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

NCT05579327 / RecruitingPhase 3

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]

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

531

Literatures (Medical) associated with Tiratricol

01 Dec 2024·ENVIRONMENTAL GEOCHEMISTRY AND HEALTH

Effects of microplastics on 3,5-dichloroaniline adsorption, degradation, bioaccumulation and phytotoxicity in soil-chive systems

Article

Author: Guo, Zhenxiang ; Li, Jiaohong ; Dong, Yibo ; Wu, Xiaomao ; Yang, Jing ; Zhang, Wanping

Microplastics (MPs) and pesticides are two pollutants of concern in agricultural soils. 3,5-dichloroaniline (3,5-DCA), a highly toxic metabolite of dicarboximide fungicides, commonly co-exists with MPs and poses a risk to the environment and food safety. Batch adsorption and soil incubation experiments were employed to investigate the effects of polyethylene (PE) and polylactic acid (PLA) MPs on the environmental behavior of 3,5-DCA in soil. Chive (Allium ascalonicum) was used as the experimental plant, a pot experiment was conducted to examine the effects of individual or combined exposure to MPs and 3,5-DCA on plant 3,5-DCA bioaccumulation, growth characteristics, and phytotoxicity. The results showed that PE- and PLA-MPs increased the adsorption capacity of soil to 3,5-DCA and prolonged the degradation half-life of 3,5-DCA by 6.24 and 16.07 d, respectively. Two MPs partially alleviated the negative effects of 3,5-DCA on the root length and fresh weight of chives, while PE-MPs had a positive and dose-dependent impact on the contents of photosynthetic pigment in chive leaves. Co-exposure to 3,5-DCA and MPs increased residues of 3,5-DCA in soil and chive roots but had no significant effect on 3,5-DCA residues in chive stems or leaves. Moreover, 3,5-DCA residues in PLA-MP soil were consistently higher than those in PE-MP soil. Conclusively, MPs altered the 3,5-DCA adsorption and degradation behavior in soil, as well as its bioaccumulation in chives. Co-exposure to MPs and 3,5-DCA had dose-dependent and MP-specific effects on chive plant development and phytotoxicity.

16 Sep 2024·The Journal of clinical endocrinology and metabolism

Glycerol Phenylbutyrate Treatment of 2 Patients With Monocarboxylate Transporter 8 Deficiency

Article

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

Abstract:

Context:

Monocarboxylate 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.

Objective:

We aimed to assess the efficacy and safety of glycerol phenylbutyrate (GPB) in MCT8 deficiency.

Methods:

We 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.

Results:

NaPB 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.

Conclusion:

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

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

19 Jun 2024

·www.egetis.com

Egetis announces topline results of the Phase 2 Triac Trial II with Emcitate® (tiratricol) for MCT8 deficiency

The numerical improvements versus baseline observed on the primary endpoints of neurocognitive development assessed by the GMFM-88 and BSID-III scales did not show a statistically significant improvement versus historical controls. The trial confirmed the significant and durable reduction of endogenous T3 concentrations in all patients and the well-tolerated safety profile of tiratricol seen in previous clinical studies, despite higher dosing per kg body weight compared to previous trials. The trial is complementary to the data already submitted and validated in the Marketing Authorisation Application for Emcitate® (tiratricol) for treatment of MCT8 deficiency, based on the benefit of normalization of thyrotoxicosis which has been demonstrated in patients of all ages, as agreed with the European Medicines Agency (EMA). Results from Triac Trial II will be included in the response to EMA 120-day list of questions in August 2024. The forthcoming New Drug Application in the USA, will also be based on the already observed treatment effects on T3 concentrations and the manifestations of chronic thyrotoxicosis together with results from the ongoing ReTRIACt trial, as acknowledged by the US Food and Drug Administration (FDA). The Company does not consider the approvability of the product to be affected by the Triac Trial II results and the regulatory timelines remain unchanged. Conference call for analysts and investors to be held tomorrow Thursday June 20 at 8:00am (CEST). Stockholm, Sweden, June 19, 2024. Egetis Therapeutics AB (publ) (“Egetis” or the “Company”) (Nasdaq Stockholm: EGTX), today announced that Triac Trial II for the investigational drug Emcitate® (tiratricol) in the treatment of monocarboxylate transporter 8 (MCT8) deficiency, in young patients who were less than 30 months of age at the start of the trial, did not meet its co-primary endpoints. The co-primary endpoints were assessed by changes in the Gross Motor Function Measure (GMFM)-88 total score and the Bayley Scales for Infant and toddler Development (BSID)-III Gross Motor Skill domain, compared to natural history scores from the Triac Trial I. Among key secondary endpoints, total serum thyroid hormone T3 concentrations were reduced significantly and durably in all patients, thereby verifying tiratricol’s ability to alleviate thyrotoxicosis in MCT8 deficiency patients. The trial confirmed the well-tolerated safety profile seen in previous clinical studies, despite higher dosing per kg body weight compared to previous studies. Professor Dr W. Edward Visser, Principal Investigator of Triac Trial II, Erasmus Medical Center, Rotterdam, The Netherlands, commented: “Ourresearch hypothesis when we designed the Triac Trial II, based on preclinical data and on exploratory outcomes we observed in Triac Trial I, was to investigate if young patients with MCT8 deficiency might have a neurocognitive benefit from tiratricol treatment, if the treatment is started early. Unfortunately, the study didn’t show a clinically relevant and statistically significant improvement on the primary neurocognitive endpoints, but the study confirmed the effects of tiratricol on reducing T3 concentrations, which are relevant to alleviate features of thyrotoxicosis in patients with MCT8 deficiency, regardless of age.” Nicklas Westerholm, CEO of Egetis, commented: “The safety and tolerability of Emcitate® (tiratricol) is reassuring also when given to young subjects at relatively high doses, although it is disappointing that we didn’t meet the primary endpoints in Triac Trial II. The effects on the chronic peripheral thyrotoxicosis already demonstrated in previous studies translate into important clinical benefits to patients of all ages suffering from this devastating condition and we remain confident that tiratricol will become the first approved therapy for MCT8 deficiency and regulatory timelines remain unchanged.We are grateful for the patients, their families, and the investigators who have participated in Triac Trial II.” The data will be presented at a forthcoming medical meeting, submitted to a peer-reviewed medical journal and shared with regulatory authorities. As agreed with the EMA, regulatory approval for Emcitate® (tiratricol) is based on treatment effects on T3 concentration and the manifestations of chronic thyrotoxicosis in MCT8 deficiency, demonstrated in previous clinical studies. This was reflected in the validated marketing authorisation application in the EU, submitted in October 2023. Results from Triac Trial II and will be included in the response to EMA 120-day list of questions in August 2024. The forthcoming New Drug Application in the USA will also be based on the already observed treatment effects on T3 concentrations and the manifestations of chronic thyrotoxicosis together with results from the ongoing ReTRIACt trial, as acknowledged by the US Food and Drug Administration (FDA). The timeline for regulatory review and approval in EU remain unchanged. For the US, as previously communicated, the Company will update the market with regards to timelines for NDA submission as soon as 16 evaluable patients have concluded the ongoing ReTRIACt trial. Webcast and teleconference on July 20 at 08:00am CESTIf you wish to participate via webcast please use the link below. Via the webcast you are able to ask written questions.https://ir.financialhearings.com/egetis-press-conference-june-2024/register If you wish to participate via teleconference please register on the link below. After registration you will be provided phone numbers and a conference ID to access the conference. You can ask questions verbally via the teleconference. https://conference.financialhearings.com/teleconference/?id=5007609 About Triac Trial IITrial II is conducted in patients with MCT8 deficiency, also called Allan-Herndon-Dudley Syndrome (AHDS), which is due to mutations in monocarboxylate transporter 8 (MCT8). MCT8 is a thyroid hormone transporter which is crucial for the transport of thyroid hormone from the blood into different tissues. Defective MCT8 results in a lack of thyroid hormone (hypothyroidism) in tissues that are dependent on MCT8 for thyroid hormone uptake, such as the brain. Hypothyroidism in the brain results in severe intellectual and motor disability. Another important feature of this disease is the high serum T3 concentrations in the blood. This results in thyrotoxicosis in tissues that are not dependent on MCT8 for their thyroid hormone supply. As a result, patients with MCT8 deficiency have clinical features of thyrotoxicosis such as low body weight, elevated heart rate and reduced muscle mass. Preclinical studies have shown that the T3 analogue tiratricol is transported into cells in an MCT8-independent manner. In animal models mimicking MCT8 deficiency, tiratricol has been shown to normalize brain development if administrated during early postnatal life. Triac Trial I (NCT02060474) has shown that tiratricol treatment in patients with MCT8 deficiency improves key clinical and biochemical features caused by the toxic effects of the high T3 concentrations. No drug related serious adverse events occurred during Triac Trial I. Triac Trial II investigated the effect of treatment with tiratricol in young boys (≤30 months) with MCT8 deficiency. The hypothesis tested is that treatment with tiratricol will have a beneficial effect on the hypothyroid state in the brain as well as the hyperthyroid state in peripheral organs and tissues in these patients. Patients were initially treated for 96 weeks with tiratricol, and the treatment effect was evaluated after 96 weeks. After the 96-week treatment period, patients could enter Part II of the trial, evaluating long-term treatment. Patients will be followed for an additional 2 years, and treatment effect will be evaluated after 3 years and 4 years respectively from start of treatment. For further information about Triac Trial II, please see https://clinicaltrials.gov/study/NCT02396459 About MCT8 deficiencyMCT8 deficiency, also called Allan-Herndon-Dudley Syndrome, is an ultra-rare genetic disorder. As one of the first X-linked neurodevelopmental syndromes to be described, MCT8 deficiency was later associated with mutations in the SLC16A2 gene in 2004. The core mechanism driving the pathogenesis of MCT8 deficiency is dysfunction of the thyroid hormone transporter, monocarboxylate transporter 8 (MCT8). MCT8 has a major role in regulating thyroid hormone levels, including the cellular uptake and efflux of tri-iodothyronine (T3) and thyroxine (T4). MCT8 serves an important role in the transport of thyroid hormone across the blood–brain barrier and is also widely expressed in tissues in the thyroid, liver, kidneys, heart, and muscle. This disrupted thyroid hormone homeostasis leads to neurological and endocrinological symptoms. The neurological symptoms are a consequence of too little T3 in the brain during neurodevelopment, whereas the endocrinological symptoms are due to elevated T3 in other organs outside the brain. Parents of children with MCT8 deficiency usually report the pregnancy and birth as uneventful, and infants appear to develop as expected for the first few months of life. Early signs, such as inadequate head control due to hypotonia and failure to thrive may start to appear from around three months of age, but it usually takes a few more months before medical attention is sought. Recognizing symptoms and making an early diagnosis may help patients and their families. For further information about MCT8 deficiency, please see www.mct8deficiency.com

Phase 2Clinical ResultNDA

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

02 Nov 2020

·www.egetis.com

PledPharma completes the acquisition of Rare Thyroid Therapeutics

PledPharma AB (publ) has today completed the acquisition of Rare Thyroid Therapeutics International AB. As previously announced, PledPharma AB (publ) (“PledPharma” or the “Company”) entered into an agreement on 5 October 2020 to acquire all outstanding shares in Rare Thyroid Therapeutics International AB (“RTT” or “Rare Thyroid Therapeutics”), a privately held drug development company with the ultra-orphan asset Emcitate. The purchase price for the shares in RTT consists of a cash purchase price in the amount of MSEK 60, funded from own cash-in-hand and a share purchase price consisting of 63,773,345 new shares in PledPharma. In addition, the sellers of RTT are entitled to earnout payments based on the future net sales of Emcitate as well an earnout which is payable in connection with a potential sale of a so-called US Rare Pediatric Disease Priority Review Voucher. On 5 October 2020 the board of directors also resolved, subject to the general meeting’s subsequent approval, on an issue of up to 63,773,345 shares to the current shareholders of RTT against payment in kind in the form of shares in RTT. The extraordinary general meeting in PledPharma held on 28 October 2020 resolved to approve the board of directors’ resolution regarding the in-kind issue as part of the purchase consideration for RTT. Today on 3 November 2020 the acquisition of RTT was completed. The share issue in kind will lead to an increase in the number of shares of PledPharma by 63,773,345 from 53,533,321 to 117,306,666, which will result in a dilution of approx. 54,4 percent for existing shareholders. The completion of the acquisition has also resulted in that Peder Walberg assumes the position as member of the board of directors of PledPharma, in accordance with the resolution on the extraordinary general meeting on 28 October 2020. “The acquisition of RTT is an important step, building a new company with a strategic focus on the attractive orphan drug segment, with Aladote and Emcitate as the company’s key assets in late stage development. The RTT team, specialized in orphan drugs, will complement PledPharma’ s late stage development focused organization, building a new orphan drug company named Egetis Therapeutics, dedicated to development and commercialization of therapies for rare diseases,” said Nicklas Westerholm, CEO, PledPharma.

AcquisitionOrphan Drug

100 Deals associated with Tiratricol

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D07214	Tiratricol	D11AX08 H03AA04	DB03604

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Indication	Highest Phase	Country/Location	Organization	Date
Allan-Herndon-Dudley Syndrome	NDA/BLA	EU	Rare Thyroid Therapeutics International AB	12 Dec 2024

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