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

198

Literatures (Medical) associated with Tetrahydrouridine

01 Jan 2026·EUROPEAN JOURNAL OF PHARMACEUTICAL SCIENCES

Effects of Tetrahydrouridine Pre-dosing on Absorption, Metabolism, and Excretion of Decitabine in the Mouse

Article

Author: Helleberg, Hans ; Bjørnsdottir, Inga ; Offenberg, Hanne Kjær

BACKGROUND:

Elevated fetal hemoglobin (HbF) levels improve outcomes in sickle cell disease (SCD). decitabine (DEC), a DNA methyltransferase 1 inhibitor, reactivates silenced HbF but is rapidly degraded by cytidine deaminase (CDA). Co-administered tetrahydrouridine (THU) inhibits CDA, enhancing DEC bioavailability. NDec, a novel oral, fixed-dose combination of DEC and THU, has been developed as treatment for people with SCD. NDec is currently undergoing clinical evaluation, beginning with the Phase II ASCENT1 study (NCT05405114).

OBJECTIVE:

This study aimed to evaluate the impact of THU pre-dosing on the pharmacokinetics (PK), metabolism, and excretion profile of DEC in mice.

METHODS:

Mice were orally administered with either radiolabeled DEC ([¹⁴C]-DEC; 1 mg/kg) or with two different doses of THU (10 and 170 mg/kg) one hour before a fixed-dose of [¹⁴C]-DEC (0.4 mg/kg). Liquid scintillation counting (LSC), high-performance liquid chromatography (HPLC), LC-mass spectrometry (LC-MS), and LC-radioactivity monitor-MS (LC-RAM-MS) analyses were used to detect the presence of [¹⁴C]-DEC and its metabolites in plasma and urine at different time points after dosing.

RESULTS:

DEC metabolism occurs by either deamination (CDA metabolism) or by competitive hydrolysis and oxidation pathways (non-CDA metabolism), generating six DEC metabolites. THU pre-treatment increased DEC plasma exposure and shifted the metabolite profile towards non-CDA mediated metabolism. Finally, DEC and its metabolites were primarily excreted via the urinary tract, independently of THU pre-dosing.

CONCLUSION:

These findings provide crucial insights into DEC metabolism, highlighting the impact of THU pre-treatment on DEC plasma exposure, metabolism, and excretion.

01 Oct 2023·Journal of pharmaceutical sciences

In Vitro Interaction of Tetrahydrouridine with Key Human Nucleoside Transporters

Article

Author: Koncsos, Gábor ; Klukovits, Anna ; 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·Biochemical and biophysical research communications

Mycoplasma infection of cancer cells enhances anti-tumor effect of oxidized methylcytidines

Article

Author: Wang, Yuan-Xian ; Pang, Guo-Zheng ; Gao, Hai ; Rong, Shao-Qin ; Zhao, Ya-Hui ; Zhou, Dan

Oxidized methylcytidines 5-hydroxymethyl-2'deoxycytidine (5hmdC) and 5-formy-2'deoxycytidine (5fdC) are deaminated by cytidine deaminase (CDA) into genome-toxic variants of uridine, triggering DNA damage and cell death. These compounds are promising chemotherapeutic agents for cancer cells that are resistant to pyrimidine derivative drugs, such as decitabine and cytarabine, which are inactivated by CDA. In our study, we found that cancer cells infected with mycoplasma exhibited a markedly increased sensitivity to 5hmdC and 5fdC, which was independent of CDA expression of cancer cells. In vitro biochemical assay showed that the homologous CDA protein from mycoplasma was capable of deaminating 5hmdC and 5fdC into their uridine form. Moreover, mycoplasma infection increased the sensitivity of cancer cells to 5hmdC and 5fdC, whereas administration of Tetrahydrouridine (THU) attenuated this effect, suggesting that mycoplasma CDA confers a similar effect as human CDA. As mycoplasma infection occurs in many primary tumors, our findings suggest that intratumoral microbes could enhance the tumor-killing effect and expand the utility of oxidized methylcytidines in 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

06 Apr 2018

·www.biospace.com

Novo Nordisk Ties Up Sickle Cell Disease Treatment in $400M Deal

A Novo Nordisk flag flies in the wind/Courtesy jor Danish pharma giant Novo Nordisk tied up a sickle cell and beta-thalassemia program in a $400 million deal with Ohio-based EpiDestiny. Danish pharma giant Novo Nordisk tied up a sickle cell and beta-thalassemia program in a $400 million deal with Ohio-based EpiDestiny. Novo Nordisk will acquire the gene control therapy EPI01, which recently finished Phase I testing for sickle cell disease. Phase I testing of EPI01, which is a combination of tetrahydrouridine and decitabine, in a small group of patients showed that EPI01 increased levels of fetal hemoglobin. An increase in fetal hemoglobin is important to both sickle cell and beta-thalassemia patients. Elevated HbF correlated with increased red blood cell half-life, reduced number of pain crises and increased life expectancy, Novo Nordisk said in its announcement. “This is a great opportunity for Novo Nordisk to enter into a new therapeutic area closely related to our existing biopharmaceutical business and thereby utilize our core R&D and commercial capabilities to make a significant difference for patients living with a serious chronic disease. We are looking forward to working closely with EpiDestiny and their great network among sickle cell disease experts and the sickle cell community. We are confident that together we can make a significant difference for SCD patients and their families globally,” Novo Nordisk Chief Science Officer Mads Krogsgaard Thomsen said in a statement. Under terms of the deal, the $400 million paid to EpiDestiny will include upfront fees, as well as developmental and commercial milestone payments. The companies did not disclose a breakdown in the way the money will be paid out. The two companies will collaborate on the development of EPI01 for both sickle cell disease and beta-thalassemia. With Phase I data in hand the Danish company is looking to take orally-administered EPI01 to the next stage of clinical testing. If the drug continues to impress it’s likely to be a contender with hydroxyurea, a standard sickle cell drug. That standard care though does have some toxicity issues. There is currently no treatment for sickle cell disease that targets the cause. Sickle cell disease can cause blood vessels to become blocked. That blockage can damage organs and cause death. Following the small Phase I trial EpiDestiny said EPI01 provided an effective way of controlling gene expression, without causing the toxicity problems of hydroxyurea. The acquisition of the EpiDestiny product comes at a time when Novo Nordisk, known for its diabetes products, is looking to boost its hematology program. Last year Novo snagged approval from the U.S. Food and Drug Administration for Rebinyn , a hemophilia B treatment for adults and children.

Phase 1AcquisitionDrug ApprovalGene TherapyLicense out/in

100 Deals associated with Tetrahydrouridine

External Link

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R&D Status

10 top R&D records.

to view more data

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

Clinical Result

Indication

Phase

Evaluation

View All Results

Study	Phase	Population	Analyzed Enrollment	Group	Results	Evaluation	Publication Date


NCT03233724 (CTgov)	Phase 1/2	Malignant Pleural Mesothelioma \| Esophageal Carcinoma \| metastatic non-small cell lung cancer ... View more	9	Decitabine+Tetrahydrouridine (Decitabine 0.2mg/kg + Tetrahydrouridine 10mg/kg Sunday, Monday, Tuesday (SuMT))	ydyhkmooyx = wluylamimo foyrimgugj (jpynyyluxy, etafndobua - yqqqiwudtk) View more	-	31 May 2023
NCT03233724 (CTgov)	Phase 1/2		9	Decitabine+Tetrahydrouridine (Decitabine 0.2mg/kg + Tetrahydrouridine 10mg/kg Monday-Tuesday (MT))	ydyhkmooyx = vfzzmcjudq foyrimgugj (jpynyyluxy, qqclawitsm - ymcbuljyka) View more	-	31 May 2023
NCT02664181 (PRECISE \| P295, CTgov)	Phase 2	Non-Small Cell Lung Cancer \| metastatic non-small cell lung cancer	13	Nivolumab (Nivolumab)	osqhoiiddg: P-Value = 0.05 View more	-	10 Dec 2020
NCT02664181 (PRECISE \| P295, CTgov)	Phase 2		13	Nivolumab+Oral decitabine+Tetrahydrouridine (Oral THU/Decitabine + Nivolumab)	osqhoiiddg: P-Value = 0.05 View more	-	10 Dec 2020
NCT01479348 (CTgov)	Early Phase 1	Lung Cancer \| Breast Cancer \| Bladder Cancer ... View more	5	Positron emission tomography (PET)/Computed tomography (CT)+Tetrahydrouridine intravenous (IV)+[F-18]-5-FLUORO-2'-DEOXYCYTIDINE	idqragceps = sopggofzhq genwvimjjf (yionprmyjo, fotcexfzac - gbuafdmeiv) View more	-	22 May 2020
NCT00978250 (CTgov)	Phase 2	Lung Cancer \| Breast Cancer \| Non-Small Cell Lung Cancer ... View more	95	Tetrahydrouridine (THU)+5-Fluoro-2'-Deoxycytidine (FdCyd)	skfyexfkkd = mfsyngnrzs kyywbarjoq (labddidxtm, djplivdaqb - drdbztpefu) View more	-	27 Dec 2019
NCT00359606 (Pubmed \| Cancer Chemother Pharmacol) Manual	Phase 1	Solid tumor	-	tetrahydrouridine+FdCyd	orzytocwkl(bpqlvwnlqq) = 100 mg/m2/day FdCyd with 350 mg/m2/day THU mrrzsbbaao (kcqkzqsbuh ) View more	Positive	01 Mar 2015

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