A Phase III Multi-center, Randomized, Open-label Study to Evaluate the Efficacy and Safety of [177Lu]Lu-DOTA-TATE in Patients Newly Diagnosed With Grade 1 and Grade 2 (Ki-67 <10%) Advanced GEP-NET With High Disease Burden (NETTER-3)

The purpose of the current study is to evaluate the efficacy and safety of [177Lu]Lu-DOTA-TATE plus octreotide long-acting release (LAR) versus octreotide LAR alone in newly diagnosed patients with somatostatin receptor positive (SSTR+), well differentiated Grade1 and Grade 2 (G1 and G2) (Ki-67 <10%) advanced gastroenteropancreatic neuroendocrine tumors (GEP-NETs) with high disease burden

Start Date06 May 2025

Sponsor / Collaborator

Novartis Pharmaceuticals Corp.

NCT06456359

/ RecruitingPhase 2IIT

Pasireotide as Maintenance Treatment With Monthly Deep Intramuscular Injection in SSTR2/3/5-Expressing Synovial Sarcoma and Desmoplastic Small Round Cell Tumor

PAMSARC is a non-commercial interventional Phase 2 clinical trial of academic research institutions, with its primary goal being to improve medical treatment of fusion driven Desmoplastic small round cell tumor (DSRCT) and Synovial sarcoma (SySa) in young adults and adolsecents with male predominance.
Current management of DSRCT and SySa includes chemotherapy, radiation and aggressive cytoreductive surgery. Despite advances in multimodal therapy, outcomes remain poor with frequent disease recurrence and very limited options for patients with advanced disease.
Selected somatostatin receptor (SSTR) family members, i.e., SSTR2, SSTR3 and SSTR5, are frequently overexpressed in DSRCT and SySa, providing the rationale for treatment with somatostatin analogues (SSA).
Pasireotide is a SSA with high affinity for SSTR1, -2, -3, and -5 and is approved for the treatment of Cushing's disease and acromegaly and has also shown activity in other cancers. In patients with advanced stage DSRCT and SySa, conventional chemotherapeutic approaches frequently lead to disease response, however, the duration of progression-free time after chemotherapy is short. The targeted approach with pasireotide after initial intensive multimodal treatment may have the potential to significantly improve outcome.

Start Date19 Dec 2024

Sponsor / Collaborator

University Hospital Heidelberg

NL-OMON57054

/ SuspendedNot ApplicableIIT

*Managing pasireotide-associated hyperglycaemia in acromegaly with eucaloric very-low carbohydrate ketogenic diet versus diabetes medication: a multicentre, randomized, open-label proof-of-concept study* - PasiAcroKeto

Start Date01 Jul 2024

Sponsor / Collaborator-

100 Clinical Results associated with Pasireotide Diaspartate

100 Translational Medicine associated with Pasireotide Diaspartate

100 Patents (Medical) associated with Pasireotide Diaspartate

788

Literatures (Medical) associated with Pasireotide Diaspartate

01 Feb 2025·MOLECULAR DIVERSITY

Investigation into in silico and in vitro approaches for inhibitors targeting MCM10 in Leishmania donovani: a comprehensive study

Article

Author: Sharma, Anupama ; Saha, Satabdi ; Kumar, Diwakar ; Bhowmik, Deep

Visceral Leishmaniasis (VL), the second neglected tropical disease caused by various Leishmania species, presents a significant public health challenge due to limited treatment options and the absence of vaccines. The agent responsible for visceral leishmaniasis, also referred to as "black fever" in India, is Leishmania donovani. This study focuses on L. donovani Minichromosome maintenance 10 (LdMcm10), a crucial protein in the DNA replication machinery, as a potential therapeutic target in Leishmania therapy using in silico and in vitro approaches. We employed bioinformatics tools, molecular docking, and molecular dynamics simulations to predict potential inhibitors against the target protein. The research revealed that the target protein lacks homologues in the host, emphasizing its potential as a drug target. Ligands from the DrugBank database were screened against LdMcm10 using PyRx software. The top three compounds, namely suramin, vapreotide, and pasireotide, exhibiting the best docking scores, underwent further investigation through molecular dynamic simulation and in vitro analysis. The observed structural dynamics suggested that LdMcm10-ligand complexes maintained consistent binding throughout the 300 ns simulation period, with minimal variations in their backbone. These findings suggest that these three compounds hold promise as potential lead compounds for developing new drugs against leishmaniasis. In vitro experiments also demonstrated a dose-dependent reduction in L. donovani viability for suramin, vapreotide, and pasireotide, with computed IC₅₀ values providing quantitative metrics of their anti-leishmanial efficacy. The research offers a comprehensive understanding of LdMcm10 as a drug target and provides a foundation for further investigations and clinical exploration, ultimately advancing drug discovery strategies for leishmaniasis treatment.

01 Feb 2025·Pituitary

Medical management pathways for Cushing’s disease in pituitary tumors centers of excellence (PTCOEs)

Article

Author: Laws, E ; Nachtigall, L B ; Haberbosch, L ; Chanson, P ; Casanueva, F F ; Barkan, A ; Popovic, V ; Lely, A J van der ; Lamberts, S ; Freda, P ; Biermasz, N R ; Frara, S ; Schilbach, K ; Melmed, S ; Uygur, M M ; Kaiser, U B ; Giustina, A ; Gadelha, M ; Wass, J A H

PURPOSE:

A recent update of consensus guidelines for the management of Cushing's disease (CD) included indications for medical therapy. However, there is limited evidence regarding their implementation in clinical practice. This study aimed to evaluate current medical therapy approaches by expert pituitary centers through an audit conducted to validate the criteria of Pituitary Tumors Centers of Excellence (PTCOEs) and provide an initial standard of medical care for CD.

METHODS:

Based on the activities of nine international PTCOEs between 2018 and 2020, we evaluated patients under medical treatment and their biochemical control rates.

RESULTS:

The median number of active patients with CD per center was 117 (35-279), with a median number of 10 new patients with CD managed annually in the endocrinology units of PTCOEs (4-42). The median percentage of patients with CD receiving medical treatment was 13.3% (4.8-82.9). Ketoconazole was the most frequently used drug, with a median rate of usage of 26.5% (5-66.7) of those receiving medical therapy. The median rates of metyrapone and pasireotide use were 17.2% (0-50) and 9.3% (0-51.7), respectively. For cabergoline and osilodrostat, therapy, the median rates of use were 2.8% (0-33.3), and 1.7% (0-25), respectively. Combination therapy was reported to be utilized in 13.6% (0-45.5) of medically treated patients. Mifepristone was used in a single center, representing 1.1% of its medically treated patients. Overall, the median control rate in patients with CD receiving medical treatment was 75% (10-100).

CONCLUSION:

Adrenal steroidogenesis inhibitors were the most commonly used medications amongst the centers. Despite the use of combination therapy, up to 25% of patients did not achieve disease control even in PTCOEs, highlighting the need for either more efficient combination therapies or novel therapeutic options.

01 Feb 2025·REVIEWS IN ENDOCRINE & METABOLIC DISORDERS

Real-world evidence of effectiveness and safety of pasireotide in the treatment of acromegaly: a systematic review and meta-analysis

Review

Author: Biagetti, Betina ; Marazuela, Mónica ; Puig-Domingo, Manel ; Tebe, Cristian ; Araujo-Castro, Marta

Pasireotide long-acting release (PAS-LAR) is a second-generation somatostatin receptor ligand (SRL) approved for acromegaly treatment. This meta-analysis aimed to evaluate the real-world effectiveness and safety of PAS-LAR in patients with acromegaly resistant to first-generation somatostatin receptor ligands (fgSRL). A systematic literature search was conducted in PubMed and Web of Science for real-world studies on PAS-LAR in acromegaly published between 2014 and 2023. Random-effects meta-analyses were performed on biochemical control rates, tumor shrinkage, and metabolic parameters. Twelve studies comprising 409 patients were included. The pooled rate of insulin-like growth factor 1 (IGF-1) control was 57.9% [95% CI: 48.4-66.8] and the percentage of patients with tumor shrinkage was 33.3% [95%CI: 19.7-50.4]. Significant reductions were observed in growth hormone standardized mean difference (SMD) 0.6 ng/mL [95% CI: 0.3 to 1.0] and IGF-1 levels SMD 0.9 ULN [95% CI: 0.4 to 1.4]. However, as expected, a worsening in glucose metabolism was noted as an increase in fasting glucose SMD - 0.8 mg/dL [95% CI: -1.0 to -0.5, p < 0.01], glycated hemoglobin SMD - 0.5% [95% CI: -0.7 to -0.2]. and type 2 diabetes mellitus prevalence SMD - 11.5% (95% CI: -17.5 to -5.5). PAS-LAR demonstrated higher effectiveness in real-world settings, with over 60% of patients achieving IGF-1 control compared to the around 30% efficacy observed in clinical trials. These findings suggest that PAS-LAR is an effective option for acromegaly patients resistant to fgSRL, but careful monitoring of glucose levels is essential. The high heterogeneity observed across studies emphasizes the need for identifying PAS-LAR response biomarkers to set-up individualized treatment approaches for optimizing patient outcomes.

News (Medical) associated with Pasireotide Diaspartate

03 Mar 2025

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Development Trends of Peptide Pharmaceuticals

Over the past year, peptide-based pharmaceuticals have garnered significant market attention. On one hand, GLP-1 peptide drugs have sparked the treatment market for obesity and metabolic diseases; on the other hand, several nuclear medicine companies, long dedicated to the development of peptide-receptor radionuclide therapy (PRRT), have been successively acquired by international pharmaceutical giants. This article provides an interpretation of a review published in the 2021 issue of "Nature Reviews Drug Discovery", which analyzes the history and trends of peptide drug development over the past 100 years. Since the first medical application of insulin in 1922, peptide drugs have played a significant role in treating a variety of diseases, including diabetes, cancer, osteoporosis, multiple sclerosis, HIV infection, and chronic pain. Currently, there are approximately 80 peptide drugs on the global market, with more than 150 in the clinical development stage, and an additional 400 to 600 undergoing preclinical research. This article not only reviews early research methods, such as chemical modification of natural hormones like insulin to enhance their stability and pharmacological activity, which still hold important lessons for today, but also investigates emerging strategies. Venomics and peptide display libraries are among these new strategies that have opened new avenues for the discovery of peptide drugs. Furthermore, the article analyzes areas where peptide drugs might offer unique value within the current pharmaceutical landscape, especially in therapeutic areas where traditional small molecule drugs or biologic agents are ineffective. However, to fully realize the potential of peptide drugs, a series of challenges need to be addressed, including improving oral bioavailability, enhancing plasma stability, prolonging half-life in the body, and reducing production costs. Development in the Field of Peptide TherapeuticsThe origin of peptide drugs can be traced back to the era of peptide hormones, among which insulin, as the first therapy derived from endogenous hormones, was initially extracted from the pancreases of cows and pigs, thus opening the door to peptide drug research and development. In 1954, the research team led by Vincent du Vigneaud completed the total synthesis of oxytocin and vasopressin, and as a result, won the Nobel Prize in Chemistry in 1955. This represented a major breakthrough in the chemical synthesis of peptide compounds. In the 1950s, artificially synthesized peptide hormones such as oxytocin and vasopressin entered clinical use, and the involvement of industrial groups like Swiss companies Ciba and Sandoz further propelled the interest in and commercialization process of the peptide drug industry. However, the efficiency of the early solution-phase chemical synthesis methods was low. It was not until the invention of solid-phase peptide synthesis technology in 1963 and its combination with high-performance liquid chromatography purification techniques that the development of peptide drugs began to attract widespread attention in the pharmaceutical industry. Bruce Merrifield proposed the concept of assembling amino acids on a solid phase to automate peptide synthesis, thereby inventing solid-phase peptide synthesis technology. This revolutionary method greatly improved the efficiency and precision of peptide synthesis and ultimately earned him the Nobel Prize in Chemistry in 1984. As the understanding of the critical role of peptide biomediators deepens, their exceptional activity, selectivity, and low toxicity characteristics are recognized. However, the limitations of peptide drugs, including low oral bioavailability, poor plasma stability, and short in vivo half-life, are also noted. Despite this, during the golden age of small molecule drugs in the 1970s and 1980s, research on peptide drugs did not come to a halt. Instead, it progressed by continually improving drug delivery technologies, formulations, and synthesis processes, overcoming these challenges. Entering the 1980s, with the advent of recombinant technology, scientists were able to produce larger molecular weight peptides more cleanly. In the late 1980s, with the support of venture capital and biotech companies, the development of peptide drugs witnessed a second surge. The successful commercialization of recombinant human insulin and the approval of gonadotropin-releasing hormone analogs such as leuprolide and goserelin verified the market viability of peptide drugs and spurred further investment and research activity. In the late 1990s, researchers adopted a series of strategies to increase the molecular weight of peptides, such as coupling peptides with lipids, larger proteins, or polyethylene glycol. These strategies effectively addressed the issue of rapid renal clearance of peptide drugs, extending their circulation time in the plasma. In addition, advancements in display technologies played a significant role; for instance, phage display technology enabled researchers to directionally discover peptide sequences with better pharmacological properties and higher drug-likeness from large-scale libraries. As time progressed, the peptide drug market continued to expand, with approved drugs covering the treatment of various diseases such as diabetes, cancer, and osteoporosis. Moreover, through continuous technological innovation and deepening biological understanding, the research and development of peptide drugs is continuing to evolve towards greater efficiency, safety, and adaptability. From 2000 to 2010, the number of peptide drugs entering clinical trials almost doubled compared to the 1990s. The Peptide Therapeutics MarketThe peptide drug market occupies a unique pharmacological domain that lies between small molecule drugs and biological products. In the global pharmaceutical market, peptide drugs account for 5%, with a worldwide sales exceeding 50 billion USD in 2019. Over the past sixty years, the number of approved peptide drugs has steadily increased, with the global peptide therapeutics market experiencing an average growth rate of approximately 7.7%. In the sales revenue of peptide-based pharmaceuticals, insulin and its analogs account for approximately half of the market share (about $25 billion), demonstrating their dominant position in the field. Following closely are a series of important peptide drug products: for instance, the GLP-1 receptor agonist dulaglutide (brand name Trulicity), which is used for diabetes treatment, achieved sales of $4.4 billion in 2019; another GLP-1 receptor agonist, liraglutide, marketed under the brands Victoza and Saxenda for diabetes and obesity treatments respectively, reached sales of $4.1 billion; and the synthetic gonadotropin-releasing hormone analog leuprorelin (brand names Lupron and Eligard), mainly used for cancer treatment, with a sales volume of $2 billion. Based on currently approved peptide drugs, the majority are categorized as agonists, and the most frequently targeted indications are related to endocrinology, metabolism, and oncology. Peptide Drug Sales Ranking in 2019Peptide drugs approved for the market prior to 2021Peptide drugs based on synthetic human hormones Peptide Drugs Based on Recombinant Human Hormones Peptide Drugs Based on Hormone Extracts Peptide-based Diagnostic Products Peptide drugs extracted from animals, plants, and bacteria Peptide drugs based on serendipitous discovery and rational design Sustained-release formulations of peptide drugs based on injectable poly(lactic-co-glycolic acid) (PLGA) or poly(lactic acid) (PLA) delivery systems (This technology leverages biodegradable polymers such as PLGA and PLA, which form long-acting delivery carriers in the form of microparticles or microspheres by combining with peptide drugs. Since PLGA and PLA gradually degrade into non-toxic byproducts in the body and are metabolized and excreted, they are known for their excellent biocompatibility and safety as drug delivery materials.) Representative peptide drugsCalcitonin and Parathyroid Hormone (PTH) Calcitonin is a peptide hormone composed of 32 amino acid residues, discovered in 1961 to effectively lower calcium ion levels in dog blood. Subsequent research has proven that calcitonin can strongly inhibit the bone resorption process. Salmon calcitonin differs from human calcitonin in sequence by 16 amino acid residues, yet its potency is 40 to 50 times higher. Salmon calcitonin was approved in 1978 for the treatment of hypercalcemia and postmenopausal osteoporosis. Initially, salmon calcitonin was a natural substance extracted from a gland analog to the thyroid gland in salmon, but a synthetic version was approved for use in 1978, and further advancements in 2005 led to the development of salmon calcitonin produced using recombinant technology. Parathyroid hormone (PTH), which contains 84 amino acid residues, was discovered in 1925. Its action is the opposite of calcitonin's, primarily activating PTH1 and PTH2 receptors to promote the release of calcium ions from the bone's calcium stores, significantly raising the calcium content in the blood. However, prolonged elevated levels of PTH can lead to the depletion of calcium reserves in the bone, detrimental to maintaining bone health. Due to the extremely short half-life of PTH and its analogs in the body, they are not suitable for clinical therapy. With the advancement of chemical modification techniques, researchers have adopted various strategies to extend the activity and stability of PTH analogs, such as the introduction of non-natural amino acids, N-terminal or C-terminal extensions, and disulfide bond mimetics, among others. These improvements have allowed PTH-like drugs to exert biological effects more effectively in the human body and to reduce clearance rates. The first PTH-based therapy was Teriparatide, a recombinant fragment of the first 34 amino acid residues of human PTH, which is the biologically active portion. It was approved in 2002 for the treatment of osteoporosis. Teriparatide not only inhibits bone resorption but is also the first drug that can promote new bone formation rather than merely inhibiting the loss of old bone. This significantly improves the management of bone density and the risk of fractures. Subsequently, with the overcoming of PTH's instability, a full-length PTH therapy was developed to control blood calcium levels in patients with hypocalcemia, which was approved in 2015. In addition, a synthetic analog similar to Parathyroid Hormone-Related Protein (PTHrP), abaloparatide, was developed. This drug shares 41% sequence homology with PTH and was approved in 2017 for the treatment of osteoporosis. Somatostatin Somatostatin is an endogenous hormone composed of 14 amino acid residues, which has the ability to inhibit the secretion of a variety of endocrine glands. This includes its inhibitory effects on growth hormone, insulin, gastric acid, and cholecystokinin. Due to its extremely short half-life in the body, it is not suitable for direct clinical treatment. Therefore, researchers have improved it through a series of chemical modification techniques. Firstly, by truncating somatostatin, substituting specific amino acid residues, as well as cyclizing the N- to C-terminus, scientists have successfully enhanced the stability and biological activity of the hormone and its analogs. For instance, employing methods such as d-amino acid substitutions, incorporation of unnatural amino acids, terminal protection at the N or C end, and mimicking disulfide bonds, a series of drugs widely used in clinical practice has been developed, such as octreotide. Octreotide effectively treats conditions like acromegaly, certain types of tumors, and other related diseases, and it has a significantly prolonged duration of action in the body. Additionally, research on somatostatin receptors has revealed that many tumor cells overexpress different subtypes of these receptors. This has not only propelled the development of subtype-selective somatostatin analogs such as lanreotide, vapreotide, and pasireotide but has also given rise to a new therapeutic field of peptide receptor radionuclide therapy (PRRT). By conjugating radioactive isotopes with somatostatin analogs, radiopharmaceuticals are formed that can be used for the diagnosis and treatment of diseases such as neuroendocrine tumors, for instance, In 111 pentetreotide, Ga 68 DOTA-TATE, and others. Insulin Insulin was the first peptide drug used for the treatment of disease, first extracted from the pancreases of animals (cattle and pigs) in 1922 and applied in clinical practice. It successfully transformed the treatment approach for patients with Type 1 diabetes and remains one of the most commercially successful peptide drugs to this day, with market demand maintaining an annual compound growth rate of about 10% due to the rising incidence of obesity. In response to the inherent limitations of insulin, such as its short metabolic half-life, researchers have employed various medicinal chemistry strategies for optimization. These include the introduction of non-natural amino acids, protection and extension at the N-terminus or C-terminus, and mimicking disulfide bond structures to enhance the stability and biological activity of insulin. These improvements not only increased the efficacy and selectivity of insulin analogs but also improved their pharmacokinetic properties. As a result, a range of insulin formulations with better therapeutic effects and more convenient usage have been developed, such as long-acting insulins and their analogs. Moreover, with the development of recombinant DNA technology in the 1980s, insulin production entered a new phase, enabling the efficient and clean manufacturing of larger-scale peptides, overcoming the limitations of early extraction methods. By combining with lipids, large molecular proteins, and polyethylene glycol, the molecular weight of insulin molecules was further increased, effectively addressing the problem of rapid renal clearance. This extended the drug’s circulation time in plasma, thus ensuring that the medication has a more prolonged glucose-lowering effect. Oxytocin and Vasopressin Analogs Oxytocin is an endogenous hormone consisting of nine amino acid residues, first synthesized in its entirety by Vincent du Vigneaud's team in 1954, and is renowned for its critical role in childbirth, lactation, and social behaviors. Oxytocin, due to its short half-life in the body (only a few minutes), has its potential as a therapeutic drug limited. To overcome this limitation, researchers have employed a range of innovative medicinal chemistry approaches for structural modification. These include, but are not limited to: the use of D-amino acids to increase stability; the introduction of non-natural amino acids to alter pharmacological properties; N-terminal or C-terminal protection and extension to slow down degradation; and the exploration of disulfide bond mimetics to enhance conformational and metabolic stability. Through these chemical modification techniques, oxytocin analogs have been developed that possess longer duration of action, higher activity, and selectivity. For example, desmopressin is a modified vasopressin analog that has shown superior effects to natural hormones in the treatment of diabetes insipidus. Moreover, oxytocin analogs are used clinically to induce uterine contractions to facilitate childbirth and play an important role in reducing postpartum hemorrhage, treating certain gynecological disorders, and more. Vasopressin and Lys8-vasopressin were once used to treat central diabetes insipidus, but later were replaced by desmopressin, which has greater proteolytic stability. Desmopressin is one of the first peptide medications capable of being administered orally and via the nasal route, with a half-life of approximately 1.5 to 2.5 hours. Gonadotropin-Releasing Hormone Analogs Gonadotropin-Releasing Hormone (GnRH) analogs are synthetic drugs designed by modifying the naturally occurring GnRH, a hormone that plays a critical role in the regulation of gonadal sex hormone secretion. In the production process of GnRH superagonists, glycine at position 6 is replaced by a different D-amino acid, which enhances the binding affinity to its receptor and imparts resistance to proteolytic enzymes. By substituting the C-terminal glycinamide with ethylamine or a bio-mimetic hydrazide glycine derivative, it not only prevents degradation by carboxypeptidase like the natural amide but also imparts increased hydrophobicity, thus increasing the potency and duration of action of the molecule. Initial attempts at preparing antagonists involved the introduction of D-amino acids at position 6; however, histaminergic skin reactions after subcutaneous injection in rats hindered further clinical development. To avoid the risk of edema, researchers replaced D-arginine with a neutral D-urethane-alkyl-amino acid. In comparison to agonists, antagonists utilize a greater number of non-natural amino acid components, with every residue being modified in at least one antagonist except for positions 4, 7, and 9. Amylin analogs Amylin is an endocrine hormone composed of 37 amino acids that is primarily secreted by pancreatic beta cells. It plays a key role in blood glucose regulation within the body, particularly in suppressing the release of glucagon after meals and slowing down the rate of gastric emptying. Pramlintide, composed of 31 amino acids, is a synthetic analogue of human amylin, which is a peptide hormone co-secreted with insulin from pancreatic β-cells following a meal. Patients with Type 1 diabetes exhibit abnormally low levels of insulin, while those with Type 2 diabetes have levels that are higher than normal. Due to the high propensity for amyloidogenesis in endogenous human amylin, researchers have taken inspiration from the highly homologous but non-amyloidogenic rat amylin, specifically the proline residues known to disrupt secondary structure, and incorporated them into the human amylin sequence, resulting in the development of pramlintide. GLP-1 Peptide GLP-1 (Glucagon-like peptide-1) is an endogenous incretin hormone composed of 31 amino acid residues. It significantly enhances glucose-dependent insulin secretion, and is capable of inhibiting postprandial glucagon release, slowing gastric emptying, and affecting appetite. Thus, it plays a crucial role in the treatment of diabetes. Early research found that intravenous infusion of GLP-1(7–37) has a significant impact on insulin secretion and blood glucose levels in type 2 diabetes patients, which led to substantial efforts to develop it into a therapeutic drug. However, GLP-1(7–37) is rapidly degraded by dipeptidyl peptidase-4 (DPP4) and cleared through the kidneys within 1 to 2 minutes. Although substituting other short side-chain amino acids for alanine at position 2 can protect the molecule from enzymatic degradation, the rapid renal clearance rate still renders it unsuitable for therapeutic use. In the early 1990s, a 39-residue peptide with 53% homology to GLP-1(7–37) was isolated from the venom of the Gila monster and named "exendin-4." Studies found that exendin-4 is a full agonist for the GLP-1 receptor, stable against DPP4 degradation, and has a lower rate of renal clearance in humans (5 to 7 hours). This peptide was later developed into a drug (with the trade name exenatide, administered subcutaneously twice a day) for the treatment of type 2 diabetes. Since then, several other GLP-1 receptor agonists, including liraglutide, albiglutide, dulaglutide, lixisenatide, and semaglutide, as well as a long-acting formulation of exenatide, have subsequently been approved for the treatment of type 2 diabetes or obesity. The text also mentions peptide drug discovery strategies, including venomomics and display technologies. The former utilizes bioinformatics to analyze the genomes and transcriptomes of venomous creatures such as venomous snakes, combined with proteomic data obtained from raw venom samples, to identify a large number of potential therapeutic toxin peptides. The latter involves constructing large-scale peptide libraries and screening for high-affinity ligands against specific targets. For example, the cyclic peptide zilucoplan, derived from Ra Pharmaceuticals' mRNA display platform, has entered phase III clinical trials for the treatment of generalized myasthenia gravis. In terms of medicinal chemistry strategies, researchers are focused on improving the metabolic stability and plasma half-life of peptide drugs by employing techniques such as N-terminal acetylation, N-methylation, the use of D-amino acids or non-natural amino acids, and amide bond analogs (such as thioamides, peptide mimetics, and β-amino acids). Additionally, cyclization from N to C termini and disulfide bond mimetics (specifically thioether bonds) are increasingly being applied in peptide drug design to modify their metabolic stability and bioavailability. Simultaneously, highly stable cyclic structural frameworks such as cyclic thioethers and sunflower trypsin inhibitor analogs can serve as carriers to embed pharmacophores of therapeutic significance into their rings, thereby developing more stable and targeted oral peptide drugs, such as the marketed linaclotide and plecanatide for the treatment of constipation-predominant irritable bowel syndrome. In the Future Outlook section, the author mentions that the trend in development of peptide drugs is expected to accelerate due to the success of biologics in breaking the traditional notion that drugs must be administered orally. The field of peptide therapeutics has matured and is capable of reliable and rapid scale-up production of structurally complex peptides of up to approximately 100 amino acids, as well as conducting effective structure-activity relationship (SAR) studies and lead compound optimization. Emerging peptide drug discovery technologies can efficiently generate potent candidate compounds with high selectivity and activity in a short amount of time. With the integration of novel delivery technologies and innovative chemical strategies, the field of peptide therapeutics is set to continue its robust growth. Lastly, the author notes that, in particular, antimicrobial, antiviral, and anti-aging peptides have considerable potential for growth in the future. In the cosmetics industry, peptides are gaining increasing attention, as evidenced by market-available products like Argireline, a hexapeptide that acts as a botulinum toxin analogue to reduce wrinkles, the pentapeptide Palmitoyl Pentapeptide-4 (Matrixyl) which helps to mitigate wrinkles by stimulating extracellular matrix renewal in fibroblasts, and GHK-Cu, a natural tripeptide with high copper ion affinity that possesses anti-inflammatory properties and promotes the synthesis of collagen and glycosaminoglycans in skin fibroblasts. Overall, the steady approval of peptide drugs over the past 60 years has witnessed the growth of this niche, and with advances in new drug discovery and delivery technologies, peptide therapeutics are expected to continue to hold a unique position in the pharmaceutical market, becoming a strong competitor situated between small molecule drugs and larger biological agents. 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03 Mar 2025

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Progress in the Discovery of New Drugs Targeting GPCR Class for Gastric Cancer

Gastric Cancer (GC), also known simply as GC, is one of the most lethal malignancies worldwide, with over one hundred million new cases reported in 2022, leading to the death of 783,000 individuals. Globally, the incidence and mortality rates of gastric cancer have been on the decline in most regions over the past few decades. This considerable change is largely attributed to economic development and improved practices in food preservation associated with refrigeration technology during food transport and storage. In 2020, it was estimated that there were 1.1 million cases of stomach cancer diagnosed globally, with 720,000 in males and 370,000 in females. Stomach cancer ranks among the top three most common cancers in 19 countries worldwide and is the most common cancer in four countries: Bhutan, Kyrgyzstan, Cape Verde, and Tajikistan. Sixty percent of all stomach cancer cases occur in East Asia, with China alone accounting for 43.9% of cases. The incidence of stomach cancer is higher in males, with 66% of all cases occurring in men. There are significant differences in the incidence rates across different regions; in several African countries, the incidence rate is less than 5 cases per 100,000 person-years in males, whereas in East Asian countries, it exceeds 30 cases per 100,000 person-years. This indicates that factors such as gender, region, and level of economic development have a significant impact on the incidence of stomach cancer. Moreover, in high-incidence areas such as East Asia, especially China, the prevention and control of stomach cancer represent a considerable challenge. In 2020, it was estimated that there were 1.1 million cases of stomach cancer diagnosed globally, with 720,000 in males and 370,000 in females. Stomach cancer ranks among the top three most common cancers in 19 countries worldwide and is the most common cancer in four countries: Bhutan, Kyrgyzstan, Cape Verde, and Tajikistan. Sixty percent of all stomach cancer cases occur in East Asia, with China alone accounting for 43.9% of cases. The incidence of stomach cancer is higher in males, with 66% of all cases occurring in men. There are significant differences in the incidence rates across different regions; in several African countries, the incidence rate is less than 5 cases per 100,000 person-years in males, whereas in East Asian countries, it exceeds 30 cases per 100,000 person-years. This indicates that factors such as gender, region, and level of economic development have a significant impact on the incidence of stomach cancer. Moreover, in high-incidence areas such as East Asia, especially China, the prevention and control of stomach cancer represent a considerable challenge. From: DOI: 10.1016/j.eclinm.2022.101404However, unlike the previously reported continuous decline in the overall incidence rate across all age groups, recent reports indicate an increase in the incidence of gastric cancer among young adults (under the age of 50), particularly a noticeable growth in the incidence of non-cardia tumors among the more affluent population. Gastric cancer can be roughly divided into two major anatomical sub-sites: although the majority of gastric cancers occur in the distal part of the stomach (non-cardia), globally, about 18% of gastric cancers originate in the cardia, which is the region adjacent to the gastroesophageal junction. Both anatomical locations of gastric cancer have overlapping risk factors, such as smoking, heavy alcohol consumption, and consumption of pickled foods; however, they also have their distinct etiologies. Cardia gastric cancer is often associated with gastroesophageal reflux disease and obesity, while approximately 90% of non-cardia gastric cancers can be attributed to Helicobacter pylori (H. pylori) infection. This implies that prevention and treatment strategies for different types of gastric cancer may need to be distinct, especially considering the rising incidence rates in young populations and the etiological differences between cardia and non-cardia gastric cancers. From: DOI: 10.1016/ S0140-6736(16)30354-3Timeline of Significant Discoveries and Key Advances in the Treatment of Gastric Cancer: In recent years, targeted therapies against specific molecular targets have been introduced into clinical practice, such as the anti-HER2 antibody trastuzumab and the anti-VEGFR-2 antibody ramucirumab. Claudin 18.2 is also a significant target for gastric cancer treatment, as the gene is associated with specific molecular subtypes involved in the development and progression of gastric cancer. This gene and its interaction pathways serve as potential targets for the development of new personalized treatment strategies. The G protein-coupled receptor (GPCR) signaling pathway is one of those pathways. Abnormal activation of GPCRs and G proteins can promote the progression of gastric cancer. Activated GPCRs/G proteins may serve as effective biomarkers for early diagnosis, prognostic prediction, and clinical therapeutic targets. This indicates that through the detection and intervention of these receptors and their aberrant activation states, it is possible to achieve early detection, accurate prognostic assessment, and targeted treatment of gastric cancer, thereby improving patient survival rates and quality of life. GPCR and Gastric CancerAs early as 1986, a study by Young et al. was the first to link G protein-coupled receptors (GPCRs) with tumorigenic activity. They demonstrated through experiments that the Mas proto-oncogene could confer tumorigenicity to NIH 3T3 cells in vivo in nude mice. Mas encodes a typical GPCR and, unlike most oncogenes, does not carry activating oncogenic mutations. Instead, tumorigenicity is caused by its overexpression and the abundance of ligands in the circulation system or locally produced ligands. There is now a substantial body of evidence suggesting that various wild-type GPCRs, acting under the influence of excessive circulating agonists or agonists produced within the tumor microenvironment, can induce oncogenic transformation and drive tumor progression. Specific neuropeptides, particularly neurotransmitters and intestinal hormones, play an autocrine and paracrine role in various cancers. These neuropeptides include Gastrin-Releasing Peptide (GRP), Endothelin, Bradykinin, Neuromedin B, Neuropeptide Y, Gastrin, Cholecystokinin, Arginine Vasopressin, and Angiotensin II, among others. Each, upon binding to their respective GPCRs, triggers sustained activation, thereby stimulating proliferation in a variety of cell types and playing a crucial role in many malignant human cancers, such as small cell lung carcinoma, pancreatic cancer, head and neck squamous cell carcinoma, prostate cancer, and gastric cancer. From: DOI: 10.3390/cancers15030736Progress in the development of new drugs for gastric cancer targeting GPCR-class receptorsAccording to statistics from the Synapse database, there are currently nearly 1000 research and development pipelines for gastric cancer globally, of which 38 are GPCR (G protein-coupled receptor) type target pipelines. Popular pipeline targets include SSTR, EP2R, EP4R, CCR8, CCKR, SMO, NTSR1, A2bR, CCR7, among others. The leading indications related to gastric cancer include gastric cancer, gastro-enteropancreatic neuroendocrine tumors, gastroesophageal junction tumors, and Her2-negative gastric cancer, among others. The principal types of therapeutic agents include radiopharmaceuticals, peptide conjugates, radionuclide-conjugated drugs, synthetic peptides, monoclonal antibodies, and fusion proteins. In the field of clinical research, the major regions for clinical studies on gastric medications are the United States, China, Japan, Europe, Australia, and others. Several drugs are currently in the late stages of clinical trials (Phase 2, Phase 2/3, Phase 3, etc.). Representative investigational drugs include: Representative Pipeline: (177Lu) Lutetium-DOTATATE and SSTRs ReceptorLutetium-177 Dotatate (LU-177 Lutetium Dotatate, also known as Lutathera) is a radiopharmaceutical developed by Advanced Accelerator Applications. It is primarily used for the treatment of gastroenteropancreatic neuroendocrine tumors (GEP-NETs). This medicinal product is formed by the conjugation of the somatostatin analogue Dotatate with the radioactive isotope Lutetium-177. Dotatate is a compound that can specifically bind to somatostatin receptors (SSTRs) that are overexpressed on neuroendocrine tumor cells. Lutetium-177 is a beta-emitting radioisotope. When combined with Dotatate, the resultant Lutetium-177 Dotatate can accurately target and accumulate within tumor cells that express high levels of somatostatin receptors. The radioactive decay of Lutetium-177 releases beta radiation, which destroys the cancer cells, thereby achieving a localized radiation therapy effect. Somatostatin is a peptide hormone composed of 14 amino acid residues and features a single disulfide bond. This hormone is capable of inhibiting the secretion of growth hormone, insulin, glucagon, gastrin, cholecystokinin, and thyrotropin, but due to its extremely short half-life in the body (less than 3 minutes), its value in therapy is limited. Research has identified the β-turn pharmacophore of somatostatin, which has become the lead sequence for the development of analogs with greater biological stability and potency. Based on this, octreotide was developed and approved for the treatment of acromegaly, adenomas, and pancreatic, breast, and prostate tumors. Subsequent research has spurred the development of selective receptor antagonists, such as lanreotide, vapreotide, and pasireotide, and has introduced the fields of peptide imaging and peptide receptor radionuclide therapy. In these radionuclide therapies, radioactive elements such as ^111In, ^90Y, ^68Ga, or ^99mTc are linked to selective somatostatin analogs through chelating groups, leading to approved radiopharmaceutical formulations. These drugs can be used for tumor detection. In 2001, a preclinical animal model study on Lutetium Dotatate LU-177 was published in the International Journal of Cancer. It reported on the investigation of the biologic distribution of the drug in a rat model of pancreatic tumors, and these data were used to estimate the absorbed doses in normal human tissue. A 2004 study on the treatment effectiveness in patients with metastatic gastroenteropancreatic tumors positive for the somatostatin receptor revealed that, out of 50 patients treated with Lutetium Dotatate LU-177, disease stabilization was achieved in 24 patients, 19 patients experienced stable disease, the condition of 6 patients progressed, and 1 patient's disease status could not be assessed. The therapy significantly improved their overall health condition, quality of life, and scores for various functions and symptoms. In 2005, a clinical study on the use of Lutetium Dotatate LU-177 in 131 patients with metastatic or inoperable somatostatin receptor-positive gastroenteropancreatic neuroendocrine tumors was announced. After treatment with a maximum cumulative dose of 600 to 800 mCi of Lutetium Dotatate LU-177, 3 patients (2%) achieved complete remission, 32 patients (26%) had partial remission, 24 patients (19%) showed a minor response (tumor size reduction of 25% to 50%), 44 patients (35%) had stable disease, whereas 22 patients (18%) experienced disease progression. A high remission rate correlated positively with high uptake shown on pre-treatment somatostatin receptor imaging and fewer liver metastases. In contrast, patients with lower performance scores and extensive disease distribution had a significantly higher frequency of disease progression. Severe side effects were very rare, and the median time to disease progression was comparable to that with chemotherapy, with better effectiveness in patients with a limited tumor burden. An expanded clinical study published in 2008 further validated the safety and efficacy of Lutetium Dotatate LU-177. In a study involving 310 patients with gastroenteropancreatic neuroendocrine tumors, complete and partial tumor response rates were observed at 2% and 28%, respectively, with minor response rates (tumor size reduction of over 25% but less than 50%) at 16%. Compared with historical controls, this treatment method provided a survival benefit of 40 to 72 months from the point of diagnosis. From: DOI: 10.1200/JCO.2007.15.2553In 2017, results from a Phase 3 clinical study published in The New England Journal of Medicine indicated that, in a randomized, controlled trial involving 210 patients with gastroenteropancreatic neuroendocrine tumors, the experimental group (116 patients) receiving intravenous injections of 7.4 GBq dose of Lutetium Lu 177 Dotatate every 8 weeks for a total of four times, along with a concurrent intramuscular injection of 30 mg of long-acting octreotide every 4 weeks, had a significantly higher estimated progression-free survival rate at 20 months (65.2%) compared to the control group (10.8%), which consisted of 113 patients treated only with intramuscular injections of 60 mg of long-acting octreotide every 4 weeks. Additionally, the response rate for the Lutetium Lu 177 Dotatate group was 18%, markedly higher than the 3% observed in the control group. From: DOI: 10.1056/NEJMoa1607427Based on this, at the end of 2017, the U.S. FDA approved Lutetium Dotatate LU-177 for the treatment of patients with somatostatin receptor-positive gastroenteropancreatic neuroendocrine tumors. Due to its targeted nature and relatively low systemic toxicity, this therapy has received widespread attention and application in the field of precision medicine. In October 2017, Novartis acquired the French innovative pharmaceutical company Advanced Accelerator Applications for $3.9 billion to build and expand its radioligand therapy platform. In 2018, Novartis invested an additional $2.1 billion to acquire the biopharmaceutical company Endocyte, securing several more radiopharmaceutical candidates. Through these acquisitions, Novartis has established and extended its radioligand therapy platform, comprising multiple marketed products: Lutathera (177Lu-DOTATATE) and 68Ga-Edotreotide, as well as several products in development: 177Lu-PSMA-617, 177Lu-PSMA-R2, 177Lu-NeoB, 177Lu-FF58, 225Ac-PSMA-617, etc. Furthermore, Lanreotide Acetate is a non-selective somatostatin receptor (SSTRs) antagonist that was first approved for marketing in 2002 for the treatment of acromegaly. Its investigational indications include gastroenteropancreatic neuroendocrine tumors. 68Ga-Edotreotide is a non-selective SSTRs antagonist product developed by Advanced Accelerator Applications. It is a radioactive diagnostic agent used in PET scans to detect somatostatin receptor-positive neuroendocrine tumors in both adult and pediatric patients. Other related R&D pipelinesMisoprostol is a medication primarily used to reduce the risk of stomach ulcers in users of non-steroidal anti-inflammatory drugs (NSAIDs). Its mechanism of action involves stimulating prostaglandin receptors in the stomach, enhancing gastric protection against acidic substances, and reducing gastric acid secretion, thereby protecting the gastric mucosa from damage. Additionally, Misoprostol is used for various medical applications: in the field of gynecology, it can be used to manage early miscarriage, prevent postpartum hemorrhage, and perform abortion surgery during early pregnancy. When Misoprostol acts on prostaglandin receptors in the uterus and cervix, it increases the strength and frequency of uterine contractions and decreases cervical tension, thus playing a key role in the management of miscarriage. ONO-4578, developed by Ono Pharmaceutical, is a highly selective antagonist of the EP4 receptor and is currently being studied for its safety and efficacy as monotherapy and in combination with nivolumab in patients with advanced or metastatic solid tumors, including gastric cancer. Based on the results of a Phase 1 clinical study, ONO-4578 has demonstrated good tolerability and certain antitumor activity. YY-001 and HTL-0039732 are selective EP4 receptor antagonists developed by Shanghai Yu Yao and Sosei Group, respectively, and are currently involved in clinical studies for various solid tumors, including gastric cancer. BMS-986340 is an IgG1 subtype monoclonal antibody product targeting CCR8, originally researched and developed by BMS. This drug possesses enhanced non-fucosylated (NF) Fc region features. As the CCR8 receptor is a chemokine receptor expressed on the surface of regulatory T cells (Tregs) and participates in the regulation of the immune system, BMS-986340 has been engineered to specifically bind CCR8. Due to its non-fucosylated Fc segment, it enhances effector functions against target cells. This optimization enables BMS-986340 to effectively deplete regulatory T cells (Tregs), which may modulate the immune response for treating diseases associated with excessive immunosuppression or dysfunctional Tregs. Currently, clinical trials for various solid tumors, including gastric cancer, are underway involving BMS-986340. FPI-2059 is a small molecule radiopharmaceutical that targets the Neurotensin Receptor 1 (NTSR1). This receptor is overexpressed in a variety of solid tumors, including pancreatic ductal adenocarcinoma, colorectal cancer, head and neck squamous cell carcinoma, gastric cancer, Ewing sarcoma, and neuroendocrine-differentiated prostate cancer. FPI-2059 is developed based on compounds previously known as IPN-1087 and 3BP-227. These compounds have been studied as beta-emitting radiopharmaceuticals in researcher-initiated studies and phase I clinical trials. In 2021, Fusion Pharmaceuticals acquired this asset and transformed it into an alpha-emitting radiopharmaceutical, labeled with Actinium-225. Concurrently, FPI-2058 is a diagnostic analog of FPI-2059, replacing Actinium-225 with Indium-111 as the radioactive isotope for medical imaging and diagnostic purposes. This targeted radiopharmaceutical design aims to achieve precise targeted therapy and diagnosis for the aforementioned types of tumors. TT-4 is a selective A2B receptor antagonist developed by Tarus Therapeutics that is currently in phase 1/2 clinical development. The trial aims to evaluate its therapeutic effect in patients with various advanced solid tumors, including gastric cancer. 177Lu-PP-F11N is a radioactive drug complex that combines PP-F11N (a gastrin analog) with the beta-emitting radioactive isotope Lutetium-177. This drug exhibits potential antitumor activity and may be used as an agent for single-photon emission computerized tomography (SPECT) imaging. After intravenous injection, PP-F11N specifically binds to the Cholecystokinin-2 Receptor (CCK2R). This allows visualization of the tumor cells expressing the CCK-2 receptor using nuclear medicine imaging techniques. Additionally, the Lutetium-177 radioactive isotope delivers cytotoxic doses of beta-radiation to the tumor cells expressing the CCK-2 receptor, providing targeted destruction of these cells. As the CCK-2 receptor is widely expressed in various types of tumor cells, 177Lu-PP-F11N has the potential for the treatment of these specific types of tumors and offers targeted imaging for personalized, precise cancer diagnosis and therapy. The content above comes from the network. if any infringement, please contact us to modify.

08 Nov 2024

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RECORDATI: CONTINUED DOUBLE-DIGIT GROWTH IN THE FIRST NINE MONTHS OF 2024 - REVENUE +12.0%, EBITDA(1) +11.8%, ADJUSTED NET INCOME(2) +9.5%

Consolidated net revenue of € 1,743.1 million in the first nine months, +12.0% or +9.3% on a like-for-like basis(3) and at constant exchange rates (CER)EBITDA(1) of € 665.7 million, +11.8%, revenue margin of 38.2% Adjusted net income(2) of € 445.4 million, +9.5% Net income of € 338.4 million, +11.1% Free cash flow(4) at € 434.3 million, +€ 42.5 million vs prior yearNet debt(5) at € 1,317.3 million, just below 1.6x EBITDAFinancial targets for FY 2024 confirmed, excluding any potential contribution from Enjaymo® Global Rare Diseases business to be further strengthened by announced agreement with Sanofi to acquire the global rights to Enjaymo®; deal expected to close by end of 2024, subject to regulatory approvals Isturisa®approved in China for the treatment of adult patients with Cushing syndromeResolution to distribute an interim 2024 dividend of € 0.60 per shareApproval of a new share buy-back program to service the stock option and performance shares plans Milan, November 8th, 2024 – The Board of Directors of Recordati S.p.A. approved the Group’s Interim Report on 30th September 2024, representing additional voluntary financial reporting (6). The Report was prepared using the assessment, measurement and recognition criteria prescribed by international accounting standards (IFRS). The Group’s Interim Report dated 30th September 2024 will be available on 11th November at the company’s offices and on the company’s website (www.recordati.com) and can also be viewed on the authorized storage system 1Info (www.1Info.it). Rob Koremans, Chief Executive Officer of Recordati, commented: “During the first nine months, we delivered double-digit revenue and profit growth, reflecting the strong performance across the business with more patients benefiting from our therapies. These results reflect the continued commitment of all our people, who are instrumental to our success. With a positive outlook for the remainder of the year, we are well positioned to achieve our upgraded financial objectives for FY 2024. Together, we will continue to build on our momentum and create lasting value for our stakeholders. “I am also pleased to highlight our recent agreement with Sanofi to acquire the global rights to Enjaymo®, the only approved treatment option for patients with cold agglutinin disease. This transaction will reinforce our strong commitment to serving patients with rare diseases and is a strong strategic fit to our portfolio, bringing a product with a robust profile, supported by a strong team, with attractive financial contributions expected on both the top and bottom lines.” Financial highlights Consolidated net revenue for the first nine months of 2024 was € 1,743.1 million, up 12.0% versus the first nine months of 2023 or 9.3% on a like-for-like(3) basis at CER. This was driven by strong business momentum across both Specialty & Primary Care and Rare Diseases. The adverse FX impact for the first nine months of 2024 was € 35.9 million (-2.3%), mainly driven by the devaluation of the Turkish lira, particularly in the first and third quarters, which was compensated by high price inflation in Türkiye. Specialty & Primary Care revenue totaled € 1,094.4 million in the first nine months of 2024, growing 11.1% or 6.5% on a like-for-like(3) basis at CER (+2.6% excluding Türkiye). This reflects a particularly strong performance from the Urology franchise with 51.4% growth versus the previous year, driven by the double-digit growth of Eligard® and the € 82.9 million contribution of Avodart® and Combodart®/Duodart®(7) (versus € 3.8 million in the third quarter of 2023). The Cardiovascular and Gastrointestinal franchises remained resilient and delivered slight growth, while the Cough and Cold business reflected solid in-market performance in the context of a softer flu season as compared to the previous year.Rare Diseases revenue totaled € 605.6 million in the first nine months of 2024, up 14.1% as compared to the first nine months of 2023, or 14.5% at CER, driven by the key growth franchises of Oncology and Endocrinology which continue to show substantial further growth potential. The Endocrinology franchise achieved net revenue of € 239.4 million, an increase of 36.0% and reflecting the continued strong performance of Isturisa® and double-digit growth of Signifor®. The Oncology franchise achieved net revenue of € 175.9 million, an increase of 17.1%, driven by double-digit growth from both Qarziba® and Sylvant®. The Metabolic franchise achieved net revenue of € 190.2 million, a decrease of 6.9%, mainly due to generic competition for Carbaglu® in the US and EMEA, with growth in other international markets. Adjusted operating income(8) was € 539.5 million for the first nine months of 2024, up 9.7% over the previous year, and 31.0% of net revenue versus 31.6% in the same period last year. Operating income was € 504.1 million in the first nine months of 2024, up 14.9% over the first nine months of 2023, absorbing gross margin-related non-cash charges of € 28.1 million (versus € 47.2 million in first nine months of 2023), arising from the unwind of the fair value step up of the acquired rare oncology inventory. Non-recurring costs were € 7.3 million in the first nine months of 2024, versus € 5.4 million in the first nine months of 2023, which includes € 2.5 million related to the agreement with Sanofi for the global rights to Enjaymo®.EBITDA(1) was € 665.7 million for the first nine months of 2024, up 11.8% compared to the first nine months of 2023, with margin of 38.2% of net revenue, in line with the previous year. Strong revenue and operating leverage were, in part, offset by a reduction in adjusted gross profit margin due to the consolidation of Avodart® and Combodart®/ Duodart® and product mix.Financial expenses were € 62.3 million, up by € 13.3 million compared to the previous year, including € 2.8 million in FX losses (mostly unrealized, compared to losses of € 0.3 million in the first nine months of 2023) and € 3.9 million of net monetary losses from hyperinflation accounting (compared to a gain of € 1.8 million in the first nine months of 2023). Adjusted net income(2) was € 445.4 million, 25.6% of revenue, up by 9.5% compared to the same period of 2023, with higher adjusted operating income partially offset by an increase in financial expenses and a higher tax rate, following a statutory tax rate increase in some countries. Net income was € 338.4 million, 19.4% of revenue, an increase of 11.1% versus first nine months of 2023, with the higher tax rate and financing expenses offsetting the higher operating income. Free cash flow(4) was € 434.3 million for the first nine months of 2024, an increase of € 42.5 million versus the the first nine months of 2023, driven by higher EBITDA which was slightly offset by higher interests and income taxes paid. Net debt(5) as of 30th September 2024 was € 1,317.3 million, or leverage of just below 1.6x EBITDA(6), compared to net debt of € 1,579.4 million on 31st December 2023. Shareholders’ equity was € 1,876.1 million. Pipeline and Corporate Development The Isturisa® new drug application (NDA) was approved by the China National Medical Products Administration (NMPA) in September for the treatment of adult patients with Cushing syndrome. On October 4th, the Group announced an agreement with Sanofi to acquire the global rights to Enjaymo®, a biologic which is the only approved targeted product for the treatment of cold agglutinin disease (CAD), a rare B-cell lymphoproliferative disorder. In 2022, Enjaymo® was granted approval by the U.S. Food and Drug Administration (FDA), the European Commission (EC) and the Japanese Ministry of Health, Labor and Welfare. Enjaymo® generated approximately € 100 million in revenue over the last 12 months as of August 2024 and is expected to generate revenue in excess of € 150 million in FY 2025, with peak sales potential of € 250-300 million. The transaction is expected to be immediately accretive at the EBITDA level, with margin above the current Rare Diseases average as of 2025. Under the terms of the agreement, Recordati will make an upfront payment of US$ 825 million and additional commercial milestone payments of up to US$ 250 million if net sales reach certain thresholds at or above the top end of peak year sales expectations. The transaction is expected to close by the end of 2024, subject to regulatory clearances (see also press release issued on October 4th 2024). The deal will be funded by existing cash and new committed bank debt facilities. Business outlook Thanks to continued strong momentum, the Group is on track to deliver the targets for FY 2024 as adjusted upward on July 30th (excluding any potential contribution from Enjaymo®): Net revenue between € 2,300 and € 2,340 millionEBITDA(1) between € 845 and € 865 million; margin of +/- 37%Adjusted net income(2) between € 560 and € 580 million; margin of +/- 24.5%Minimal contribution expected from Enjaymo®, subject to timing of regulatory approvals Additional resolutions Interim dividend 2024 The Board of Directors passed a resolution to distribute an interim 2024 dividend to shareholders of € 0.60 (gross of tax withholdings) per share outstanding at the ex-dividend date, thus excluding treasury stock held in the Company’s portfolio on that date. The 2024 interim dividend will be payable as of 20th November 2024 (record date 19th November 2024), with coupon no. 34, to shareholders registered on 18th November 2024. The Independent Auditor EY S.p.A. has issued the opinion required by Art. 2433 – bis, paragraph 5 of the Italian Civil Code, which is available at the company’s offices. The Directors’ Report and Recordati S.p.A. financial statements as of 30th June 2024, based on which the latter’s Board of Directors resolved the distribution of the interim dividend, are available at the company’s office and website (www.recordati.com), and can also be viewed on the authorized storage system 1Info (www.1Info.it). Limited assurance on sustainability reporting In compliance with the Italian Legislative Decree No. 125/2024 – transposing in Italy the EU Directive No. 2022/2464 on Corporate Sustainability Reporting (so called “CSRD”) – the Board of Directors, upon proposal of the Board of Statutory Auditors, has resolved to integrate – starting from this financial year 2024 - the mandate for activities regarding the limited assurance attestation on sustainability reporting, set forth by the aforementioned decree, to Ernst & Young S.p.A., by extending to such activities the current engagement granted by the Shareholders Meeting held on 29th April 2020 with respect to the attestation of the non-financial disclosure. Appointment of the new Financial Reporting Officer pursuant to art.154-bis of TUF The Board of Directors has appointed, until revocation and upon favourable opinion of the Board of Statutory Auditors Niccolo Giovannini - VP Group Finance, reporting to Luigi La Corte, Group Chief Financial Officer - as Financial Reporting Officer pursuant to art.154-bis of TUF and art.25 of the Articles of Association. The appointment is effective as of today, following the approval of Group’s Interim Report on 30th September 2024. Approval of a new share buy-back program to service the stock option and performance shares plans Today, the Board of Directors has also approved the launch of a new share buy-back program under art. 5 of (EU) Regulation no. 596/2014 for a maximum of 1,500,000 ordinary shares with a maximum cash outlay of € 90,000,000. This implements the resolution adopted by the Shareholders’ meeting held on 22nd April 2024 to purchase Recordati ordinary shares in order to service current and future stock option/performance shares plans in favour of the Recordati Group’s management or share-based incentive plans that might be approved by the Company in the future. All details required by the applicable regulations on the launch of the share buy-back program - whose start is envisaged on 12th November 2024 until 15th April 2025, following the end of the current buyback programme envisaged by 11th November 2024 as announced on 9th May 2024 - will be included in a specific press release that will be issued according to law and to which reference is made. (1) Net income before income taxes, financial income and expenses, depreciation, amortization and write-downs of property, plant and equipment, intangible assets and goodwill, non-recurring items and non-cash charges arising from the allocation of the purchase price of EUSA Pharma to the gross margin of acquired inventory according to IFRS 3. (2) Net income excluding the amortization and write-down of intangible assets (except software) and goodwill, non-recurring items, non-cash charges arising from the allocation of the purchase price of EUSA Pharma to the gross margin of acquired inventory pursuant to IFRS 3, and monetary net gains/losses from hyperinflation (IAS 29), net of tax effects. (3) Pro-forma growth calculated excluding revenue of Avodart® and Combodart®/ Duodart® for both 2024 and 2023.(4) Total cash flow excluding financing items, milestones, dividends, purchases of treasury shares net of proceeds from exercise of stock options.(5) Cash and cash equivalents, less bank debts and loans, which include the measurement at fair value of hedging derivatives. (6) Please note that Italian Legislative Decree 25/2016, which implements Directive 2013/50/EU, no longer stipulates the submission of an interim management report, which was previously required in terms of paragraph 5 of Art. 154- ter of Italian Legislative Decree 58/1998.(7) Trademarks are owned by or licensed to the GSK group of companies. Transition of commercialization effectively concluded.(8) Net income before income taxes, financial income and expenses and non-recurring items, non-cash charges arising from the allocation of the purchase price of EUSA Pharma to the gross margin of acquired inventory according to IFRS 3. Conference Call Recordati will host a conference call today, November 8th at 4:00 p.m. CET (3:00 p.m. GMT) to present the results for the first nine months of 2024. The dial-in numbers for the conference call service are: Italy + 39 02 802 09 11, toll free 800 231 525UK + 44 1 212818004, toll free (44) 0 800 0156371USA +1 718 7058796, toll free (1) 1 855 2656958France +33 1 70918704Germany +49 6917415712 Participants are invited to dial in 10 minutes before conference time. If conference operator assistance is required to connect, please dial *0. The slides that will be referenced during the call will be available at www.recordati.com under Investors/Company Presentations. The audio conference live webcast will also be available at the following link Recordati is an international pharmaceutical group listed on the Italian Stock Exchange (XMIL: REC), with roots dating back to a family-run pharmacy in Northern Italy in the 1920s. We are uniquely structured to provide treatments across specialty and primary care, and rare diseases. Our fully integrated operations span clinical development, chemical and finished product manufacturing, commercialization and licensing. We operate in approximately 150 countries across EMEA, the Americas and APAC with over 4,450 employees. We believe that health is a fundamental right, not a privilege. Today, our purpose of “unlocking the full potential of life” aims at empowering individuals to live life to the fullest, whether addressing common health challenges or the rarest. Investor Relations Eugenia Litz +44 7824 394 750 investorelations@recordati.itGianluca Saletta +39 348 979 4876 investorelations@recordati.itMedia Relations ICR Healthcare US:Alexis Feinberg +1 203 939 2225 recordatiuspr@westwicke.com UK, Europe & Rest of World:Jessica Hodgson +44 7561 424 788recordati@consilium-comms.com This document contains forward-looking statements relating to future events and future operating, economic and financial results of the Recordati group. By their nature, forward-looking statements involve risk and uncertainty because they depend on the occurrence of future events and circumstances. Actual results may therefore differ materially from those forecast for a variety of reasons, most of which are beyond the Recordati group’s control. The information on the pharmaceutical specialties and other products of the Recordati group contained in this document is intended solely as information on the activities of the Recordati Group, and, as such, it is not intended as a medical scientific indication or recommendation, or as advertising. RECORDATI GROUP Summary of the consolidated results,prepared in accordance with International Financial Reporting Standards (IFRS)(€ thousands) INCOME STATEMENTFirst nine months 2024First nine months 2023Change %NET REVENUE1,743,0811,556,17412.0Cost of sales(556,171)(490,495)13.4GROSS PROFIT1,186,9101,065,67911.4Selling expenses(360,709)(345,506)4.4Research and development expenses(204,849)(182,239)12.4General and administrative expenses(110,014)(93,630)17.5Other income/(expenses), net(7,240)(5,553)30.4OPERATING INCOME504,098438,75114.9Financial income/(expenses), net(62,319)(49,054)27.0PRE-TAX INCOME441,779389,69713.4Income taxes(103,379)(85,205)21.3NET INCOME 338,400304,49211.1Adjusted gross profit (1)1,214,9861,113,1679.1Adjusted operating income (2)539,518491,6089.7Adjusted net income (3)445,361406,5669.5EBITDA (4)665,666595,57311.8Net income attributable to: Equity holders of the Parent338,400304,49211.1Non-controlling interests00n.s.EARNINGS PER SHARE (euro) Basic(5)1.6401.48110.7Diluted(6)1.6181.45611.1(1) Gross profit adjusted from impact of non-cash charges arising from the allocation of the purchase price of EUSA Pharma to the gross margin of acquired inventory according to IFRS 3. (2) Net income before income taxes, financial income and expenses, non-recurring items and non-cash charges arising from the allocation of the purchase price of EUSA Pharma to the gross margin of acquired inventory according to IFRS 3.(3) Net income excluding amortization and write-downs of intangible assets (except software) and goodwill, non-recurring items, non-cash charges arising from the allocation of the purchase price of EUSA Pharma to the gross margin of acquired inventory (IFRS 3) and monetary net gains/losses from hyperinflation (IAS 29), net of tax effects.(4) Net income before income taxes, financial income and expenses, depreciation, amortization and write-downs of property, plant and equipment, intangible assets and goodwill, non-recurring items and non-cash charges arising from the allocation of the purchase price of EUSA Pharma to the gross margin of acquired inventory according to IFRS 3.(5) Earnings per share (EPS) are based on average shares outstanding during the respective period, 206.299.160 in 2024 and 205.421.410 in 2023. These amounts are calculated deducting treasury shares in the portfolio, the average of which was 2.825.996 shares in 2024 and 3.703.746 shares in 2023.(6) Diluted earnings per share is calculated by taking into account rights granted to employees.COMPOSITION OF NET REVENUEFirst nine months 2024First nine months 2023Change % Total revenue1,743,0811,556,17412.0 Italy258,631234,30410.4 International1,484,4501,321,87012.3 RECORDATI GROUP(€ thousands) Reconciliation of Net income to EBITDA(1) First nine months 2024First nine months 2023Net income338,400304,492Income taxes103,37985,205Financial income/(expenses), net62,31949,054Non-recurring expenses7,3445,369Non-cash charges from PPA inventory uplift28,07647,488Adjusted operating income(2)539,518491,608Depreciation, amortization and write-downs126,148103,965EBITDA(1)665,666595,573 Reconciliation of Net income to Adjusted Net income(3) First nine months 2024First nine months 2023Net income338,400304,492Amortization and write-downs of intangible assets(excluding software)100,15781,180Tax effect(22,619)(17,405)Non-recurring operating expenses7,3445,369Tax effect(1,943)(1,340)Non-cash charges from PPA inventory uplift28,07647,488Tax effect(7,019)(11,881)Monetary net (gain)/losses from hyperinflation (IAS29)3,900(1,759)Tax effect(935)422Adjusted net income(3)445,361406,566 (1) Net income before income taxes, financial income and expenses, depreciation, amortization and write-downs of property, plant and equipment, intangible assets and goodwill, non-recurring items and non-cash charges arising from the allocation of the purchase price of EUSA Pharma to the gross margin of acquired inventory (IFRS 3).(2) Net income before income taxes, financial income and expenses, non-recurring items and non-cash charges arising from the allocation of the purchase price of EUSA Pharma to the gross margin of acquired inventory (IFRS 3).(3) Net income excluding amortization and write-downs of intangible assets (except software) and goodwill, non-recurring items, non-cash charges arising from the allocation of the purchase price of EUSA Pharma to the gross margin of acquired inventory (IFRS 3) and monetary net gains/losses from hyperinflation (IAS 29), net of tax effects. RECORDATI GROUPSummary of the consolidated results, prepared in accordance with International Financial Reporting Standards (IFRS)(€ thousands) ASSETS30.09.202431.12.2023Property, plant and equipment187,848178,657Intangible assets1,847,7041,938,197Goodwill789,123778,350Other equity investments and securities16,86521,555Other non-current assets13,87112,458Deferred tax assets92,56776,674TOTAL NON-CURRRENT ASSETS2,947,9783,005,891 Inventories410,107404,831Trade receivables474,514445,193Other receivables102,46699,401Other current assets26,78219,924Derivative instruments measured at fair value6,71011,079Cash and cash equivalents235,020221,812TOTAL CURRENT ASSETS1,255,5991,202,240TOTAL ASSETS4,203,5774,208,131 RECORDATI GROUPSummary of the consolidated results, prepared in accordance with International Financial Reporting Standards (IFRS)(€ thousands) EQUITY AND LIABILITIES30.09.202431.12.2023 Share capital26,14126,141Share premium reserve83,71983,719Treasury shares(139,881)(127,970)Reserve for derivative instruments(2,180)(286)Translation reserve(301,627)(264,700)Other reserves61,53761,219Profits carried forward1,809,9971,636,451Net income338,400389,214Interim dividend0(117,396)Shareholders’ equity attributable to equity holders of the Parent1,876,1061,686,392Shareholders’ equity attributable to non-controlling interests00TOTAL SHAREHOLDERS’ EQUITY1,876,1061,686,392 Loans - due after one year1,264,8841,353,216Provisions for employee benefits21,40521,239Deferred tax liabilities134,488144,208TOTAL NON-CURRENT LIABILITIES1,420,7771,518,663 Trade payables276,907263,979Other payables198,213174,407Tax liabilities100,73867,110Other current liabilities4,6165,307Provisions for risks and charges19,24116,596Derivative instruments measured at fair value14,21219,993Loans - due within one year270,337355,752Short-term debts to banks and other lenders22,43099,932TOTAL CURRENT LIABILITIES906,6941,003,076TOTAL SHAREHOLDERS’ EQUITY AND LIABILITIES4,203,5774,208,131 RECORDATI GROUPSummary of consolidated results prepared in accordance with International Financial Reporting Standards (IFRS) (€ thousands) CASH FLOW STATEMENTFirst nine months 2024First nine months 2023OPERATING ACTIVITIES Net income338,400304,492Income taxes103,37985,206Net interest54,41848,158Depreciation of property, plant and equipment24,00321,577Amortization of intangible assets97,59182,304Write-downs4,55484Equity-settled share-based payment transactions10,1207,515Other non-monetary components41,06955,772Change in other assets and other liabilities(11,985)(20,538)Cash flow generated/(used) by operating activities before change in working capital661,549584,570Change in: - inventories(41,813)(31,681)- trade receivables(36,418)(73,753)- trade payables14,22330,082Change in working capital(64,008)(75,352)Interest received4,0073,923Interest paid(64,284)(50,314)Income taxes paid(82,634)(53,282)Cash flow generated/(used) by operating activities454,630409,545INVESTMENT ACTIVITIES Investments in property, plant and equipment(21,743)(17,998)Disposals of property, plant and equipment1,385329Investments in intangible assets(15,377)(345,597)Disposals of intangible assets2,351287Sale of non-current assets held for sale2,0003,000Cash flow generated/(used) by investment activities(31,384)(359,979)FINANCING ACTIVITIES Opening of loans144,872348,256Repayment of loans(320,185)(214,701)Payment of lease liabilities(8,311)(8,116)Change in short-term debts to banks and other lenders(71,722)(45,008)Dividends paid(130,220)(129,071)Purchase of treasury shares(78,087)(6,483)Sale of treasury shares52,74419,681Cash flow generated/(used) by financing activities(410,909)(35,442)Change in cash and cash equivalents12,33714,124Opening cash and cash equivalents221,812284,734Currency translation effect8713,422Closing cash and cash equivalents235,020302,280 DECLARATION BY THE FINANCIAL REPORTING OFFICERThe Financial Reporting Officer, Luigi La Corte, declares, pursuant to paragraph 2 of Article 154-bis of the Consolidated Law on Finance, that the accounting information contained in this press release corresponds to the Company’s documentation, books and accounting records.

Executive ChangeFinancial StatementDrug ApprovalAcquisition

100 Deals associated with Pasireotide Diaspartate

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KEGG	Wiki	ATC	Drug Bank
D10497	Pasireotide Diaspartate	H01CB05	DB06663

R&D Status

Approved

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Indication	Country/Location	Organization	Date
Growth Hormone Excess	JP	Recordati Rare Diseases, Inc.	28 Sep 2016
Cushing Syndrome	CN	Novartis Europharm Ltd.	27 May 2015
HIV Infections	AU	Recordati Rare Diseases	01 Nov 2013
Acromegaly	EU	Recordati Rare Diseases, Inc.	24 Apr 2012
Acromegaly	IS	Recordati Rare Diseases, Inc.	24 Apr 2012
Acromegaly	LI	Recordati Rare Diseases, Inc.	24 Apr 2012
Acromegaly	NO	Recordati Rare Diseases, Inc.	24 Apr 2012
Pituitary ACTH Hypersecretion	EU	Recordati Rare Diseases, Inc.	24 Apr 2012
Pituitary ACTH Hypersecretion	IS	Recordati Rare Diseases, Inc.	24 Apr 2012
Pituitary ACTH Hypersecretion	LI	Recordati Rare Diseases, Inc.	24 Apr 2012
Pituitary ACTH Hypersecretion	NO	Recordati Rare Diseases, Inc.	24 Apr 2012

Developing

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Indication	Highest Phase	Country/Location	Organization	Date
Gastro-Enteropancreatic Neuroendocrine Tumor	Phase 3	-	Novartis Pharmaceuticals Corp.	06 May 2025
Pancreatic Cancer	Phase 3	US	Novartis Pharmaceuticals Corp.	01 Oct 2009
Pancreatic Fistula	Phase 3	US	Novartis Pharmaceuticals Corp.	01 Oct 2009
Malignant Carcinoid Syndrome	Phase 3	US	Novartis Pharmaceuticals Corp.	01 Apr 2008
Malignant Carcinoid Syndrome	Phase 3	AR	Novartis Pharmaceuticals Corp.	01 Apr 2008
Malignant Carcinoid Syndrome	Phase 3	AT	Novartis Pharmaceuticals Corp.	01 Apr 2008
Malignant Carcinoid Syndrome	Phase 3	BE	Novartis Pharmaceuticals Corp.	01 Apr 2008
Malignant Carcinoid Syndrome	Phase 3	BR	Novartis Pharmaceuticals Corp.	01 Apr 2008
Malignant Carcinoid Syndrome	Phase 3	CA	Novartis Pharmaceuticals Corp.	01 Apr 2008
Malignant Carcinoid Syndrome	Phase 3	FR	Novartis Pharmaceuticals Corp.	01 Apr 2008

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Study	Phase	Population	Analyzed Enrollment	Group	Results	Evaluation	Publication Date


NCT01794793 (B2412, CTgov)	Phase 4	Pituitary ACTH Hypersecretion \| Dumping Syndrome \| Pituitary Neoplasms ... View more	337	Cabergoline+Pasireotide (Pasireotide Subcutaneous)	xitfrwwisu(aiynpfjohf) = jmzwszbgpv jlcgblsnvk (iaerbosnow, lyptrbfwje - llnymmflhd) View more	-	28 Aug 2024
NCT01794793 (B2412, CTgov)	Phase 4		337	Pasireotide LAR (Pasireotide Long Acting Release (LAR))	xitfrwwisu(aiynpfjohf) = nqusdvzzbd jlcgblsnvk (iaerbosnow, ovejbevkia - kykwtkcqdk) View more	-	28 Aug 2024
NCT02310269 (ENDO2024)	Phase 3	Pituitary ACTH Hypersecretion	152	Pasireotide sc (new use)	qhvojngqck(rqisdjammj) = bbasoinvgm mkvrzjcnen (drnziacekm, 49 - 141) View more	Positive	01 Jun 2024
NCT02310269 (ENDO2024)	Phase 3	Pituitary ACTH Hypersecretion	152	Pasireotide sc (prior use)	qhvojngqck(rqisdjammj) = fzzytnyuun mkvrzjcnen (drnziacekm, 41 - 152) View more	Positive	01 Jun 2024
IMBANACO CLINIC CALI -COLOMBIA (ENDO2024)	Not Applicable	Acromegaly GH \| IGF-1 \| HbA1c	14	Pasireotide	zzjpcnwmvl(noyllllabg) = hyvcjrhfhq vcgallvqyc (wohfkkrrud, 3.2) View more	Positive	01 Jun 2024
NCT01794793 (B2412, ENDO2023)	Phase 4	-	341	Pasireotide LAR	knlrqnhqvd(bcrhbqwwbv) = lyfsxigzga ngdtpjujgh (aboygmyghn )	Positive	05 Oct 2023
NCT01794793 (B2412, ENDO2023)	Phase 4	-	341	Pasireotide sc	knlrqnhqvd(bcrhbqwwbv) = lrgrzloxio ngdtpjujgh (aboygmyghn )	Positive	05 Oct 2023
NCT01253161 (CTgov)	Phase 2	Carcinoid Tumor \| Neuroendocrine Carcinoma	29	Pasireotide Long Acting Release (LAR)	lbijkgksbr(cypfsahqbg) = duleferiua dpajvorpyg (bkitgmyrkw, yweexjrktw - pkiwubbzdj) View more	-	18 Jan 2022
NCT02215070 (Pubmed \| J Biol Chem) Manual	Phase 2	Acute Graft Versus Host Disease	78	pasireotide	upftgvfmxt(umjexdhhlv) = ymbitpvsis kpzkcwhkws (ipmzdvmchf ) View more	Negative	25 Jun 2021
NCT02215070 (Pubmed \| J Biol Chem) Manual	Phase 2	Acute Graft Versus Host Disease	78	contemporaneous controls	upftgvfmxt(umjexdhhlv) = hfvitxvmud kpzkcwhkws (ipmzdvmchf ) View more	Negative	25 Jun 2021
NCT00171951 (CTgov)	Phase 2	Pituitary ACTH Hypersecretion	19	Pasireotide	ibjdijfsvt(ckgjnsotva) = zvvrxymyqb lrgpgetxhx (jhmcngvbcd, gompqqievb - flnyobzpfb) View more	-	02 Jun 2021
NCT00171730 (CTgov)	Phase 2	Acromegaly	30	Pasireotide	szeubvzylc(zeqjcecjnt) = pgjyaqimcv adwocdtruu (omfejppebs, sbvguojjag - vsjrelgopp) View more	-	02 Jun 2021
ENDO2021	Not Applicable	Pituitary ACTH Hypersecretion urinary free cortisol \| ACTH \| serum cortisol	34	Pasireotide	jtkisbdumt(ocxiftqnbl) = Although hyperglycemia is the most common side effect, it is successfully controlled with antidiabetic medication qzsihoelrc (goywtgcvld )	Positive	03 May 2021
NCT02749227 (PASSILCORT, CTgov)	Phase 2	Pituitary ACTH Hypersecretion \| ACTH-Secreting Pituitary Adenoma	4	Pasireotide LAR	snxzoyqfbb(vkaeawbmpm) = ummlizpfdq icidffqwqm (cjlchnqlnc, pnazohkltx - pablycyozs) View more	-	27 Apr 2021

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