REC-2282 / Ohio State University, Recursion Pharma - LARVOL DELTA

POPLAR-NF2: Efficacy and Safety of REC-2282 in Patients With Progressive Neurofibromatosis Type 2 (NF2) Mutated Meningiomas (clinicaltrials.gov) - P2/3 | N=25 | Terminated | Sponsor: Recursion Pharmaceuticals Inc. | N=92 ➔ 25 | Trial completion date: Jul 2027 ➔ Aug 2025 | Recruiting ➔ Terminated | Trial primary completion date: Jan 2027 ➔ Aug 2025; Study was terminated due to sponsor decision. This decision was not related to safety concerns with REC-2282.

Enrollment change • Trial completion date • Trial primary completion date • Trial termination • Brain Cancer • Genetic Disorders • Meningioma • Neurofibromatosis • Oncology • Solid Tumor • NF2

The effect of coadministration of D156844 and AR42 (REC-2282) on the survival and motor phenotype of mice with spinal muscular atrophy. (PubMed, Sci Rep) - "Additionally, coadministration of D156844 and AR42 produced improvements in motor phenotype in SMNΔ7 SMA mice. This study provides further evidence underlying the potential benefit of a combination therapeutics approach to treating SMA."

Journal • Preclinical • Amyotrophic Lateral Sclerosis • Genetic Disorders • Movement Disorders • Muscular Atrophy • Pediatrics • Rare Diseases • SMA4 • SMN1 • SMN2

Recursion Reports First Quarter 2025 Financial Results and Provides Business Update (GlobeNewswire) - "As part of this prioritization, the Company will discontinue development and/or pursue partnering opportunities for the following clinical programs: REC-2282 (NF2): Totality of data supports the discontinuation of the study...New findings: Phase 2 passed the futility threshold primarily driven by the 40mg cohort, however the 60mg and combined dose arms did not pass the futility criteria. Limited overall tumor shrinkage and clinical activity across all arms."

Discontinued • Neurofibromatosis

Recursion Provides Business Updates and Reports Third Quarter 2024 Financial Results (GlobeNewswire) - "Summary of Business Highlights:...(i) Neurofibromatosis Type 2 (NF2) (REC-2282): Our adaptive Phase 2/3 POPLAR clinical trial is an open label, two part study of REC-2282 in participants with progressive NF2-mutated meningiomas....Enrollment of adult patients in Part 1 of the study is complete (n=24). We expect to share an update in Q4 2024....(ii) APC or AXIN1 Mutant Cancers (REC-4881): Our Phase 2 LILAC clinical trial is an open label, multicenter study of REC-4881 in participants with unresectable, locally advanced or metastatic cancer with AXIN1 or APC mutations. We expect to share Phase 2 safety and preliminary efficacy data in H1 2025."

Enrollment status • P2 data • P2/3 data • Neurofibromatosis • Solid Tumor

POPLAR-NF2: Efficacy and Safety of REC-2282 in Patients With Progressive Neurofibromatosis Type 2 (NF2) Mutated Meningiomas (clinicaltrials.gov) - P2/3 | N=89 | Recruiting | Sponsor: Recursion Pharmaceuticals Inc.

Trial completion date • Trial primary completion date • Brain Cancer • CNS Tumor • Fibrosis • Genetic Disorders • Meningioma • Neurofibromatosis • Oncology • Solid Tumor • NF2

Evaluation of the orally bioavailable 4-phenylbutyrate-tethered trichostatin A analogue AR42 in models of spinal muscular atrophy. (PubMed, Sci Rep) - "AKT and GSK3β phosphorylation were both significantly increased in SMNΔ7 SMA mouse spinal cords. In conclusion, presymptomatic administration of the HDAC inhibitor AR42 ameliorates the disease phenotype in SMNΔ7 SMA mice in a SMN-independent manner possibly by increasing AKT neuroprotective signaling."

Journal • Genetic Disorders • Movement Disorders • Muscular Atrophy • Rare Diseases • AKT1

Recursion Provides Business Updates and Reports First Quarter 2023 Financial Results (GlobeNewswire) - "Neurofibromatosis Type 2 (NF2) (REC-2282): Our Phase 2/3 POPLAR clinical trial is a parallel group, two stage, randomized, multicenter study of this drug candidate in approximately 90 participants with progressive NF2-mutated meningiomas. Enrollment is ongoing and we expect to share a Phase 2 interim safety analysis in 2024....AXIN1 or APC Mutant Cancers (REC-4881)…We expect to initiate a Phase 2 biomarker enriched study across select AXIN1 or APC mutant solid tumors in early 2024."

New P2 trial • P2 data • Neurofibromatosis • Oncology • Solid Tumor

POPLAR-NF2: Efficacy and Safety of REC-2282 in Patients With Progressive Neurofibromatosis Type 2 (NF2) Mutated Meningiomas (clinicaltrials.gov) - P2/3 | N=89 | Recruiting | Sponsor: Recursion Pharmaceuticals Inc. | Not yet recruiting ➔ Recruiting | Initiation date: Dec 2021 ➔ Apr 2022

Enrollment open • Trial initiation date • Brain Cancer • Fibrosis • Genetic Disorders • Meningioma • Neurofibromatosis • Oncology • Solid Tumor

POPLAR-NF2: Efficacy and Safety of REC-2282 in Patients With Progressive Neurofibromatosis Type 2 (NF2) Mutated Meningiomas (clinicaltrials.gov) - P2/3; N=89; Not yet recruiting; Sponsor: Recursion Pharmaceuticals Inc.

Clinical • New P2/3 trial • Brain Cancer • Fibrosis • Genetic Disorders • Meningioma • Neurofibromatosis • Oncology • Solid Tumor

The Effect of a Histone Deacetylase Inhibitor (AR-42) and Zoledronic Acid on Adult T-Cell Leukemia/Lymphoma Osteolytic Bone Tumors. (PubMed, Cancers (Basel)) - "AR-42 alone had no significant effect on tumor growth or osteolysis in mice. These findings indicate that Zol adjuvant therapy has the potential to reduce growth of ATL in bone and its associated osteolysis."

Clinical • Epigenetic controller • Journal • Adult T-Cell Leukemia-Lymphoma • Hematological Malignancies • Leukemia • Lymphoma • Non-Hodgkin’s Lymphoma • Oncology • Osteosarcoma • Solid Tumor

Early phase clinical studies of AR-42, a histone deacetylase inhibitor, for neurofibromatosis type 2-associated vestibular schwannomas and meningiomas. (PubMed, Laryngoscope Investig Otolaryngol) - P1 | "A phase 2 study of AR-42 for NF2-associated tumors appears warranted. 1b, 4."

Clinical • Epigenetic controller • Journal • Brain Cancer • Fibrosis • Genetic Disorders • Meningioma • Neurofibromatosis • Oncology • Solid Tumor • NF2

Population Pharmacokinetic Analysis from First-in-Human Data for HDAC Inhibitor, REC-2282 (AR-42), in Patients with Solid Tumors and Hematologic Malignancies: A Case Study for Evaluating Flat vs. Body Size Normalized Dosing. (PubMed, Eur J Drug Metab Pharmacokinet) - P1 | "FFM was identified as a significant covariate on CL; however, it explained only a very small portion of the IIV; major factors contributing significantly to REC-2282 pharmacokinetic variability remain unidentified."

Clinical • Journal • P1 data • PK/PD data • Acute Myelogenous Leukemia • Hematological Disorders • Hematological Malignancies • Leukemia • Oncology • Solid Tumor

Targeting DNA damage repair functions of two histone deacetylases, HDAC8 and SIRT6, sensitizes acute myeloid leukemia to NAMPT inhibition. (PubMed, Clin Cancer Res) - "Our findings provide evidence that HDAC8 inhibition- or shSIRT6-induced DNA repair deficiencies are potently synergistic with NAMPT targeting, with minimal toxicity towards normal cells, providing a rationale for a novel-novel combination-based treatment for AML."

Journal • Acute Myelogenous Leukemia • Hematological Malignancies • Leukemia • Oncology • NAMPT • PARP1 • SIRT6

HDAC Inhibitor AR-42 and Pomalidomide in Treating Patients With Relapsed Multiple Myeloma (clinicaltrials.gov) - P1b; N=9; Completed; Sponsor: Ohio State University Comprehensive Cancer Center; Suspended ➔ Completed; N=72 ➔ 9

Enrollment change • Trial completion • Hematological Malignancies • Multiple Myeloma • Oncology

Exploratory Evaluation of AR-42 Histone Deacetylase Inhibitor in the Treatment of Vestibular Schwannoma and Meningioma (clinicaltrials.gov) - P1; N=5; Active, not recruiting; Sponsor: Massachusetts Eye and Ear Infirmary; Recruiting ➔ Active, not recruiting; N=20 ➔ 5

Enrollment change • Enrollment closed • Epigenetic controller • Brain Cancer • Fibrosis • Genetic Disorders • Meningioma • Neurofibromatosis • Oncology • Solid Tumor • MRI

Exploratory Evaluation of AR-42 Histone Deacetylase Inhibitor in the Treatment of Vestibular Schwannoma and Meningioma (clinicaltrials.gov) - P1; N=5; Active, not recruiting; Sponsor: Massachusetts Eye and Ear Infirmary; Trial completion date: Oct 2018 ➔ Oct 2022; Trial primary completion date: Oct 2018 ➔ Oct 2020

Epigenetic controller • Trial completion date • Trial primary completion date • Brain Cancer • Fibrosis • Genetic Disorders • Meningioma • Neurofibromatosis • Oncology • Solid Tumor • MRI

Exploratory Evaluation of AR-42 Histone Deacetylase Inhibitor in the Treatment of Vestibular Schwannoma and Meningioma (clinicaltrials.gov) - P; N=20; Recruiting; Sponsor: Massachusetts Eye and Ear Infirmary; Phase classification: P=N/A ➔ P; Trial primary completion date: Apr 2017 ➔ Oct 2017

Epigenetic controller • IO biomarker • Phase classification • Trial primary completion date • Brain Cancer • Fibrosis • Genetic Disorders • Meningioma • Neurofibromatosis • Oncology • Solid Tumor • MRI

Exploratory Evaluation of AR-42 Histone Deacetylase Inhibitor in the Treatment of Vestibular Schwannoma and Meningioma (clinicaltrials.gov) - P1; N=20; Recruiting; Sponsor: Massachusetts Eye and Ear Infirmary; Trial primary completion date: Oct 2017 ➔ Aug 2018

Epigenetic controller • IO biomarker • Trial primary completion date • Brain Cancer • Fibrosis • Genetic Disorders • Meningioma • Neurofibromatosis • Solid Tumor • MRI

Exploratory Evaluation of AR-42 Histone Deacetylase Inhibitor in the Treatment of Vestibular Schwannoma and Meningioma (clinicaltrials.gov) - P0; N=20; Not yet recruiting; Sponsor: Massachusetts Eye and Ear Infirmary

Epigenetic controller • IO biomarker • Brain Cancer • Fibrosis • Genetic Disorders • Meningioma • Neurofibromatosis • Oncology • Solid Tumor • MRI

Exploratory Evaluation of AR-42 Histone Deacetylase Inhibitor in the Treatment of Vestibular Schwannoma and Meningioma (clinicaltrials.gov) - P1; N=5; Active, not recruiting; Sponsor: Massachusetts Eye and Ear Infirmary; Trial completion date: Oct 2022 ➔ Oct 2023; Trial primary completion date: Oct 2020 ➔ Oct 2021

Epigenetic controller • Trial completion date • Trial primary completion date • Brain Cancer • Fibrosis • Genetic Disorders • Meningioma • Neurofibromatosis • Oncology • Solid Tumor • MRI

Exploratory Evaluation of AR-42 Histone Deacetylase Inhibitor in the Treatment of Vestibular Schwannoma and Meningioma (clinicaltrials.gov) - P0; N=20; Recruiting; Sponsor: Massachusetts Eye and Ear Infirmary; Not yet recruiting ➔ Recruiting; Initiation date: Oct 2014 ➔ Sep 2015

Enrollment open • Epigenetic controller • IO biomarker • Trial initiation date • Brain Cancer • Fibrosis • Genetic Disorders • Meningioma • Neurofibromatosis • Oncology • Solid Tumor • MRI

A phase 1 trial of the histone deacetylase inhibitor AR-42 in patients with neurofibromatosis type 2-associated tumors and advanced solid malignancies. (PubMed, Cancer Chemother Pharmacol) - P1 | "Single-agent AR-42 is safe and well tolerated. Further studies may consider AR-42 in a larger cohort of patients with NF2 or in combination with other agents in advanced solid tumors."

Clinical • Journal • P1 data • Breast Cancer • CNS Disorders • Eye Cancer • Fatigue • Fibrosis • Genetic Disorders • Hematological Disorders • Hematological Malignancies • Lung Cancer • Melanoma • Meningioma • Neurofibromatosis • Oncology • Psychiatry • Small Cell Lung Cancer • Solid Tumor • Thrombocytopenia • Urothelial Cancer • Uveal Melanoma

The histone H3-lysine 4-methyltransferase Mll4 regulates the development of growth hormone-releasing hormone-producing neurons in the mouse hypothalamus. (PubMed, Nat Commun) - "Interestingly, the deficiency of Mll4 results in a marked reduction of histone marks of active transcription, while treatment with the histone deacetylase inhibitor AR-42 rescues the histone mark signature and restores GHRH-neuronal production in Mll4 mutant mice. Our results suggest that the developmental dysregulation of Mll4-directed epigenetic control of transcription plays a role in the development of GHRH-neurons and dwarfism phenotype in mice."

Journal • Endocrine Disorders • KMT2D • NRF1

Achiral Derivatives of Hydroxamate AR-42 Potently Inhibit Class I HDAC Enzymes and Cancer Cell Proliferation. (PubMed, J Med Chem) - "Molecular modelling and structure-activity relationships support binding to HDAC1 with tetrahydropyran acting as a hydrophobic shield from water at the enzyme surface. Such potent inhibitors of class I HDACs may show benefit in diseases (cancers, parasitic infections, inflammatory conditions) where AR-42 is active."

Journal • Leukemia • Lymphoma • Melanoma • Multiple Myeloma • Oncology

FOXA1 Regulation Turns Benzamide HDACi Treatment Effect-Specific in BC, Promoting NIS Gene-Mediated Targeted Radioiodine Therapy. (PubMed, Mol Ther Oncolytics) - "Further, AR-42 and MS-275 treatment shows enhanced NIS expression in an orthotopic breast tumor model. Cerenkov imaging revealed higher accumulation of I in MS-275-treated tumors. Thus, bHDACi-mediated selective enhancement ensuring minimal off-target effect is a step further toward using NIS as a therapeutic target for BC."

Journal • Anaplastic Thyroid Cancer • Breast Cancer • Oncology • Solid Tumor • Thyroid Cancer • FOXA1