On April 10, 2024 Aptevo Therapeutics Inc. (NASDAQ:APVO), a clinical-stage biotechnology company focused on developing novel immune-oncology therapeutics based on its proprietary ADAPTIR and ADAPTIR-FLEX platform technologies, reported advancements in both clinical programs and one preclinical program (Press release, Aptevo Therapeutics, APR 10, 2024, View Source [SID1234641991]).

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A heavily pretreated breast cancer patient, enrolled in the ALG.APV-527 Phase 1 open-label, multi-center, multi-cohort trial for the treatment of multiple solid tumor types, entered the trial and improved from progressive disease to long-lasting stable disease (SD) while on therapy. The patient has remained on study for more than nine months and been successfully transitioned to a higher dose level, which may allow for increased clinical benefit. The trial is more than 50% enrolled and dosing in cohort five (of six) is imminent.

"I’m encouraged by the promise that ALG.APV-527 brings to the treatment of solid tumor patients. Witnessing a patient maintaining a stable disease, especially for more than nine months, and then moving to a higher dose level within a Phase 1 trial is uncommon, but we believe it can be therapeutically beneficial for this patient and is a testament to the drug’s clinical potential," stated Dirk Huebner, MD, Chief Medical Officer at Aptevo.

The Company is on track to initiate part 1 of its upcoming two-part Phase 1b/2 trial in 1H 2024. The study will further evaluate APVO436 for the treatment of acute myeloid leukemia (AML). Aptevo has partnered with premier CRO, Prometrika, for the upcoming study. The first part is a dose optimization trial evaluating standard of care venetoclax + azacitidine along with APVO436 as a frontline treatment for AML patients. It is planned as an open-label, multi-center, multi-cohort study. The trial will evaluate safety/tolerability and efficacy of the triplet combination at multiple dose levels.

The therapeutic combination of venetoclax + azacitidine + APVO436 was selected based on outcomes from the Company’s dose expansion trial that showed promising outcomes across all categories of evaluation including safety, efficacy, and duration of remission.

"We are eager to initiate the next phase of development in support of lead candidate APVO436 as a therapeutic option in combination therapy for the treatment of AML," said Marvin White, President and CEO of Aptevo. "APVO436 results have been positive across the board. For example, we demonstrate an exemplary safety profile, noting that patients experienced cytokine release syndrome at rates that are about one-third the benchmarks demonstrated in literature. Similarly, efficacy results demonstrate clinical responses that are almost double the benchmarks in literature. We anticipate that our dose optimization results will reinforce our growing body of data and demonstrate the clinical potential of APVO436 in patients with frontline AML."

APVO711 is currently progressing through preclinical evaluation intended to target a broad range of solid tumors. The Company continues to move this anticancer checkpoint inhibitor with added dual mechanism of action functionality toward the clinic. Key learnings to date include:

APVO711 imparts beneficial attributes to both antigen presenting cells and T cells that boost the immune response targeted at controlling tumor cells
Experiments in cultured cells have confirmed that APVO711 enhances tumor cell killing by T cells
In vivo studies have confirmed that APVO711 reduces the size of PD-L1-expressing tumors
"We are pleased with the progress we have made to date in preclinical studies for our dual mechanism checkpoint inhibitor APVO711. This PD-L1 x CD40 molecule, represents an anticancer approach that combines a checkpoint inhibitor with a potent immune mediator. This innovative therapeutic strategy holds promise for unleashing the full potential of the immune system to combat cancer, offering new hope for patients in need of more effective treatments," said Michelle H. Nelson, Ph.D., Director of Immunobiology at Aptevo Therapeutics.

More About the Programs

ALG.APV-527
ALG.APV-527 is a conditional 4-1BB agonist bispecific that is designed for activation only upon simultaneous binding to 4-1BB and 5T4. It is designed to target cancer cells by activating both T cells and natural killer cells and is intended to bind to tumor-specific antigens while sparing healthy cells and maximizing immune response. This has the potential to be clinically important because 4-1BB can stimulate the immune cells (antitumor-specific T cells and NK cells) involved in tumor control, making 4-1BB a particularly compelling target for cancer immunotherapy. The compound is currently being evaluated for multiple solid tumor types in a multi-center, dose escalation trial that is more than 50% enrolled.

Additional promising preliminary data includes:

In addition to the patient described above, a second heavily pretreated breast cancer patient who was progressing prior to enrolling in the trial has sustained long lasting stable disease and remained on study drug for seven months. Analysis demonstrated measurable level of drug in circulation (pharmacokinetic) and reproducible elevation of serum pharmacodynamic markers with dosing, suggesting the drug is biologically active
Treatment to date has been overall well-tolerated, and a maximum tolerated dose has not yet been determined, dose-escalation in higher-dose cohorts is ongoing as the Company moves into cohort five (of six)
ALG.APV-527 has been measurable in all patients with plasma concentration of ALG.APV-527 consistent with the administered dose
Biomarker analyses indicate the expression of the targets (4-1BB and 5T4) in tumor biopsies and confirm biological activity of ALG.APV-527
"We are excited by the emerging data from the ALG.APV-527 clinical trial, indicating biological activity and generating stable disease even at the lowest dose levels tested in heavily pretreated patients. This molecule is engineered to target cancer cells while preserving healthy tissues, all the while amplifying a specific immune response. We eagerly anticipate sharing forthcoming data and continuing to unveil the immense potential of this bispecific candidate in the solid tumor space," expressed Dirk Huebner, MD, Chief Medical Officer at Aptevo.

APVO436
Aptevo’s wholly owned lead proprietary drug candidate, APVO436 is targeting AML and is differentiated by design to redirect the immune system of the patient to destroy leukemic cells and leukemic stem cells expressing the target antigen CD123, which is a compelling target for AML due to its overexpression on leukemic stem cells and AML blasts . This antibody-like recombinant protein therapeutic is designed to engage both leukemic cells and T cells of the immune system and bring them closely together to trigger the destruction of leukemic cells. APVO436 is purposefully designed to reduce the likelihood and severity of CRS by use of a unique CD3 derived from CRIS-7 vs. the CD3 used by other competitors. APVO436 has received orphan drug designation ("orphan status") for AML according to the Orphan Drug Act.

The Phase 1b Dose escalation trial results showed a 91% clinical benefit rate in combination with venetoclax + azacitidine in venetoclax naïve patients, a 27% incidence of CRS across all trial cohorts (the majority were grades 1 & 2) and meaningful duration of remission, including three patients who transitioned to transplant after receiving therapy, the best possible outcome for AML patients.

The Company is planning to commence the first part of the Phase 1b/2 dose optimization program in the first half of 2024.

APVO711
APVO711, a bispecific checkpoint inhibitor with added functionality, targets PD-L1 and CD40, and is designed to function to synergistically induce a biological response. This is achieved by simultaneously engaging in two clinically validated T cell activating mechanisms: 1) blocking of PD-L1/PD-1 inhibitory pathway and 2) CD40 signaling augments APC maturation resulting in enhanced T cell stimulation. APVO711 is designed to activate CD40 only in the presence of PD-L1 binding for an improved safety profile. The Company believes APVO711 has the potential to positively impact the treatment paradigm of multiple solid tumor types for which there is currently significant unmet medical need.