Pharmacotherapy for Chronic Idiopathic Constipation and Constipation-Predominant Irritable Bowel Syndrome Beyond Conventional Laxatives: A Narrative Review

Review

作者: Sahu, Manoj K ; Giri, Suprabhat ; Sahu, Saroj K ; Anand, Anil C ; Panigrahi, Sarat Chandra ; Nath, Preetam ; Mallick, Bipadabhanjan ; Praharaj, Dibyalochan

Chronic idiopathic constipation (CIC) and constipation-predominant irritable bowel syndrome (IBS-C) are two highly prevalent functional gastrointestinal disorders that share overlapping features but differ in their pathophysiology and symptom profiles. Both conditions impose a significant socioeconomic burden due to their high prevalence, chronic nature, and impact on daily life. Treatment for chronic constipation begins with lifestyle modifications, including fiber supplementation, and progresses to osmotic and/or stimulant laxatives if the response is inadequate. About half of the patients treated with conventional laxatives do not respond sufficiently, which is due to multiple factors and requires additional therapy. Newer pharmacological agents for CIC and IBS-C are characterized by their targeted mechanisms, including enterokinetics, secretagogues, bile acid modulators, and sodium/hydrogen exchanger-3 inhibitors. Secretagogues like linaclotide improve both motility and sensory symptoms, which are often poorly managed by conventional laxatives. A drug-free treatment called the Vibrant capsule has been approved for CIC, enhancing peristalsis and bowel movements in patients unresponsive to traditional laxatives. Correct differentiation between CIC and IBS-C is essential, as misclassification can lead to suboptimal treatment outcomes. Future therapies are expected to better address the distinct yet overlapping features of these disorders, providing patient-specific treatment, improving symptom relief, and enhancing overall quality of life. The insights synthesized in this review may enhance our understanding of the mechanisms behind pharmacotherapy for chronic constipation and support their application in clinical practice to better patient outcomes.

2025-02-01·KIDNEY INTERNATIONAL

Shaking it off: loss of NHE3-mediated calcium reabsorption is compensated by the distal nephron

Article

作者: Alexander, R Todd ; Ulrich, Emma H

Sodium reabsorption is tightly coupled to calcium reabsorption in the proximal tubule via the action of the Na⁺/H⁺ exchanger isoform 3 (NHE3). Poulsen et al. provide evidence of reduced proximal calcium reabsorption in kidney tubule-specific NHE3-deficient mice that is compensated distally, unaltered phosphate homeostasis, and NHE3 involvement in the hypocalciuric effect of thiazides. These results provide support that gastrointestinal NHE3 inhibitors, used for hyperphosphatemia treatment, are unlikely to cause long-term impact on bone mineralization.

2024-11-01·Nefrologia

Effectivity and safety profile of tenapanor, a sodium-hydrogen exchanger isoform 3 inhibitor, as an innovative treatment for hyperphosphatemia in chronic kidney disease: A systematic review of clinical studies

Review

作者: Suciangto, William ; Suciangto, Winny ; Rasyid, Haerani ; Vicente, Anastasya Angelica

BACKGROUND:

Chronic kidney disease (CKD) is a major global health problem. Hyperphosphatemia is frequent in CKD and a reason for increased morbidity and mortality as it generates hyperparathyroidism, high fibroblast growth factor 23 (FGF23), and hypocalcemia. Available hyperphosphatemia therapies still have limitations, including risk of metal overload, cardiovascular calcification, and systemic adverse effects (AEs). Tenapanor is a new hyperphosphatemia treatment in CKD with sodium-hydrogen exchanger isoform 3 (NHE3) inhibition mechanism and low systemic AEs.

OBJECTIVES:

Discovering the effectivity and safety of tenapanor as hyperphosphatemia management in CKD.

METHOD:

Literature searching is performed by using "pubmed" and "science direct" with "tenapanor", "chronic kidney disease", and "hyperphosphatemia" as keywords. The literatures were selected using PRISMA algorithm version 2020. Literature was screened based on Population, Intervention, Comparison, and Outcome (PICO) criteria which are: CKD patients requiring dialysis as population, tenapanor or its combination with dialysis or phosphate binders as intervention, placebo or other phosphate binders without tenapanor as comparison, and serum phosphate, safety profile, and other pleiotropic benefits related to hyperphosphatemia management as the outcome. The included studies then assessed for risk of bias and qualitatively reviewed.

OUTCOME:

Tenapanor was able to reduce serum phosphate, generally in a dose-dependent manner. Tenapanor also suppressed FGF23 and parathyroid hormone, probably due to decreased serum phosphate. The frequent AEs were transient mild-to-moderate diarrhea in a dose-dependent manner. Tenapanor was generally well-tolerated with low systemic AEs due to its non-calcium, metal-free, and low-absorbed properties.

CONCLUSION:

Tenapanor is an effective and safe option for hyperphosphatemia management in CKD.

项与 RDX-011 相关的新闻（医药）

2024-12-31

·echemi

7 New Drugs Expected to Be Approved in 2025

In 2024, China approved several new drugs, and more blockbuster drugs are expected to be launched in 2025, covering oncology, autoimmune diseases, rare diseases, and other therapeutic areas. Drug Name Mechanism of Action Indications Development Institutions Evantuzumab c-Met/EGFR bispecific antibody Non-small cell lung cancer Johnson & Johnson; Genmab Taqetuzumab CD3/GPRC5D bispecific antibody Multiple myeloma Johnson & Johnson; Genmab Zenidatuzumab Anti-HER2 bispecific antibody Biliary tract cancer Zymeworks; Jazz Pharmaceuticals; BeiGene Inalises PI3Kα inhibitor HR-positive breast cancer Roche; Chugai Pharmaceutical Asunitinib STAMP allosteric inhibitor Speculated use for chronic myeloid leukemia treatment Novartis Tazemetostat EZH2 inhibitor Follicular lymphoma Epizyme; Huadong Medicine; Eisai Relatuzumab-alpha PDL1/TGF-β bispecific antibody Stomach cancer; gastroesophageal junction cancer Hengrui Medicine; Dong-A Pharma Vabysmo EGFR antibody-drug conjugate Nasopharyngeal cancer Lepu Biopharma Tenapanor NHE3 inhibitor Chronic kidney disease hyperphosphatemia Ardelyx; Kyowa Kirin; Fosun Pharma; AstraZeneca Mersutide OXM analog; GLP-1R/GCGR agonist Obesity Eli Lilly; Innovent Biologics Vusirumab IL-1β monoclonal antibody Gouty arthritis Junshi Biosciences Romosozumab SOST monoclonal antibody Osteoporosis Astellas; Amgen; UCB Teplizumab CD3 monoclonal antibody Type 1 diabetes Ligand Pharmaceuticals; Johnson & Johnson; Sanofi Solrepinib Syk inhibitor Immune thrombocytopenic purpura Huadong Medicine BBM-H901 Factor IX gene therapy Hemophilia B Gene Therapy Fitusiran RNAi therapy Hemophilia A; Hemophilia B Sanofi; Alnylam Andexanet alfa Recombinant factor Xa Factor Xa inhibitor antidote Portola Pharmaceuticals Lisocabtagene maraleucel IL-23p19 monoclonal antibody Crohn's disease Boehringer Ingelheim; AbbVie Lemborexant & Daridorexant OX1R antagonist; OX2R antagonist Insomnia Eisai & Idorsia; Sihuan Pharmaceutical; Nxera Pharma Highlights of new drug approvals in 2024 include: 1. Oncology: The world’s first antibody-drug conjugate (ADC) targeting folate receptor alpha (FRα) for ovarian cancer: Mirvetuximab soravtansine. PD-1/VEGF bispecific antibody envafolimab and Nectin-4 ADC enfortumab vedotin. 2. Autoimmune diseases: IL-17A/F monoclonal antibody bimekizumab for ankylosing spondylitis. 3. Rare diseases: Novartis’ complement factor B inhibitor for paroxysmal nocturnal hemoglobinuria (PNH). Blockbuster drugs expected to be approved in 2025 include: Oncology: Amivantamab (Q1) The world’s first c-Met/EGFR bispecific antibody. Highlight: Phase III study showed significant extension of median progression-free survival (mPFS). Talquetamab (Q2) A CD3/GPRC5D bispecific antibody and the world’s first drug targeting GPRC5D. Clinical results: Objective response rate (ORR) in Chinese patients was 69.0%-73.6%. Zanidatamab (Q2) A HER2-targeting bispecific antibody based on Azymetric™ technology. Indication: HER2-positive biliary tract cancer (BTC) with an ORR of up to 52%. Inavolisib (Q3) Roche’s highly selective PI3Kα inhibitor for PIK3CA-mutated breast cancer. Asciminib (Q3) Novartis’ Bcr-Abl allosteric inhibitor for Philadelphia chromosome-positive chronic myeloid leukemia (CML). SHR-1701 (Q4) A PD-L1/TGF-βRII bifunctional fusion protein for first-line treatment of gastric cancer. Phase III study demonstrated significant extension in median overall survival. MRG003 (Q4) China’s first EGFR-targeting ADC with remarkable efficacy in nasopharyngeal carcinoma. Endocrinology and Metabolism: Tenapanor (Q1) The world’s only approved NHE3 inhibitor for controlling hyperphosphatemia in chronic kidney disease patients. Trend Analysis: Continued Innovation in Oncology: The emergence of multiple bispecific antibodies and ADC drugs is making targets and treatment options more precise and diverse. Breakthroughs in Autoimmune and Rare Diseases: New biologics are gradually addressing drug resistance and limited treatment options in previous therapies. Emergence of Domestic Innovative Drugs: Examples include SHR-1701 and MRG003, highlighting the growing research and development capabilities of Chinese pharmaceutical companies. The sequential launch of these drugs will provide new therapeutic options for Chinese patients and enhance China’s position in the global pharmaceutical market.

上市批准临床3期临床结果抗体药物偶联物免疫疗法

2022-11-14

·BioSpace

FDA Briefing Documents Cast Doubt on Ardelyx’s CKD Drug (Updated)

Sarah Silbiger/Getty Images The FDA raised doubts Monday about the future of Ardelyx's experimental chronic kidney disease drug tenapanor in briefing documents released ahead of a Wednesday advisory committee meeting. The regulator highlighted concerns about the overall efficacy of the medication. In its briefing documents, the FDA suggested that the “magnitude of treatment effect” is lower than that with approved medications for the control of serum phosphorus in adult patients with CKD who are on dialysis. On Wednesday, the FDA’s Cardiovascular and Renal Drugs Advisory Committee will hold a meeting to evaluate the New Drug Application for tenapanor, a sodium hydrogen exchanger 3 inhibitor designed to control serum phosphorus by inhibiting the sodium hydrogen exchanger 3. This is the second time tenapanor has come up in front of the FDA. Last year, the regulatory agency issued a Complete Response Letter for the drug candidate despite the candidate hitting its primary endpoint in late-stage studies. The clinical data showed tenapanor reduces serum phosphorus in CKD patients on dialysis but at the time of the CRL, the regulator called the results “small and of unclear clinical significance.” Monday's briefing documents suggest scientists with the regulatory agency may be leaning that way again. The review team suggested the efficacious data seen in tenapanor clinical programs may not provide a significant improvement over the current standard of care, which is phosphate binders. “We expect that tenapanor’s average treatment effect on s-P (serum phosphate) when used in patients who tolerate and remain on therapy is about 0.7 mg/dL. The magnitude of the treatment effect appears to be less than that observed with approved agents,” the reviewers wrote. When the committee meets Wednesday, the members will not only evaluate the available clinical data from tenapanor’s trials but nephrologists and experts in treating dialysis patients, including those who cannot control serum phosphorous levels, will provide their input. Mike Raab, president and chief executive officer of Ardelyx, told BioSpace the company is looking forward to a robust discussion with the advisory committee. “The nephrology community has spoken loudly and clearly that they want innovation for chronic kidney disease patients on dialysis and at Ardelyx we are committed to finding a path forward for [tenapanor],” he said. Although the FDA previously rejected tenapanor, Ardelyx has been adamant about the potential of the medication for these patients. The company has continued to push for potential approval of the drug in this indication, which has a high unmet need. An inability to control serum phosphate levels is called hyperphosphatemia. It leads to leaching of the calcium in the bones. That causes the bones to become weak and leads to the leached calcium forming deposits in other parts of the body. Earlier this month, BioSpace spoke with some nephrologists about the seriousness of the condition. Patients who cannot control serum phosphorous levels are required to maintain a strict diet that includes phosphate binders taken with each meal. Patients typically take between 10 and 20 phosphate binders per day, depending on how many times they eat. Dr. Jay Wish, professor of clinical medicine at Indiana University School of Medicine and chief medical officer for outpatient dialysis at Indiana University Health, said beyond the pill burden, side effects of phosphorous binders include bloating and constipation. One side effect of tenapanor is potential diarrhea, which he said might provide some welcome relief to these patients. Tenapanor was previously approved by the FDA as a treatment for irritable bowel disease with constipation.

上市批准

2022-11-14

·BioSpace

FDA Briefing Documents Cast Doubt on Ardelyx’s CKD Drug (Updated)

The FDA raised doubts about the future of Ardelyx’s experimental chronic kidney disease drug tenapanor in briefing documents released ahead of a Wednesday advisory committee meeting. Sarah Silbiger/Getty Images The FDA raised doubts Monday about the future of Ardelyx ‘s experimental chronic kidney disease drug tenapanor in briefing documents released ahead of a Wednesday advisory committee meeting. The regulator highlighted concerns about the overall efficacy of the medication. In its briefing documents, the FDA suggested that the “magnitude of treatment effect” is lower than that with approved medications for the control of serum phosphorus in adult patients with CKD who are on dialysis. On Wednesday, the FDA’s Cardiovascular and Renal Drugs Advisory Committee will hold a meeting to evaluate the New Drug Application for tenapanor, a sodium hydrogen exchanger 3 inhibitor designed to control serum phosphorus by inhibiting the sodium hydrogen exchanger 3. This is the second time tenapanor has come up in front of the FDA. Last year, the regulatory agency issued a Complete Response Letter for the drug candidate despite the candidate hitting its primary endpoint in late-stage studies. The clinical data showed tenapanor reduces serum phosphorus in CKD patients on dialysis but at the time of the CRL, the regulator called the results “small and of unclear clinical significance.” Monday’s briefing documents suggest scientists with the regulatory agency may be leaning that way again. The review team suggested the efficacious data seen in tenapanor clinical programs may not provide a significant improvement over the current standard of care, which is phosphate binders. “We expect that tenapanor’s average treatment effect on s-P (serum phosphate) when used in patients who tolerate and remain on therapy is about 0.7 mg/dL. The magnitude of the treatment effect appears to be less than that observed with approved agents,” the reviewers wrote. When the committee meets Wednesday, the members will not only evaluate the available clinical data from tenapanor’s trials but nephrologists and experts in treating dialysis patients, including those who cannot control serum phosphorous levels, will provide their input. Mike Raab, president and chief executive officer of Ardelyx, told BioSpace the company is looking forward to a robust discussion with the advisory committee. “The nephrology community has spoken loudly and clearly that they want innovation for chronic kidney disease patients on dialysis and at Ardelyx we are committed to finding a path forward for [tenapanor],” he said. Although the FDA previously rejected tenapanor, Ardelyx has been adamant about the potential of the medication for these patients. The company has continued to push for potential approval of the drug in this indication, which has a high unmet need. An inability to control serum phosphate levels is called hyperphosphatemia. It leads to leaching of the calcium in the bones. That causes the bones to become weak and leads to the leached calcium forming deposits in other parts of the body. Earlier this month, BioSpace spoke with some nephrologists about the seriousness of the condition. Patients who cannot control serum phosphorous levels are required to maintain a strict diet that includes phosphate binders taken with each meal. Patients typically take between 10 and 20 phosphate binders per day, depending on how many times they eat. Dr. Jay Wish, professor of clinical medicine at Indiana University School of Medicine and chief medical officer for outpatient dialysis at Indiana University Health, said beyond the pill burden, side effects of phosphorous binders include bloating and constipation. One side effect of tenapanor is potential diarrhea, which he said might provide some welcome relief to these patients. Tenapanor was previously approved by the FDA as a treatment for irritable bowel disease with constipation.

上市批准

100 项与 RDX-011 相关的药物交易

登录后查看更多信息