On December 11, 2022 Vincerx Pharma, Inc. (Nasdaq: VINC), a biopharmaceutical company aspiring to address the unmet medical needs of patients with cancer through paradigm-shifting therapeutics, reported that a poster presentation of preclinical data of Vincerx’s proprietary payload and linker technology and VIP943, the Company’s internalizing ADC targeting CD123, at the 64th American Society of Hematology (ASH) (Free ASH Whitepaper) Annual Meeting 2022 (Press release, Vincerx Pharma, DEC 11, 2022, View Source [SID1234625034]).

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VIP943 is a novel ADC, which binds to the IL3-receptor alpha chain (CD123). VIP943 combines the unique payload class of kinesin spindle protein inhibitors (KSPi) with a proprietary legumain-cleavable linker. Vincerx’s CellTrapper modification of the KSPi prevents diffusion out of the cell, allowing intracellular accumulation. The nonpermeability of the payload prevents off-target toxicities, leading to favorable efficacy and safety profiles.

"I am truly excited about the preclinical results for VIP943 and our proprietary payload and linker technology presented at ASH (Free ASH Whitepaper)," said Ahmed Hamdy, M.D., Chief Executive Officer of Vincerx. "For the first time, we showed a significant improvement in safety over an approved ADC, demonstrating in non-human primates the benefit of our KSPi payload and CellTrapper technology specifically designed to address some of the well-known challenges of ADCs on the market. The in vivo AML mouse model results also showed improved efficacy and survival for VIP943 in combination with venetoclax and azacitidine. This triple combination resulted in significant tumor regression as demonstrated by five complete responses and significantly prolonged survival time without increased toxicity," added Dr. Hamdy.

Dr. Anthony Tolcher, M.D., Chief Executive Officer, Founder and Director of Clinical Research at NEXT Oncology, added, "This ADC is innovative and exciting. The target is well understood and the novel payload that targets myeloid cells suggests this could be a valuable agent for patients with AML."

"Current standard of care for AML patients is combination therapy with venetoclax and azacitidine, yet most patients eventually relapse with progressive disease. The efficacy and safety data for VIP943 we see in our studies suggest it may be a promising option for treating AML as a monotherapy in relapse/refractory elderly, unfit and high-risk patients as well as in combination with venetoclax and azacitidine. Our results also provide compelling evidence that VIP943 represents a substantial advancement and potential paradigm-shift in ADC technology. We look forward to continuing to advance the IND-enabling studies for VIP943 and expect to file our IND in mid-2023," concluded Dr. Hamdy.

Key Presentation Highlights:

Poster presentation titled, "VIP943 is a Novel CD123 Antibody Drug Conjugate with In Vitro and In Vivo Efficacy in Acute Myeloid Leukemia (AML) Models", presented by Beatrix Stelte-Ludwig, Ph.D., Vincerx Pharma GmbH, Monheim, Germany, includes:

Bone marrow samples derived from patients with AML were used to evaluate VIP943 monotherapy at different concentrations (0.1 pM to 1µM) in a depletion (without cytokine addition) and a proliferation assay. Combination treatment of VIP943 (using 8 different doses) and venetoclax (one fixed dose of 16.5 nM) was evaluated. All patient samples were analyzed by flow cytometry and were positive for CD123 cell surface expression. In the depletion assay, only the samples which showed spontaneous proliferation were sensitive to VIP943 treatment in accordance with the mode of action of the KSPi payload.

In a patient-derived AML xenograft model, the triple combination of VIP943 with venetoclax and azacitidine increased the number of complete responses (56% vs 22%) and the overall survival (>107 vs 83 days) compared with venetoclax and azacitidine.

VIP943 did not induce cytokine release in a human cytokine release assay when compared with positive controls. One dose of VIP943 in an immunophenotyping study in NHP resulted in a reversible reduction in CD123+ basophils.
In a NHP safety study, a newly generated ADC using a gemtuzumab biosimilar as the targeting antibody conjugated to our effector chemistry comprised of a proprietary linker and payload (Gem-KSPi ADC) and VIP943 (anti-CD123-KSPi ADC) were directly compared with Mylotarg.

CD33+/CD123+ basophils showed an expected decrease across treatments; however, the VIP943 and Gem-KSPi ADC groups demonstrated a full recovery over the observation period, whereas Mylotarg showed an increased severity. Over time, a significant deleterious effect was seen with a single dose of Mylotarg on platelets, WBC count, reticulocytes, hemoglobin, hematocrit and lymphocytes. In contrast, a single dose of Gem-KSPi ADC and VIP943 showed no effects on hematology parameters other than the aforementioned transient reduction of CD123+ basophils.

Evaluation of serum chemistry showed increases in liver function enzymes, bilirubin and urea nitrogen in the Mylotarg group. The female monkey treated with Mylotarg died before the end of the observation period and the male monkey had to be euthanized. All monkeys from the Gem-KSPi ADC and VIP943 groups were healthy and returned to the colony with no remarkable changes in serum chemistry.
Overall, these results demonstrate the substantial advancement in ADC technology with the development of VIP943. Further IND-enabling studies are ongoing, and the Company expects to file an IND in mid-2023.
A copy of this presentation can now be accessed on the Investors section of the Company’s website at www.vincerx.com. Other Vincerx presentations related to enitociclib will be available on the company website on Monday, December 12 at 9:00AM CST.