Sitaxentan Sodium

On March 22, Johnson & Johnson announced that the U.S. FDA had approved its new medication, OPSYNVI®, for the treatment of Group 1 pulmonary arterial hypertension (PAH) as classified by the World Health Organization, and for patients with WHO functional class II-III PAH in adults. OPSYNVI® is a single tablet combination therapy that contains an endothelin receptor antagonist (macitentan) and a phosphodiesterase 5 (PDE5) inhibitor (tadalafil). PAH is a rare, progressive, and life-threatening vascular disease characterized by the narrowing of small arteries in the lungs and elevation of blood pressure in the pulmonary circulation, potentially leading to right heart failure. In the United States, there are approximately 500 to 1000 new cases of PAH each year, classifying it as a rare disease. According to the classification system updated by the cause of the disease at the 6th World Symposium on Pulmonary Hypertension: ·Group 1 pulmonary hypertension (PH), also known as pulmonary arterial hypertension (PAH), encompasses various causes, including: connective tissue diseases (most commonly systemic sclerosis), HIV infection, portopulmonary hypertension due to liver diseases, drug and toxin-induced PAH, congenital heart diseases leading to systemic-to-pulmonary shunts, as well as idiopathic and heritable pulmonary arterial hypertension.  ·Group 2 pulmonary hypertension (PH) is caused by left heart diseases and is also known as post-capillary or pulmonary venous hypertension. It covers issues such as left ventricular systolic dysfunction and/or diastolic heart failure, as well as heart failure associated with diseases of the valves on the left side of the heart.  ·Group 3 pulmonary hypertension (PH) is induced by chronic hypoxemia and respiratory system diseases.  ·Group 4 pulmonary hypertension (PH) is associated with chronic thromboembolic obstruction in the pulmonary arteries, with chronic thromboembolic pulmonary hypertension (CTEPH) being the most common manifestation.  ·Group 5 pulmonary hypertension (PH) includes miscellaneous causes such as sarcoidosis, thyroid disorders, end-stage renal disease (whether treated with dialysis or not), and other diseases leading to pulmonary hypertension. In 2022, the European Society of Cardiology (ESC) and the European Respiratory Society (ERS) published clinical guidelines recommending initial combination therapy with endothelin receptor antagonists and PDE5 inhibitors for patients with low to intermediate risk idiopathic PAH, heritable drug-related PAH, or PAH associated with connective tissue disease without cardiovascular lung complications. The emergence of OPSYNVI®, a single-pill combination medication, not only simplifies the medication administration process for patients but also aligns more closely with the multidisciplinary treatment philosophy of current PAH guidelines, potentially improving treatment adherence and efficacy. About MacitentanMacitentan is a dual endothelin receptor antagonist specifically designed for the treatment of pulmonary arterial hypertension (PAH). This medication was first approved by the U.S. Food and Drug Administration (FDA) in 2013 for the purpose of alleviating disease progression in PAH patients. Compared to its predecessor, bosentan, an important advantage of Macitentan lies in its reduced risk of hepatotoxicity, which means it has less impact on patients' livers during long-term treatment. In terms of its mechanism of action, Macitentan works by blocking endothelin receptors ETA and ETB, reducing pathological processes such as pulmonary arterial constriction, smooth muscle cell proliferation, and fibrosis. As a result, it helps to decrease pulmonary vascular resistance, improve cardiac function, prevent or delay the worsening of PAH patients' condition, and enhance their quality of life. Macitentan's role in the treatment of pulmonary arterial hypertension involves counteracting the adverse effects of the abnormal activation of the endothelin system, aiming to help control disease progression and reduce the risk of hospitalization and other clinical deteriorations due to PAH. According to clinical research data published in 2024 (NCT03904693), this multicenter, double-blind, adaptive phase III A DUE study compared the efficacy and safety of a fixed-dose combination of Macitentan/Tadalafil (M/T) to monotherapy with Macitentan 10 mg and monotherapy with Tadalafil 40 mg in the treatment of pulmonary arterial hypertension patients, including those who were untreated and those who had previously only received treatment with endothelin receptor antagonists or phosphodiesterase type 5 inhibitors as monotherapy. Research findings indicate that a total of 187 patients were randomized to either the single-pill M/T FDC group (108 patients), the Macitentan group (35 patients), or the Tadalafil group (44 patients). In comparison to Macitentan monotherapy, treatment with the M/T FDC significantly reduced pulmonary vascular resistance (PVR) by 29%, with a geometric mean ratio of 0.71; the reduction in PVR was also significant compared to Tadalafil monotherapy, amounting to a 28% decrease, with a geometric mean ratio of 0.72. There were three patient deaths in the M/T FDC treatment group, but these were judged to be unrelated to the treatment. The M/T FDC group experienced more adverse events (AEs) leading to discontinuation of the drug, serious adverse events, and adverse events of special interest (anemia, hypotension, and edema). In conclusion, the fixed-dose combination therapy substantially improved the efficacy in lowering pulmonary vascular resistance in PAH patients compared to monotherapy, with safety and tolerability profiles consistent with its individual components. Another multicenter, double-blind, randomized phase 3b clinical study, TRITON, published in 2021, also evaluated the efficacy and safety of initial triple oral therapy (macitentan, tadalafil, and selexipag) versus initial double oral therapy (macitentan, tadalafil plus placebo) in patients newly diagnosed with pulmonary arterial hypertension (PAH) who had not previously received treatment. The results indicated that at week 26, both treatment approaches significantly reduced the pulmonary vascular resistance in patients compared to baseline (by 54% and 52%, respectively), yet the difference in reduction between the two groups was not statistically significant. At week 26, both the initial triple-combination therapy group and the initial dual-combination therapy group showed improvements in the 6-minute walk distance and N-terminal pro-brain natriuretic peptide levels, with no notable differences between the two groups. It is noteworthy that at the end of the primary observation period, there were 2 deaths in the initial triple-combination therapy group compared to 9 deaths in the initial dual-combination therapy group. Exploratory analysis suggests that initial triple-oral therapy may offer a better long-term treatment outcome compared to initial dual therapy. Current Status of Endothelin Receptor Antagonist Development Endothelin-1 (ET-1) was identified in 1988 when Japanese scientist Yanagisawa and colleagues reported the discovery of endothelin-1, an elusive "endothelium-derived vasoconstrictor factor," which ignited the field of biomedical research. Endothelin-1 exhibits significant pharmacological properties: it has a sustained vasoconstrictive effect on the smooth muscle of the coronary arteries, with a potency an order of magnitude greater than that of angiotensin II or other vasoactive agents. Endothelin-1 is expressed in the endothelial cells of all inspected human vascular beds. In a pioneering human study, a key finding with the use of a selective ETA receptor antagonist was that endothelin-1 maintains normal vascular tone through the ETA receptors expressed on smooth muscle cells. Conversely, the ETB receptors expressed by endothelial cells release the vasodilator nitric oxide in an autocrine manner, thereby relaxing the underlying smooth muscle. DOI: 10.1016/j.cell.2022.12.014 ETA and ETB receptors, as key components of the endothelin system, hold significant value in clinical research and therapy. These two G-protein-coupled receptors are activated by the endothelin peptides 1-3, which are produced by endothelial cells and various other cell types, including renal cells, neurons, and macrophages. They are crucial in regulating physiological functions of the cardiovascular system, kidneys, and metabolism. To date, the FDA has approved a total of 5 ETA or ETB antagonists, including Bosentan (2001, dual antagonist), Sitaxentan (2006, withdrawn), Ambrisentan (2007, ETA receptor-selective), Macitentan (2013, dual antagonist), and Sparsentan (2023, dual ETA+AT1R antagonist). Bosentan (Ro-47-0203) is a potent dual antagonist for the ETA and ETB receptors, developed by the research team at Roche in Switzerland. Its activity has been studied in various preclinical disease models. In 1996, the Roche team published the first study on the pharmacokinetics and pharmacodynamics of Bosentan in healthy humans in the journal "Clin Pharmacol Ther." The results revealed that the systemic plasma clearance and the volume of distribution for Bosentan decreased with increasing doses, with approximate values of 6 L/h and 0.2 L/kg, respectively. The absolute bioavailability was around 50% and appeared to decrease with doses exceeding 600 mg. The maximal increase in plasma ET-1 was 2-fold (oral) and 3-fold (intravenous). Bosentan reversed the vasoconstrictive effects of ET-1 measured in the skin microcirculation, leading to a trend of decreasing blood pressure (by about 5 mm Hg) and an increase in heart rate (by about 5 beats/min). The oral administration of Bosentan was well tolerated, while higher doses administered intravenously caused vomiting and local intolerance. PIVLAZ® (Clazosentan) is a potent and selective endothelin ETA receptor antagonist developed by Idorsia Pharmaceuticals. It is indicated for the prevention of cerebral vasospasm, vasospasm-related cerebral infarction, and cerebral ischemic symptoms following aneurysmal subarachnoid hemorrhage (aSAH). PIVLAZ® was successfully launched in Japan in April 2022 for the treatment of cerebral vasospasm. Sosei Heptares holds the marketing rights for PIVLAZ® in Japan and the Asia-Pacific region, excluding China. It is reported that between 40% and 70% of patients experience cerebral vasospasm within 4 to 14 days after aneurysmal subarachnoid hemorrhage (aSAH). Of these patients with cerebral vasospasm, 17% to 40% develop delayed ischemic neurological deficits, with approximately half of them suffering from cerebral infarction. Post-acute cerebral infarction, endothelin levels are elevated under the induction of oxyhemoglobin and released from red blood cells. This leads to cerebral vasospasm through the endothelin ETA receptor. According to a clinical study report published by the Idorsia team in 2022, in each study, 221 patients underwent random treatment, with 220 patients included in the full analysis set for the primary analysis (109 patients in the Clazosentan group and 111 patients in the placebo group). Compared with placebo, a 150 mg intravenous infusion of Clazosentan significantly reduced the incidence of vasospasm-related morbidity and all-cause mortality following aSAH. Aprocitentan is a novel oral dual endothelin receptor antagonist being developed by Idorsia Pharmaceuticals that effectively inhibits the binding of ET-1 to both ETA and ETB receptors. It is reported that the potential for drug-drug interactions with Aprocitentan is low, and its mechanism of action is very well suited to the pathophysiology of resistant hypertension. In November 2022, the team from Idorsia and Johnson & Johnson authored an article in The Lancet journal, reporting phase 3 clinical study data for aprocitentan in the treatment of patients with treatment-resistant hypertension. The results indicated that aprocitentan was well tolerated in patients with treatment-resistant hypertension, demonstrating superior blood pressure lowering effects compared to placebo at week 4, with sustained effectiveness at week 40. Sparsentan (BMS-346567) was developed by the BMS research team in 2005 and is the first orally active therapeutic among its class. Sparsentan is a fusion of structural elements from the AT1R antagonist irbesartan and the ETAR antagonist biphenylsulfonamide. It exhibits high affinity for both receptors, with an affinity of 9.3 nM for ETAR and 0.8 nM for AT1R. In May 2023, the esteemed medical journal The Lancet online published clinical research findings by Travere Therapeutics regarding Sparsentan in patients with IgA nephropathy. The study showed that, compared to the AT1R antagonist irbesartan alone, daily treatment with the dual-acting agent Sparsentan significantly reduced proteinuria in adult patients with IgA nephropathy. ETA, as a classically validated scientific and clinical target, has led to numerous developmental projects for ET antagonists centered around ETA. In addition to standalone ETA antagonists, the combination of ETA with multiple targets, including ETA+ETB, ETA+NF-κB, ETA+AT1R, ETA+ETB+PDE5A, ETA+PDE5A, ETA+CD3, ETA+TGF-β, has become an important approach in the development of innovative clinical candidate compounds. In the context of drug types, in addition to classic small molecule therapeutics, synthetic peptides, monoclonal antibodies, and bispecific antibodies have also become new directions for the development of clinical candidate drugs. While Pfizer and MSD (Japan) have either terminated or seen no progress in their research on synthetic peptides targeting ETA, Gmax Biopharm, a Chinese company, has independently led the antibody development in this area. Several branch pipelines are at the preclinical or clinical development stages. Given the historical data from the development of multi-target combinations with small molecule drugs targeting ETA, there is significant potential in developing bispecific antibodies that target ETA and a second therapeutic target.

On March 20th, the Swiss pharmaceutical company Idorsia announced that the U.S. FDA has approved TRYVIO™ (aprocitentan) for use in combination with other antihypertensive medications to treat adult hypertension, in order to lower blood pressure levels in the adult patient population whose blood pressure has not been effectively controlled. Hypertension is a common chronic condition characterized by persistently high blood pressure readings (140/90 mmHg or higher). Lowering high blood pressure can reduce the risk of fatal and non-fatal cardiovascular events, with stroke and myocardial infarction being the primary concerns. ·TRYVIO acts by targeting endothelin-1 (ET-1), which is a potent vasoconstrictor closely associated with the mechanisms leading to hypertension. It mitigates the detrimental effects of ET-1 by preventing its binding to ETA and ETB receptors, thereby reducing the vasoconstrictive, fibrotic, cellular proliferative, and inflammatory responses induced by ET-1. ·TRYVIO tablets are required to be taken only once daily and can be ingested with or without food. ·TRYVIO comes with a black box warning, indicating its teratogenic toxicity. It is contraindicated for use in pregnant women. Effective contraceptive measures must be taken before starting treatment, throughout the course of treatment, and for one month after discontinuation. ·Warnings and precautions associated with TRYVIO include risks of hepatotoxicity, fluid retention, decrease in hemoglobin, and reduced sperm count. Common adverse reactions comprise edema/fluid retention and anemia. The following is a retrospective review of TRYVIO's R&D milestones over the past 10 years at various time points: 2023: Submitted a Marketing Authorization Application (MAA) to the European Medicines Agency (EMA). 2022: Filed a New Drug Application (NDA) with the U.S. FDA, and in the same year, presented the work as a late-stage breakthrough study at an American Heart Association (AHA) meeting, with relevant Phase III clinical trial data published in the prestigious medical journal The Lancet. 2022: Successfully completed Phase III clinical studies, demonstrating the drug's safety and efficacy in the targeted patient population. 2018: Initiated Phase III clinical trial, a crucial step in validating the drug's therapeutic effectiveness and safety in a large population. 2017: The dose-response study yielded positive results, confirming the pharmacodynamic response of Aprocitentan at different dosages, laying the foundation for subsequent research. 2015: Began Phase II dose-response relationship studies aimed at further exploring the optimal dosage range of the drug and its response in humans. 2014: Launched Phase I clinical trial program, marking the first step for Aprocitentan to move from laboratory to human clinical testing, primarily to assess the drug's safety, tolerability, and preliminary pharmacokinetic characteristics in humans. Hypertension Medication Returned by Johnson & JohnsonOn January 26, 2017, Johnson & Johnson announced a proposal to acquire the Swiss pharmaceutical company Actelion in an all-cash tender offer, at a price of $280 per share (totaling $30 billion in cash) for all of Actelion's outstanding shares. As part of the transaction, Actelion will spin off its drug research and early-stage clinical development assets into a newly formed Swiss biopharmaceutical company called Idorsia. Idorsia will be listed on the Swiss Stock Exchange, and Johnson & Johnson will initially hold a 16% stake in the newly established R&D company. In November 2017, the newly formed Idorsia announced a collaboration with Janssen Biotech, a subsidiary of Johnson & Johnson, focusing on Aprocitentan. As part of the agreement, Idorsia will receive about $230 million in milestone payments; Idorsia and Janssen Biotech will share the development costs of aprocitentan during the Phase III clinical trials; and Idorsia will be entitled to royalty fees on potential future net sales. On September 6th, 2023, Idorsia announced that the company had reached an agreement with Janssen Biotech, a subsidiary of Janssen Pharmaceuticals, to reacquire the rights to Aprocitentan. It was reported that, although Phase 3 clinical trial results of the drug showed a significant reduction in blood pressure compared to placebo, they also revealed an issue where 18% of patients on high doses experienced mild to moderate fluid retention. Johnson & Johnson deemed that the drug might not meet their commercial development objectives and therefore decided to return the rights. In return, Idorsia will pay Janssen Biotech approximately 306 million Swiss francs, contingent upon the approval of Aprocitentan's marketing application by the US FDA and the European EMA. Additionally, Idorsia is currently exploring the best approach to maximize the value of aprocitentan." Aprocitentan is a novel oral dual endothelin receptor antagonist currently being developed by Idorsia Pharmaceuticals. It effectively inhibits the binding of ET-1 to both ETA and ETB receptors. It is reported that the potential for drug-drug interactions with Aprocitentan is low, and its mechanism of action is highly suitable for the pathophysiology of resistant hypertension. The Latest Clinical Data on AprocitentanIn November 2022, the team from Idorsia and Johnson & Johnson published an article in The Lancet journal, presenting Phase 3 clinical study data of aprocitentan for the treatment of resistant hypertension. The results indicated that aprocitentan was well-tolerated in patients with resistant hypertension, showing a superior blood pressure-lowering effect compared to placebo at week 4 and sustained efficacy at week 40. The data demonstrated that among the 730 patients enrolled in the study, the least squares mean changes in systolic blood pressure after the first 4 weeks of treatment were -15.3 mm Hg for aprocitentan 12.5 mg, -15.2 mm Hg for aprocitentan 25 mg, and -11.5 mm Hg for placebo. The differences compared to placebo were -3.8 mm Hg and -3.7 mm Hg, respectively. Four weeks after discontinuation of the medication, systolic blood pressure significantly increased by 5.8 mm Hg compared to placebo. The most common adverse events were mild to moderate edema or fluid retention, leading to discontinuation of aprocitentan treatment in 7 patients. There were 11 cases of sudden death during the trial, which the researchers considered unrelated to the treatment. Based on this positive Phase 3 clinical data, Idorsia and Johnson & Johnson submitted marketing authorization applications for Aprocitentan to the United States in December 2022 and to the European Union in January 2023. About Endothelin (ET)Endothelin (ET) is a potent peptide vasoconstrictor, discovered in 1988 by Japanese scientist Yanagisawa and colleagues. It regulates blood pressure through its actions on blood vessels, the heart, and kidneys. The ET peptide family consists of three members: ET-1, ET-2, and ET-3. These ET peptides are each 21 amino acids in length and their overall structure is constrained by two disulfide bonds. The carboxyl-terminal sequence is essential for their activity. Taking ET-1 as an example, the translated ET-1 exists in the form of a precursor. Under the action of endothelin-converting enzyme (ECE), it undergoes proteolytic processing from an inactive precursor to a mature peptide, providing a potential pathway for inhibiting the production and action of ET-1. From, DOI: 10.1038/s41569-019-0176-3Humans have two types of ET receptors, the ETA receptor (ETA) has a higher binding affinity with ET-1 and ET-2 than with ET-3; the ETB receptor (ETB) has comparable binding affinity with all three isoforms. The figure below shows the relative mRNA expression levels of the ETA receptor and ETB receptor in 41 types of adult mouse tissues. The ETA receptor is highly expressed in the cardiovascular and pulmonary tissues, whereas the ETB receptor is highly expressed in the brain tissue. From,DOI: 10.1038/s41569-019-0176-3About Endothelin Receptor AntagonistsEndothelin receptors are widely known for their involvement in the physiological regulation of vascular tone due to their potent vasoconstrictive action. Excessive secretion of endothelin in the lungs can lead to pulmonary arterial hypertension. Endothelin autoregulates itself through physical and chemical factors such as blood flow, mechanical stretch, or pH changes and triggers the production of growth factors. Moreover, chronic endothelin stimulation has been shown to be associated with a variety of human cardiovascular, inflammatory, fibrotic, and neoplastic diseases. Additionally, endothelin may also play a role in conditions such as heart failure, renal insufficiency, septic shock, atherosclerosis, and hemorrhage-associated cerebrovascular diseases. Therefore, drugs that act on endothelin receptors may be beneficial in the treatment of a multitude of diseases. Source: DOI: 10.3390/jcm9030824Currently, several companies are screening antagonists targeting the ETA and ETB receptors, including selective antagonists for the ETA receptor, selective antagonists for the ETB receptor, or dual antagonists. Multiple endothelin receptor antagonists have been approved for the treatment of this disease. Current Status of Drug Development According to statistics from the Synapse database, there are a total of 5 endothein receptor antagonists (ETA or ETB antagonists) approved by the FDA, including Bosentan (2001, dual antagonist), Sitaxentan (2006, withdrawn), Ambrisentan (2007, ETA receptor selective), Macitentan (2013, dual antagonist), and Sparsentan (2023, ETA+AT1R dual antagonist). In February 2023, a dual antagonist targeting the inner ETA receptor and angiotensin II (Ang II) type 1 receptor (AT1R) named Filspari (Sparsentan) was approved by the FDA for marketing. The pharmaceutical is indicated for adults with primary immunoglobulin A nephropathy who are at risk of rapid disease progression and aims to reduce proteinuria. In May 2023, an ETA receptor selective agonist developed by the biopharmaceutical company Pharmazz, Sovateltide injectable solution, was approved for marketing in India for the treatment of patients with acute ischemic stroke. On September 14, Pharmazz entered into a licensing agreement with the Indian pharmaceutical company Sun Pharma. Under this agreement, Sun Pharma will have the rights to sell Sovateltide in India under the brand name Tyvalzi™. Pharmazz will be entitled to upfront and milestone payments, including royalties. Regarding Endothelin and Antitumor Drugs Aside from the symptoms of hypertension, endothelin receptors have multiple functions related to fundamental cellular processes such as cell proliferation and apoptosis. Aberrant expression of ET1 or overexpression of endothelin receptors or their associated signaling pathways can promote the occurrence and development of tumors through autocrine and paracrine mechanisms. These altered mechanisms can originate from genetic and epigenetic changes. In addition, a complex crosstalk network between ET1 signaling and other growth factor pathways propels tumor progression. This includes the interactions between endothelin receptors and receptors for epidermal growth factor and vascular endothelial growth factor. The ET1 signal can promote cell proliferation, survival, epithelial-mesenchymal transition (EMT), angiogenesis, immune cell responses, and drug resistance, with its mechanisms of action depending on specific contexts. Consequently, endothelin receptors have become key targets in cancer therapy. The figure below shows the expression of endothelin receptors in some human malignancies. According to statistics from the Synapse database, there are currently several clinical candidate drugs globally targeting ETA or ETB receptors for research into various types of solid tumors. This includes the ETB receptor antagonist VRP-1620, developed by the University of Illinois for breast cancer research, and ENB Medical's selective ETB receptor small molecule antagonist ENB-003, both of which are in clinical research stages. Chinese innovative pharmaceutical company Gmax Biopharm LLC is conducting research on GMA202, a bispecific M-Body molecule consisting of an antibody targeting the ETA receptor and an antibody fragment targeting CD3. Reportedly, GMA202 achieves a unique and precise tumor immunotherapy effect by pairing activated T cells with ovarian cancer cells that highly express the ETA receptor. RG-7636 (DEDN6526A) is an ADC product developed by Genentech, which uses the ETB receptor as the mAb target linked to MMAE. Preclinical studies have shown that RG-7636 exhibits dose-dependent antitumor activity against xenografts expressing the ETB receptor. Phase 1 clinical trials have demonstrated that RG-7636 has antitumor activity in patients with melanoma.