KIF11

Poster on VIP943, a novel CD123-targeted antibody-drug conjugate (ADC) from our VersAptx™ platform, showcases selectivity, activity, and safety of VIP943 Poster on VIP924, a first-in-class CXCR5-targeted ADC from our VersAptx platform, shows superior activity and safety compared with commercially available B-cell targeted ADCs PALO ALTO, Calif., Dec. 10, 2023 (GLOBE NEWSWIRE) -- Vincerx Pharma, Inc. (Nasdaq: VINC)(“Vincerx”), a biopharmaceutical company aspiring to address the unmet medical needs of patients with cancer through paradigm-shifting therapeutics, today announced the presentation of two preclinical posters at the 65th Annual Meeting of the American Society for Hematology (ASH 2023) for VIP943, for leukemias and myelodysplastic syndrome, and VIP924, for B-cell malignancies. “We are excited to share new preclinical data for VIP943 and VIP94 with our stakeholders,” said Ahmed Hamdy, M.D., Chief Executive Officer of Vincerx. “The compelling data from these studies underscore the differentiation of our next-generation ADCs and the power of VersAptx, our versatile and adaptable bioconjugation platform used to develop these ADCs.” “The preclinical data from the VIP943 poster highlight the on-target selectivity and activity of VIP943 in acute myeloid leukemia (AML) cell lines, including those with common AML mutations such as TP53. We also show that repeat dosing of VIP943 in cynomolgus monkeys has good overall tolerability without the myelosuppression and hepatotoxicity typically associated with ADCs, which is consistent with the favorable safety profile seen to date in our VIP943 Phase 1 dose-escalation trial. The first dosing cohort enrolled rapidly and completed the 28-day safety evaluation without evidence of drug-related adverse events. One of the three patients from this cohort continues treatment, and the second cohort is enrolling.” “The preclinical data from the VIP924 poster highlight the superior efficacy of VIP924 when compared with two commercially available ADCs, Polivy® and Zynlonta®, in a mouse model of mantle cell lymphoma. In this study, VIP924 shows significant efficacy (i.e., significant tumor growth inhibition and increased survival) with no substantial change in body weight, an indication of safety, while Polivy and Zynlonta show no improvement in tumor growth inhibition or survival. Based on the side-effect profile of current ADC and CAR-T therapies for B-cell malignancies, we believe VIP924 may have the potential to be used in earlier lines of therapy, either as a monotherapy or in combination with other targeted drugs (e.g., BTK or BCL2 inhibitors), to improve efficacy and safety,” concluded Dr. Hamdy. Poster Highlights VIP943: CD123-KSPi ADC for leukemias and myelodysplastic syndrome Poster #1435: Selectivity and Safety of VIP943: A novel CD123 Targeting Antibody-Drug Conjugate (ADC) Using a Proprietary Linker and Payload Class. Objective: The poster outlines a series of assays used to characterize the preclinical properties of VIP943, including biochemistry, pharmacology, on-target selectivity and activity, safety, and toxicokinetics. Results: On-target selectivity and activity show that VIP943 is highly selective for the kinesin spindle protein (KSP) target, aka EG5, versus other members of the related KIF super family. This on-target activity translates to cell cycle arrest at the G2/M phase of mitosis, resulting in apoptosis in AML cell lines.In vitro cytotoxicity assays show that most hematologic cell lines (n=56) are sensitive to VIP943’s payload and that DNA alterations (including common AML mutations such as TP53) did not reduce its cytotoxicity.Nonhuman primate safety and toxicokinetic studies show that repeat dosing of VIP943 in cynomolgus monkeys has good overall tolerability without the myelosuppression and hepatotoxicity seen with other ADCs. This is consistent with the favorable safety profile seen to date in the VIP943 Phase 1 dose-escalation trial. VIP924: CXCR5-KSPi ADC for B-cell malignancies Poster #2809: Comparison of the CXCR5-Antibody Drug Conjugate (ADC; VIP924) to a CD19-ADC and a CD79b-ADC in a Humanized REC-1 Mantle Cell Lymphoma (MCL) Mouse Model. Objective: To evaluate target expression (CXCR5, CD19, and CD79b) in human patient samples and to compare the activity of VIP924 to two commercially available, B-cell targeted ADCs, Polivy (a CD19-ADC, polatuzumab vedotin) and Zynlonta (CD79b-ADC, loncastuximab tesirine), in a humanized mouse model of MCL by evaluating in vivo activity, immunophenotyping of key tissues, and complete blood counts. VIP924 data are based on a dose level of 10 mg/kg compared with 3 mg/kg for Polivy and 0.66 mg/kg for Zynlonta. Doses were selected based on the literature as effective doses in mouse xenograft experiments and higher doses lead to toxicity in these models. Tumor growth was measured at day 25; blood work was assessed at days 0, 5, and 18. Results: Target expression analysis in a panel of 20 human MCL samples shows that CXCR5 and CD19 expression was medium to high in all samples, while CD79b showed slightly lower expression.In vivo activity in a humanized mouse model shows that VIP924 demonstrates significant efficacy (i.e., tumor growth inhibition and increased survival) with no substantial change in body weight (an indication of safety). In comparison, the commercially available ADCs, Polivy and Zynlonta, show no improvement in tumor growth inhibition or survival in this setting. Immunophenotyping of key immune tissues show that: VIP924 treatment yielded no difference in the percent of CD45+ cells versus the control, while the other two ADCs showed a clear reduction in CD45+ cells.VIP924 treatment reduced T-follicular helper cells (Tfhs) in the blood, tumor and spleen; significantly increased T-regs; and had no meaningful impact on myeloid-derived suppressor cells (MDSCs) compared with controls. Zynlonta also reduced peripheral blood Tfhs and significantly increased MDSCs compared with control. Complete blood counts (CBCs) show that VIP924 had minimal impact on the six elements of the CBC reported in these studies. Zynlonta reduced the levels of all cell populations in the CBC, except for platelets. About VIP943 VIP943, the first ADC from our VersAptx platform, consists of an anti-CD123 antibody, a unique linker cleaved intracellularly by legumain, and a novel kinesin spindle protein inhibitor (KSPi) payload enhanced with our CellTrapper® technology. Our proprietary effector chemistry (linker + payload) was designed to reduce non-specific release of the payload and ensure payload accumulation in cancer cells versus healthy cells. The increased therapeutic index has the potential to address challenges associated with many ADCs by improving efficacy and reducing severe toxicities. VIP943 is in a Phase 1 dose-escalation trial evaluating patients with relapsed/refractory acute myeloid leukemia, myelodysplastic syndrome, and B-cell acute lymphoblastic leukemia who have exhausted standard therapeutic options (NCT06034275). We expect to expand into these CD123-positive indications, including TP53 mutated AML both as monotherapy and in combination, as safety and efficacy data are generated. Preliminary Phase 1 data are expected in mid-2024. About VIP924 VIP924, the second ADC from our VersAptx Platform, consists of an anti-CXCR5 antibody, a unique linker cleaved intracellularly by legumain, and a novel KSPi payload enhanced with our CellTrapper technology. Our proprietary effector chemistry (linker + payload) was designed to reduce non-specific release of the payload and ensure payload accumulation in cancer cells versus healthy cells. The increased therapeutic index has the potential to address challenges associated with many ADCs by improving efficacy and reducing severe toxicities. VIP924 has the potential to be evaluated in B-cell malignancies, such as mantle cell lymphoma, follicular lymphoma, diffuse large B-cell lymphoma (DLBCL), and chronic lymphocytic leukemia, both as monotherapy and in combination. We continue to judiciously pace our investment in VIP924 to focus resources on VIP236 and VIP943. About VersAptx Platform VersAptx is our versatile and adaptable, next-generation bioconjugation platform. The modular nature of this innovative platform allows us to combine different targeting, linker, and payload technologies to develop bespoke bioconjugates to address different cancer biologies. With this platform (i) antibodies and small molecules can be used to target different tumor antigens (ii) linkers can be designed to reduce non-specific release of the payload, cleave intracellularly or extracellularly, and conjugate to single or multiple payloads, and (iii) payloads can be designed with reduced permeability using our CellTrapper technology to ensure accumulation in cancer cells or to be permeable for release in the tumor microenvironment. The VersAptx platform allows us to optimize these technologies to a specific target and develop bioconjugates designed to address the safety and efficacy challenges of many ADCs and the needs of cancer patients. About Enitociclib Enitociclib is a highly selective CDK9 inhibitor that prevents activation of RNA polymerase II, resulting in reduction of known oncogenes MYC and MCL1. It is currently in a dose-escalation Phase 1 trial (NTC05371054) in collaboration with the National Institutes of Health evaluating the combination of enitociclib, venetoclax, and prednisone in DLBCL and peripheral T-cell lymphoma (PTCL). The first dose level completed enrollment with no drug-related safety signal (n=3; 1=DLBCL, 2=PTCL). The first patient on the second dose level (n=1; 1=PTCL) remains on study with a partial response due to an 80% reduction in the pulmonary lesion on computerized tomography (CT) scan and resolved skin lesions. Investigators are pleased with the safety profile of this novel combination and continue with enrollment. Early-stage clinical studies in patients with hematologic malignancies and solid tumors provided monotherapy proof-of-concept. Additional combination studies will be determined based on financing/partnering support. About Vincerx Pharma, Inc. Vincerx Pharma, Inc. is a clinical-stage biopharmaceutical company committed to developing differentiated and novel therapies to address the unmet medical needs of patients with cancer. Vincerx has assembled a seasoned management team with a proven track record of successful oncology drug development, approvals, and value creation. Vincerx’s diverse pipeline consists of the next-generation antibody-drug conjugate, VIP943, in Phase 1; small molecule-drug conjugate, VIP236, in Phase 1; preclinical antibody-drug conjugate, VIP924; CDK9 inhibitor, enitociclib, in an NIH-sponsored Phase 1; and VersAptx, its versatile and adaptable, next-generation bioconjugation platform. Vincerx is based in Palo Alto, California, and has a research facility in Monheim, Germany. For more information, please visit www.vincerx.com. 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Forward-looking statements include, but are not limited to: Vincerx’s business model, pipeline, strategy, timeline, product candidates and attributes, and preclinical and clinical development, timing, and results. Forward-looking statements are neither historical facts nor assurances of future performance or events. Instead, they are based only on current beliefs, expectations, and assumptions regarding future business developments, future plans and strategies, projections, anticipated events and trends, the economy, and other future conditions. Forward-looking statements are subject to inherent uncertainties, risks, and changes in circumstances that are difficult to predict and many of which are outside of Vincerx’s control. Actual results, conditions, and events may differ materially from those indicated in the forward-looking statements. Therefore, you should not rely on any of these forward-looking statements. Important factors that could cause actual results, conditions, and events to differ materially from those indicated in the forward-looking statements include, but are not limited to: general economic, financial, legal, political, and business conditions; risks associated with preclinical or clinical development and trials, including those conducted prior to Vincerx’s in-licensing; failure to realize the benefits of Vincerx’s license agreement with Bayer; risks related to the rollout of Vincerx’s business and the timing of expected business and product development milestones; changes in the assumptions underlying Vincerx’s expectations regarding its future business or business model; Vincerx’s ability to successfully develop and commercialize product candidates; Vincerx’s capital requirements and availability and uses of capital; and the risks and uncertainties set forth in Form 10-Q for the quarter ended September 30, 2023 and other reports filed with the Securities and Exchange Commission by Vincerx. Forward-looking statements speak only as of the date hereof, and Vincerx disclaims any obligation to update any forward-looking statements. Vincerx, the Vincerx logo, CellTrapper, and VersAptx are our trademarks. This press release also contains trademarks and trade names that are the property of their respective owners. Contacts Joyce LonerganLifeSci Advisors, LLC781-528-5276jlonergan@lifesciadvisors.com

The overexpression of a gene tied to cell division and the structure and function of neurons may prevent and protect against cognitive decline in both mice and humans with Alzheimer's disease (AD), according to a new study. The overexpression of a gene tied to cell division and the structure and function of neurons may prevent and protect against cognitive decline in both mice and humans with Alzheimer's disease (AD), according to a new study by scientists at the University of Colorado Anschutz Medical Campus. The gene, Kinesin-5 or KIF11, does this despite the presence of amyloid beta (Abeta), the main component of plaques in the brains of those with AD. Scientists have traditionally targeted the plaques when looking for treatments for the fatal disease. In this case, they went around them. The study was published online last week in the journal iScience. "Overexpressing KIF11 in mice did not affect the amyloid levels in the brain," said the study's co-senior author Huntington Potter, PhD, professor of neurology and director of the University of Colorado Alzheimer's and Cognition Center and of Alzheimer's research at the Linda Crnic Institute for Down Syndrome at the University of Colorado School of Medicine. "Yet they were still cognitively normal despite the plaques. This is one of the best indications that you can maintain cognition without getting rid of the plaques." KIF11 is a motor protein best known for its role in mitosis or cell division in non-neuronal cells. But it also plays a critical role in the formation of the dendrites and dendritic spines of neurons, which are used to communicate with other neurons and are important for learning and memory. Yet the main component of Alzheimer's plaques, Abeta, can inhibit KIF11 and cause damage to these structures. The researchers found that overexpressing the gene in mice with AD led to improved performance on cognitive tests compared to AD mice with normal levels of KIF11. Then they analyzed genetic data from human AD patients provided by the Religious Orders Study and the Rush Memory and Aging Project (ROS/MAP) at Rush University in Chicago. They wanted to know if naturally occurring variations in KIF11 levels correlated with better cognitive performance in adults with or without amyloid plaques. "Our results from analyzing the human data indicate that higher levels of KIF11 correlate with better cognitive performance in a cohort of older adults with amyloid pathology," said the study's lead author Esteban Lucero, PhD, from the University of Colorado School of Medicine. "Thus, our results suggest that higher KIF11expression levels may partially prevent cognitive loss during the course of AD in humans, which aligns with our findings regarding the role of KIF11 in animal models of AD," Lucero said. Potter and co-senior author Heidi Chial, PhD, assistant professor of neurology and director of grant strategy and development at the University of Colorado Alzheimer's and Cognition Center, said this information paves the way for researchers to begin testing new or existing drugs that can safely create this effect in humans. "Many current experimental treatments for AD have focused on reducing Abeta production or on increasing the clearance of Abeta plaques," Chial said. "Most of these approaches have failed to prevent or reverse cognitive decline in clinical trials. Clearly, alternative approaches to the development of AD therapeutics are needed."