vamotinib (PF-114) / AstraZeneca - LARVOL DELTA

Differential in Vitro Sensitivity of BCR::ABL1 Kinase Domain Mutations to Tyrosine Kinase Inhibitors Depending on the p190 or p210 Background (ASH 2024) - "The resulting wildtype and 134 mutant Ba/F3 cell lines generated in this way, i.e. 67 cell lines carrying a large spectrum of single and compound mutations in the p190 and p210 background, respectively, were tested in vitro against different concentrations of eight TKIs including imatinib, nilotinib, dasatinib, bosutinib, ponatinib, vamotinib, asciminib, and flumatinib using the CellTiter-Glo® luminescent cell viability assay (Promega). The findings of the present study provided the basis for extending and supplementing the existing heatmaps for various mutations and TKIs in the background of p210 by a corresponding heatmap established specifically for mutations occurring in the background of p190, thus filling a clinically important information gap. Once appropriately evaluated in the clinical setting, the comprehensive heatmaps emanating from the present study may provide support for adequate TKI selection (and potentially for selection of the appropriate dose) in..."

Preclinical • Acute Lymphocytic Leukemia • Hematological Malignancies • Leukemia • Oncology • ABL1

PREVALENCE OF ARTERIAL HYPERTENSION AMONG PATIENTS WITH CHRONIC PHASE CHRONIC MYELOID LEUKEMIA ON PONATINIB THERAPY (EHA 2024) - "Patients obtained the following TKIs: imatinib (n=41; 95%),dasatinib (n=26; 60,5%), nilotinib (n=29; 67%), bosutinib (n=9; 21%), and PF-114 (n=3; 7%). In our observation ponatinib therapy led to occurrence of new cases or to worsening the course of existed AHthrough unknown mechanisms. There was no obvious relationship between AH and aCVE. We may speculatethat close blood pressure monitoring and aggressive AHT might reduce the contribution of AH in thedevelopment of aCVE in our patients."

Clinical • Cardiovascular • Chronic Myeloid Leukemia • Hematological Malignancies • Leukemia • Nephrology • Oncology • Pulmonary Arterial Hypertension • Renal Disease

Role of CDK8/19 inhibition in sensitization of chronic myelogenous leukemia cells to Bcr-Abl antagonists (EACR 2023) - "Selective inhibitors of Bcr-Abl (prototype – imatinib mesylate, IM, Gleevec®) cause a therapeutic effect in the treatment of the primary process...Senexin B (SenB) and SNX631 were used for selective inhibition of CDK8/19, to suppress Bcr-Abl – IM, dasatinib, nilotinib, PF-114.Results and DiscussionsIt was found that CDK8/19 inhibition by SenB alone does not have an antiproliferative effect on CML cells...These changes were not demonstrated in KU812, where neither SenB sensitization, nor changes in expression of CKIs and c-Myc level were detected.ConclusionInhibition of CDK8/19 helps to overcome the delay of the cell cycle caused by the Bcr-Abl antagonist in CML cells and increase the death of tumor cells. The absence of general toxicity of CDK8/19 inhibitors during prolonged treatment under experimental conditions allows us to recommend CDK8/19 inhibition with targeted therapy of Bcr-Abl-positive tumors in prospect."

Chronic Myeloid Leukemia • Hematological Malignancies • Leukemia • Oncology • ABL1 • BCR • CASP9 • CDK9 • CDKN2C • MYC • STAT3

PF-114 in Patients Failing Prior Tyrosine Kinase-Inhibitor Therapy Including BCR::ABL1T315I (ASH 2021) - P1/2 | "PF-114 was safe and effective in subjects failing ≥ 2 TKIs and those with BCR::ABL1 T315I including those failing ponatinib. The PF-114 dose for further study is 300 mg/d."

Clinical • Dermatology • Hematological Disorders • Immunology • Psoriasis • ABL1

Novel BCR-ABL1 tyrosine kinase inhibitors in the treatment of chronic myeloid leukemia. (PubMed, Expert Rev Hematol) - No abstract available

Journal • Chronic Myeloid Leukemia • Hematological Malignancies • Leukemia • Oncology • ABL1 • BCR

PF-114: A 4th Generation Tyrosine Kinase-Inhibitor for Chronic Phase Chronic Myeloid Leukaemia Including BCRABL1T315I (ASH 2019) - P1/2; "PF-114 was safe and effective in patients with CML failing ≥2 TKIs or with BCR-ABL1T315I. The most effective dose was 300 mg/d. Five of 12 patients with BCR-ABL1T315I responded."

ABL1

Dr. Cortes on Emerging Therapies in CML (OncLive) - "Jorge E. Cortes, MD...discusses emerging therapies in chronic myeloid leukemia (CML)....Additionally, other novel agents, including the BCR-ABL TKIs vodobatinib (K0706), HQP1351, and PF-114, have demonstrated early efficacy signals in CML and are under further investigation in phase 2 studies, Cortes concludes."

Video

CML: New TKIs and combos show promise for resistant, intolerant disease (MDedge Hematology & Oncology) - "The allosteric inhibitor asciminib (ABL-001), for example, has completed phase 1/2 trials evaluating its use as a single agent and in combination with other therapies in the first-line setting, and a pivotal phase 3 study comparing it with bosutinib in the third-line setting is underway, Dr. Cortes said....'It is important that we have new therapeutic options to be able to help these patients who are going to be in need of additional therapies,' he said."

Media quote

Pharmasyntez to Help Skolkovo Resident Commercialize Drug Against Leukemia (Skolkovo Foundation) - "Fusion Pharma, a resident of the Skolkovo Foundation's Biomedical Technologies Cluster, signed a license agreement with Pharmasyntez to commercialize an innovative antileukemic drug. The licencing deal implies an upfront payment, milestones and royalties...Pharmasyntez will conduct the phase three clinical trial, register the drug and commercialize it in the EAEU countries."

Licensing / partnership • Chronic Myeloid Leukemia • Hematological Malignancies • Oncology

Study to Evaluate Tolerability, Safety, Pharmacokinetics and Preliminary Efficacy of PF-114 for Oral Administration in Adults With Ph+ Chronic Myeloid Leukemia, Which is Resistant to the 2-nd Generation Bcr-Abl Inhibitors or Has T315I Mutation in the BCR-ABL Gene (clinicaltrials.gov) - P1/2; N=65; Active, not recruiting; Sponsor: Fusion Pharma LLC; Recruiting ➔ Active, not recruiting; N=44 ➔ 65; Trial completion date: Apr 2019 ➔ May 2020

Clinical • Enrollment change • Enrollment closed • Trial completion date • PCR

PF‑114, a novel selective inhibitor of BCR‑ABL tyrosine kinase, is a potent inducer of apoptosis in chronic myelogenous leukemia cells. (PubMed, Int J Oncol) - "Pharmacological inhibition of BCR‑ABL with imatinib (Gleevec) has been reported as an effective targeted therapy; however, mutations (including the kinase domain of ABL) suppress the efficacy of inhibitors. PF‑114, a derivative of the third generation BCR‑ABL inhibitor ponatinib, demonstrated a high inhibitory activity against wild-type and mutant BCR‑ABL forms, such as the clinically important T315I...Nevertheless, activation of STAT3 phosphorylation in response to PF‑114 may permit cell rescue; thus, a combination of BCR‑ABL and STAT3 inhibitors should be considered for improved therapeutic outcome. Collectively, the targeted killing of BCR‑ABL‑positive cells, along with other beneficial properties, such as in vivo characteristics, suggests PF‑114 as a potential candidate for analysis in clinical trials with CML patients."

Journal

Comparative Cardiotoxicity of Tyrosine Kinase Inhibitors Ponatinib and PF114 (BCVS 2019) - "Additionally, the allosteric tyrosine kinase inhibitor ABL001(Asciminib) in combination with PF114 depicts less pronounced cardiotoxic effects than ponatinib in similar settings. This study provides further rationale to utilize zebrafish for the prediction of cardiotoxicity of anticancer drugs. The comparative cardiotoxicity of ponatinib and PF114 suggest that PF114 is a significantly less cardiotoxic analogue and safer treatment option than ponatinib for CML patients harboring BCR/ABL-T315I “gatekeeper” mutation."