On May 26 2021 Aptevo Therapeutics Inc. ("Aptevo") (NASDAQ:APVO), a clinical-stage biotechnology company focused on developing novel immuno-oncology therapeutics based on its proprietary ADAPTIR and ADAPTIR-FLEX platform technologies, reported positive results from the Company’s Phase 1 dose escalation trial evaluating lead ADAPTIR candidate, APVO436, for the treatment of acute myeloid leukemia and myelodysplastic syndromes (AML/MDS) (Press release, Aptevo Therapeutics, MAY 26, 2021, View Source [SID1234580634]). APVO436 was generally well tolerated and demonstrated a favorable side effect profile, including the absence of severe or prolonged neutropenia, an often serious condition associated with CD123-targeting therapies. Further, APVO436 showed encouraging single agent activity and a promising benefit to risk profile in patients with relapsed, advanced stage AML.
Schedule your 30 min Free 1stOncology Demo!
Discover why more than 1,500 members use 1stOncology™ to excel in:
Early/Late Stage Pipeline Development - Target Scouting - Clinical Biomarkers - Indication Selection & Expansion - BD&L Contacts - Conference Reports - Combinatorial Drug Settings - Companion Diagnostics - Drug Repositioning - First-in-class Analysis - Competitive Analysis - Deals & Licensing
Schedule Your 30 min Free Demo!
The Phase 1 dose escalation study, conducted at leading cancer centers across the United States (US), as listed in www.clinicaltrials.gov as NCT03647800, enrolled 46 patients with AML or myelodysplastic syndromes, each of whom received escalated intravenous infusions of APVO436 ranging in dose from 0.3 micrograms to 60 micrograms. The long half-life of APVO436 enabled its administration over short infusion times. The study met its primary endpoint – identification of an active dose level for advanced studies. The Company plans to submit the data for publication later this year.
AML is the most common form of adult acute leukemia with >20,000 estimated new cases and >10,000 deaths in the United States (US) for 2021 (SEER Program, www.seer.cancer.gov).
The therapeutic landscape for leukemias is rapidly evolving in the era of personalized medicine but development of new drugs capable of killing chemotherapy resistant leukemia cells that can be used to improve the efficacy of standard of care induction and consolidation regimens remains an unmet medical need.
Unlike the potency of chemotherapy drugs, the clinical activity of bispecific antibodies in leukemia patients is often not "dose-linear," so a higher dose may potentially be less effective than a much lower dose. Likewise, the most effective concentrations are frequently not concentrations that are achieved at the highest tolerated dose levels. This is because these antibodies can be captured by normal cells, including T-cells that bind to the CD3 directed portion of the bispecific antibody. In order to avoid such a "sink effect", a dose level needs to be carefully identified at which the likelihood of excessive binding to normal cells in blood and bone marrow is very low. That is to say, an optimal dose needs to be identified at which leukemia cells are selectively killed without causing severe neutropenia, a complication reported for CD123-targeting drugs that can lead to life-threatening infections and sepsis. Therefore, the contemporary strategy in clinical development of bispecific antibodies is to identify a biologically optimal dose level, ideally a dose level much lower than the maximum tolerated dose level. Importantly, the APTEVO study 5001 has met the primary endpoint of its Part 1, identifying Cohort 6 dose as an active dose level for advanced studies of APVO436, also known as the recommended Phase 2 dose (RP2D).
"We observed, as preliminary signs of clinical activity both stabilization of leukemia as well as complete remissions," reported Dr. Fatih Uckun, leukemia expert and Chief Clinical Advisor, who is coordinating the APVO436 clinical development program. Of seven evaluable relapsed AML patients treated in Cohort 6, four showed stabilization of their leukemias. Of those four patients with disease stabilization, three patients lived 246+ days, 261+ days, and 281+ days, respectively and one progressed after a month. Two relapsed AML patients, who experienced stabilization of their leukemia, achieved a partial remission (PR) and subsequently a complete remission (CR). No partial or complete remissions have been observed at APVO436 dose levels either lower or higher than the Cohort 6 dose level. Therefore, APVO436 will be used at the Cohort 6 dose level in Part 2 of the study.
"We are very pleased to see lead ADAPTIR platform candidate, APVO436, progress in the clinic. APVO436 has demonstrated the potential to address a significant unmet need for patients with AML and provide the foundation for new and more effective multi-modality standard of care regimens that offer renewed hope for leukemia patients," said Jane Gross, PhD, the Chief Scientific Officer for Aptevo.
One of the most significant and frequent side effects associated with the use of bispecific, T-cell engaging antibodies are neurologic toxicities. Neurological toxicities may be severe, life-threatening, or fatal. Serious neurologic toxicity has not been a frequent complication associated with APVO436 treatments in this study. Another potential complication associated with treatment using bispecific, T-cell engaging antibodies is a systemic inflammatory syndrome known as Cytokine Release Syndrome (CRS). CRS has occurred in some patients and has been managed using the generally recommended standard CRS treatments. In Cohort 6, of 9 AML/MDS patients evaluable for toxicity, 2 patients developed a Grade 1 CRS and one patient developed a transient Grade 3 CRS related to APVO436 which resolved with routine clinical management.
CD123, although highly expressed on AML blasts, is also expressed on normal bone marrow hematopoietic stem cells and myeloid progenitor cells that give rise to the infection-fighting white blood cells. Therefore, treatment platforms targeting CD123 have been associated with a prolonged and profound decrease of white blood cell counts, known as severe neutropenia, and infections, especially pneumonias. This side effect caused by CD123 targeting overlaps with the blood count lowering side effects of standard chemotherapy drugs is among the main hurdles impeding the desired incorporation of CD123 targeting drugs into contemporary frontline as well as second-line standard of care treatment regimens. Notably, Aptevo researchers discovered that APVO436 does not cause severe or prolonged neutropenia at doses that resulted in complete remissions. None of the 46 patients treated with APVO436 developed severe or prolonged neutropenia as a side effect of the drug.
"This finding will inform the clinical development path for APVO436, as a novel drug candidate for blood cancers," stated Dr. Uckun. "AML patients are in urgent need of active new drugs capable of destroying leukemia cells without causing profound neutropenia. We will diligently advance the clinical development of APVO436 and evaluate its potential clinical impact for leukemia patients." Dr. Uckun added.
"We are pleased to report progress in the clinical development of our ADAPTIR platform candidate, APVO436," said Marvin White, President and CEO of Aptevo. "We remain confident about the breakthrough potential of APVO436 and look forward to sharing interim data from Part 2 of our study later this year. The scientific data from multiple studies so far suggest tremendous therapeutic potential for the APVO436 ADAPTIR platform and provides the foundation for our optimism regarding the potential commercialization of APVO436.",