On October 7, 2024 Vincerx Pharma, Inc. (Nasdaq: VINC), a biopharmaceutical company aspiring to address the unmet medical needs of patients with cancer through paradigm-shifting therapeutics, reported two complete responses in the ongoing first-in-human, Phase 1 dose-escalation study of VIP943, the Company’s next-generation antibody-drug conjugate (ADC) being evaluated in relapsed/refractory acute myeloid leukemia (AML), higher-risk myelodysplastic syndrome (HR-MDS), and B-cell acute lymphoblastic leukemia (B-ALL) (Press release, Vincerx Pharma, OCT 7, 2024, View Source [SID1234647064]). The Company also provided pipeline and corporate updates.
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VIP943 Data Highlights
The ongoing Phase 1 dose-escalation study of VIP943 has enrolled 22 patients to date across several escalating dose cohorts (0.2 to 1.3 mg/kg once weekly). These 22 patients represent a ‘hard-to-treat’ salvage population, which rarely responds to monotherapy. Nine patients (six AML; three HR-MDS) have received at least three doses of an efficacious dose of VIP943 (i.e., ≥1.0 mg/kg). Of these nine patients, four (44%) remain on study. So far, one patient with relapsed AML has achieved complete remission with incomplete hematologic improvement (CRi) and one patient with HR-MDS has achieved complete remission with limited count recovery (CRL) based on international consensus response criteria. These response criteria are widely recognized as an approvable benchmark in AML and MDS studies, further underscoring the significance of these early results.
"We are excited by the emerging data from our Phase 1 study of VIP943, showing clinical responses in difficult-to-treat patients," said Ahmed Hamdy, M.D., Chief Executive Officer of Vincerx. "We believe these promising clinical responses highlight the potential of VIP943 as a best-in-class therapy for CD123+ hematologic malignancies and validate our VersAptx platform’s ability to create safer, more effective bioconjugates by overcoming the challenges of historical ADCs."
As of August 2024, VIP943 has shown favorable safety and tolerability, with no dose-limiting toxicities reported in 22 patients. Serious adverse events (SAEs) have been consistent with expectations for this patient population. The most common SAEs included pneumonia (three patients, 14%), and cellulitis and febrile neutropenia (two patients each, 9%). Only one patient (5%) experienced a drug-related SAE (Grade 3 diarrhea).
Target engagement (i.e., receptor occupancy) has been demonstrated by binding of VIP943 to CD123+ peripheral blood blasts from patients with AML from the Phase 1 study. Maximal receptor occupancy of 84% was achieved in the highest dose cohort (1.3 mg/kg). Across all the cohorts, receptor occupancy was retained for less than 96 hours. Concurrent decreases in CD123+ peripheral blood blasts were also observed after dosing. These pharmacodynamic (PD) markers show that VIP943 is binding to and eliminating CD123+ malignant cells. Preliminary pharmacokinetic (PK) data continues to show low release of payload (≤1% in plasma). The half-life of VIP943 is less than 96 hours, and no accumulation occurs with repeat dosing. These PK and PD results have prompted evaluation of twice weekly dosing of VIP943 as a potential "induction" regimen. Enrollment in the once weekly and twice weekly dosing cohorts is ongoing.
Dr. Hamdy continued, "Our initial clinical results demonstrate that VersAptx is a next-generation platform that overcomes key challenges associated with traditional ADCs. The PK profile shows that our linker is stable, cleaving exclusively inside cells without extracellular degradation. Our PD results coupled with clinical responses confirm the payload effectively kills cancer cells in peripheral blood and bone marrow without harming nearby healthy tissue. This innovative design with proof-of-concept in Phase 1 reinforces our confidence in VersAptx as a transformative platform for ADC development."
The company anticipates providing another data update on the ongoing Phase 1 VIP943 study by the end of the year.
Dr. M. Yair Levy, Director of Hematologic Malignancies Research at Texas Oncology added, "Although this is still early data, VIP943 is clearly differentiated from other ADCs, particularly with its favorable safety profile. We’re not seeing neutropenia as a dose-limiting toxicity, which is encouraging and may allow the drug to move into earlier lines of therapy in combination. I look forward to the continued development of VIP943 and its potential to improve treatment options for patients with CD123+ malignancies."
VIP236 Update
VIP236 is Vincerx’s first-in-class small molecule drug conjugate (SMDC) being evaluated in an ongoing first-in-human, Phase 1 dose-escalation study as a monotherapy in patients with advanced solid tumors. As of September 2024, 29 patients have been enrolled. Of these patients, 20 were evaluable per-protocol for response from the every 2- or 3-week schedule; nine of 20 patients had stable disease for a disease control rate of 45%. In addition, one of these subjects has been on treatment for over 300 days and four additional patients were on study for more than 120 days, demonstrating promising monotherapy duration of response in patients with advanced cancer. VIP236 continued to show a favorable safety and tolerability profile in these 29 patients, with no instances of the dose-limiting side effects commonly associated with camptothecins, such as life-threatening diarrhea, severe stomatitis/mucositis, or interstitial lung disease. These results support the potential role of VIP236 as a strong combination agent for the treatment of advanced cancers.
Considering the promising VIP236 clinical data, the Company intends to pursue a strategic partner to champion its future development for the benefit of patients.
"We’ve made significant progress in identifying an effective dose and schedule. We believe it is now crucial to study VIP236 in the right patient population, which could include triple-negative breast cancer and gastric cancer, where camptothecins are used, especially in combination with other anticancer agents," added Dr. Hamdy.
By transitioning VIP236 to a partnering asset, the Company plans to streamline its operations and focus its efforts on the continued development of its lead ADC, VIP943.
Enitociclib Update
Enitociclib, a highly selective CDK9 inhibitor, is currently being evaluated in a Phase 1 dose-escalation study in combination with venetoclax and prednisone for relapsed/refractory diffuse large B-cell lymphoma (DLBCL) and peripheral T-cell lymphoma (PTCL), in collaboration with the National Institutes of Health (NIH). As of September 2024, the study reported four partial responses (PRs) in seven patients (57% overall response rate), including one patient with double hit lymphoma (DH-DLBCL) and three patients with PTCL. All responses occurred in patients considered refractory by SCHOLAR-1 criteria and included one patient with prior CAR-T therapy. The study is currently enrolling in the third dose level (enitociclib 30 mg [efficacious dose] and venetoclax 600 mg) with two patients enrolled to date.
Additionally, in a separate Phase 1 study of enitociclib as a monotherapy (30 mg), one patient with transformed follicular lymphoma achieved a metabolic PR. As of September 2024, this patient remains on enitociclib monotherapy after more than 26 months. Overall, these clinical results continue to show the promising safety, tolerability, and efficacy of enitociclib for the treatment of relapsed/refractory lymphoma. The Company is actively focused on finding a strategic partner to continue the development of this asset.
Corporate Webcast
Vincerx will host a corporate webcast today at 5:00 PM EDT. The webcast will provide a pipeline and corporate update, including discussing the initial clinical data from the Phase 1 dose-escalation study of VIP943, followed by commentary with key opinion leader, Dr. M. Yair Levy (Texas Oncology), and live Q&A with Vincerx leadership.
The webcast may be accessed through the "Corporate Overview & Events" in the Investors section of the Company’s website, located at investors.vincerx.com. An archived replay will be available shortly following the webcast.
About VIP236
VIP236, the first-in-class SMDC from the VersAptx Platform, consists of an αvβ3 integrin binder, a neutrophil elastase linker cleaved in the tumor microenvironment, and a camptothecin payload optimized for high permeability and low active efflux. VIP236 was designed to deliver its payload to advanced/metastatic solid tumors that express αvβ3. VIP236 is being evaluated in a first-in-human, Phase 1 dose escalation study in patients with advanced malignancies (NCT05712889).
About VIP943
VIP943, the first ADC from the 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 Vincerx’s CellTrapper technology. Vincerx’s 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 being evaluated in a Phase 1 dose-escalation trial in patients with relapsed/refractory AML, HR-MDS, and B-ALL who have exhausted standard therapeutic options (NCT06034275).
About Enitociclib
Enitociclib, a highly selective CDK9 inhibitor, is currently being evaluated in a Phase 1 dose-escalation study (NCT05371054) in combination with venetoclax and prednisone for DLBCL and PTCL, in collaboration with the NIH. Enitociclib has demonstrated favorable safety and PK, with significant clinical benefits across various indications, including durable complete metabolic remissions in patients with double-hit (DH)-DLBCL and stable disease in solid tumors, notably in ovarian cancer, suggesting promising potential for future combination studies.
About VersAptx Platform
VersAptx is a versatile and adaptable next-generation bioconjugation platform. The modular nature of this innovative platform allows the combination of different targeting, linker, and payload technologies to develop bespoke bioconjugates that 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 the development of bioconjugates designed to address the safety and efficacy challenges of historical ADCs.