decitabine/ tetrahydrouridine (EPI01) / EpiDestiny, Novo Nordisk - LARVOL DELTA

Modified-release formulation of decitabine and tetrahydrouridine combination not only increases exposure to decitabine but reduces exposure to unfavorable decitabine metabolites in healthy volunteers (ASH 2025) - "Staggered release of THU with decitabine in NDec resulted in optimal decitabine exposure with nounexpected safety concerns. A decrease in exposure to unfavorable CDA-mediated uridine metaboliteswith NDec compared with IR indicates that delaying release of decitabine after THU may reduce toxicityby promoting the oxidative degradation pathway of decitabine in preference to the phosphorylationpathway. These findings support the planned use of NDec to investigate clinical efficacy and safety inPhase 3 trials."

Clinical • Genetic Disorders • Hematological Disorders • Sickle Cell Disease • DNMT1

Concizumab plasma concentration measurements for personalized dose adjustment in patients with Hemophilia A/B with and without inhibitors: Data from the Phase 3 explorer7 and explorer8 studies (ASH 2025) - P3 | "After dose adjustment to 0.15 mg/kg, the mean concizumab plasma concentrationdecreased from 5,525 ng/mL to 766 ng/mL from week 4 to week 12. Mean ABR in the 4,000 ng/mL plasma concizumab, observed mean ABR after dose adjustment was 3.8(SD: 4.8; mean observation period 340 days), similar to the 200–4,000 ng/mL group (3.1; SD: 6.5; meanobservation period 287 days).ConclusionsThese findings support the use of concizumab plasma concentration-guided dose adjustments tooptimize prophylaxis in patients with hemophilia A or B, with or without inhibitors. Exposure-responseanalyses confirmed the validity of the selected lower (200 ng/mL) and upper (4,000 ng/mL) limits ofconcizumab plasma concentration and showed that dose adjustments can effectively personalize therapyto reduce bleeding rates."

Clinical • P3 data • Cardiovascular • Hematological Disorders • Hemophilia • Hemophilia A • Hemophilia B • Rare Diseases

How People with Sickle Cell Disease Rate Motivators is Associated with the Likelihood of Wanting to Participate in a Clinical Trial: Findings from the Global LISTEN Survey (ASH 2024) - "This awareness is crucial, as 23% of PwSCD who responded to the LISTEN Survey were undecided about participating in a clinical trial, highlighting a need to raise awareness and understanding of clinical trials. Ensuring clinical trial opportunities are accessible to all PwSCD and understanding the reasons that motivate individuals may improve participation in SCD clinical trials."

Clinical • Genetic Disorders • Hematological Disorders • Sickle Cell Disease

Effects of Tetrahydrouridine Pre-dosing on Absorption, Metabolism, and Excretion of Decitabine in the Mouse. (PubMed, Eur J Pharm Sci) - P2 | "These findings provide crucial insights into DEC metabolism, highlighting the impact of THU pre-treatment on DEC plasma exposure, metabolism, and excretion."

Journal • Preclinical • Genetic Disorders • Hematological Disorders • Sickle Cell Disease • DNMT1

ASCENT1: Research Study Investigating How Well NDec Works in People With Sickle Cell Disease (clinicaltrials.gov) - P2 | N=96 | Completed | Sponsor: Novo Nordisk A/S | Active, not recruiting ➔ Completed | Trial primary completion date: Aug 2025 ➔ Dec 2024

Trial completion • Trial primary completion date • Genetic Disorders • Hematological Disorders • Sickle Cell Disease

A Study of Oral Tetrahydrouridine-Decitabine in Relapsed or Refractory Myelodysplastic Syndromes (MDS) (clinicaltrials.gov) - P1 | N=20 | Recruiting | Sponsor: EpiDestiny, Inc. | Not yet recruiting ➔ Recruiting

Enrollment open • Hematological Malignancies • Myelodysplastic Syndrome • Oncology

A Study of Oral Tetrahydrouridine-Decitabine in Relapsed or Refractory Myelodysplastic Syndromes (MDS) (clinicaltrials.gov) - P1 | N=20 | Not yet recruiting | Sponsor: EpiDestiny, Inc.

New P1 trial • Hematological Malignancies • Myelodysplastic Syndrome • Oncology

A Study of Nicotinamide With Oral Tetrahydrouridine and Decitabine to Treat High Risk Sickle Cell Disease (clinicaltrials.gov) - P1 | N=20 | Recruiting | Sponsor: EpiDestiny, Inc. | Trial completion date: Apr 2024 ➔ Apr 2027 | Trial primary completion date: Mar 2024 ➔ Oct 2026

Trial completion date • Trial primary completion date • Genetic Disorders • Hematological Disorders • Sickle Cell Disease

To Study the Oral Bioavailability of a New Combination Formation of Decitabine and Tetrahydrouridine in Healthy Males (clinicaltrials.gov) - P1 | N=10 | Completed | Sponsor: EpiDestiny, Inc. | Recruiting ➔ Completed

Trial completion

ASCENT1: Research Study Investigating How Well NDec Works in People With Sickle Cell Disease (clinicaltrials.gov) - P2 | N=84 | Active, not recruiting | Sponsor: Novo Nordisk A/S | Trial primary completion date: Dec 2024 ➔ Aug 2025 | Recruiting ➔ Active, not recruiting

Enrollment closed • Trial primary completion date • Genetic Disorders • Hematological Disorders • Sickle Cell Disease

A Study to Test How Either a Capsule or a Tablet With NDec (Decitabine and Tetrahydrouridine) Works in the Body of Healthy People (clinicaltrials.gov) - P1 | N=44 | Completed | Sponsor: Novo Nordisk A/S | Recruiting ➔ Completed

Trial completion

A Study to Test How Either a Capsule or a Tablet With NDec (Decitabine and Tetrahydrouridine) Works in the Body of Healthy People (clinicaltrials.gov) - P1 | N=48 | Recruiting | Sponsor: Novo Nordisk A/S | Not yet recruiting ➔ Recruiting

Enrollment open

A Study to Test How Either a Capsule or a Tablet With NDec (Decitabine and Tetrahydrouridine) Works in the Body of Healthy People (clinicaltrials.gov) - P1 | N=48 | Not yet recruiting | Sponsor: Novo Nordisk A/S

New P1 trial

ASCENT1: Research Study Investigating How Well NDec Works in People With Sickle Cell Disease (clinicaltrials.gov) - P2 | N=84 | Recruiting | Sponsor: Novo Nordisk A/S | Trial primary completion date: Nov 2023 ➔ Oct 2024

Trial primary completion date • Genetic Disorders • Hematological Disorders • Sickle Cell Disease

Production of (hydroxy)benzoate-derived polyketides by engineered Pseudomonas with in situ extraction. (PubMed, Bioresour Technol) - "A solvent screening yielded 2-undecanone as biocompatible, extraction-efficient solvent with good phase separation...Complete de novo synthesis from glucose of all (hydroxy)benzoate-derived polyketides was achieved in two-phase cultivations with metabolically engineered strains. Additionally, mutasynthesis was applied to obtain fluorinated benzophenone derivatives."

Journal

To Study the Oral Bioavailability of a New Combination Formation of Decitabine and Tetrahydrouridine in Healthy Males (clinicaltrials.gov) - P1 | N=10 | Recruiting | Sponsor: EpiDestiny, Inc. | Trial completion date: Jul 2023 ➔ Oct 2023

Trial completion date

ASCENT1: Research Study Investigating How Well NDec Works in People With Sickle Cell Disease (clinicaltrials.gov) - P2 | N=84 | Recruiting | Sponsor: Novo Nordisk A/S | Trial completion date: Jun 2024 ➔ Feb 2025

Trial completion date • Genetic Disorders • Hematological Disorders • Sickle Cell Disease • DNMT1

Pharmacokinetics and pharmacodynamics of an oral formulation of decitabine and tetrahydrouridine. (PubMed, Eur J Haematol) - "Combination oral formulations of THU with decitabine produced pharmacokinetics and pharmacodynamics suitable for oral DNMT1-targeted therapy."

Journal • PK/PD data • Genetic Disorders • Hematological Disorders • Sickle Cell Disease • DNMT1

In vitro interaction of tetrahydrouridine with key human nucleoside transporters. (PubMed, J Pharm Sci) - "Potent CNT3 inhibitors are a class of drugs not generally prescribed to patients with SCD, except in certain specific circumstances. These data suggest that NDec can be administered safely with drugs that act as substrates and inhibitors of the nucleoside transporters included in this study."

Journal • Preclinical • Genetic Disorders • Hematological Disorders • Sickle Cell Disease • SLC29A1

To Study the Oral Bioavailability of a New Combination Formation of Decitabine and Tetrahydrouridine in Healthy Males (clinicaltrials.gov) - P1 | N=10 | Recruiting | Sponsor: EpiDestiny, Inc.

New P1 trial

A Study of Nicotinamide With Oral Tetrahydrouridine and Decitabine to Treat High Risk Sickle Cell Disease (clinicaltrials.gov) - P1 | N=20 | Recruiting | Sponsor: EpiDestiny, Inc. | Trial completion date: Mar 2023 ➔ Apr 2024 | Trial primary completion date: Feb 2023 ➔ Mar 2024

Trial completion date • Trial primary completion date • Genetic Disorders • Hematological Disorders • Sickle Cell Disease

ASCENT1: Research Study Investigating How Well NDec Works in People With Sickle Cell Disease (clinicaltrials.gov) - P2 | N=84 | Recruiting | Sponsor: Novo Nordisk A/S | Trial primary completion date: Jan 2023 ➔ Nov 2023

Trial primary completion date • Genetic Disorders • Hematological Disorders • Sickle Cell Disease • DNMT1

Research study investigating how well NDec works in people with sickle cell disease (clinicaltrialsregister.eu) - P2 | N=84 | Ongoing | Sponsor: Novo Nordisk A/S

New P2 trial • Genetic Disorders • Hematological Disorders • Sickle Cell Disease • DNMT1

ASCENT1: Research Study Investigating How Well NDec Works in People With Sickle Cell Disease (clinicaltrials.gov) - P2 | N=84 | Recruiting | Sponsor: Novo Nordisk A/S | Not yet recruiting ➔ Recruiting

Enrollment open • Genetic Disorders • Hematological Disorders • Sickle Cell Disease • DNMT1

Metabolic systems analysis identifies a novel mechanism contributing to shock in patients with endotheliopathy of trauma (EoT) involving thromboxane A2 and LTC. (PubMed, Matrix Biol Plus) - "Endotheliopathy of trauma (EoT), as defined by circulating levels of syndecan-1 ≥ 40 ng/mL, has been reported to be associated with significantly increased transfusion requirements and a doubled 30-day mortality...Reduced thromboxane A2 and leukotriene availability in the microvasculature impairs vasoconstriction ability and may thus contribute to shock in EoT patients. These findings are supported by extensive scientific literature; however, further investigations are required on these findings."

Journal • SDC1