Withdrawal of Tiratricol Treatment in Males with Monocarboxylate Transporter 8 Deficiency (MCT8 Deficiency): a Double-blind, Randomized, Placebo-controlled Study

This is a double-blind, randomized phase 3 multicenter placebo-controlled study in at least 16 evaluable male participants diagnosed with MCT8 deficiency. Male participants, from 4 years of age (at randomization) and having demonstrated stable maintenance treatment with tiratricol, will be randomized to receive placebo or tiratricol for 30 days or until reaching rescue criterion (serum total triiodothyronine [T3] > upper limit of normal [ULN] of the participant's normal range, for a sample collected during the 30-day Randomized Treatment Period). The research hypothesis to be tested is that, for participants in the placebo group, removal of tiratricol will lead to an increase of serum total T3 concentration, measured by liquid chromatography with tandem mass spectrometry (LC/MS/MS), above the ULN and requirement of rescue treatment with tiratricol, compared to those who continue to receive tiratricol.

Start Date21 Jul 2023

Sponsor / Collaborator

Rare Thyroid Therapeutics International AB

[+2]

CTIS2024-516124-34-00 / Recruiting

Withdrawal of Tiratricol Treatment in Males with Monocarboxylate Transporter 8 Deficiency (MCT8 Deficiency): A Doubleblind, Randomized, Placebocontrolled Study (MCT8-2021-3 (ReTRIACt)) - MCT8-2021-3

Start Date21 Jul 2023

Sponsor / Collaborator

Rare Thyroid Therapeutics International AB

ISRCTN98332431 / CompletedPhase 1

Bioequivalence of two tiratricol tablets and relative bioavailability of tiratricol in the fasted and fed state in healthy male subjects combined with an assessment of dose-proportionality: a randomised, five-period crossover study

Start Date06 Jul 2023

Sponsor / Collaborator

Rare Thyroid Therapeutics International AB

100 Clinical Results associated with Tiratricol

100 Translational Medicine associated with Tiratricol

100 Patents (Medical) associated with Tiratricol

533

Literatures (Medical) associated with Tiratricol

01 Oct 2024·World Journal of Microbiology and Biotechnology

Metabolomic analysis in Amycolatopsis keratiniphila disrupted the competing ECO0501 pathway for enhancing the accumulation of vancomycin.

Article

Author: Chen, Shuo ; Chen, Daijie ; Qian, Xiuping ; Hu, Mengyi ; Rao, Min ; Ge, Mei ; Jin, Wenxiang ; Mao, Wenwei

Vancomycin is a clinically important glycopeptide antibiotic against Gram-positive pathogenic bacteria, especially methicillin-resistant Staphylococcus aureus. In the mutant strain of Amycolatopsis keratiniphila HCCB10007 Δeco-cds4-27, the production of ECO-0501 was disrupted, but enhanced vancomycin yield by 55% was observed compared with the original strain of A. keratiniphila HCCB10007. To gain insights into the mechanism of the enhanced production of vancomycin in the mutant strain, comparative metabolomics analyses were performed between the mutant strain and the original strain, A. keratiniphila HCCB10007 via GC-TOF-MS and UPLC-HRMS. The results of PCA and OPLS-DA revealed a significant distinction of the intracellular metabolites between the two strains during the fermentation process. 64 intracellular metabolites, which involved in amino acids, fatty acids and central carbon metabolism, were identified as differential metabolites. The high-yield mutant strain maintained high levels of glucose-1-phosphate and glucose-6-phosphate and they declined with the increases of vancomycin production. Particularly, a strong association of fatty acids accumulation as well as 3,5-dihydroxyphenylacetic acid and non-proteinogenic amino acid 3,5-dihydroxyphenylglycine (Dpg) with enhancement of vancomycin production was observed in the high-yield mutant strain, indicating that the consumption of fatty acid pools might be beneficial for giving rise to 3,5-dihydroxyphenylacetic acid and Dpg which further lead to improve vancomycin production. In addition, the lower levels of glyoxylic acid and lactic acid and the higher levels of sulfur amino acids might be beneficial for improving vancomycin production. These findings proposed more advanced elucidation of metabolomic characteristics in the high-yield strain for vancomycin production and could provide potential strategies to enhance the vancomycin production.

16 Sep 2024·The Journal of Clinical Endocrinology & Metabolism

Glycerol Phenylbutyrate Treatment of 2 Patients With Monocarboxylate Transporter 8 Deficiency

Article

Author: Sonntag, Niklas ; Braun, Doreen ; Schweizer, Ulrich ; Banne, Ehud ; Zung, Amnon

AbstractContextMonocarboxylate transporter 8 (MCT8) deficiency is a rare genetic disease that leads to severe global developmental delay. MCT8 facilitates thyroid hormone (TH) transport across the cell membrane, and the serum TH profile is characterized by high T3 and low T4 levels. Recent studies have shown that the chemical chaperone sodium phenylbutyrate (NaPB) restored mutant MCT8 function and increased TH content in patient-derived induced pluripotent stem cells, making it a potential treatment for MCT8 deficiency.ObjectiveWe aimed to assess the efficacy and safety of glycerol phenylbutyrate (GPB) in MCT8 deficiency.MethodsWe treated 2 monozygotic twins aged 14.5 years with MCT8 deficiency due to P321L mutation with escalating doses of GPB over 13 months. We recorded TH, vital signs, anthropometric measurements, and neurocognitive functions. Resting metabolic rate (RMR) was measured by indirect calorimetry. Serum metabolites of GPB were monitored as a safety measure. In vitro effects of NaPB were evaluated in MDCK1 cells stably expressing the MCT8P321L mutation. The effects of GPB were compared to the effects of DITPA and TRIAC, thyromimetic medications that the patients had received in the past.ResultsNaPB restored mutant MCT8 expression in MDCK1 cells and increased T3 transport into cells carrying the P321L mutation. GPB treatment reduced high T3 and increased low T4 levels. The patients showed a significant weight gain simultaneously with a reduction in RMR. Only minor neurocognitive improvement was observed, in hyperreflexia score and in cognitive functions. Serum metabolites did not exceed the toxic range, but elevated liver transaminases were observed.ConclusionIn the first report of GPB treatment in MCT8 deficiency we found an improvement in TH profile and body mass index, with minor neurodevelopmental changes.

01 Aug 2024·Thyroid®

3,3′,5-Triiodothyroacetic Acid Transporters

Article

Author: de Rooij, Linda J ; Hamers, Timo ; Yildiz, Sena ; Leeuwenburgh, Selmar ; Meima, Marcel E ; Markova, Boyka ; Chen, Zhongli ; Peeters, Robin P ; Heuer, Heike ; Visser, W Edward

Introduction: Thyroid hormone transporters are essential for thyroid hormones to enter target cells. Monocarboxylate transporter (MCT) 8 is a key transporter and is expressed at the blood-brain barrier (BBB), in neural cells and many other tissues. Patients with MCT8 deficiency have severe neurodevelopmental delays because of cerebral hypothyroidism and chronic sequelae of peripheral thyrotoxicosis. The T3 analog 3,3',5-triiodothyroacetic acid (TRIAC) rescued neurodevelopmental features in animal models mimicking MCT8 deficiency and improved key metabolic features in patients with MCT8 deficiency. However, the identity of the transporter(s) that facilitate TRIAC transport are unknown. Here, we screened candidate transporters that are expressed at the human BBB and/or brain-cerebrospinal fluid barrier and known thyroid hormone transporters for TRIAC transport. Materials and Methods: Plasma membrane expression was determined by cell surface biotinylation assays. Intracellular accumulation of 1 nM TRIAC was assessed in COS-1 cells expressing candidate transporters in Dulbecco's phosphate-buffered saline (DPBS)/0.1% glucose or Dulbecco's modified Eagle's medium (DMEM) with or without 0.1% bovine serum albumin (BSA). Expression of Slc22a8 was determined by fluorescent in situ hybridization in brain sections from wild-type and Mct8/Oatp1c1 knockout mice at postnatal days 12, 21, and 120. Results: In total, 59 plasma membrane transporters were selected for screening of TRIAC accumulation (n = 40 based on expression at the human BBB and/or brain-cerebrospinal fluid barrier and having small organic molecules as substrates; n = 19 known thyroid hormone transporters). Screening of the selected transporter panel showed that 18 transporters facilitated significant intracellular accumulation of TRIAC in DPBS/0.1% glucose or DMEM in the absence of BSA. In the presence of BSA, substantial transport was noted for SLCO1B1 and SLC22A8 (in DPBS/0.1% glucose and DMEM) and SLC10A1, SLC22A6, and SLC22A24 (in DMEM). The zebrafish and mouse orthologs of these transporters similarly facilitated intracellular accumulation of TRIAC. Highest Slc22a8 mRNA expression was detected in mouse brain capillary endothelial cells and choroid plexus epithelial cells at early postnatal time points, but was reduced at P120. Conclusions: Human SLC10A1, SLCO1B1, SLC22A6, SLC22A8, and SLC22A24 as well as their mouse and zebrafish orthologs are efficient TRIAC transporters. These findings contribute to the understanding of TRIAC treatment in patients with MCT8 deficiency and animal models thereof.

News (Medical) associated with Tiratricol

31 Mar 2023

·www.fiercebiotech.com

What M&A slowdown? Buyers circle GreenLight Biosciences, Egetis Therapeutics

Both GreenLight and Egetis pointed out that they hadn't accepted an offer yet. While biotech M&A may have cooled down over the past year, no one has told GreenLight Biosciences or Egetis Therapeutics, which are both mulling takeover offers. RNA-focused GreenLight announced yesterday that it has received an offer from VC firm Fall Line Capital’s Fall Line Endurance Fund to acquire all outstanding stock of the biotech for 60 cents per share. GreenLight— which spreads itself across vaccines and therapies for humans as well as agricultural solutions—only went public via a special purpose acquisition company (SPAC) merger in February 2022. The merger agreement valued the company at $1.2 billion and GreenLight’s stock hit a high of over $12 per share in the following weeks. But it’s been dropping ever since, with a closing price Thursday of just 43 cents. Still, the biotech emphasized that no sale has been agreed yet, with the company’s board of directors due to “carefully evaluate Fall Line’s indication of interest within the context of the ongoing review of various alternatives and in consultation with any financial and legal advisors it may retain.” GreenLight ended 2022 with $68.1 million in cash and equivalents. Despite pausing its gene therapy program for sickle cell anemia and cutting 25% of staff in October 2022 to save money, the company still expects reserves to run dry by June. The biotech had already announced it was looking at a range of measures to eke out its runway, including “further management of program spending, additional platform licensing collaborations and potential further financing activities.” Even with human health ambitions now limited to preclinical vaccine candidates for pan-sarbecovirus and shingles, as well as a cancer vaccine collab with EpiVax, it’s not surprising the company is open to external offers. Less is known about Egetis’ offer. The biotech released a concise note yesterday responding to “existing rumors” by confirming that the company “has ongoing discussions with certain external parties regarding a potential acquisition.” Again, Egetis was keen to stress that no offer has yet been agreed. The Swedish company’s lead product is Emcitate, which is in phase 2 trials for Allan-Herndon-Dudley syndrome, a rare genetic disorder that impacts a child's cognition, mobility and overall health and for which there is currently no available treatment. Egetis plans to submit a request for EU approval in the second quarter of the year based on existing clinical data.

VaccineAcquisitionPhase 2

100 Deals associated with Tiratricol

External Link

KEGG	Wiki	ATC	Drug Bank
D07214	Tiratricol	D11AX08 H03AA04	DB03604

R&D Status

10 top R&D records.

to view more data

Indication	Highest Phase	Country/Location	Organization	Date
Allan-Herndon-Dudley Syndrome	NDA/BLA	-	Egetis Therapeutics AB	-

Clinical Result

Indication

Phase

Evaluation

View All Results

Translational Medicine

Boost your research with our translational medicine data.

view full example data

Deal

Boost your decision using our deal data.

view full example data

Core Patent

Boost your research with our Core Patent data.

view full example data

Clinical Trial

Identify the latest clinical trials across global registries.

view full example data

Approval

Accelerate your research with the latest regulatory approval information.

view full example data

Regulation

Understand key drug designations in just a few clicks with Synapse.

view full example data

Chat with Hiro

Get started for free today!

Accelerate Strategic R&D decision making with Synapse, PatSnap’s AI-powered Connected Innovation Intelligence Platform Built for Life Sciences Professionals.

Start your data trial now!

Synapse data is also accessible to external entities via APIs or data packages. Empower better decisions with the latest in pharmaceutical intelligence.

Bio

Bio Sequences Search & Analysis

Chemical

Chemical Structures Search & Analysis