AB Science Announces Initial Phase 1 Data for AB8939 and Venetoclax Combination in Refractory or Relapsed Acute Myeloid Leukemia

Analysis reveals significant industry trends and economic implications

Release Date

2025-10-17

Category

Clinical Trial Event

Reference

Source

Breakthrough Clinical Results

AB Science SA announced initial Phase 1 data for the combination of AB8939 with venetoclax for treating refractory or relapsed acute myeloid leukemia (AML). The combination showed a 100% disease control rate and partial response rate in patients receiving third- or fourth-line treatment. AB8939, as a monotherapy, has shown activity in MECOM. The company plans to finish Phase 1 and launch an expansion study in AML patients eligible for AB8939 + Venetoclax.

Key Highlights

  • AB8939 monotherapy shows activity in MECOM with long OS benefit.
  • Combination of AB8939 and Venetoclax is well-tolerated with complementary targets in cancer cells.
  • The combination therapy achieved a 100% disease control rate and partial response rate after the first cycle of treatment.
  • AB8939 targets both cancer cells and cancer stem cells, reducing the frequency of relapses.

Incidence and Prevalence

Global Incidence and Prevalence of Acute Myeloid Leukemia

Global Burden Trends

The global burden of Acute Myeloid Leukemia (AML) has shown a significant increase in recent decades. According to a comprehensive 2022 study analyzing data from the Global Burden of Disease online database, the number of AML cases worldwide increased substantially from 63.8 thousand in 1990 to 119.8 thousand in 2017. This represents a concerning upward trend in the global incidence of this aggressive hematological malignancy.

The age-standardized incidence rate (ASIR) of AML has also increased from 1.35 per 100,000 population in 1990 to 1.54 per 100,000 in 2017, with an estimated average percentage change (EAPC) of 0.56 (95% CI 0.49, 0.62). This increase is particularly noteworthy as it occurred during a period when the overall leukemia incidence decreased by 0.43% per year.

Regional Distribution

The burden of AML shows significant regional variations across the globe:

  • Asia accounts for 48.6% of leukemia cases worldwide, making it the region with the highest burden
  • India alone reports approximately 10.2% of all leukemia cases globally
  • In the United States, AML is the second most common leukemia among adults with a median age of 69 years
  • Canada has an age-standardized incidence rate of 3.46 cases per 100,000 person-years
  • In Calgary, Canada, the incidence rate is lower at 2.79 cases per 100,000 person-years with a median age of 60
  • In Georgia (US), age-adjusted incidence rates of adult AML (4.6/100,000) were comparable to the national rates (5.2/100,000)

Demographic Patterns

Several important demographic patterns have emerged in AML epidemiology:

  • AML incidence and mortality increased with age and were consistently higher in males
  • The highest incidence occurs at approximately age 85 in developed countries
  • In Japan, cigarette smoking increases the risk of AML in men, with current heavy smokers showing a significantly increased risk (HR 2.21; 95% CI, 1.01-4.83)
  • AML burdens are more pronounced in higher-SDI regions (Socio-Demographic Index), while ALL (Acute Lymphoid Leukemia) shows higher burdens in low-SDI regions

Proportion of Leukemia Cases

AML represents an increasing proportion of total leukemia cases. In 1990, AML accounted for 18.0% of total leukemia cases worldwide, but this proportion increased to 23.1% in 2017. Regional studies show varying proportions:

  • In Saudi Arabia, a 2024 study found AML to be the second most common subtype of leukemia (17.6%) after chronic myeloid leukemia
  • In Southwest China, a 2023 study reported that 43.63% of hematological malignancies were AML

With 127 countries or territories experiencing a significant increase in AML incidence rates, researchers conclude that AML might become a major global public health concern in the coming years.

Key Unmet Needs in Acute Myeloid Leukemia

Demographic and Geographic Disparities

  • Significant demographic under-representation exists in pivotal clinical trials for AML
  • 81.6% of trial participants are White, with Blacks, Native Americans, and Hispanics significantly under-represented
  • Females are under-represented in AML trials (44.7% vs 60.5%)
  • Geographic distribution of trials shows inadequate regional participation

Tumor Heterogeneity and Resistance

  • AML is a highly heterogeneous malignancy with complex genomic features
  • Drug resistance and relapse remain major treatment challenges
  • Single cell RNA-seq analysis reveals extensive expression differences between diagnosis-relapse pairs
  • Clonal evolution can lead to switching from one signaling pathway to another (e.g., from AP-1 regulated clone to mTOR signaling driven clone)

Immunotherapy Challenges

  • Safe and effective immune therapies have not been fully developed for AML
  • AML lacks specific target antigens, causing unacceptable bone marrow toxicity
  • AML has few neo-antigens compared to solid cancers
  • PD-1/PD-L1 blockade shows promise but with significant limitations
  • Immune-related adverse events can be severe, including fatal complications

Targeted Populations

  • Elderly and unfit patients ineligible for intensive chemotherapy or transplantation
  • Patients with refractory or relapsed AML requiring combination therapies
  • Patients with specific mutations: TP53-mutated, FLT3-mutated, and IDH1/2-mutated AML
  • High-risk AML patients after allogeneic stem cell transplantation
  • Younger patients with newly diagnosed or relapsed/refractory AML

Emerging Therapeutic Approaches

  • Small molecule agents targeting specific molecular defects show promise
  • FDA-approved inhibitors of IDH1, IDH2, FLT3, and BCL-2 have established new standards
  • Emerging molecules include MCL-1 inhibitors, TP53 inhibitors, menin inhibitors, and E-selectin antagonists
  • Combination therapies including PD-1 inhibitors with hypomethylating agents show encouraging outcomes
  • CTLA-4 inhibitor ipilimumab shows potential for relapsed AML with extramedullary disease

Remaining Challenges

  • Despite recent advances with eleven novel FDA-approved medications since 2017, significant gaps remain
  • No widely available immune-based therapies for AML except gemtuzumab ozogamicin
  • Relapse after transplantation remains the primary source of mortality
  • Immune toxicities (GVHD) remain a barrier to successful immunotherapy outcomes
  • Need for more targeted antibody-based therapeutics that can perform tumor-specific cytotoxic functions
  • Development of synergistic combination therapies tailored to specific biology and clinical context

Drugs with Similar Mechanism of Action to Venetoclax and Their Clinical Trial Models

Venetoclax-Related Drugs and Trials

Venetoclax is an orally bioavailable small molecule BCL-2 inhibitor that has shown synergistic effects when combined with hypomethylating agents. For similar indications, several menin inhibitors (MENINis) represent a novel therapeutic class that can enhance the effects of venetoclax-based regimens in specific leukemia subtypes.

The following drugs share similar indications to Venetoclax:

  • Revumenib - A specific menin inhibitor being trialed for acute leukemia
  • Bleximenib - Another menin inhibitor in clinical trials
  • Enzomenib - A menin inhibitor showing promise in trials
  • BN104 - A menin inhibitor under investigation

These menin inhibitors have demonstrated considerable efficacy in KMT2Ar- and NPM1m-AML patients with good tolerance. Approximately 40-50% of acute myeloid leukemia (AML) and 5-15% of acute lymphoblastic leukemia (ALL) patients may potentially benefit from MENINi-based therapy.

Additionally, ibrutinib in combination with venetoclax has shown effectiveness in patients with relapsed/refractory mantle cell lymphoma (MCL), indicating potential for fixed-duration therapy.

Intervention Models in Clinical Trials

The clinical trial intervention models for Venetoclax and similar drugs include:

  • Combination therapy models:

  • Venetoclax with azacitidine (Ven-Aza) for newly diagnosed AML patients ineligible for intensive chemotherapy

  • Venetoclax with low-dose cytarabine for AML patients ineligible for intensive chemotherapy

  • Post-HSCT maintenance therapy using hypomethylating agents with venetoclax in T-ALL

  • Trial design models:

  • Phase 1-2 trial design with dose-escalation and dose-expansion phases

  • 3+3 study design to determine maximum tolerated dose and recommended phase 2 dose

  • Randomized controlled trials with 2:1 randomization (venetoclax-azacitidine vs. placebo-azacitidine)

  • Network meta-analysis models comparing venetoclax plus azacitidine to other regimens

  • Dosing regimens:

  • Venetoclax typically at 400mg given orally once daily

  • Azacitidine (75mg/m²) administered subcutaneously or intravenously on Days 1-7 of each 28-day cycle

  • Venetoclax (100-400mg) for 7-14 days combined with azacitidine (75mg/m²) for 5 days in some trials

  • Analysis methods:

  • Retrospective analysis comparing combination therapy (venetoclax and azacitidine) versus monotherapy (azacitidine alone)

Regarding AB8939, the available information does not provide details about its mechanism of action or other drugs being trialed with similar mechanisms.