Aptevo Therapeutics Reports Positive Phase 1 Clinical Data for Its Lead Leukemia Drug Candidate APVO436 in Adults With Relapsed Acute Myeloid Leukemia
- Dose Escalation Study of APVO436 Shows Favorable Safety Profile and No Severe Neutropenia, a Potentially Life-threatening Side Effect, Reported in a Significant Number of Patients Receiving CD123-Targeting Drugs
- Dosing Level Established For Advanced Clinical Trials
The Phase 1 dose escalation study, conducted at leading cancer centers across
AML is the most common form of adult acute leukemia with >20,000 estimated new cases and >10,000 deaths in
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.
"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
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
"We are pleased to report progress in the clinical development of our ADAPTIR platform candidate, APVO436," said
Overexpression of CD123 is the hallmark of many forms of leukemia. Aptevo's lead proprietary drug candidate, APVO436 is a bispecific ADAPTIR that targets CD123 x CD3 and is designed to redirect the immune system of the patient to destroy leukemia cells expressing the target CD123 molecule on their surface. This antibody-like recombinant protein therapeutic is designed to engage both leukemia cells and T-cells of the immune system and bring them closely together to trigger a rapid and complete destruction of leukemia cells. APVO436 has been engineered using Aptevo's proprietary and enabling bioengineering methods and is designed to reduce the likelihood and severity of an unintended and potentially harmful activation of the immune system. APVO436 has been engineered to stay in the blood circulation long enough to locate, bind with and destroy target leukemia cells. APVO436 has received orphan drug designation ("orphan status") for AML according to the Orphan Drug Act.
Safe Harbor Statement
This press release includes forward-looking statements within the meaning of the Private Securities Litigation Reform Act of 1995. All statements, other than statements of historical fact, including, without limitation, Aptevo's expectations about the activity, efficacy and safety of its therapeutic candidates and potential use of any such candidates as therapeutics for treatment of disease, advancement of its clinical trials and its expectations regarding the effectiveness of its ADAPTIR and ADAPTIR-FLEX platforms, and any other statements containing the words "may," "believes," "expects," "anticipates," "hopes," "intends," "optimism," "potential," "designed," "engineered," "breakthrough," "innovative," "innovation," "promising," "plans," "forecasts," "estimates," "will" and similar expressions are intended to identify forward-looking statements. These forward-looking statements are based on Aptevo's current intentions, beliefs and expectations regarding future events. Aptevo cannot guarantee that any forward-looking statement will be accurate. Investors should realize that if underlying assumptions prove inaccurate or unknown risks or uncertainties materialize, actual results could differ materially from Aptevo's expectations. Investors are, therefore, cautioned not to place undue reliance on any forward-looking statement.
There are a number of important factors that could cause Aptevo's actual results to differ materially from those indicated by such forward-looking statements, including a deterioration in Aptevo's business or prospects; adverse developments in clinical development, including unexpected safety issues observed during a clinical trial; adverse developments in the