On August 13, 2024 Aptevo Therapeutics ("Aptevo") (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 initiation of the Company’s Phase 1b/2 dose optimization trial, "RAINIER," as part of its ongoing program to evaluate APVO436 in combination with venetoclax + azacitidine for frontline patients with acute myeloid leukemia (AML) (Press release, Aptevo Therapeutics, AUG 13, 2024, View Source [SID1234645829]). RAINIER will be conducted in two parts. First, a Phase 1b frontline AML study followed by a Phase 2 study. The Company also announced that APVO436 has received its generic name, mipletamig (mih-ple’-tah-mig) and will refer to its lead candidate by this name moving forward.
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"With a strong foundation of positive clinical data demonstrating safety, tolerability, efficacy, and durability, we are thrilled to announce the initiation of our Phase 1b/2 RAINIER study. This trial aims to identify the recommended Phase 2 dose and further evaluate key indicators-such as safety, tolerability, and efficacy-of mipletamig when combined with standard of care venetoclax and azacitidine in frontline AML patients," stated Marvin White, President and CEO of Aptevo. "Mipletamig has already been administered to 90 patients across two trials, both as a monotherapy and in combination therapy, with results showing an exceptional safety profile and efficacy outcomes more than double those reported in the literature and a 75% complete response rate among frontline patients. We believe the RAINIER trial will not only confirm these earlier outcomes but also establish the recommended Phase 2 dose and further demonstrate mipletamig’s potential to transform AML treatment when used alongside the existing standard of care."
This frontline AML study is a multi-center, multi-cohort, open label dose finding study of up to 39 patients across five dose levels ranging from 9 mcg – 140 mcg in combination with venetoclax and azacitidine (ven/aza). Subjects will be adults aged 18 or older, newly diagnosed with AML who are not eligible for intensive induction chemotherapy. Phase 1b consists of 28-day cycles of treatment in five sequential cohorts. Aptevo has partnered with Prometrika (View Source), a premier contract research organization, for the RAINIER trial.
Primary endpoints:
Evaluate the safety, tolerability, and maximum tolerated dose (MTD) of increasing doses of APVO436 in combination with venetoclax and azacitidine in patients with newly diagnosed AML
Determine the recommended Phase 2 dose
Assess incidence of cytokine release syndrome (CRS) at each dose level
*Benchmark Composite References: Aldoss 2019, Maiti 2021, Morsia 2020, Garciaz 2022, Feld 2021
Secondary Endpoint:
Determine the efficacy of increasing doses of APVO436 in combination with venetoclax and azacitidine in patients with newly diagnosed AML
"The initiation of our RAINIER trial marks a critical milestone in the clinical development of our lead candidate, mipletamig, in combination therapy for frontline AML," said Dirk Huebner, MD, Chief Medical Officer at Aptevo. "In this dose optimization trial, we will administer a combination of venetoclax, azacitidine, and mipletamig across up to five different dose levels. Our primary objective is to identify the optimal Phase 2 dose while continuing to assess the safety, tolerability, efficacy, and durability of remission. By focusing on frontline patients with this combination therapy, we aim to gain deeper insights into the role of mipletamig within the triplet regimen and its potential to improve treatment outcomes."
Prior Outcomes: Compelling Results to Date
Dose Escalation (monotherapy)
2 complete remissions (CRs) reported in AML patients who received the drug as a monotherapy
Most CRS cases were low-grade and clinically manageable
Dose Expansion (combination therapy)
91% clinical benefit rate in combination with standard of care venetoclax + azacitidine in venetoclax naïve patients which exceeds our benchmark (Benchmark Composite References: Aldoss 2019, Maiti 2021, Morsia 2020, Garciaz 2022, Feld 2021)
75% of frontline patients experienced a CR
Clinically meaningful duration of remission, with no median reached – multiple patients either stayed on treatment or moved to transplant
Only 27% of patients experienced CRS (cytokine release syndrome), which is favorable compared to competitor drugs.
Most CRS cases were low-grade and clinically manageable
About Mipletamig
Aptevo’s wholly owned lead proprietary drug candidate, mipletamig, targeting AML, MDS and other leukemias, 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. Mipletamig 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. Mipletamig has received orphan drug designation ("orphan status") for AML according to the Orphan Drug Act. Mipletamig has been evaluated in 90 patients over two trials to date. RAINIER, Aptevo’s Phase 1b/2 frontline AML program, was initiated in 3Q24.