized medicine to autoimmunity. Based on our work to-date, we have initiated drug discovery efforts in a number of programs and we look forward to providing further updates as we continue to make progress."

On December 12, 2019 Silverback Therapeutics, Inc., a biopharmaceutical company developing a pipeline of systemically delivered, locally active therapies, reported the presentation of preclinical data supporting development of its lead ImmunoTAC candidate, SBT6050, at the San Antonio Breast Cancer Symposium (SABCS) (Press release, Silverback Therapeutics, DEC 12, 2019, View Source [SID1234552325]). The data were presented today in Spotlight Oral and Poster Presentations at the Henry B. Gonzalez Convention Center in San Antonio, Texas (Program #PD4-09, Abstract #924).

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"Our preclinical data continue to highlight the potential for single agent clinical activity with SBT6050, even in settings with diminished or absent T cell infiltrates, and now demonstrate the opportunity for enhanced activity in combination with trastuzumab. We are excited to rapidly advance SBT6050 into the clinic."

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The presentation, titled "Preclinical studies support the development of SBT6050, an anti-HER2 antibody conjugated to a potent TLR8 agonist, for treatment of moderate and high HER2 expressing tumors," shows that SBT6050 effectively activates human myeloid cells and drives multiple anti-tumor immune mechanisms in a HER2 dependent manner in vitro, and an SBT6050 mouse surrogate exhibits potent anti-tumor efficacy as a single agent and in combination with trastuzumab in vivo. Unlike other innate immune agonists that have been limited to topical or intratumoral administration, SBT6050 is designed for systemic delivery and tumor-localized activity.

In preclinical studies, robust, durable single agent activity is observed with the SBT6050 mouse surrogate in multiple syngeneic mouse tumor models, including those with low tumor infiltrating lymphocytes, a feature commonly observed in HER2-expressing malignancies. Importantly, the SBT6050 mouse surrogate is curative as a single agent in a human xenograft model lacking T, B, and NK cells, demonstrating the potential of myeloid cells to mediate strong anti-tumor activity. SBT6050 and trastuzumab bind to distinct epitopes on HER2, enabling potential trastuzumab-based combinations in patients. A combination of low dose SBT6050 mouse surrogate with trastuzumab in a HER2-positive human xenograft model greatly enhanced the anti-tumor activity observed with either agent alone. Collectively, these data demonstrate the potential for clinical activity with SBT6050 in HER2-expressing malignancies and highlight development opportunities in clinical combination with trastuzumab.

"SBT6050’s ability to drive a broad spectrum of anti-tumor immune responses through localized and potent activation of human myeloid cells has not been achieved by other cancer immunotherapies," said Valerie Odegard, Ph.D., Silverback’s chief scientific officer. "Our preclinical data continue to highlight the potential for single agent clinical activity with SBT6050, even in settings with diminished or absent T cell infiltrates, and now demonstrate the opportunity for enhanced activity in combination with trastuzumab. We are excited to rapidly advance SBT6050 into the clinic."

Added Naomi Hunder, M.D., Silverback’s senior vice president of clinical development, "Despite advances in treatment options for patients with HER2-expressing tumors, significant unmet medical need remains, and immune checkpoint inhibitors have demonstrated activity in only a subset of these patients. Preclinical data indicate SBT6050 may be useful as a single agent therapeutic or in combination with trastuzumab-based therapies, providing a much needed immunotherapeutic option for patients with HER2-expressing disease. We plan to initiate clinical investigation of SBT6050 in 2020."

About Silverback’s Platform Technology

Silverback’s proprietary technology and integrated R&D approach enables the design and development of ImmunoTAC therapeutics that can be administered systemically but act only at the sites of disease. This approach is designed to spare healthy tissues from unwanted side effects, while modifying disease processes in a targeted and potent manner. Silverback’s platform is useful for developing systemic therapies that can modulate fundamental pathways underlying serious or life-threatening diseases in a targeted manner, in contrast to traditional antibody and small molecule-based approaches that have not been successful due to inadequate activity and/or unacceptable toxicities. Silverback has over 20 patent families directed to the platform and related product candidates.