VIP943 Generates Early Complete Responses, Is Safe in Advanced CD123+ Hematologic Malignancies

VIP943, a next-generation antibody-drug conjugate (ADC), generated initial complete responses (CRs) and demonstrated tolerability among patients with advanced CD123-positive hematologic malignancies, according to early data from an ongoing phase 1 dose-escalation study (NCT06034275).¹

Responders included 1 patient with relapsed acute myeloid leukemia (AML), who achieved a CR with incomplete hematologic improvement, and 1 patient with high-risk myelodysplastic syndrome (HR-MDS), who achieved a CR with limited count recovery per international consensus response criteria.

Among the 22 patients treated with escalating doses of VIP943 at 0.2 mg/kg to 1.3 mg/kg once weekly in the study to date, 9 patients (6 with AML, 3 with HR-MDS) were treated with at least 3 doses of VIP943 at efficacious doses of 1.0 mg/kg or greater. Four of these patients remain on study to date. These patients represent those with difficult-to-treat tumors, which do not typically respond to salvage monotherapy.

Additional data from the study are expected to read out by the end of 2024.

VIP943 comprises an anti-CD123 antibody, a legumain-cleavable linker, and a novel kinesin spindle protein inhibitor payload. This proprietary effector chemistry is designed to limit non-specific payload release, ensuring that the payload accumulates primarily in tumor cells rather than healthy cells. This approach could improve the therapeutic index of VIP943 and mitigate severe toxicities commonly associated with many ADCs.

“We are excited by the emerging data from our phase 1 study of VIP943, showing clinical responses in difficult-to-treat patients,” Ahmed Hamdy, MD, chief executive officer of Vincerx, the drug’s developer, stated in a news release. “We believe these promising clinical responses highlight the potential of VIP943 as a best-in-class therapy for CD123-positive hematologic malignancies and validate our VersAptx platform’s ability to create safer, more effective bioconjugates by overcoming the challenges of historical ADCs.”

Trial Overview

The open-label, multicenter, phase 1 dose-escalation study is evaluating VIP943 as a monotherapy in patients with histologically confirmed AML, HR-MDS, or B-cell acute lymphoblastic leukemia who have exhausted all available standard therapies or are not candidates for other available therapies.² Patients must have an ECOG performance status of 0 to 2. Exclusion criteria include known central nervous system metastases and/or carcinomatous meningitis, and clinically significant cardiac disease.

Upon enrollment onto the dose-escalation arm, patients will receive weekly intravenous infusions of VIP-943 in sequential, ascending doses.

The study’s primary end point is the incidence of dose-limiting toxicities (DLTs). Response rates, maximum observed drug concentration after single-dose administration, and area under the curve serve as secondary end points.

Additional Safety and Pharmacokinetic Data

Regarding pharmacodynamics, the agent has demonstrated receptor occupancy through binding to CD123-positive peripheral blood blasts in patients with AML.¹ In the highest dose cohort (1.3 mg/kg), maximal receptor occupancy reached 84%, with retention lasting less than 96 hours across all cohorts. Concurrent decreases in CD123-positive peripheral blood blasts were noted following dosing, indicating effective binding and elimination of CD123-positive malignant cells. Pharmacokinetically, VIP943 shows minimal payload release (≤ 1% in plasma) and a half-life of less than 96 hours, with no accumulation on repeat dosing. Based on these results, a twice-weekly dosing scheduled for VIP943 is being evaluated as a potential induction regimen. Enrollment onto both the once-weekly and twice-weekly dosing cohorts is ongoing.

Dr Hamdy noted that, “Our initial clinical results demonstrate that VersAptx is a next-generation platform that overcomes key challenges associated with traditional ADCs. The pharmacokinetic profile shows that our linker is stable, cleaving exclusively inside cells without extracellular degradation. Our pharmacodynamic 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.”

As of August 2024, VIP943 has shown a favorable safety profile and has been well tolerated in this patient population. No DLTs have been reported, and the incidence of serious adverse effects (SAEs) has been as expected. The most frequently reported SAEs comprise pneumonia (14%), cellulitis (9%), and febrile neutropenia (9%). Treatment-related SAEs were observed in 1 patient, who experienced grade 3 diarrhea.

“Although [these are] still early data, VIP943 is clearly differentiated from other ADCs, particularly with its favorable safety profile,” ​​M. Yair Levy, MD, director of Hematologic Malignancies Research at Texas Oncology, concluded. “We’re not seeing neutropenia as a DLT, which is encouraging and may allow the drug to move into earlier lines of therapy in combination [regimens]. I look forward to the continued development of VIP943 and its potential to improve treatment options for patients with CD123-positive malignancies.”

References

1. Vincerx reports positive initial clinical data from ongoing VIP943 phase 1 dose-escalation study and provides pipeline and corporate updates.News release. Vincerx Pharmaceuticals. October 7, 2024. Accessed October 9, 2024. https://investors.vincerx.com/news-releases/news-release-details/vincerx-reports-positive-initial-clinical-data-ongoing-vip943
2. Study of VIP943 in subjects with advanced CD123+ hematologic malignancies. ClinicalTrials.gov. Updated January 12, 2024. Accessed October 9, 2024. https://clinicaltrials.gov/study/NCT06034275?term=vip943&rank=1