PMD-026 / Phoenix Molecular Designs - LARVOL DELTA

Dauntless-1: A Phase 2 Clinical Trial to Evaluate PMD-026, a First-in-Class Pan-RSK Inhibitor, Combined with Fulvestrant to Overcome Resistance to CDK4/6 Inhibitors in Advanced or Metastatic HR+/HER2- Breast Cancer (SABCS 2025) - P1/2 | "In addition, PMD-026 inhibits the nuclear translocation of RSK2 (with no change to levels of nuclear ERα), reduces ERα transcription as a single agent equal to or better than fulvestrant or elacestrant, and synergizes with fulvestrant, oral selective estrogen receptor degraders (SERDs) or vepdegestrant to substantially inhibit tumor growth in CDK4/6i sensitive and resistant models. RSK2 is highly expressed in most front-line mBC patients receiving CDK4/6i + ET therapy. PMD-026 inhibits ER signalling and is highly synergistic with fulvestrant in preclinical studies, the translation of which into potentially meaningful clinical benefit is being explored in the Dauntless-1 study."

Clinical • Metastases • P2 data • Breast Cancer • HER2 Breast Cancer • HER2 Negative Breast Cancer • HER2 Positive Breast Cancer • Hormone Receptor Positive Breast Cancer • Oncology • Solid Tumor • ER • HER-2 • PIK3CA • RPS6KA3 • TP53

RSK1 Is an Exploitable Dependency in Myeloid Malignancies (ASH 2023) - P1/2 | "We further extended our findings to de novo AML harboring FLT3 internal tandem duplication (FLT3-ITD), where FLT3-ITD patients exhibited elevated RPS6KA1 expression, and those who developed resistance to gilteritinib demonstrated progressively increased RPS6KA1 expression...Through cycloheximide, MG-132, and ubiquitination assays, we found that RSK1 regulates FLT3-ITD activity and protein stability through deubiqutinase USP1, and where either RPS6KA1 or USP1 inhibition resulted in concomitant downregulation of FLT3 protein and cell lethality...Our findings uncover a novel therapeutic avenue for a conserved RSK1 dependency across chronic and acute myeloid neoplasms. The potent and consistent disease-ameliorating effects across numerous leukemia mouse models demonstrates promise for repurposing PMD-026 for the treatment of myeloid malignancies."

Acute Myelogenous Leukemia • Breast Cancer • Chronic Myelomonocytic Leukemia • Fibrosis • Hematological Malignancies • Immunology • Leukemia • Myelofibrosis • Myeloproliferative Neoplasm • Oncology • Solid Tumor • Targeted Protein Degradation • Triple Negative Breast Cancer • CCL3 • CCNA1 • CD14 • CD34 • CDK1 • CXCL8 • FLT3 • IL1B • IL6 • PTPRC • RELA • USP1

Roles of Ribosomal S6 Kinases in Acute Leukemia and Normal Hematopoiesis (ASH 2023) - "Isoform expression influences early-fate decisions to differentiate into erythroid and myeloid lineages. RSK inhibitors PMD-026 and TAS0612 are effective at targeting AML and ALL cells with limited cytotoxicity to healthy cells, making them promising candidates for translation into clinical trials for AML and ALL."

Acute Lymphocytic Leukemia • Acute Myelogenous Leukemia • Hematological Malignancies • Leukemia • Oncology • Pediatrics • T Acute Lymphoblastic Leukemia • CD14 • CD34 • ITGAM • RPS6KA3 • TFRC

Dauntless-1: Phase 1/1b/2 Study of Oral PMD-026 in Patients With Metastatic Breast Cancer (clinicaltrials.gov) - P1/2 | N=61 | Recruiting | Sponsor: Phoenix Molecular Designs | Trial completion date: Mar 2026 ➔ Oct 2026 | Trial primary completion date: Dec 2025 ➔ Sep 2026

Trial completion date • Trial primary completion date • Breast Cancer • HER2 Negative Breast Cancer • Hormone Receptor Positive Breast Cancer • Oncology • Solid Tumor • ER • HER-2

RSK1/2 Are Drivers of Immune Evasion in TNBC. (ENDO 2025) - "We hypothesize that a RSK1/2 inhibitor will work synergistically with an anti-PD-L1 therapy to increase tumor immunogenicity and improve TNBC patient survival. A RSK1/2 inhibitor may be beneficial over a pan-RSK inhibitor, e.g. PMD-026, as it specifically targets a number of known tumor agonists in TNBC."

IO biomarker • Breast Cancer • HER2 Breast Cancer • HER2 Negative Breast Cancer • HER2 Positive Breast Cancer • Hormone Receptor Breast Cancer • Hormone Receptor Positive Breast Cancer • Melanoma • Oncology • Solid Tumor • Triple Negative Breast Cancer • CD4 • HER-2 • HLA-DRB1

Dauntless-1, a phase 2 clinical trial to evaluate PMD-026, a first-in-class pan-RSK inhibitor, combined with fulvestrant to overcome resistance to CDK4/6 inhibitors in advanced or metastatic HR+/HER2- breast cancer. (ASCO 2025) - P1/2 | "Inhibiting RSK with PMD-026, a first-in-class oral small molecule inhibitor, halts G2/M progression and blocks growth in CDK4/6i-resistant models, including those cross-resistant to abemaciclib and palbociclib. Secondary objectives include duration of response, overall response and overall survival. Exploratory objectives will evaluate PMD-026 in the context of mutations (ESR1, PIK3CA, AKT1, p53, KRAS) at baseline using ctDNA."

Clinical • Metastases • P2 data • Breast Cancer • HER2 Breast Cancer • HER2 Negative Breast Cancer • HER2 Positive Breast Cancer • Hormone Receptor Positive Breast Cancer • Oncology • Solid Tumor • AKT1 • ER • HER-2 • KRAS • PIK3CA • RPS6KA3

Targeting ribosomal S6 kinase for the treatment of pediatric acute leukemia (AACR 2025) - "Both compounds have minimal toxicity to healthy hematopoietic cells. Therefore, PMD-026 and TAS0612 are strong candidates for translation into future clinical trials for AML and ALL."

Clinical • Acute Lymphocytic Leukemia • Acute Myelogenous Leukemia • Breast Cancer • Hematological Malignancies • Leukemia • Oncology • Solid Tumor • T Acute Lymphoblastic Leukemia • IL6

Phoenix Molecular Designs Dosed First Patient in Dauntless-1, a Phase 2 Clinical Trial of PMD-026 in Combination with Fulvestrant for RSK2-high Breast Cancer (GlobeNewswire) - "Phoenix Molecular Designs (PhoenixMD)...announced the dosing of the first patient in their Phase 2 clinical trial, Dauntless-1. The Dauntless-1 trial will evaluate the therapeutic potential of PMD-026 (a first-in-class oral pan-RSK inhibitor) in combination with fulvestrant, and clinical efficacy in +HR/HER2-/ RSK2-high patients with locally advanced or metastatic breast cancer. This trial will enroll second-line HR+/HER2-/RSK2-high metastatic breast cancer patients who have been treated previously with a CDK4/6 inhibitor and have developed resistance to it."

Trial status • Breast Cancer • HER2 Negative Breast Cancer • Hormone Receptor Positive Breast Cancer

RSK1 is an exploitable dependency in myeloproliferative neoplasms and secondary acute myeloid leukemia. (PubMed, Nat Commun) - "Treatment with PMD-026 suppressed disease burden across seven syngeneic and patient-derived xenograft leukemia mouse models spanning the spectrum of driver and disease-modifying mutations. These findings uncover a therapeutic avenue for a conserved dependency across MPN and sAML."

Journal • Acute Myelogenous Leukemia • Breast Cancer • Hematological Malignancies • Leukemia • Myeloproliferative Neoplasm • Oncology • Solid Tumor • CD14 • CD34 • RPS6 • TNFA

PMD-026, a First-in-Class RSK Inhibitor, Overcomes Acquired Resistance to CDK4/6 Inhibitors or Aromatase Inhibitors in HR+/HER2- Breast Cancer Preclinical Models (SABCS 2024) - P1/2 | "Its emerging role in resistance is underscored by a study showing that RSK2 is the most highly induced protein in the MAPK pathway following the development of acquired resistance to the aromatase inhibitor letrozole. The synergistic effect observed with PMD-026 and fulvestrant supports Dauntless-1, our newly launched Phase 2 clinical trial (NCT04115306) for second-line patients with RSK2+ tumors. This trial is for patients who have progressed on one prior line of CDK4/6i and aromatase inhibitors."

Preclinical • Breast Cancer • Estrogen Receptor Positive Breast Cancer • HER2 Breast Cancer • HER2 Negative Breast Cancer • HER2 Positive Breast Cancer • Hormone Receptor Positive Breast Cancer • Oncology • Solid Tumor • Triple Negative Breast Cancer • BRCA1 • BRCA2 • ER • HER-2 • PIK3CA • RPS6KA3 • RPS6KA6 • YBX1

RSK1 and RSK2 as therapeutic targets: an up-to-date snapshot of emerging data. (PubMed, Expert Opin Ther Targets) - "However, there is a paucity of the literature addressing RSK function in inflammation, which is critical to know as the pan RSK inhibitor, PMD-026, is entering phase II clinical trials for metastatic breast cancer. A RSK inhibitor has the potential to be used in numerous diverse diseases and disorders."

Journal • Review • Breast Cancer • Cardiovascular • Oncology • Solid Tumor • RPS6KA3

RSK1 dependency in FLT3-ITD acute myeloid leukemia. (PubMed, Blood Cancer J) - "Using cycloheximide, MG-132, and ubiquitination assays, we further demonstrate mechanistically that RSK1 regulates FLT3-ITD activity, and protein stability through deubiqutinase USP1, which we identify as a second dependency. Lastly, RSK1 inhibition utilizing a first-in-class RSK inhibitor, PMD-026, that is currently undergoing Phase 2 development for breast cancer, diminished leukemic disease burden in MV4-11 xenograft and syngeneic Flt3ITDTet2KO leukemia models. These findings illustrate an unconventional and promising therapeutic strategy targeting FLT3-ITD leukemia."

Journal • Acute Myelogenous Leukemia • Breast Cancer • Hematological Malignancies • Leukemia • Oncology • Solid Tumor • Targeted Protein Degradation • FLT3 • RPS6 • USP1

PMD-026-1-001: Phase 1/1b/2 Study of Oral PMD-026 in Patients With Metastatic Breast Cancer (clinicaltrials.gov) - P1/2 | N=61 | Recruiting | Sponsor: Phoenix Molecular Designs | Active, not recruiting ➔ Recruiting

Enrollment open • Metastases • Breast Cancer • HER2 Breast Cancer • Hormone Receptor Breast Cancer • Oncology • Solid Tumor • Triple Negative Breast Cancer • ER • HER-2

PMD-026-1-001: Phase 1/1b/2 Study of Oral PMD-026 in Patients With Metastatic Breast Cancer (clinicaltrials.gov) - P1/2 | N=61 | Active, not recruiting | Sponsor: Phoenix Molecular Designs | Phase classification: P1 ➔ P1/2 | Trial completion date: Mar 2025 ➔ Mar 2026 | Trial primary completion date: Dec 2024 ➔ Dec 2025

Metastases • Phase classification • Trial completion date • Trial primary completion date • Breast Cancer • HER2 Breast Cancer • Hormone Receptor Breast Cancer • Oncology • Solid Tumor • Triple Negative Breast Cancer • ER • HER-2

Leveraging dysregulated signaling networks for therapeutic benefit in myeloproliferative neoplasm (ICKSH 2024) - P1 | "Taken together, our findings uncover a novel therapeutic avenue for a conserved RSK1 dependency in MPNs. The potent and consistent dis- ease-ameliorating effects demonstrates promise for repurposing PMD-026 for the treatment of MPNs."

Acute Myelogenous Leukemia • Breast Cancer • Immunology • Leukemia • Myelofibrosis • Myeloproliferative Neoplasm • Oncology • Solid Tumor • CCL3 • CD14 • CD34 • CXCL8 • IL1B • IL6 • RELA

Therapeutic targeting of p90 ribosomal S6 kinase. (PubMed, Front Cell Dev Biol) - "Importantly, a pan-RSK inhibitor, PMD-026, is currently in phase I/1b clinical trials for metastatic breast cancer...Thus, a problem for transitioning a RSK inhibitor to the clinic may be the necessity to develop isoform specific inhibitors, which will be challenging as the NTKDs are very similar to each other. CTKD inhibitors have limited use as therapeutics as they are not able to inhibit the activity of the NTKD but could be used in the development of proteolysis-targeting chimeras."

Journal • Review • Breast Cancer • Oncology • Solid Tumor • Targeted Protein Degradation

Patient selection for high RSK2 expression is key for achieving improved PFS in metastatic breast cancer in the PMD-026 Phase 1/1b study (SABCS 2023) - "In this Phase 1/1b study, PMD-026 was evaluated in an ethnically diverse population of women across all breast cancer subtypes. Patients had a median of 5 prior lines of therapy and PMD-026 achieved stable disease in 44% (11/25) of the subjects. Consistent with the MOA, PMD-026 inhibited pCDK2Y15 in PBMCs from patients at C1D15."

Clinical • Metastases • P1 data • Breast Cancer • Hormone Receptor Breast Cancer • Oncology • Solid Tumor • Triple Negative Breast Cancer • RPS6KA3

PMD-026-1-001: Phase 1/1b Study of Oral PMD-026 in Patients With Metastatic Breast Cancer and Metastatic Triple Negative Breast Cancer (clinicaltrials.gov) - P1 | N=50 | Active, not recruiting | Sponsor: Phoenix Molecular Designs | Trial completion date: Mar 2024 ➔ Mar 2025 | Trial primary completion date: Dec 2023 ➔ Dec 2024

Metastases • Trial completion date • Trial primary completion date • Breast Cancer • HER2 Breast Cancer • Hormone Receptor Breast Cancer • Oncology • Solid Tumor • Triple Negative Breast Cancer • ER • HER-2

High levels of RSK2 in breast cancer patients is associated with longer PFS in patients treated with PMD-026, a first in class RSK inhibitor (SABCS 2022) - P1 | "These findings demonstrate that in patients treated with PMD-026 who had received < 5 prior treatment regimens, had de novo TNBC or CDK4/6 refractory HR+ disease and had high RSK2 scores had longer PFS. Overall, PMD-026 is a well-tolerated, orally available RSK2 inhibitor that will be evaluated further for efficacy in TNBC and CDK4/6i refractory HR+ mBC, in a trial that will prospectively enroll patients based on RSK2 activation as defined by the RSK2 IHC H-scores. Clinical trial information: NCT04115306."

Clinical • Breast Cancer • HER2 Breast Cancer • HER2 Negative Breast Cancer • Hormone Receptor Breast Cancer • Hormone Receptor Positive Breast Cancer • Oncology • Solid Tumor • Triple Negative Breast Cancer • CDK4 • HER-2 • RPS6KA3

Targeting RSK1-Mediated Dependency and Inflammation in Myeloid Malignancies (ASH 2022) - "Moreover, PMD-026 potently alleviated leukocytosis and disease burden in conjunction with prolonged survival in the MPL W515L retroviral MF mouse model, both alone and in combination with ruxolitinib (Fig. Thus, RSK1 may play a critical role in augmenting the pro-inflammatory microenvironment through potent effector monocytes. Our findings are first in demonstrating pre-clinical efficacy of a clinical grade RSK1 inhibitor, PMD-026, for the treatment of myeloid malignancies and highlight RSK1 inhibition to be two-pronged, by suppressing oncogenic signaling and inhibiting the CD14+ monocyte-driven pro-inflammatory milieu."

Acute Myelogenous Leukemia • Breast Cancer • Hematological Disorders • Hematological Malignancies • Immunology • Inflammation • Leukemia • Myelofibrosis • Myeloproliferative Neoplasm • Oncology • Solid Tumor • Transplantation • CD14 • CD34 • CXCL8 • IL6 • NDUFA2 • NFKB2 • RELA

First-in-human expansion study of oral PMD-026 in metastatic triple negative breast cancer patients (SABCS 2021) - P1 | "Updated safety, clinical activity, PK, and biomarker analyses will be presented. Clinical trial information: NCT04115306. a Bardia et al, N Engl J Med 2021; 384:1529-154"

Clinical • P1 data • Breast Cancer • HER2 Breast Cancer • Oncology • Solid Tumor • Triple Negative Breast Cancer • HER-2 • RPS6KA3

PMD-026-1-001: Phase 1/1b Study of Oral PMD-026 in Patients With Metastatic Breast Cancer and Metastatic Triple Negative Breast Cancer (clinicaltrials.gov) - P1 | N=50 | Active, not recruiting | Sponsor: Phoenix Molecular Designs | Recruiting ➔ Active, not recruiting | Trial completion date: Feb 2022 ➔ Mar 2024 | Trial primary completion date: Feb 2022 ➔ Dec 2023

Enrollment closed • Trial completion date • Trial primary completion date • Breast Cancer • HER2 Breast Cancer • Hormone Receptor Breast Cancer • Oncology • Solid Tumor • Triple Negative Breast Cancer • ER • HER-2

An oral first-in-class small molecule RSK inhibitor suppresses AR variants and tumor growth in prostate cancer (AUA 2022) - "PMD-026 suppressed cell proliferation alone and in combination with the second-generation antiandrogens enzalutamide and darolutamide by inducing cellular apoptosis and G2/M arrest. Conclusions : Our results demonstrate an excellent antitumor effect of the novel ribosomal S6 kinase inhibitor PMD-026 and the combination effect with the antiandrogen enzalutamide in castration-resistant prostate cancer. These findings warrant a clinical trial of PMD-026 in prostate cancer patients."

Genito-urinary Cancer • Oncology • Prostate Cancer • Solid Tumor

PMD-026, a first in class oral RSK inhibitor, demonstrates activity against hormone receptor positive breast cancer with acquired CDK4/6 inhibitor resistance (AACR 2022) - "For that purpose, MCF-7 and T47D cells were treated with increasing concentrations of the CDK4/6 inhibitor palbociclib (Ibrance) up to 2 µM for several months...In addition, cross-resistance to an additional CDK4/6 inhibitor, abemaciclib (Verzenio), was observed in the resistant cell lines, but the parental lines remained sensitive at IC50 values ranging from 0.15 to 0.25 µM...Together, these data support the application of PMD-026 and fulvestrant as a novel method to stop the growth of HR+ BC with acquired resistance to CDK4/6 inhibitors. Additionally, given that the MAPK pathway is upregulated in response to PI3K inhibition, the PMD-026 and fulvestrant combination is a potential alternative treatment for HR+ BC patients."

Breast Cancer • Hormone Receptor Breast Cancer • Hormone Receptor Positive Breast Cancer • Oncology • Solid Tumor • RPS6KA3

Phoenix Molecular Designs Successfully Completes Patient Enrollment in Phase 1/1b Clinical Trial of PMD-026 (PRNewswire) - "Phoenix Molecular Designs...announced the completion of patient enrollment and dosing of PMD-026 in their Phase 1b monotherapy clinical trial. The successful completion of patient enrollment in this Phase 1/1b trial is an important step forward for PhoenixMD as they advance PMD-026 into Phase 2 combination trials for triple negative breast cancer (TNBC) and hormone-positive breast cancer....The Company's Phase 1/1b clinical trial was conducted at nine leading cancer centers across the United States."

Enrollment closed • Breast Cancer • Oncology • Solid Tumor • Triple Negative Breast Cancer