Aankondiging • Jun 29
AB Science Reports Completion of Step 3 of Phase 1 Evaluating Combination of Ab8939 with Venetoclax for Treatment of Refractory or Relapsed Acute Myeloid Leukemia
AB Science SA has provided an update on the Phase 1 study of the molecule AB8939 and the completion of Step 3, evaluating the combination of AB8939 + venetoclax in patients with acute myeloid leukemia (AML) associated with a very unfavorable genetic profile. Step 3 evaluated the combination of AB8939 plus venetoclax administered over a 14-day cycle. A total of six patients were treated across two dose levels of AB8939 (16 mg/m² and 21.3 mg/m²), each in combination with venetoclax. The combination was well-tolerated, with no dose-limiting toxicity (DLT) and no hematological toxicity observed at either dose level, allowing selection of the recommended Phase 2 dose (RP2D). Encouraging preliminary signs of efficacy were observed. Of the six patients treated, four achieved an objective response (one complete remission with incomplete hematologic recovery and three partial responses), corresponding to a 67% overall response rate (ORR). The two remaining patients achieved stable disease, resulting in a 100% disease control rate (DCR). These responses were achieved after a single cycle of treatment (14 days) in heavily pre-treated patients receiving second- to fourth-line therapy. Notably, two of the responding patients had previously progressed on venetoclax in combination with other chemotherapies. The patients treated all have very difficult to treat cytogenetic profiles, including complex karyotype, TP53 mutation, NRAS mutation, monosomy 5 and 7 and MECOM-rearrangement, that typically have a poor prognosis due to their aggressive disease course and treatment resistance. This is a high response rate in a population where standard-of-care therapies achieve ORR of 10–30% in adverse-risk, multiply pre-treated AML. Response after the first 14 days cycle in the six patients treated in Step 3 (AB8939 + venetoclax): Patient 1, AB8939 dose 16 mg/m², 2nd line of therapy, RUNX1 and NRAS mutations, best response CRi; Patient 2, AB8939 dose 16 mg/m², 2nd line of therapy, MECOM-rearrangement, complex karyotype, monosomy 5 and 7, best response PR; Patient 3, AB8939 dose 16 mg/m², 4th line of therapy, TP53 mutation, complex karyotype, monosomy 5 and 7, best response PR; Patient 4, AB8939 dose 21.3 mg/m², 3rd line of therapy, TP53 mutation, complex karyotype, monosomy 5 and 7, best response PR; Patient 5, AB8939 dose 21.3 mg/m², 2nd line of therapy, TP53 mutation, best response SD; Patient 6, AB8939 dose 21.3 mg/m², 2nd line of therapy, TP53 mutation (very high-risk MDS), best response SD. Complete remission (CRc) is defined as CRc = CR + CRh + CRi + CRp. AB8939 is a drug candidate that targets (i) cancer cells by destabilizing microtubules (essential for cell division) and (ii) cancer stem cells by inhibiting ALDH1A1 and ALDH2 (enzymes essential for maintaining their physiological state and survival). AB8939 has shown in vitro activity in Ara-C (cytarabine, which is one of the standards of care) resistant patient cell lines, including adverse genetic MECOM and TP53 mutations. Analysis of cell lines responsive to AB8939 showed that AB8939 is effective in cell lines with TP53 mutations, MECOM, and complex karyotypes, whereas ARAC and azacitidine are not effective. AB8939 increased survival and had an additive effect in combination with venetoclax (another standard of care) in vivo in a MECOM-grafted PDX mouse model. AB8939 increased survival and had an additive effect in combination with Vidaza (azacitidine, another standard of care) in vivo in the MECOM PDX#C1005 mouse model of leukemia. AB8939 eradicated Leukemia Cancer Stem Cells in vivo in a human PDX AML mouse model, which is compatible with targeting stem cells via ALDH. AB8939 is currently being evaluated in a Phase 1 clinical trial (study AB18001, NCT05211570) in patients with refractory and relapsed AML. The Phase 1 clinical trial of AB8939 has completed its first three steps. The first two steps determined the maximum tolerated dose (MTD) after 3 and 14 consecutive days of monotherapy. In both cases, the MTD was 21.3 mg/m². The third step, now completed, evaluated the combination of AB8939 and venetoclax. Six patients were treated across two dose levels (AB8939 14 days at a dose of 16 mg/m² + venetoclax 14 days, then AB8939 14 days at a dose of 21.3 mg/m² + venetoclax 14 days), with no dose-limiting toxicity observed, supporting selection of the recommended Phase 2 dose. The next step (Step 4) will evaluate the triple combination of AB8939 + venetoclax + azacitidine. Although several drugs have been registered for AML, 70% of patients still relapse and die, creating a persistent unmet medical need for effective treatments. Acute myeloid leukemia remains the most lethal form of leukemia in humans. AML is a heterogeneous disease, and its outcome is highly dependent on genetic factors. TP53 mutation has a very poor prognosis, with a median overall survival (OS) of 5.5 months. NRAS and KRAS mutants have a poor prognosis, with a median OS of 12.1 months. MECOM also has a very poor prognosis in AML, with a median OS of 5.5 months in relapsed or refractory settings. The challenge in AML is the recurrence of tumors due to a combination of two factors: the resistance of cancer cells to chemotherapy and relapse due to the persistence of cancer stem cells. This challenge may be overcome by AB8939’s dual mechanism of action. First, AB8939 blocks the proliferation of leukemia cells through microtubule disruption. It is not subject to multi-drug resistance as it does not bind to PgP, which is responsible for efflux outside the cells, and is not degraded by myeloperoxidase. Second, AB8939 targets leukemia cancer stem cells by inhibiting ALDH and promotes bone marrow repopulation of normal progenitors. There is a strong rationale to combine AB8939 with venetoclax. Both molecules exhibit low hematologic toxicity. This combination is expected to be less toxic than azacitidine + venetoclax as first-line treatment for AML. These molecules have different and complementary targets in cancer cells. There is an additive, even synergistic, efficacy potential for the combination, with three mechanisms of action in a single treatment. Venetoclax’s mechanism of action inhibits the BCL2 pathway, a protein that prevents apoptosis (programmed cell death) in cancer cells.