In this phase 3b, noninferiority trial, vadadustat once daily was noninferior to darbepoetin alfa (DA) in the correction and maintenance of hemoglobin in dialysis-dependent CKD.Vadadustat three times weekly treatment resulted in similar changes in mean hemoglobin levels compared with vadadustat once daily, but was not noninferior to DA.The safety profiles of vadadustat once daily and vadadustat three times weekly were comparable with that of DA.

Background:

Vadadustat is an oral hypoxia-inducible factor prolyl hydroxylase inhibitor for treating anemia in CKD. This study investigated the safety and efficacy of once-daily and three-times-weekly dosing in patients with dialysis-dependent CKD compared with darbepoetin alfa (DA).

Methods:

This phase 3b, randomized (1:1:1; vadadustat once daily [starting dose: 300 or 450 mg], vadadustat three times weekly [starting dose: 600 or 750 mg], DA), open-label, active-controlled, noninferiority trial included conversion (weeks 0–20) and maintenance (weeks 20–52) periods. Primary and secondary efficacy end points were mean change in hemoglobin from baseline during the primary evaluation period (PEP, weeks 20–26) and secondary evaluation period (weeks 46–52). Other end points included proportion of patients requiring erythropoiesis-stimulating agent (ESA) rescue (hemoglobin <9.5 g/dl or with increases in dose ≥50% or ≥100% in the DA group). Safety end points included treatment-emergent adverse events (AEs) and serious AEs.

Results:

The least-squares (LS) mean treatment difference between vadadustat once daily and DA from baseline to PEP was −0.27 g/dl (95% confidence interval [CI], −0.55 to 0.01); the lower bound met the noninferiority threshold (−0.75 g/dl). The LS mean treatment difference between vadadustat three times weekly and DA from baseline to PEP was −0.53 g/dl (95% CI, −0.80 to −0.25), which did not meet the lower bound noninferiority threshold. The LS mean change from baseline to the secondary evaluation period between DA and vadadustat once daily was −0.40 (95% CI, −0.79 to −0.02) and for vadadustat three times weekly was −0.42 (95% CI, −0.81 to −0.02). The proportion of patients who received ESA rescue during weeks 2–52 was higher in the DA group than vadadustat groups. Similar treatment-emergent AEs and treatment-emergent serious AEs were observed across groups.

Conclusions:

Vadadustat once daily, but not three times weekly, was noninferior to DA in the correction and maintenance of hemoglobin in patients with dialysis-dependent CKD converted from an ESA; safety profiles were similar across groups.

Clinical Trial registry name and registration number::

EudraCT 2019-004851-36/ClinicalTrials.gov identifier: NCT04313153.

2024-10-09·Giornale italiano di nefrologia : organo ufficiale della Societa italiana di nefrologia

[Hypoxia-Inducible Factor Prolyl Hydroxylase Enzyme Inhibitors: A Novel Therapy for Anemia Treatment in CKD Patients].

Review

作者: Magagnoli, Lorenza ; Stucchi, Andrea ; Cozzolino, Mario ; Cara, Anila

Anemia is a major complication of chronic kidney disease (CKD). Its prevalence increases with advancing age and progression of kidney disease. The main cause of anemia linked to CKD is represented by the reduction erythropoietin secretion. The increase in cardiovascular risk and mortality is strongly associated with the presence of anemia, and grows with the severity of the anemia, as described in numerous studies. The main therapies for the control of anemia have so far been represented by iron supplementation, the use of synthetic erythropoietin and blood transfusions. Despite the availability of adequate therapies, the prevalence of anemia in CKD continues to be significant. Drugs that inhibit the enzyme prolyl hydroxylase of hypoxia inducible factor (HIF-PHi) are able to mimic a condition of hypoxia and increase the production of endogenous erythropoietin. HIF-PHi therefore represents an important therapeutic alternative for the control of anemia linked to CKD. Numerous studies have confirmed the ability of HIF-PHi to correct anemia and maintain hemoglobin at adequate values; they also highlighted other potential beneficial pleiotropic factors on cholesterol control and iron homeostasis. Further studies are needed to confirm the safety of the drug, especially regarding cardiovascular risk, vascular thrombosis and neoplastic growth. This document highlights the mechanism of action, effects and pharmacological characteristics of HIF-PHi.

2024-10-01·Drug testing and analysis

Detection of FG‐4592 and metabolites in equine plasma, urine and hair following oral administration

Article

作者: Habershon‐Butcher, Jocelyn ; Hincks, Pamela ; Scarth, James ; Gray, Bobby ; Taylor, Polly ; Cutler, Charlotte ; Viljanto, Marjaana

Abstract:

FG‐4592 is a hypoxia‐inducible factor inhibitor that has been approved for therapeutic use in some countries. This class of compounds can increase the oxygen carrying capacity of the blood and thus have the potential to be used as performance enhancing agents in sports. The purpose of this study was to investigate the detection of FG‐4592 and metabolites in equine plasma and mane hair following a multiple dose oral administration to two Thoroughbred racehorses, to identify the best analytical targets for doping control laboratories. Urine samples were also analysed, and the results compared to previously published urine data. Liquid chromatography‐high resolution mass spectrometry was used for metabolite identification in urine and plasma. Liquid chromatography–tandem mass spectrometry was used for full sample analysis of urine, plasma and hair samples and generation of urine and plasma profiles. FG‐4592 and a mono‐hydroxylated metabolite were detected in plasma. FG‐4592 was detected with the greatest abundance and gave the longest duration of detection, up to 312 h post‐administration, and would be the recommended target in routine doping samples. FG‐4592 was detected in all mane hair samples collected post‐administration, up to 166 days following the final dose, showing extended detection can be achieved with this matrix. To the best of the authors' knowledge, this is the first report of FG‐4592 and metabolites in equine plasma and hair samples. Urine results were consistent with the previously published data, with FG‐4592 offering the best target for detection and longest detection periods.

项与 Hypoxia inducible factors inhibitors (Curve Therapeutics) 相关的新闻（医药）

2024-08-09

·fda.gov

FDA approves belzutifan for cancers associated with von Hippel-Lindau disease

On August 13, 2021, the Food and Drug Administration approved belzutifan (Welireg, Merck), a hypoxia-inducible factor inhibitor for adult patients with von Hippel-Lindau (VHL) disease who require therapy for associated renal cell carcinoma (RCC), central nervous system (CNS) hemangioblastomas, or pancreatic neuroendocrine tumors (pNET), not requiring immediate surgery. Belzutifan was investigated in the ongoing Study 004 (NCT03401788), an open-label clinical trial in 61 patients with VHL-associated RCC (VHL-RCC) diagnosed based on a VHL germline alteration and with at least one measurable solid tumor localized to the kidney. Enrolled patients had other VHL-associated tumors, including CNS hemangioblastomas and pNET. Patients received belzutifan 120 mg once daily until disease progression or unacceptable toxicity. The primary efficacy endpoint was overall response rate (ORR) measured by radiology assessment, as assessed by an independent review committee using RECIST v1.1. Additional efficacy endpoints included duration of response (DoR), and time- to- response (TTR). An ORR of 49% (95% CI:36, 62) was reported in patients with VHL-associated RCC. All patients with VHL-RCC with a response were followed for a minimum of 18 months from the start of treatment. The median DoR was not reached; 56% of responders had DoR ≥ 12 months and a median TTR of 8 months. In patients with other VHL-associated non-RCC tumors, 24 patients with measurable CNS hemangioblastomas had an ORR of 63% and 12 patients with measurable pNET had an ORR of 83%. Median DoR was not reached, with 73% and 50% of patients having response durations ≥ 12 months for CNS hemangioblastomas and pNET, respectively. The most common adverse reactions, including laboratory abnormalities, reported in ≥ 20% of patients who received belzutifan were decreased hemoglobin, anemia, fatigue, increased creatinine, headache, dizziness, increased glucose, and nausea. Anemia and hypoxia from belzutifan use can be severe. In Study 004, anemia occurred in 90% of patients and 7% had Grade 3 anemia. Patients should be transfused as clinically indicated. The use of erythropoiesis stimulating agents for treatment of anemia is not recommended in patients treated with belzutifan. In Study 004, hypoxia occurred in 1.6% of patients. Belzutifan can render some hormonal contraceptives ineffective, and belzutifan exposure during pregnancy can cause embryo-fetal harm. The recommended belzutifan dosage is 120 mg administered orally once daily with or without food. View full prescribing information for Welireg. This review was conducted under Project Orbis, an initiative of the FDA Oncology Center of Excellence. Project Orbis provides a framework for concurrent submission and review of oncology drugs among international partners. For this review, FDA collaborated with the Australian Therapeutic Goods Administration (TGA), Health Canada, and the Medicines and Healthcare products Regulatory Agency (MHRA) of the United Kingdom. The application reviews are ongoing at the other regulatory agencies. This review used the Real-Time Oncology Review (RTOR) pilot program, which streamlined data submission prior to the filing of the entire clinical application, as well as the Assessment Aid and the Product Quality Assessment Aid, voluntary submissions from the applicant to facilitate the FDA’s assessment. The FDA approved this application approximately 1 month ahead of the FDA goal date. This application was granted priority review for this indication. A description of FDA expedited programs is in the Guidance for Industry: Expedited Programs for Serious Conditions-Drugs and Biologics. Healthcare professionals should report all serious adverse events suspected to be associated with the use of any medicine and device to FDA’s MedWatch Reporting System or by calling 1-800-FDA-1088. For assistance with single-patient INDs for investigational oncology products, healthcare professionals may contact OCE’s Project Facilitate at 240-402-0004 or email OncProjectFacilitate@fda.hhs.gov. For information on the COVID-19 pandemic, see the following resources: FDA: Coronavirus Disease 2019 (COVID-19) NCI: Coronavirus: What People With Cancer Should Know CDC: Coronavirus (COVID-19) Follow the Oncology Center of Excellence on Twitter @FDAOncologyExternal Link Disclaimer. Content current as of: 02/01/2022 Regulated Product(s) Drugs 02/01/2022 Drugs Resources for Information | Approved Drugs Oncology (Cancer)/Hematologic Malignancies Approval Notifications Ongoing | Cancer Accelerated Approvals Verified Clinical Benefit | Cancer Accelerated Approvals Withdrawn | Cancer Accelerated Approvals Other | Cancer Accelerated Approvals Approved Drug Products with Therapeutic Equivalence Evaluations (Orange Book) Short Description Oncology (Cancer)/Hematologic Malignancies Approval Notifications Ongoing | Cancer Accelerated Approvals Verified Clinical Benefit | Cancer Accelerated Approvals Withdrawn | Cancer Accelerated Approvals Other | Cancer Accelerated Approvals Approved Drug Products with Therapeutic Equivalence Evaluations (Orange Book) Short Description

优先审批临床结果上市批准加速审批

2024-01-09

·BioSpace

Akebia Therapeutics Announces Appointment of Nicholas Grund as Chief Commercial Officer

CAMBRIDGE, Mass., Jan. 9, 2024 /PRNewswire/ -- Akebia Therapeutics®, Inc. (Nasdaq: AKBA), a biopharmaceutical company with the purpose to better the lives of people impacted by kidney disease, today announced the appointment of Nicholas Grund as Chief Commercial Officer. Mr. Grund is a seasoned pharmaceutical executive with significant operational, commercial and strategic leadership experience across renal and specialty markets. "Nik is a profoundly knowledgeable executive with an impressive track record of leading commercial initiatives within the renal market," said John P. Butler, Chief Executive Officer of Akebia. "His operational versatility and breadth of expertise in customer facing roles will be critical for Akebia as we prepare for the vadadustat launch in the U.S., if approved, and continue our goal to maximize Auryxia® (ferric citrate) revenue. We are pleased to welcome Nik to Akebia as he further strengthens our leadership team." Prior to joining Akebia, Mr. Grund served as President of Eurofins Transplant Genomics where he steered organizational change and facilitated continuous operating efficiency improvements and revenue growth. He was also Chief Commercial Officer of AMAG Pharmaceuticals where he managed commercial activities across four business units. Mr. Grund also held positions of increasing responsibility at Sanofi in its specialty care business and oversaw operations of its renal business unit. "I am delighted to join the Akebia team at this pivotal moment," said Mr. Grund. "Akebia has already built an impressive renal-focused commercial organization and their deep commitment to patients and connection to providers is evident. I am keen to build on the teams' efforts to prepare for the potential vadadustat launch with the ultimate goal of serving dialysis patients." About Akebia Therapeutics Akebia Therapeutics, Inc. is a fully integrated biopharmaceutical company with the purpose to better the lives of people impacted by kidney disease. Akebia was founded in 2007 and is headquartered in Cambridge, Massachusetts. For more information, please visit our website at , which does not form a part of this release. About Vadadustat Vadadustat is an oral hypoxia-inducible factor prolyl hydroxylase inhibitor designed to mimic the physiologic effect of altitude on oxygen availability. At higher altitudes, the body responds to lower oxygen availability with stabilization of hypoxia-inducible factor, which can lead to increased red blood cell production and improved oxygen delivery to tissues. Vadadustat is not approved by the U.S. Food and Drug Administration. Vadadustat is approved in Europe and Australia for the treatment of symptomatic anemia due to CKD in adult patients on chronic maintenance dialysis. In Japan, vadadustat is approved as a treatment for anemia due to CKD in both dialysis-dependent and non-dialysis dependent adult patients. Forward-Looking Statements Statements in this press release regarding Akebia Therapeutics, Inc.'s ("Akebia's") strategy, plans, prospects, expectations, beliefs, intentions and goals are forward-looking statements within the meaning of the U.S. Private Securities Litigation Reform Act of 1995, as amended, and include, but are not limited to, statements regarding: expectations regarding a decision by the FDA on its NDA for vadadustat; Akebia's plans with respect to commercializing vadadustat in the U.S. if approved, including the potential launch thereof; expectations regarding maximizing Auryxia revenue; and its goal to serve patients. The terms "intend," "believe," "plan," "goal," "expect," "potential," "anticipate," "will," "continue," derivatives of these words, and similar references are intended to identify forward-looking statements, although not all forward-looking statements contain these identifying words. Actual results, performance or experience may differ materially from those expressed or implied by any forward-looking statement as a result of various risks, uncertainties and other factors, including, but not limited to, risks associated with: decisions made by health authorities, such as the FDA, with respect to regulatory filings, including the anticipated FDA decision on the NDA for vadadustat; the potential therapeutic benefits, safety profile, and effectiveness of vadadustat; the potential demand and market potential and acceptance of, as well as coverage and reimbursement related to, Auryxia, including estimates regarding the potential market opportunity; the competitive landscape for Auryxia, including potential generic entrants; the ability of Akebia to attract and retain qualified personnel; the results of preclinical and clinical research; the direct or indirect impact of the COVID-19 pandemic on regulators and Akebia's business, operations, and the markets and communities in which Akebia and its partners, collaborators, vendors and customers operate; manufacturing, supply chain and quality matters and any recalls, write-downs, impairments or other related consequences or potential consequences; and early termination of any of Akebia's collaborations. Other risks and uncertainties include those identified under the heading "Risk Factors" in Akebia's Quarterly Report on Form 10-Q for the quarter ended September 30, 2023, and other filings that Akebia may make with the U.S. Securities and Exchange Commission in the future. These forward-looking statements (except as otherwise noted) speak only as of the date of this press release, and, except as required by law, Akebia does not undertake, and specifically disclaims, any obligation to update any forward-looking statements contained in this press release. Akebia Therapeutics® and Auryxia® are registered trademarks of Akebia Therapeutics, Inc. and its affiliates. Akebia Therapeutics Contact Mercedes Carrasco mcarrasco@akebia.com Company Codes: NASDAQ-NMS:AKBA

上市批准高管变更

100 项与 Hypoxia inducible factors inhibitors (Curve Therapeutics) 相关的药物交易

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