APVO436 (anti-CD123 x anti-CD3)

Description

APVO436 is an optimized ADAPTIR bispecific antibody candidate designed to redirect T-cell cytotoxicity through the dual targeting of CD3, a T-cell co-receptor that promotes cytotoxicity, and CD123, a cell surface receptor highly expressed in several hematological malignancies, including acute myeloid leukemia, acute lymphoblastic leukemia, hairy cell leukemia, myelodysplastic syndrome, and blastic plasmacytoid dendritic cell neoplasm.

Aptevo is currently testing APVO436 in a Phase 1/1b open label clinical trial in patients with Acute Myeloid Leukemia (AML) and High-Grade Myelodysplastic Syndrome (MDS).

APVO436 is currently being evaluated for the treatment of acute myeloid leukemia (AML) and myelodysplastic syndromes (MDS) in a Phase 1b multi-center, multi-arm open-label clinical trial.

Multi-Part, Multi-Center Phase 1 Trial Overview

Dose escalation: Determine recommended Phase 2 dose (RP2D) for the Expansion part of the trial.
Administration: Intravenous (IV) dosing weekly for six 28-day cycles.
Subjects: 46
Status: Aptevo reported positive data from the escalation part of the trial on May 26, 2021. (Add live link to the PR on website)
Dose Expansion: Assess clinical activity at recommended dose (Initiated)
Administration: IV administration, 4 cycles of therapy. Each cycle consists of four weekly infusions over 28 days
Subjects : 5 cohorts of 18 patients per cohort (N=90)
Trial Status: Aptevo reported activation of the expansion part of the trial on May 27, 2021 (Add live link to the PR on website)

Summary of Dose Escalation Trial Results
The trial included 46 patients with AML or MDS. The primary endpoint, identification of the recommended Phase 2 dose (RP2D), was achieved. Additionally, APVO436 demonstrated manageable side effects and was well tolerated in the patient population. Signs of clinical activity – both stabilization of leukemia and complete remissions, were also observed.

Summary of Dose Expansion Trial Structure
Aptevo announced activation of the Part 2/Expansion phase of the APVO436 trial on May 27, 2021. This phase will evaluate 90 patients in 5 distinct cohorts of 18 AML patients in both combination and monotherapy settings at up to 20 clinical trial sites in the U.S.
The expansion part of the Phase 1b trial has been purposefully designed to produce a maximum amount of data to inform the advanced clinical program in the shortest time.

Overview of Cohorts

Cohort 1
Combination therapy in relapsed patients and those with primary, refractory AML with leukemia that failed to respond to frontline standard induction chemotherapy.

Cohort 2
Combination therapy for AML patients in first relapse and as frontline in newly diagnosed AML patients with poor prognosis.

Cohort 3
Monotherapy for consolidation after induction chemotherapy in AML patients with poor prognosis and AML patients with early first relapse (within one year of receiving frontline therapy).

Cohort 4
Combination therapy in AML patients who are in first remission with residual leukemia.

Cohort 5
Monotherapy in AML patients who are in second remission with residual leukemia.

Preclinical Development

In preclinical studies, APVO436 was shown to redirect T-cell cytotoxicity against CD123-expressing tumor cells in both in vitro and in vivo assays. These data show that APVO436:

Has an antibody-like serum half-life in mice of up to 12.5 days – significantly longer than first generation ADAPTIR candidates and other bispecific candidates in development
Induced potent, dose-dependent T-cell mediated lysis (killing) of CD123-expressing AML cell lines, accompanied by target-specific T-cell activation and proliferation
Possesses low (nM) binding affinity; bound with high affinity to human and cynomolgus CD123-expressing cells with EC50 values in the low nanomolar range
Dose-dependently inhibited tumor growth and significantly prolonged survival compared to vehicle-treated animals in a Xenograft tumor model of AML

Preclinical data presented at the 2018 and 2019 American Association for Cancer Research Annual Meeting compared APVO436 with an Aptevo-generated version of Macrogenics’ CD123 x CD3 dual-affinity re-targeting (D.A.R.T.) molecule, MGD006. This preclinical study evaluated T-cell activation, proliferation, cytotoxicity and cytokine secretion.

The data showed that APVO436 and the Aptevo-generated version of MDG006 were both effective at stimulating a tumor-directed immune response by inducing comparable T-cell activation, proliferation and cytotoxicity. However, in these preclinical studies, APVO436 induced lower levels of several T-cell cytokines, suggesting a potential safety advantage with APVO436.

Cytokine release syndrome (CRS) is a significant concern with T-cell activating therapies and has been associated with severe complications in clinical trials. The preclinical data demonstrating potent T-cell cytotoxicity of tumors expressing CD123 with limited cytokine release, suggest that APVO436 has the potential for increased clinical benefit and a favorable safety profile.

Additional data presented at the 2018 and 2019 AACR annual meetings show that APVO436:

Induces the generation of functional memory T cells with cytolytic function from naive T cells
Has good tolerability, antibody-like clearance and volume of distribution parameters
Has an extended serum half-life of 4.5 days in a relevant non-clinical species
Binds human CD123 and CD3-expressing cells with EC50 values in the low nM range and demonstrates potent target specific activity against CD123 expressing tumor cell lines at low effector to target ratios
Potently induces endogenous T-cell activation and proliferation accompanied by depletion of CD123 expressing cells in experiments with primary AML subject samples and normal donor samples
Demonstrates potent cytotoxic activity from antigen-expanded T cells from both normal and AML subject samples in the presence of CD123+ tumor cells upon re-exposure to APVO436
Results in rapid and significant reduction in skeletal tumor burden indicating migration and engagement of T cells at the tumor site, in mice with established disseminated Molm-13 tumors and IV-implanted human T cells in therapeutic preclinical animal studies
Induces lower levels of multiple cytokines compared to a different CD123 x CD3 format, when T cells were stimulated in the presence of CD123+ tumor cells

Presentations

APVO436, a Bispecific anti-CD123 x anti-CD3 ADAPTIR™ Molecule for Redirected T-cell Cytotoxicity with Limited Cytokine Release, is Well Tolerated in Repeat Dose Toxicology Studies in Cynomolgus Macaques
AACR Annual Meeting 2019

APVO436, a Bispecific anti-CD123 x anti-CD3 ADAPTIR™ Molecule for Redirected T-cell Cytotoxicity, Induces Potent T-cell Activation, Proliferation and Cytotoxicity with Limited Cytokine Release
AACR Annual Meeting, April 2018

Bispecific Anti-CD123 x Anti-CD3 ADAPTIR™ Molecules APVO436 and APVO437 Have Broad Activity Against Primary Human AML Cells In Vitro
American Society of Hematology Annual Meeting, December 2017

Bispecific anti-CD123 x anti-CD3 ADAPTIR™ Molecules for Redirected T-cell Cytotoxicity in Hematological Malignancies
AACR Annual Meeting, April 2017