Thyrotoxicosis

The FDA approved five fewer novel medicines than in 2023 while the EMA improved its tally by seven. Image credit: Shutterstock / Tamakhin Mykhailo. The US Food and Drug Administration (FDA) has narrowly beaten the European Medicines Agency (EMA) to the most approved drugs with a new active substance in 2024. On 15 January, the two agencies released respective lists of medicines approved last year. The FDA approved 50 novel drugs that contained an active ingredient not previously approved by the agency, whilst the EMA authorised 46 new medicines. Whilst racking up 50 novel drug approvals, the FDA approved fewer than it did in 2023, when there were 55 greenlit to market . Conversely, the EMA’s 2024 figure of 46 was a step up from the 39 new active substance drugs approved in 2023. The highest proportion of new drugs approved by the EMA came in haematology/haemostaseology indications, with ten of the 12 approved medicines in this area containing a new active ingredient. Overall, however, oncology had the highest number of new drugs, matching trends seen in previous years. The FDA meanwhile highlighted the importance of rare diseases, reporting that over half its novel approvals came in orphan diseases that affect fewer than 200,000 people in the US. The FDA added that 68% of its novel drugs were approved in the US before any other country. Mirrored approvals Both the FDA and EMA approved Pfizer’s Hympavzi (marstacimab-hncq) for the treatment of adults and adolescents with severe haemophilia A or B without inhibitors. Hympavzi’s entry to market marked a significant advancement in treatment options available for patients with the rare disease, becoming the first approved anti-tissue factor pathway inhibitor. In the hepatological space, both the FDA and EMA have approved Ipsen’s Iqirvo (elafibranor) and Gilead’s Livdelzi (seladelpar), the latter being marketed at Seladelpar Gilead in Europe. The drugs were approved for the treatment of primary biliary cholangitis, a chronic disease that can eventually lead to liver failure. The agencies were also aligned on ARS Pharmaceuticals adrenaline-based nasal spray for anaphylaxis treatment. Marketed as neffy in the US and Eurneffy in Europe, the drug became the first needle-free adrenaline option for emergency treatment of allergic reactions. Its entry to market, despite a hiccup in 2023 when the FDA declined to approve it, is seen as a more convenient alternative to EpiPen. Neuro differences Perhaps the most significant contrasts came in neurological indications. First came the approval of the new Alzheimer’s treatment Kisunla (donanemab) by the FDA in July 2024. The drug, which is still being reviewed by the EMA, provides direct competition to Eisai and Biogen’s Leqembi (lecanemab), which the EMA approved in late 2024, more than a year later than the FDA. Both treatments are monoclonal antibodies that target beta plaques in the brain, though Kisunla is infused every four weeks rather than Leqembi’s two. In September 2024, the FDA approved the first new schizophrenia drug in more than 30 years, courtesy of Bristol Myers Squibb’s (BMS) Cobenfy (xanomeline and trospium chloride). The approval validated the company’s $14bn acquisition deal for Karuna Therapeutics in which it gained rights to the candidate. BMS has not yet submitted Cobenfy to the EMA for marketing authorisation, though there are plans to run a UK trial in Oxford in 2025. Cobenfy is forecast to reach blockbuster status by 2028, as per GlobalData’s Pharma Intelligence Center. GlobalData is the parent company of Pharmaceutical Technology . Medications that received EMA approval but not FDA approval last year include Egetis Therapeutics’ Emcitate (tiratricol) and Pfizer’s Emblaveo (aztreonam-avibactam). Emcitate is the first treatment approved for peripheral thyrotoxicosis in patients with the ultra-rare chronic disease Allan-Herndon-Dudley syndrome while Emblaveo is indicated for certain types of infections by aerobic Gram-negative bacteria resistant to antibiotics.

This article will inventory the anti-tumor targets in the GPCR family and the therapeutic drugs that have been marketed. 01 GnRHRGonadotropin-Releasing Hormone Receptor is a member of the seven-transmembrane GPCR (G protein-coupled receptor) family. It is expressed on the surface of pituitary gonadotropin cells, as well as lymphocytes, mammary glands, ovaries, and prostates. Upon binding with gonadotropin-releasing hormone, the receptor associates with G proteins that activate the phosphatidylinositol-calcium second messenger system. Activation of the receptor ultimately leads to the release of gonadotropins: luteinizing hormone (LH) and follicle-stimulating hormone (FSH). Leuprolide (Leuprorelin) is a synthetic analogue of gonadotropin-releasing hormone (GnRH) developed by Takeda Pharmaceuticals, commonly used for treating certain types of hormone-dependent cancers, such as prostate and breast cancers, as well as non-cancerous conditions like endometriosis, uterine fibroids, and certain types of infertility. Leuprolide mimics the natural GnRH signals in the brain, initially causing a transient increase in hormone levels, followed by suppression of hormone production, thereby reducing symptoms and growth of these hormone-dependent diseases. Leuprolide is an injectable, administered via subcutaneous or intramuscular injection. Due to its control over hormone levels, Leuprolide is also used in treating precocious puberty in children. Additionally, GnRH analogues such as Goserelin developed by AstraZeneca, Buserelin by Sanofi, Nafarelin by Pfizer, and Gonadorelin by Mitsubishi Tanabe are all agnostic drugs of the GnRHR type. In recent years, antagonist drugs targeting GnRHR have also been reported for the treatment of certain hormone-dependent diseases. For instance: Degarelix is a GnRH receptor antagonist developed by Ferring Pharmaceuticals for the treatment of prostate cancer. It is also the first antagonist drug targeting the GnRHR globally, inhibiting the production of sex hormones (such as testosterone) by blocking the GnRH receptor, thereby suppressing the growth of prostate cancer cells. It is typically administered as an injection, rapidly reducing testosterone levels to castration levels. Ferring Pharmaceuticals subsequently licensed the commercial rights for Degarelix to Astellas and Pfizer. Relugolix is another GnRH receptor antagonist used for treating advanced prostate cancer. It also works by blocking the GnRH receptor and lowering sex hormone levels. Relugolix is also under investigation for the treatment of uterine fibroids and endometriosis. Relugolix was originally developed by Takeda Pharmaceuticals and is the first small molecule drug globally targeting the GnRH receptor. Linzagolix is an oral GnRH receptor antagonist for the treatment of various hormone-dependent diseases including endometriosis and uterine fibroids. Linzagolix has been approved in the European Union and the UK for treating moderate to severe symptoms associated with uterine fibroids. 02 SSTRThe Somatostatin Receptor Type (SSTR) belongs to the GPCR (G-protein-coupled receptor) family and comprises five subtypes (SSTR1-SSTR5). SSTRs play a critical role in the endocrine and nervous systems and are potential targets for the treatment of multiple diseases, particularly neuroendocrine tumors (NETs). Somatostatin (SST) is the natural ligand for SSTRs, and cortistatin (CST) is a neuropeptide that also binds with high affinity to all subtypes of SSTRs. Due to the high sequence homology between different SSTR subtypes, developing drugs that can selectively modulate specific subtypes presents a challenge, but this is essential for minimizing off-target effects. In targeted SSTR therapies, peptide radioligand therapies represent a significant research focus. For instance, Novartis's (177Lu)Lutathera, a peptide radioligand therapy targeting SSTR2, has been approved for the treatment of adult patients with SSTR-positive gastroenteropancreatic neuroendocrine tumors. The illustration below shows the differential tissue distribution of various SSTRs. Exploring dual-target drugs is an innovative direction, where the advantage of bi-targeted radiopharmaceuticals lies in the potential synergistic effects between the two targets, thereby enhancing safety and efficacy. Radiopharmaceutical development is exploring new indications such as pancreatic cancer, renal cancer, stomach cancer, thyroid cancer, lung cancer, and Parkinson's disease to broaden the therapeutic spectrum. Somatostatin is a polypeptide hormone composed of 14 amino acid residues, including a single disulfide bond. This hormone inhibits the secretion of growth hormone, insulin, glucagon, gastrin, pancreatic enzymes, and thyrotropin. However, due to its very short half-life in the body (less than 3 minutes), its therapeutic value is limited. Research on the β-turn pharmacophore of somatostatin has led to the development of more biologically stable and potent analogs. Octreotide was developed based on this lead sequence and approved for treating acromegaly, adenomas, and pancreatic, breast, and prostate tumors. DOI: 10.3390/molecules25174012 Subsequent research has pushed the development of selective receptor antagonists such as lanreotide, vapreotide, and pasireotide, and has introduced peptide imaging and peptide receptor radionuclide therapy. In these radiological therapies, radioactive elements like 111In, 90Y, 68Ga, or 99mTc are linked to selective somatostatin analogs through chelating groups, which led to the approval of radiopharmaceutical preparations such as 111In-labeled pentetreotide, 99mTc-labeled depreotide, 68Ga-labeled DOTA-TATE and DOTA-TOC, and 64Cu-labeled DOTA-TATE. These drugs are used for tumor detection. Several synthetic peptides and radiopharmaceuticals targeting SSTRs have been approved for market, with representative drugs including: Octreotide, developed by Novartis as a synthetic octapeptide somatostatin analog, is an SSTR agonist. Clinically, it is primarily used to treat conditions such as acromegaly, thyrotoxicosis, gastrointestinal fistulas, and symptoms and signs associated with gastroenteropancreatic neuroendocrine tumors. Octreotide inhibits the secretion of growth hormone, thyroid-stimulating hormone, insulin, and glucagon by binding to SSTRs, especially subtypes SSTR2 and SSTR5. Pentetreotide is another synthetic octapeptide that, unlike Octreotide, forms the radioactive drug 111In-pentetreotide by binding to the radiolabeled isotope Indium-111 via the chelator DTPA. This compound enables the use of Pentetreotide in single photon emission computed tomography (SPECT) imaging to detect tumors expressing SSTRs. It has a relatively fast renal clearance rate, offering a significant advantage over the first-generation [123I-Tyr3]-octreotide, a radioactive iodine-labeled octapeptide somatostatin analog. However, it has shortcomings, such as the need for a high tumor/noise intensity ratio, lower imaging resolution, medium affinity for receptors, and high γ-energy, which results in a higher radiation dose to patients. 111In-pentetreotide Lanreotide is a synthetic somatostatin analog, belonging to octapeptide derivatives. It has structural and functional similarities to Octreotide, but with different pharmacokinetic properties that make it a long-acting somatostatin analog. Gallium Dotatate Ga-68, developed by Advanced Accelerator Applications, is a radioactive diagnostic agent that uses DOTA to chelate Gallium-68 for positron emission tomography (PET) imaging, mainly targeting neuroendocrine tumors (NETs) expressing somatostatin receptors. The three radioactive drugs differ slightly in pharmacokinetic properties, primarily due to variations in affinity for specific receptor subtypes. [68Ga]-DOTATATE specifically binds to SSTR2, indicating its primary interaction with this receptor subtype; [68Ga]-DOTATOC has high affinity for SSTR2 and moderate affinity for SSTR5; while [68Ga]-DOTANOC shows high affinity for SSTR2, SSTR3, and SSTR5, making it a broad-target drug for multiple receptor subtypes. Lutetium Lu-177 dotatate, another therapeutic radiopharmaceutical developed by Advanced Accelerator Applications, targets tumor cells by binding to SSTR, particularly SSTR2 subtype. This binding allows the radioactive isotope Lutetium-177 to emit β-particles, thereby killing tumor cells. Yttrium-90 (a pure high-energy β-emitter with a half-life T1/2 = 64 hours) and Lutetium-177 (a moderate energy β-emitter with a half-life T1/2 = 6.7 days) are the most commonly used elements in peptide receptor radionuclide therapy. Each has specific advantages for targeted therapy. 90Y has higher particle energy and penetration, useful for treating larger tumors, while 177Lu, emitting lower-energy radiation, is better suited for smaller tumors. Additionally, its γ-radiation energy allows for scintigraphy scanning and dose determination during therapy. The image above shows [68Ga]-DOTATOC (commercial name Somakit®) and [177Lu]-DOTATATE (commercial name Lutatherav®), which are used to treat patients with progressive metastatic midgut neuroendocrine tumors. In October 2017, Novartis acquired French innovator Advanced Accelerator Applications for $3.9 billion to build and expand its radioligand therapy platform. In 2018, Novartis further invested $2.1 billion to acquire the biopharmaceutical company Endocyte, gaining more radiopharmaceutical candidates. Through these acquisitions, Novartis has established and expanded its radioligand therapy platform, holding several marketed products like Lutathera (177Lu-DOTATATE) and 68Ga-Edotreotide, along with many in development, including 177Lu-PSMA-617, 177Lu-PSMA-R2, 177Lu-NeoB, 177Lu-FF58, and 255Ac-PSMA-617. According to the Synapse database, multiple drugs targeting SSTRs or selectively targeting different SSTR subtypes are approved for the market or are in clinical research, with radiopharmaceuticals and diagnostics focusing on this target being particularly noteworthy. How to obtain the latest research advancements in the field of biopharmaceuticals? In the Synapse database, you can keep abreast of the latest research and development advances in drugs, targets, indications, organizations, etc., anywhere and anytime, on a daily or weekly basis. Click on the image below to embark on a brand new journey of drug discovery!

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