sulanemadlin (ALRN-6924) / Rein Therapeutics, Advancium Health Network - LARVOL DELTA

A new approach for elimination of apoptotic resistance caused by MDM2/MDMX amplification in chronic lymphocytic leukemia: combination of ALRN-6924 and radiofrequency exposure. (PubMed, Med Oncol) - "In mutant p53 cells, combination therapy may provide partial benefits. These findings support ALRN-6924 clinical development as targeted therapy for p53-functional CLL, particularly in combination strategies."

IO biomarker • Journal • Chronic Lymphocytic Leukemia • Hematological Malignancies • Leukemia • Oncology • BCL2 • MDM2

Mis-splicing of Mdm4 activates TRP53 and impairs HSPC growth in a mouse model of myelodysplastic syndromes (ASH 2025) - "Indeed, in two independent competitive repopulationexperiments, the clinical grade TRP53 activator sulanemadlin (a stapled peptide inhibitor ofMDM2/MDM4) preferentially killed mouse U2af1S34F HSPCs in vivo, compared to WT congenic controls(p<0.001, N=6-7 mice/group)...Our ongoing studies are testing whether MDM4 overexpression rescuesthe growth of U2af1S34F HSPCs in vivo, and whether splicing factor mutant MDS cells from patients haveabnormal splicing of MDM4 or other TP53 regulators. By understanding what drives TP53 activation insplicing factor mutant cells, we aim to identify a vulnerability that can be exploited to kill them."

Preclinical • Acute Myelogenous Leukemia • Bone Marrow Transplantation • Hematological Malignancies • Leukemia • Myelodysplastic Syndrome • CD34 • MDM4 • PTPRC • SF3B1 • SRSF2 • TP53 • U2AF1

Overcoming Challenges in the Metabolism of Peptide Therapeutics: Strategies and Case Studies for Clinical Success. (PubMed, J Med Chem) - "Low permeability and bioavailability of peptides are also briefly covered. Case studies, including semaglutide, MK-0616, LUNA18, sulanemadlin, and oxytocin analogs, illustrate successful applications of these strategies, highlighting how rational design and optimization have advanced peptide candidates from discovery to clinical stage."

Journal • Review • Cardiovascular • Diabetes • Metabolic Disorders • Oncology

ALRN-6924 and Paclitaxel in Treating Patients With Advanced, Metastatic, or Unresectable Solid Tumors (clinicaltrials.gov) - P1 | N=35 | Active, not recruiting | Sponsor: M.D. Anderson Cancer Center | Trial completion date: Jul 2025 ➔ Jul 2027 | Trial primary completion date: Jul 2025 ➔ Jul 2027

Trial completion date • Trial primary completion date • Breast Cancer • Estrogen Receptor Positive Breast Cancer • Hormone Receptor Positive Breast Cancer • Oncology • Solid Tumor • ER • HER-2 • MDM2 • MDM4 • TP53

A cancer persistent DNA repair circuit driven by MDM2, MDM4 (MDMX), and mutant p53 for recruitment of MDC1 and 53BP1 on chromatin. (PubMed, Nucleic Acids Res) - "We demonstrated that a mtp53-MDM2/MDMX complex promoted 53BP1-MDC1 interactions by showing that mtp53-MDM2/MDMX complex disruptors, Nutlin 3a and ALRN-6924, reduced the 53BP1-MDC1 nuclear interactions (especially in S-phase)...We found that MDM2-deficient cells have increased poly-ADP-ribosylation on chromatin which supports the possibility that a mtp53-MDM2/MDMX pathway promotes aberrant DNA repair. Taken together, our data suggest that a mtp53-MDM2/MDMX complex orchestrates DNA repair machinery activity on chromatin, thus priming cancer cells for persistent DNA damage repair (CPR)."

Journal • Breast Cancer • Oncology • Solid Tumor • MDM4 • TP53 • TP53BP1

Aileron Therapeutics and Advancium Health Network Announce an Exclusive Option Agreement for the Acquisition of ALRN-6924 for Retinoblastoma (PRNewswire) - "Aileron Therapeutics, Inc...and Advancium Health Network...today announced entry into an exclusive option agreement for the acquisition of ALRN-6924, a clinical-stage oncology agent developed by Aileron prior to its 2023 merger with Lung Therapeutics, Inc....Under the terms of the option agreement, Advancium paid Aileron a non-refundable fee for the exclusive option to acquire ALRN-6924 and related assets. If Advancium exercises its option, Aileron will receive an exercise payment with potential for additional development, regulatory and commercial milestone payments and sales royalties."

Licensing / partnership • Retinoblastoma

Selective protection of healthy human hair follicles and their stem cells from chemotherapy-induced damage by a novel topically effective p53-targeting peptide (EADV 2024) - "Here, we report that human hair matrix keratinocytes and eHFSCs can be protected against two key CIA-inducing drugs (paclitaxel (PTX) and 4-hydroperoxycyclophosphamide (4-HC)) ex vivo by transient, p21-dependent cell cycle arrest induced only in healthy proliferating cells by activation of p53 with ALRN-6924. We thus introduce a novel principle for the selective protection of rapidly proliferating healthy human epithelial tissues and their stem cells from chemotherapy-induced damage as a highly innovative strategy for protecting patients with TP53-mutant cancers against acute and permanent CIA."

Clinical • Alopecia • Immunology • Oncology • CASP3 • CDKN1A • SNAI2 • VIM

MDM2/MDMX inhibition by Sulanemadlin synergizes with anti-Programmed Death 1 immunotherapy in wild-type p53 tumors. (PubMed, iScience) - "We found that the p53 activating stapled peptide MDM2/MDMX inhibitor Sulanemadlin (ALRN-6924) inhibited p53 wild-type cancer cell growth in vitro and in vivo...Sulanemadlin treatment led to increased immunogenicity and combination treatment with PD-1 inhibition resulted in an increased tumor infiltration of lymphocytes. This combination treatment strategy could potentially turn partial responders into responders of immunotherapy, expanding the patient target group for PD-1-targeting immunotherapy."

Journal • Oncology

ALRN-6924 and Paclitaxel in Treating Patients With Advanced, Metastatic, or Unresectable Solid Tumors (clinicaltrials.gov) - P1 | N=35 | Active, not recruiting | Sponsor: M.D. Anderson Cancer Center | Phase classification: P1b ➔ P1

Combination therapy • Metastases • Phase classification • Breast Cancer • Estrogen Receptor Positive Breast Cancer • HER2 Breast Cancer • HER2 Negative Breast Cancer • Hormone Receptor Breast Cancer • Hormone Receptor Positive Breast Cancer • Oncology • Prostate Cancer • Solid Tumor • CASP3 • CDKN1A • ER • GDF15 • HER-2 • MDM2 • MDM4 • TP53

ALRN-6924 and Paclitaxel in Treating Patients With Advanced, Metastatic, or Unresectable Solid Tumors (clinicaltrials.gov) - P1b | N=35 | Active, not recruiting | Sponsor: M.D. Anderson Cancer Center | Trial completion date: Jul 2023 ➔ Apr 2025 | Trial primary completion date: Jul 2023 ➔ Apr 2025

Combination therapy • Metastases • Trial completion date • Trial primary completion date • Breast Cancer • Estrogen Receptor Positive Breast Cancer • HER2 Breast Cancer • HER2 Negative Breast Cancer • Hormone Receptor Breast Cancer • Hormone Receptor Positive Breast Cancer • Oncology • Prostate Cancer • Solid Tumor • ER • HER-2 • MDM2 • MDM4 • TP53

Phase 1 Study of the Dual MDM2/MDMX Inhibitor ALRN-6924 in Pediatric Cancer (clinicaltrials.gov) - P1 | N=21 | Completed | Sponsor: Dana-Farber Cancer Institute | Active, not recruiting ➔ Completed | N=69 ➔ 21

Enrollment change • Trial completion • Acute Myelogenous Leukemia • Brain Cancer • Hematological Malignancies • Leukemia • Lymphoma • Oncology • Pediatrics • Solid Tumor • MDM2 • PPM1D • SMARCB1 • TET2 • TP53

MDM2 Inhibition in the Treatment of Glioblastoma: From Concept to Clinical Investigation. (PubMed, Biomedicines) - "While some MDM2 inhibitors have progressed to early phase clinical trials in GBM, their efficacy, alone and in combination, is yet to be confirmed. In this article, we present an overview of MDM2 inhibitors currently under preclinical and clinical investigation, with a specific focus on the drugs being assessed in ongoing clinical trials for GBM patients."

Journal • Review • Brain Cancer • CNS Tumor • Glioblastoma • Oncology • Solid Tumor

Discovery of Sulanemadlin (ALRN-6924), the First Cell-Permeating, Stabilized α-Helical Peptide in Clinical Development. (PubMed, J Med Chem) - "At lower doses, ALRN-6924 transiently arrests the cell cycle in healthy tissues to protect them from chemotherapy without protecting the TP53-mutant cancer cells. These results support the continued clinical evaluation of ALRN-6924 as an anticancer and chemoprotection agent."

Journal • Oncology • Targeted Protein Degradation • MDM4

Identification of the Stapled α-Helical Peptide ATSP-7041 as a Substrate and Strong Inhibitor of OATP1B1 In Vitro. (PubMed, Biomolecules) - "A recent report describes that ALRN-6924, an ATSP-7041 analog, inhibited OATP activities in vivo; therefore, we focused on the interaction between ATSP-7041 and OATP1B1 to demonstrate that ATSP-7041, as a higher molecular weight stapled peptide, is a substrate and strong inhibitor of OATP1B1 activity. Our findings demonstrated the possibility of transporter-mediated DDI potential by high molecular weight stapled peptides and the necessity of their evaluation for drug development."

Journal • Preclinical • Breast Cancer • Oncology • Solid Tumor • CYP1A2 • CYP2C19 • CYP2C9 • CYP3A4

Phase 1 Study of the Dual MDM2/MDMX Inhibitor ALRN-6924 in Pediatric Cancer (clinicaltrials.gov) - P1 | N=69 | Active, not recruiting | Sponsor: Dana-Farber Cancer Institute | Trial completion date: Jun 2023 ➔ Sep 2023 | Trial primary completion date: Jun 2023 ➔ Sep 2023

Trial completion date • Trial primary completion date • Acute Myelogenous Leukemia • Brain Cancer • Gastrointestinal Cancer • Hematological Malignancies • Leukemia • Lymphoma • Oncology • Pediatrics • Solid Tumor • MDM2 • PPM1D • SMARCB1 • TET2 • TP53

Phase 1 Study of the Dual MDM2/MDMX Inhibitor ALRN-6924 in Pediatric Cancer (clinicaltrials.gov) - P1 | N=69 | Active, not recruiting | Sponsor: Dana-Farber Cancer Institute | Recruiting ➔ Active, not recruiting

Enrollment closed • Acute Myelogenous Leukemia • Brain Cancer • Gastrointestinal Cancer • Hematological Malignancies • Leukemia • Lymphoma • Oncology • Pediatrics • Solid Tumor • MDM2 • PPM1D • SMARCB1 • TET2 • TP53

ALRN-6924 and Paclitaxel in Treating Patients With Advanced, Metastatic, or Unresectable Solid Tumors (clinicaltrials.gov) - P1b | N=35 | Active, not recruiting | Sponsor: M.D. Anderson Cancer Center | Recruiting ➔ Active, not recruiting

Combination therapy • Enrollment closed • Metastases • Breast Cancer • Estrogen Receptor Positive Breast Cancer • HER2 Breast Cancer • HER2 Negative Breast Cancer • Hormone Receptor Breast Cancer • Hormone Receptor Positive Breast Cancer • Oncology • Prostate Cancer • Solid Tumor • ER • HER-2 • MDM2 • MDM4 • TP53

Cell cycle arrest: A breakthrough in the supportive care of older cancer patients. (PubMed, J Am Geriatr Soc) - "Two new drugs, Trilaciclib and ALRN-6924 may cause a temporary cell cycle arrest (CCA) of normal cells without blocking the proliferation of the neoplastic ones and render the normal cells temporarily invulnerable to the toxicity of chemotherapy. It may allow the treatment of frail patients with full chemotherapy doses. It is also reasonable to expect that may complications other common and sometimes lethal complications of chemotherapy such as stomatitis, esophagitis, diarrhea and dehydration."

Journal • Review • Dental Disorders • Gastrointestinal Disorder • Hematological Disorders • Hematological Malignancies • Lung Cancer • Neutropenia • Non Small Cell Lung Cancer • Oncology • Pain • Solid Tumor • Stomatitis • Thrombocytopenia • RB1 • TP53

Temporary cell cycle arrest by ALRN-6924: A novel, p53-targeting strategy to protect human scalp hair follicles against cyclophosphamide-induced alopecia (ISID 2023) - "Taken together, this shows that ALRN-6924 effectively protects human HFs from 4-HC-induced toxicity and irreversible SC damage while promoting the “dystrophic anagen” pathway of HF repair ex vivo . This suggests that ALRN-6924 can also reduce both acute and permanent alopecia induced by cyclophosphamide."

Alopecia • Oncology • CDKN1A • VIM

ALRN-6924, A DUAL INHIBITOR OF MDMX AND MDM2 THAT CAUSES MINIMAL THROMBOCYTOPENIA IN PATIENTS, DISRUPTS DIFFERENT STAGES OF THROMBOPOIESIS COMPARED TO MDM2-ONLY INHIBITION (EHA 2019) - P1/2; "Human bone marrow CD34+ cells seeded in methylcellulose semi-solid media containing IL-3 and IL-6; and TPO, Epo or GM-CSF together with ALRN-6924, RG7388 (idasanutlin), or controls. However, inhibition of less mature megakaryocyte progenitors, prior to entering terminal maturation, appears to be better tolerated. This may explain the differences in TCP grades and frequencies from published solid tumor trials for ALRN-6924 vs. MDM2-only inhibitors, and suggests that MDMX in bone marrow cells, where MDMX RNA expression is the highest of all 37 normal tissues reported in the Protein Atlas, may contribute to these differences."

Clinical

Dual Inhibition of Mdmx and Mdm2 Using an Alpha-Helical P53 Stapled Peptide (ALRN-6924) As a Novel Therapeutic Strategy in Acute Myeloid Leukemia (ASH 2017) - P1/2,P1; "Furthermore, the success of targeting p53 raises the intriguing prospect that the same development path is possible for other helix-in-groove targets, and may thus pave the way for a new class of targeted therapeutics. 1 ASCO 2017 annual meeting: J Clin Oncol 35, 2017 (suppl; abstr 2505)"

Acute Myelogenous Leukemia • Biosimilar • Lymphoma

In Vitro and pre-Clinical In Vivo evidence Support MDMX/MDM2 As Common Vulnerabilities across TP53-Wild-Type T-Cell Lymphomas That Are Targetable with the α-Helical p53 Stapled Peptide Alrn-6924 (ASH 2017) - P1/2; "At the time of extensive lymphoma engraftment (e.g. >20% splenic involvement), mice were randomized to treatment with vehicle, ALRN-6924 or the 2nd line standard-of-care agent Romidepsin (n=3/arm/model) on days 1, 4 and 7, and sacrificed on day 8. In summary, we identified MDM2/MDMX as a targetable vulnerability that is effectively targeted by the stapled peptide ALRN-6924 in TP53 WT TCLs with promising activity across multiple subtypes, supporting further clinical development of ALRN-6924 in TCL for patients requiring 2nd or frontline treatment. A Phase IIa clinical trial of ALRN-6924 in PTCL patients is currently enrolling (NCT02264613)."

Gene Expression Profile • Biosimilar • Cutaneous T-cell Lymphoma • Diffuse Large B Cell Lymphoma • Indolent Lymphoma • Leukemia • Peripheral T-cell Lymphoma

The investigational peptide drug ALRN-6924, a dual inhibitor of MDMX and MDM2, is an effective myelopreservation agent (AACR-NCI-EORTC 2019) - P1b/2; "These results support the first ALRN-6924 clinical trial for myelopreservation in topotecan-treated small-cell lung cancer patients (NCT04022876). Additional studies are underway to support ALRN-6924 as a tumor type-agnostic myelopreservation agent for cancer patients with tumors bearing p53 mutations who are treated with chemotherapy."

Phase 2a study of a novel stapled peptide ALRN-6924 disrupting MDMX- and MDM2-mediated inhibition of wild-type TP53 in patients with peripheral t-cell lymphoma (ESMO 2017) - P1/2; "Pharmacodynamic biomarkers will be measured in blood and tumor samples. Recruitment is ongoing."

P2 data • Diffuse Large B Cell Lymphoma • Peripheral T-cell Lymphoma

A Study of ALRN-6924 for Protection of Chemotherapy-Induced Side Effects in Patients With TP53-Mutant Breast Cancer (clinicaltrials.gov) - P1b | N=6 | Terminated | Sponsor: Aileron Therapeutics, Inc. | N=26 ➔ 6 | Trial completion date: Jan 2024 ➔ Feb 2023 | Recruiting ➔ Terminated | Trial primary completion date: Sep 2023 ➔ Feb 2023; The study has been terminated early given that the first four patients enrolled have experienced Grade 4 neutropenia and alopecia after cycle 1 and as such failed to meet the primary endpoint and the main secondary endpoint.

Adverse events • Enrollment change • Trial completion date • Trial primary completion date • Trial termination • Breast Cancer • HER2 Breast Cancer • HER2 Negative Breast Cancer • Oncology • Solid Tumor • HER-2 • TP53