On March 20, 2024 Clasp Therapeutics, a biotechnology company bringing unparalleled precision to immuno-oncology using next-generation T cell engagers (TCEs), reported to have launched with $150 million in financing (Press release, Clasp Therapeutics, MAR 20, 2024, View Source [SID1234641311]).

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The round was led by Catalio Capital Management, Third Rock Ventures and Novo Holdings, with participation from Vivo Capital, Cure Ventures, Blackbird BioVentures, Pictet Alternative Advisors, American Cancer Society’s Bright Edge and Alexandria Venture Investments. Clasp is developing modular TCEs tailored to each patient’s immune system that are directed to common oncogenic driver mutations, resulting in off-the-shelf, antibody-like medicines that can specifically target a wide variety of hard-to-treat tumor types.

"At Clasp we strive to help people with cancer lead longer and healthier lives by engaging each patient’s own immune cells to eradicate their cancer with absolute specificity," said Chief Executive Officer Robert Ross, M.D. "Clasp brings together leading researchers, clinicians and drug developers to develop groundbreaking cancer immunotherapies that are precise and potent, but without the toxicities commonly associated with on-target, off-tumor binding."

Clasp is leveraging advances made by its scientific founders at Johns Hopkins University, including leading cancer geneticist and HHMI investigator Bert Vogelstein, M.D., and immuno-oncology pioneer Drew Pardoll, M.D., Ph.D., who have envisioned a new approach to single out cancer cells for destruction by the immune system. The researchers’ structure-driven understanding of human leukocyte antigen (HLA)-antibody interactions enables the engineering of advanced TCEs that can precisely target common oncogenic mutations with exquisite specificity.

"We have the ability to redirect T cells to kill cancer cells while sparing healthy cells throughout the body," said Andrea Van Elsas, Ph.D., Partner at Third Rock Ventures and Chief Scientific Officer at Clasp. "Clasp’s proprietary technology enables immune targeting of intracellular oncogenic driver mutations to achieve durable tumor killing, even with low levels of surface presentation. Furthermore, the modularity of Clasp’s TCE platform gives it potential to address unmet need across a broad range of hard-to-treat tumor types."

Clasp’s TCEs are bispecific antibody-like molecules designed to simultaneously bind both a T cell and a tumor-specific mutant peptide, presented in the context of the patient’s HLA immune signature. A key aspect of this approach is Clasp’s ability to select patients for treatment by focusing on common tumor-specific driver mutations, including many that are unresponsive to standard immunotherapies. By binding both the T cell and the tumor cell with absolute specificity, this approach ensures immune activation against the tumor itself while sparing normal tissue, which lacks the tumor-specific mutated peptide.

"Clasp’s novel technology has tremendous potential to help the many cancer patients who are unable to benefit from existing treatments," said Jacob Vogelstein, Ph.D., and George Petrocheilos, Managing Partners of Catalio Capital Management. "We are excited to partner with Third Rock Ventures, Novo Holdings and the other members of the syndicate to support the company and advance immuno-oncology into a new era."

As part of the financing, Ray Camahort, Partner in the Venture Investments group at Novo Holdings U.S., and Jack Nielsen, Managing Partner of Vivo Capital, joined the Board of Directors.

On March 20, 2024 Agendia, Inc. reported new data from the I-SPY 2 trial showcasing its ImPrint signature for patients with triple negative (TN) breast cancer, shared by I-SPY 2 researchers in an oral presentation at the 14th European Breast Cancer Conference in Milan, Italy (Press release, Agendia, MAR 20, 2024, View Source [SID1234641310]). Agendia has been in partnership with Quantum Leap Healthcare Collaborative, the sponsors of the neoadjuvant biomarker-rich I-SPY 2 trial, since 2010. I-SPY 2 established a new benchmark for the efficacy of Phase 2 clinical trials and is widely regarded as the pioneer of the platform trial.

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The presentation, titled Immune subtyping in the Response Predictive Subtypes (RPS) identifies a subset of triple negative (TN) early-stage breast cancer patients with a very low likelihood of response to neoadjuvant immunotherapy (IO): results from 5 IO arms of the I-SPY 2 TRIAL (van ’t Veer, L, J., et al.), investigates the utility of a refined version of ImPrint, called ImPrintTN, designed to provide more accurate predictions to response to common immunotherapy (IO) regimens for TN patients. The study, examining the responses of patients who received a variety of IO regimens in the I-SPY 2 trial, showed that ImPrintTN predicts both response and non-response, suggesting that the test may help inform prioritization of IO versus other treatments for TN patients to best balance likely benefit versus the risk of the serious adverse effects that often accompany IO.

"Many immunotherapy treatments can have difficult, severe adverse side effects on patients that can outweigh the benefit of the treatment. It is imperative to understand what a patient’s response will be to these therapies prior to using them," said Laura van ‘t Veer, Professor of Laboratory Medicine, Co-leader of the Breast Oncology Program and Director of Applied Genomics at the Helen Diller Family Comprehensive Cancer Center, University of California, and Co-Founder of Agendia, Inc. "The data we are presenting at the European Breast Cancer Conference demonstrates ImPrintTN’s predictive ability to help patients with triple negative breast cancer avoid immunotherapy if they are not likely to benefit – these insights are critical and can be used to inform alternative treatment strategies and customize our approach to meet the needs of each patient’s cancer diagnosis."

ImPrint was developed to be used in the clinic to predict the likelihood of patients responding to immunotherapies by looking at the biology of the patient’s tumor. Agendia currently holds an FDA Investigational Device Exempt status for the ImPrint signature, allowing for its use in the I-SPY 2 trial and for other ongoing research with collaborators.

About the I-SPY TRIALs

The I-SPY TRIAL (Investigation of Serial studies to Predict Your Therapeutic Response with Imaging And moLecular analysis 2) (I-SPY 2 TRIAL) was designed to rapidly screen promising experimental treatments and identify those most effective in specific patient subgroups based on molecular characteristics (biomarker signatures). The trial is a unique collaborative effort by a consortium that includes the Food and Drug Administration (FDA), industry, patient advocates, philanthropic sponsors, and clinicians from over 40 major U.S. cancer research centers. Under the terms of the collaboration agreement, Quantum Leap Healthcare Collaborative is the trial sponsor and manages all study operations. For more information, visit www.ispytrials.org.

On March 20, 2024 Capstan Therapeutics, Inc. ("Capstan"), a biotechnology company dedicated to advancing in vivo reprogramming of cells through RNA delivery using targeted lipid nanoparticles (tLNP), reported the successful closing of a $175M oversubscribed Series B financing (Press release, Capstan Therapeutics, MAR 20, 2024, View Source [SID1234641309]).

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The Series B financing was led by RA Capital Management, with participation from new investors Forbion, Johnson & Johnson Innovation – JJDC, Mubadala Capital, Perceptive Advisors, and Sofinnova Investments. Capstan’s existing investors Alexandria Venture Investments, Bristol Myers Squibb, Eli Lilly and Company, Leaps by Bayer, Novartis Venture Fund, OrbiMed, Pfizer Ventures, Polaris Partners, and Vida Ventures, also participated in the round.

The proceeds from the Series B financing will be used to advance CPTX2309, Capstan’s lead in vivo chimeric antigen receptor T cell (CAR-T) candidate, to early clinical proof-of-concept in autoimmune disorders, and to further develop Capstan’s tLNP pipeline. CPTX2309, a product of Capstan’s tLNP platform, delivers an mRNA payload encoding for an anti-CD19 CAR to CD8-expressing T cells, effectively engineering CAR-T cells in vivo. The therapeutic goal of this approach is to achieve a reset of the immune system through rapid deep B cell depletion in both blood and lymphoid tissues, without the challenges of conventional ex vivo CAR-T.

"We are proud to support Capstan and their mission to lead in vivo CAR-T," said Nandita Shangari, Ph.D., Managing Director at RA Capital Management. "Our conviction in Capstan is a result of the confluence of a differentiated platform technology that enables efficient T cell engineering, the platform’s ideal application in a large autoimmune market being disrupted by ex vivo CAR-T therapy, and a seasoned management team that is working tirelessly to advance this technology into patients."

The Company also announced the appointment of Nanna Luneborg, Ph.D., MBA, General Partner at Forbion, to its Board of Directors. "This Series B financing brings together an exceptional syndicate of investors that recognize the potential of Capstan’s in vivo CAR-T technology," said Laura Shawver, Ph.D., President and Chief Executive Officer of Capstan. "We are grateful for the support of both new and existing investors as we enter a critical phase of execution, with the ultimate goal of bringing new therapeutic modalities to patients."

On March 20, 2024 Puma Biotechnology, Inc. (NASDAQ: PBYI), a biopharmaceutical company (the Company), reported that it has been notified by the U.S. Food and Drug Administration (FDA) that its Investigational New Drug Application (IND) submission has been reviewed, and Puma can proceed with the clinical development of alisertib for the treatment of patients with human epidermal growth factor receptor 2-negative (HER2-negative), hormone receptor-positive metastatic breast cancer in Puma’s Phase II ALISCA-Breast1 trial (Study PUMA-ALI-4201) (Press release, Puma Biotechnology, MAR 20, 2024, View Source [SID1234641308]). This trial will investigate alisertib in combination with endocrine treatment (consisting of either anastrozole, exemestane, letrozole, fulvestrant or tamoxifen) in chemotherapy-naïve patients with hormone receptor-positive, HER2-negative recurrent or metastatic breast cancer. Patients must have been previously treated with CDK 4/6 inhibitors and received at least two prior lines of endocrine therapy in the recurrent or metastatic setting to be eligible for the trial. Puma plans to initiate this trial in the second half of 2024.

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Patients will be dosed with alisertib given at either 30 mg, 40 mg or 50 mg twice daily on days 1-3, 8-10 and 15-17 on a 28-day cycle in combination with the endocrine therapy of the investigator’s choice. Patients must not have been previously treated with the endocrine treatment that will be given in combination with alisertib in the trial. Each dose level will enroll up to 50 patients. Patients must provide blood samples and tissue-based biopsies so that biomarkers can be evaluated. The primary efficacy end points will include objective response rate, duration of response, disease control rate and progression-free survival. As a secondary endpoint, the Company will be evaluating each of these efficacy endpoints within biomarker subgroups in order to determine whether any biomarker subgroup correlates with response. The goal would be to enhance the efficacy in a biomarker subgroup to improve the efficacy of alisertib as previously seen in preclinical and clinical studies in other cancers, including breast cancer and small cell lung cancer.

Once the optimal alisertib dose is identified, the Company plans to engage with global regulatory agencies regarding the design of a pivotal (Phase III) trial, which it anticipates will be a randomized trial of alisertib plus investigators choice endocrine therapy versus placebo plus investigator’s choice endocrine therapy in patients with chemotherapy naïve HER2-negative, hormone receptor-positive metastatic breast cancer.

"Although there have been new drugs approved for the treatment of ER-positive HER2-negative metastatic breast cancer, there continues to be a need for new drugs and ones that specifically can address patients who have been previously treated with CDK 4/6 inhibitors," said Alvin Wong, Pharm.D., Chief Scientific Officer of Puma Biotechnology. "The TBCRC 041 trial, which was published in JAMA Oncology in March 2023, demonstrated that alisertib is among the first investigational targeted therapies to have demonstrated encouraging clinical activity and have been generally well tolerated in the setting of endocrine and CDK 4/6 inhibitor resistant metastatic breast cancer. We look forward to the initiation of the ALISCA-Breast1 trial in the second half of 2024."

Alan H. Auerbach, Chief Executive Officer and President of Puma Biotechnology, said, "We are excited to move forward with the development of alisertib in HER2-negative hormone receptor-positive metastatic breast cancer. We believe that the data from TBCRC 041, which tested alisertib alone and with fulvestrant, and the randomized trial of alisertib plus paclitaxel versus paclitaxel alone have demonstrated that alisertib was active in patients with HER2-negative, hormone receptor-positive metastatic breast cancer and in biomarker focused subgroups. We also recognize our fiscal responsibility to the shareholders of the Company and will be carefully managing the development expenses for alisertib so as not to potentially negatively impact the Company’s profitability."

On March 20, 2024 Antennova, a clinical-stage biotech company focused on oncology reported completion of the first dosing cohort in the Phase I study for the anti-CD24 antibody, ATN-031 (also known as ATG-031) (Press release, Antengene, MAR 20, 2024, View Source [SID1234641307]). The dose escalation trial is evaluating ATN-031 in patients with advanced solid tumors or B-cell non-Hodgkin’s lymphoma (B-NHL), (NCT06028373). The PERFORM trial is being conducted at four cancer centers in the U.S., led by The University of Texas MD Anderson Cancer Center.

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A total of five late stage cancer patients have been enrolled based on the Bayesian Optimal Interval (BOIN) design of the trial in the first dosing cohort. To date, no dose-limiting toxicities (DLTs) have been reported among the 5 patients. Tumor shrinkage based on CT scan was observed in one heavily pre-treated patient (7 prior lines of therapy).

"Introducing the first anti-CD24 program for late stage cancer patients in the U.S. is a very important milestone for Antennova. We are especially grateful to the participation in the study by our patients and study centers, and encouraged to observe early clinical activity in this heavily pre-treated patient population based on clinical evaluation and translational data. We are working closely with study sites and investigators at MD Anderson, the University of California, San Francisco, the University of Colorado, and Yale University Cancer Center and look forward to providing periodic updates and presentations at major international medical conferences throughout the study." commented by Jay Mei, M.D., Ph. D., Founder and Chairman of the Board.

The PERFORM trial is a first-in-human, multi-center, open-label, Phase I dose-finding/escalation study of ATN-031 in patients with advanced solid tumors or B-NHL. The study’s primary objective is to evaluate the safety and tolerability of ATN-031 as a monotherapy, and determine the appropriate dose for Phase II studies. The secondary objective is to characterize the pharmacology, evaluate the immunogenicity, and assess the preliminary efficacy of ATN-031.

About ATN-031

ATN-031 is a first-in-class humanized anti-CD24 monoclonal antibody which inhibits the "don’t eat me" signal while stimulating the "eat me" signal, and enhances macrophage-mediated phagocytosis of cancer cells. Tumor cells evade the surveillance of the human immune system by over-expressing "don’t eat me" surface proteins that signal macrophages to prevent the detection and phagocytosis of cancer cells. CD24 is a prominent "don’t eat me" signal that plays a significant role in tumor immune evasion by suppressing macrophage-mediated phagocytosis. Compared to CD47, another "don’t eat me" target, CD24, has a more markedly restricted distribution in normal tissues and higher expression in cancerous tissues, especially solid tumors. Importantly, CD24 is differentiated from CD47 because it is not expressed on human red blood cells, allowing for a wider therapeutic window and minimal on-target-off-tumor toxicity.

CD24 acts as a novel innate immune checkpoint, orchestrating immune evasion through its interaction with the inhibitory receptor Siglec-10 (sialic-acid-binding Ig-like lectin 10), expressed on tumor-associated macrophages (TAMs). Preclinical data presented at the American Association for Cancer Research (AACR) (Free AACR Whitepaper) Annual Meeting in 2023 (AACR 2023) and the Society for Immunotherapy in Cancer Annual Meeting in 2022 (SITC 2022) demonstrated that ATN-031 can specifically bind to CD24 with nM affinity and block the interaction of CD24 and Siglec-10. Furthermore, ATN-31 induces efficient phagocytosis with a picomolar EC50 and stimulates the pro-inflammatory cytokines production by macrophages.