An Open Label, Randomized, Single Dose, Two Way Crossover, Bioavailability Study of a Combination Formulation of Decitabine/Tetrahydrouridine (2.5 mg/100 mg) Modified Release Capsules in Healthy, Fasting, Male Adults

This is an open-label, randomized, single-dose per period, two-period, crossover study to evaluate the relative bioavailability of decitabine and tetrahydrouridine ingested as a modified-release combination formulation compared to THU and decitabine ingested as immediate-release capsules

Start Date24 Mar 2023

Sponsor / Collaborator

EpiDestiny, Inc.

[+1]

NCT03233724

/ TerminatedPhase 1/2IIT

Phase I/II Evaluation of Oral Decitabine/Tetrahydrouridine as Epigenetic Priming for Pembrolizumab Immune Checkpoint Blockade in Inoperable Locally Advanced or Metastatic Non-Small Cell Lung Cancers, Esophageal Carcinomas, or Pleural Mesotheliomas

Background:
Non-small cell lung cancer (NSCLC) is the most common type of lung cancer. Lung cancer is the leading cause of cancer-related death in the United States. Most people with lung cancer are already in the advanced stages of the disease by the time they see a doctor. Researchers want to see if combining an approved drug with two new drugs can help.
Objective:
To study if tetrahydrouridine-decitabine (THU-DAC) with pembrolizumab is safe and effective in people with non-small cell lung cancer that cannot be removed by surgery.
Eligibility:
People 18 years and older who have NSCLC that cannot be removed by surgery
Design:
Participants will be screened with
Medical history
Physical exam
Blood and urine tests
Tests of heart and lung function
They may have a small tumor sample taken (biopsy). They may have tumor scans.
Before starting treatment, participants will repeat the screening tests. They will also give a stool sample.
The study will be done in 3-week cycles for up to 6 cycles.
Participants will take the 2 study drugs by mouth 3-5 days a week.
Participants will get pembrolizumab in a vein for 30 minutes 1 day each cycle.
Participants will keep a study medication diary.
During cycle 1, participants will have blood taken multiple times on days 1 and 2.
Every 3 cycles, participants will repeat screening tests.
Participants will have a mandatory tumor biopsy.
When they finish treatment, participants will have a physical exam and blood tests.

Start Date11 Apr 2018

Sponsor / Collaborator

National Cancer Institute

NCT02664181

/ CompletedPhase 2IIT

Phase II Evaluation of Nivolumab, an Immune Checkpoint Inhibitor Alone or in Combination With Oral Decitabine/Tetrahydrouridine as Second Line Therapy for Non-small Cell Lung Cancer

The purpose of this study is to assess whether treatment with the study drug tetrahydrouridine-decitabine (THU-Dec) in combination with nivolumab is more effective than treatment with nivolumab alone in patients with NSCLC.
Decitabine is an investigational (experimental) drug that works by depleting DNA methyltransferase 1 (DNMT1). DNMT1 is an enzyme, or protein that causes chemical changes, often increased in cancer. Blocking DNMT1 has been shown to reduce tumor formation. Decitabine is experimental in this study because it is not approved by the Food and Drug Administration (FDA) for patients with lung cancer. Decitabine is approved by the FDA for treating patients with a blood disease called myelodysplastic syndrome (MDS, a condition where the bone marrow does not make blood cells normally).
THU is an investigational (experimental) drug that works by blocking an enzyme that breaks down decitabine. This enzyme is highly expressed in solid tissues of the body, limiting the distribution of decitabine into these tissues, including solid cancer tissues. So, THU will increase the time cells are exposed to decitabine. The idea is that THU will also increase the time that the lung cancer cells are exposed to decitabine. THU is experimental because it is also not approved by the FDA, although it has been extensively used in clinical trials, including several cancer trials.

Start Date06 Jun 2017

Sponsor / Collaborator

The Case Comprehensive Cancer Center

[+1]

100 Clinical Results associated with Tetrahydrouridine

100 Translational Medicine associated with Tetrahydrouridine

100 Patents (Medical) associated with Tetrahydrouridine

154

Literatures (Medical) associated with Tetrahydrouridine

01 Oct 2023·Journal of pharmaceutical sciences

In Vitro Interaction of Tetrahydrouridine with Key Human Nucleoside Transporters.

Article

Author: Klukovits, Anna ; Koncsos, Gábor ; Säll, Carolina

NDec is a novel combination of oral decitabine and tetrahydrouridine that is currently under clinical development for the treatment of sickle cell disease (SCD). Here, we investigate the potential for the tetrahydrouridine component of NDec to act as an inhibitor or substrate of key concentrative nucleoside transporters (CNT1-3) and equilibrative nucleoside transporters (ENT1-2). Nucleoside transporter inhibition and tetrahydrouridine accumulation assays were performed using Madin-Darby canine kidney strain II (MDCKII) cells overexpressing human CNT1, CNT2, CNT3, ENT1, and ENT2 transporters. Results showed that tetrahydrouridine did not influence CNT- or ENT-mediated uridine/adenosine accumulation in MDCKII cells at the concentrations tested (25 and 250 µM). Accumulation of tetrahydrouridine in MDCKII cells was initially shown to be mediated by CNT3 and ENT2. However, while time- and concentration-dependence experiments showed active accumulation of tetrahydrouridine in CNT3-expressing cells, allowing for estimation of K_m (3,140 µM) and V_max (1,600 pmol/mg protein/min), accumulation of tetrahydrouridine was not observed in ENT2-expressing cells. 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.

01 Sep 2023·European Journal of Haematology

Pharmacokinetics and pharmacodynamics of an oral formulation of decitabine and tetrahydrouridine

Article

Author: Jacobberger, James W. ; Lau, Henry ; Saunthararajah, Yogen ; Friedrich, Ute ; Woost, Philip G. ; Clausen, Wan Hui Ong

AbstractBackgroundSickle cell disease (SCD) is caused by an inherited structural abnormality of adult hemoglobin causing polymerization. Fetal hemoglobin interferes with polymerization but is epigenetically silenced by DNA methyltransferase 1 (DNMT1) in adult erythropoiesis. Decitabine depletes DNMT1 and increases fetal and total hemoglobin in SCD patients, but is rapidly catabolized by cytidine deaminase (CDA) in vivo. Tetrahydrouridine (THU) inhibits CDA, safeguarding decitabine.MethodsThe pharmacokinetics and pharmacodynamics of three oral combination formulations of THU and decitabine, with different coatings producing different delays in decitabine release, were investigated in healthy participants.ResultsTetrahydrouridine and decitabine were rapidly absorbed into the systemic circulation after a single combination oral dose, with relative bioavailability of decitabine ≥74% in fasted males compared with separate oral administration of THU followed by decitabine 1 h later. THU and decitabine Cmax and area under the plasma concentration versus time curve were higher in females versus males, and fasted versus fed states. Despite sex and food effect on pharmacokinetics, the pharmacodynamic effect of DNMT1 downregulation was comparable in males and females and fasted and fed states. Treatments were well tolerated.ConclusionCombination oral formulations of THU with decitabine produced pharmacokinetics and pharmacodynamics suitable for oral DNMT1‐targeted therapy.

01 Jul 2023·Journal of Cancer Research and Clinical Oncology

Upregulation of cytidine deaminase in NAT1 knockout breast cancer cells

Article

Author: Hong, Kyung U ; Walls, Kennedy M ; Doll, Mark A ; Hein, David W ; Tagnedji, Afi H

PURPOSEArylamine N-acetyltransferase 1 (NAT1), a phase II metabolic enzyme, is frequently upregulated in breast cancer. Inhibition or depletion of NAT1 leads to growth retardation in breast cancer cells in vitro and in vivo. A previous metabolomics study of MDA-MB-231 breast cancer cells suggests that NAT1 deletion leads to a defect in de novo pyrimidine biosynthesis. In the present study, we observed that NAT1 deletion results in upregulation of cytidine deaminase (CDA), which is involved in the pyrimidine salvage pathway, in multiple breast cancer cell lines (MDA-MB-231, MCF-7 and ZR-75-1). We hypothesized that NAT1 KO MDA-MB-231 cells show differential sensitivity to drugs that either inhibit cellular pyrimidine homeostasis or are metabolized by CDA.METHODSThe cells were treated with (1) inhibitors of dihydroorotate dehydrogenase or CDA (e.g., teriflunomide and tetrahydrouridine); (2) pyrimidine/nucleoside analogs (e.g., gemcitabine and 5-azacytidine); and (3) naturally occurring, modified cytidines (e.g., 5-formyl-2'-deoxycytidine; 5fdC).RESULTSAlthough NAT1 KO cells failed to show differential sensitivity to nucleoside analogs that are metabolized by CDA, they were markedly more sensitive to 5fdC which induces DNA damage in the presence of high CDA activity. Co-treatment with 5fdC and a CDA inhibitor, tetrahydrouridine, abrogated the increase in 5fdC cytotoxicity in NAT1 KO cells, suggesting that the increased sensitivity of NAT1 KO cells to 5fdC is dependent on their increased CDA activity.CONCLUSIONSThe present findings suggest a novel therapeutic strategy to treat breast cancer with elevated NAT1 expression. For instance, NAT1 inhibition may be combined with cytotoxic nucleosides (e.g., 5fdC) for breast cancer treatment.

News (Medical) associated with Tetrahydrouridine

21 Jun 2023

·www.pharmaceutical-technology.com

CSL doses first patient with haemophilia B gene therapy Hemgenix

Aidan McNamee CSL’s Hemgenix uses an engineered adeno-associated virus (AAV) to make the body produce blood clotting proteins. Source: Shutterstock / Kateryna Kon. CSL announced the first patient with haemophilia B has been treated with its recently approved gene therapy Hemgenix (etranacogene dezaparvovec). Hemgenix is the first and only gene therapy approved for haemophilia B. At $3.5m per dose, it is the most expensive single-use gene therapy in the US. The high price tag may be hard to defend , but with lifetime treatment costs for haemophilia B reaching as high as $23m for some, the single-dose treatment could prove far more cost-effective. Despite this, the Institute for Clinical and Economic Review (ICER) claimed that a fairer price would be in the region of $2.9m. Recommended Reports Reports LOA and PTSR Model - (Decitabine + Tetrahydrouridine) in B-Cell Non-Hodgkin Lymphoma GlobalData Reports LOA and PTSR Model - Gene Therapy to Target CD22 for Relapsed and Refractory B-Cell Non-Hodgkin L... GlobalData View all Companies Intelligence UniQure NV Cytiva CSL Behring LLC Medicines and Healthcare products Regulatory Agency View all In the past year, Hemgenix has been granted approval by the US Food and Drug Administration (FDA) and has received conditional marketing authorisation from the European Commission (EC) and the UK’s Medicines and Healthcare products Regulatory Agency (MHRA). This followed positive results from CSL’s Phase III HOPE-B trial (NCT03569891). In the study, Hemgenix reduced or eliminated the need for prophylactic treatment in 94% of patients. In a 20 June press release , CSL Behring’s North America general manager and senior vice-president Bob Lojewski said that the company was “thrilled” by this latest milestone and looked forward to more patients benefitting from the therapy. Hemgenix works by dosing a patient with an engineered adeno-associated virus (AAV), containing the gene responsible for producing a protein called factor IX. This protein helps to form blood clots and stop bleeding, with haemophilia B arising when the body is partially or completely unable to produce it. Once administered, the body will then be able to produce factor IX and prevent severe bleeds. Already a big player in haemophilia treatments, CSL licensed exclusive global rights to Hemgenix from gene therapy developers UniQure back in 2021. UniQure announced that it had received $100m from this first commercial sale milestone, on top of a $450m upfront payment. It is eligible for up to $1.6bn based on future milestones, as well as royalties amounting to more than 20% of net product sales. Haemophilia B is a rare condition. It predominantly affects males, with the CDC estimating 33,000 cases in males across the US. Despite the limited market, the price tags of haemophilia make it potentially lucrative. GlobalData forecasts predict that the global market for haemophilia A and haemophilia B treatments will grow to $14.7bn by 2030, up from $9.3bn in 2020 – an annual growth of nearly 5%. Gene therapies have long been predicted as the next big thing in haemophilia treatment, and are likely to drive this growth. GlobalData is the parent company of Pharmaceutical Technology. Cell & Gene Therapy coverage on Pharmaceutical Technology is supported by Cytiva . Editorial content is independently produced and follows the highest standards of journalistic integrity. Topic sponsors are not involved in the creation of editorial content. Free Whitepaper Optimise your cell therapy process: a guide to cell thawing Typically carried out at the point of care, errors in cell therapy thawing could compromise treatment efficacy, leading to significant patient impact as well as high costs and a compromised reputation for the product’s developer. This guide addresses how cell thawing has historically developed into the new techniques used today, along with the physical and biological implications of key metrics and components such as warming rate and ice structure. Also included are reviews of key studies from scientific literature and a consideration of the interactions between cooling and warming rates, as applicable to cell and gene therapies. By Cytiva Thematic By downloading this case study, you acknowledge that GlobalData may share your information with Cytiva Thematic and that your personal data will be used as described in their Privacy Policy

Gene TherapyPhase 3Clinical ResultDrug ApprovalCell Therapy

01 Sep 2022

·medcitynews.com

Novo Nordisk to buy sickle cell disease biotech Forma Therapeutics in $1.1B deal

Novo Nordisk announced a big purchase on Thursday to augment its rare disease portfolio. The Danish pharmaceutical giant is shelling out $20 per share in cash to acquire clinical-stage biotech Forma Therapeutics, which focuses on rare hematologic diseases. The deal represents a total equity value of $1.1 billion, about $425 million more than Forma’s current market cap. The transaction is expected to close before the end of the year. Forma made its market debut in 2020 with a $278 million initial public offering. The Massachusetts-based company’s lead drug candidate is etavopivat, a once-daily selective pyruvate kinase-R activator designed to improve anemia and red blood cell health in patients with sickle cell disease (SCD). SCD is an inherited disease that causes hemoglobin, the oxygen-carrying protein in red blood cells, to become rigid and misshapen. This makes normally round and flexible red blood cells rigid, and they take on a sickle shape. The clogging of these sickle-shaped blood cells impedes blood flow, as well as the delivery of oxygen to tissues. The condition leads to complications including vaso-occlusive crisis, which occurs when sickled red blood cells block blood flow to tissues thereby depriving them of oxygen. In a Phase 1 trial, etavopivat was shown to increase hemoglobin in SCD patients, improve their red blood cell health and decrease vaso-occlusive crises. The drug is currently being studied in a global Phase 2/3 trial involving patients with SCD, as well as a Phase 2 involving patients with transfusion-dependent SCD or another inherited hemoglobinopathy called thalassemia. The first interim data release for the Phase 2/3 is slated to take place before the end of the year. The acquisition is “by no means out of the blue,” Ludovic Helfgott, Novo’s executive vice president and head of rare disease, said in an interview. The deal signals Novo’s commitment to developing more products to treat hematological disorders, which Helfgott identified as an area with a large unmet need. Novo was attracted to etavopivat for a few reasons. The drug has demonstrated a good safety profile and efficacy during its clinical testing, and it is convenient for patients given that it needs to be taken only once daily. Novo also liked how flexible the drug can be — it can be used alone or in combination with other treatments, and it is currently being developed for use in pediatric patients as well as adults, according to Helfgott. This is not the first time Novo has made an acquisition to strengthen its SCD portfolio. In 2018, the company paid $400 million for Ohio-based EpiDestiny’s early stage SCD program. Together, Novo and EpiDestiny have built NDec — an oral, fixed-dose formulation of decitabine and tetrahydrouridine for the treatment of SCD. The compound is currently in clinical development, Helfgott said. Novo’s acquisition of Forma is the second billion-dollar SCD deal the pharmaceutical industry has seen in the last 30 days. Pfizer forked over $5.4 billion in August to buy Global Blood Therapeutics, a company with one commercialized therapy for sickle cell disease and a pipeline of additional drugs in various stages of development for the blood disorder.

IPOAcquisition

100 Deals associated with Tetrahydrouridine

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R&D Status

10 top R&D records.

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Indication	Highest Phase	Country/Location	Organization	Date
Malignant Pleural Mesothelioma	Phase 2	US	National Cancer Institute	11 Apr 2018
metastatic non-small cell lung cancer	Phase 2	US	National Cancer Institute	06 Jun 2017
Acute Myeloid Leukemia	Phase 2	-	City of Hope National Medical Center	-
Acute Myeloid Leukemia	Phase 2	-	National Cancer Institute	-
Myelodysplastic Syndromes	Phase 2	-	National Cancer Institute	-
Myelodysplastic Syndromes	Phase 2	-	City of Hope National Medical Center	-
Advanced Lung Non-Small Cell Carcinoma	Preclinical	US	National Cancer Institute	20 Aug 2009
Bladder Cancer	Preclinical	US	National Cancer Institute	20 Aug 2009
Breast Cancer	Preclinical	US	National Cancer Institute	20 Aug 2009
Head and Neck Neoplasms	Preclinical	US	National Cancer Institute	20 Aug 2009

Clinical Result

Indication

Phase

Evaluation

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Study	Phase	Population	Analyzed Enrollment	Group	Results	Evaluation	Publication Date


NCT02664181 (PRECISE \| P295, CTgov)	Phase 2	Non-Small Cell Lung Cancer \| metastatic non-small cell lung cancer	13	Nivolumab (Nivolumab)	ojbdbpshhz(qqcbzfvzig): P-Value = 0.05 View more	-	10 Dec 2020
NCT02664181 (PRECISE \| P295, CTgov)	Phase 2		13	Nivolumab+Oral decitabine+Tetrahydrouridine (Oral THU/Decitabine + Nivolumab)	ojbdbpshhz(qqcbzfvzig): P-Value = 0.05 View more	-	10 Dec 2020
NCT01479348 (CTgov)	Early Phase 1	Lung Cancer \| Breast Cancer \| Bladder Cancer \| Head and Neck Neoplasms	5	Positron emission tomography (PET)/Computed tomography (CT)+Tetrahydrouridine intravenous (IV)+[F-18]-5-FLUORO-2'-DEOXYCYTIDINE	sibzojhfrf(jjifwjoxai) = otqrrvrmgs cdqlnnskov (pqojdjaldv, jtytdfjjiw - jjutadurjq) View more	-	22 May 2020
NCT00978250 (CTgov)	Phase 2	Lung Cancer \| Breast Cancer \| Bladder Cancer \| Non-Small Cell Lung Cancer \| Advanced Lung Non-Small Cell Carcinoma \| Head and Neck Neoplasms	95	Tetrahydrouridine (THU)+5-Fluoro-2'-Deoxycytidine (FdCyd)	gznqrwikff(nrgunviusw) = ndfyevqhml jnclqmgmzz (dqhxwcwqqp, bmhuuhpflp - hikrelpqiv) View more	-	27 Dec 2019
NCT00359606 (Pubmed \| Cancer Chemother Pharmacol) Manual	Phase 1	Solid tumor	-	tetrahydrouridine+FdCyd	(yxxiqqzelb) = 100 mg/m2/day FdCyd with 350 mg/m2/day THU nbcvwzffqg (roqtpxnmov ) View more	Positive	01 Mar 2015

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