A Randomised, Single Dose, 5-period, 5-treatment, Crossover Study to Assess the Relative Bioavailability of 4 Different Formulations of Verinurad and Allopurinol in Healthy Subjects

This study is a single centre, randomised, open-label, single-dose, 5-period, 5-treatment, crossover study in healthy male and female subjects. This study is intended to assess the relative bioavailability between the fixed dose combination (FDC, i.e. verinurad/allopurinol FDC capsule 12/300 mg) and free combination formulations of verinurad (i.e. verinurad prolonged release Hydroxypropyl methylcellulose [HPMC] capsule 12 mg) and allopurinol (i.e. allopurinol table 300 mg) in fasted and fed conditions. The study will also assess the relative bioavailability between a formulation only containing verinurad (i.e. verinurad prolonged release gelatin capsule 12 mg) and the FDC capsule.

Start Date13 Apr 2021

Sponsor / Collaborator

AstraZeneca PLC

[+1]

NCT04532918 / CompletedPhase 1

An Open-label, 3-Treatment, 3-Period, Fixed Sequence Study in Healthy Subjects to Assess the Pharmacokinetics of Verinurad and Allopurinol When Administered Alone, and in Combination With Single Doses of Cyclosporine or Rifampicin

This Phase 1 study aims to quantify the effects of cyclosporine, a broad transporter inhibitor, and rifampicin, an OATP1B1/3 inhibitor, on verinurad pharmacokinetics (PK). The study is conducted in accordance with Food and Drug Administration guidance on Clinical Drug Interaction Studies, 2020. Verinurad will be developed as a fixed combination since it will always be administered together with allopurinol.

Start Date10 Sep 2020

Sponsor / Collaborator

AstraZeneca PLC

[+1]

NCT04327024 / CompletedPhase 2

A Phase 2, Multicentre, Double-Blind, Placebo and Active Control Efficacy and Safety Study to Evaluate Verinurad Combined With Allopurinol in Heart Failure With Preserved Ejection Fraction

International, Multicenter, Double-Blind, Placebo and Active Control Efficacy and Safety Study to Evaluate Verinurad combined with Allopurinol in Heart Failure with Preserved Ejection Fraction

Start Date19 May 2020

Sponsor / Collaborator

AstraZeneca PLC

100 Clinical Results associated with Verinurad

100 Translational Medicine associated with Verinurad

100 Patents (Medical) associated with Verinurad

Literatures (Medical) associated with Verinurad

01 Oct 2024·JAMA Cardiology

Verinurad Plus Allopurinol for Heart Failure With Preserved Ejection Fraction

Article

Author: Kitzman, Dalane W. ; Voors, Adriaan A. ; Sjöström, C. David ; Mentz, Robert J. ; Shah, Sanjiv J. ; Källgren, Christian ; Myte, Robin ; Perl, Shira ; Lewis, Gregory D. ; Kaguthi, Grace

Importance:

Elevated serum uric acid (SUA) level may contribute to endothelial dysfunction; therefore, SUA is an attractive target for heart failure with preserved ejection fraction (HFpEF). However, to the authors’ knowledge, no prior randomized clinical trials have evaluated SUA lowering in HFpEF.

Objective:

To investigate the efficacy and safety of the novel urate transporter–1 inhibitor, verinurad, in patients with HFpEF and elevated SUA level.

Design, Setting, and Participants:

This was a phase 2, double-blind, randomized clinical trial (32-week duration) conducted from May 2020 to April 2022. The study took place at 59 centers in 12 countries and included patients 40 years and older with HFpEF and SUA level greater than 6 mg/dL. Data were analyzed from August 2022 to May 2024.

Interventions:

Eligible patients were randomized 1:1:1 to once-daily, oral verinurad, 12 mg, plus allopurinol, 300 mg; allopurinol, 300 mg, monotherapy; or placebo for 24 weeks after an 8-week titration period. Allopurinol was combined with verinurad to prevent verinurad-induced urate nephropathy, and the allopurinol monotherapy group was included to account for allopurinol effects in the combination therapy group. All patients received oral colchicine, 0.5 to 0.6 mg, daily for the first 12 weeks after randomization.

Main Outcomes and Measures:

Key end points included changes from baseline to week 32 in peak oxygen uptake (VO2), Kansas City Cardiomyopathy Questionnaire total symptom score (KCCQ-TSS), and SUA level; and safety/tolerability (including adjudicated cardiovascular events).

Results:

Among 159 randomized patients (53 per treatment group; median [IQR] age, 71 [40-86] years; 103 male [65%]) with median (IQR) N-terminal pro–brain natriuretic peptide level of 527 (239-1044) pg/mL and SUA level of 7.5 (6.6-8.4) mg/dL, verinurad plus allopurinol (mean change, −59.6%; 95% CI, −64.4% to −54.2%) lowered SUA level to a greater extent than allopurinol (mean change, −37.6%; 95% CI, −45.3% to −28.9%) or placebo (mean change, 0.8%; 95% CI, −11.8% to 15.2%; P &lt; .001). Changes in peak VO2 (verinurad plus allopurinol, 0.27 mL/kg/min; 95% CI, −0.56 to 1.10 mL/kg/min; allopurinol, −0.17 mL/kg/min; 95% CI, −1.03 to 0.69 mL/kg/min; placebo, 0.37 mL/kg/min; 95% CI, −0.45 to 1.19 mL/kg/min) and KCCQ-TSS (verinurad plus allopurinol, 4.3; 95% CI, 0.3-8.3; allopurinol, 4.5; 95% CI, 0.3-8.6; placebo, 1.2; 95% CI, −3.0 to 5.3) were similar across groups. There were no adverse safety signals. Deaths or cardiovascular events occurred in 3 patients (5.7%) in the verinurad plus allopurinol group, 8 patients (15.1%) in the allopurinol monotherapy group, and 6 patients (11.3%) in the placebo group.

Conclusions and Relevance:

Results of this randomized clinical trial show that despite substantial SUA lowering, verinurad plus allopurinol did not result in a significant improvement in peak VO2 or symptoms compared with allopurinol monotherapy or placebo in HFpEF.

Trial Registration:

ClinicalTrials.gov Identifier: NCT04327024

01 May 2024·Journal of the American Society of Nephrology : JASN

Combination Treatment with Verinurad and Allopurinol in CKD

Article

Author: Bjursell, Magnus ; Perl, Shira ; Rikte, Tord ; Stack, Austin G. ; Perkovic, Vlado ; Inker, Lesley A. ; Maklad, Noha ; Heerspink, Hiddo J.L. ; Sjöström, C. David ; Terkeltaub, Robert ; Jongs, Niels ; Eklund, Olof

Key Points:

The SAPPHIRE trial was designed to assess albuminuria-lowering effects of the urate transporter 1 inhibitor verinurad combined with allopurinol in patients with CKD.Verinurad 3, 7.5, and 12 mg in combination with allopurinol 300 mg did not reduce albuminuria during 34 weeks treatment compared with allopurinol alone or placebo.Verinurad/allopurinol combination dose-dependently reduced serum urate concentrations compared with placebo.

Background:

Hyperuricemia is associated with elevated risks of cardiovascular and chronic kidney disease (CKD). Since inhibition of urate transporter 1 has been suggested to be potentially nephroprotective, we performed a phase 2b study to assess albuminuria-lowering effects of the urate transporter 1 inhibitor verinurad combined with the xanthine oxidase inhibitor allopurinol in patients with CKD and hyperuricemia.

Methods:

In this randomized placebo and active controlled trial, we enrolled participants with serum urate concentrations ≥6.0 mg/dl, eGFR ≥25 ml/min per 1.73 m2, and a urinary albumin-creatinine ratio (UACR) 30–5000 mg/g to one of five treatment arms: placebo, placebo+allopurinol 300 mg/day, verinurad 3 mg+allopurinol 300 mg/day, verinurad 7.5 mg+allopurinol 300 mg/day, or verinurad 12 mg+allopurinol 300 mg/day in a 1:1:1:1:1 ratio. The primary end point was the change in UACR from baseline to 34 weeks. Secondary end points were changes from baseline in UACR at week 60 and changes in serum urate and eGFR at weeks 34 and 60.

Results:

Between August 2019 and November 2021, 861 adults with CKD (mean age 65 years, 33.0% female, mean eGFR 48 ml/min per 1.73 m2, median UACR 217 mg/g) were enrolled. At 34 weeks, the geometric mean percentage change in UACR from baseline did not differ among treatment groups (16.7%, 95% confidence interval [CI], −0.6 to 37.1 in the 3 mg group, 15.0% [95% CI, −1.85 to 34.6] in the 7.5 mg group, 14.0% [95% CI, −3.4 to 34.4] in the 12 mg group versus 9.9% [95% CI, −6.6 to 29.4] in the allopurinol group, and 37.3% [95% CI, 16.6 to 61.8] in the placebo group). UACR and eGFR change from baseline did not differ among treatment groups after 60 weeks. Verinurad/allopurinol combination dose-dependently reduced serum urate concentrations compared with placebo. The proportion of patients with adverse events and serious adverse events was balanced among treatment groups.

Conclusions:

Verinurad in combination with allopurinol did not decrease UACR or eGFR decline, but further reduced serum urate compared with allopurinol alone or placebo.

Clinical Trial registry name and registration number::

SAPPHIRE Trial registration number, NCT03990363.

02 Dec 2023·Expert opinion on drug metabolism & toxicology

Overview of the pharmacokinetics and pharmacodynamics of URAT1 inhibitors for the treatment of hyperuricemia and gout

Review

Author: Zhao, Xu ; Ma, Aijinxiu ; Hou, Zihan ; Mao, Jiale ; Song, Danni

INTRODUCTION:

Hyperuricemia is a common metabolic disease, which is a risk factor for gouty arthritis and ureteral stones and may also lead to cardiovascular and chronic kidney disease (CDK). Therefore, hyperuricemia should be treated early. Xanthine oxidase inhibitors (XOIs) and uricosuric agents (UAs), which target uric acid, are two types of medications that are used to treat gout and hyperuricemia. XOIs stop the body from producing excessive uric acid, while UAs eliminate it rapidly via the kidneys. Urate transporter 1 (URAT1) belongs to the organic anion transporter family (OAT) and is specifically localized to the apical membrane of the epithelial cells of proximal tubules. Unlike other organic anion transporter family members, URAT1 identifies and transports organic anions that are primarily responsible for urate transport.

AREAS COVERED:

This article reviews the pharmacokinetics and pharmacodynamics of the existing URAT1 inhibitors to serve as a reference for subsequent drug studies.

EXPERT OPINION:

The URAT1 inhibitors that are currently used as clinical drugs mainly include dotinurad, benzbromarone, and probenecid. Results indicate that RDEA3170 may be the most promising inhibitor, in addition to SHR4640, URC-102, and MBX-102, which are in the early stages of development.

News (Medical) associated with Verinurad

12 Nov 2021

·endpts.com

AstraZeneca expects 'modest profitability' for next round of Covid-19 vaccine supply deals — and prunes pipeline in Q3 update

Having sent 1.5 billion Covid-19 vaccines around the world on a not-for-profit basis, AstraZeneca says it’s time to move into “modest profitability.” While the priority is to deliver all the “pandemic doses” — a total of 3 billion are set to be delivered by the end of the year — AstraZeneca expects to be taking new orders in Q4, leading to a blend in sales. “Don’t expect massive profitability, which is sometimes the case for other vaccine makers,” Ruud Dobber, head of the biopharmaceuticals business unit, told Endpoints News . Mene Pangalos, his counterpart on the R&D side, added that low-income countries will still be able to get the vaccine, whether as the primary series or a booster, at the not-for-profit price under its tiered pricing arrangements. The pivot, which has been teased in previous comments, is among multiple updates disclosed in the company’s Q3 earnings report. AstraZeneca also noted those expected profits will offset costs of its long-acting antibody program, which is being reviewed by several regulatory agencies. Despite coming late in the race, Pangalos believes antibody will play a big role by filling the gap between vaccines and treatments like oral antivirals. “Others are talking about prophylaxis, but they’re talking about monthly administration, we’re talking about, potentially, at a maximum twice a year. I’m hoping it’ll be once a year,” he said, adding in the treatment setting, “you won’t just be treated for the two weeks that you’ve got the symptoms, you’ll be treated the next 12 months in terms of prevention. I know what I would take.” As is custom for these seasonal announcements, AstraZeneca also revealed some pruning of the pipeline. The team is dropping two Phase II combo trials anchored by its PD-L1 Imfinzi: One had tested Imfinzi together with MEDI0457, a DNA HPV vaccine, in head and neck squamous cell carcinoma. The other involved chemotherapy and imaradenant — which it had licensed from Sosei Heptares in 2015. Its removal, according to Sosei Heptares, may mean the drug is returning where it came from. Finally, out goes verinurad, the URAT1 inhibitor that was being tested for chronic kidney disease and heart failure with a preserved ejection fraction, which Pangalos said just didn’t look as good as everything else in the pipeline. “Post Alexion acquisition, we’ve spent a lot of time reviewing all of the opportunities,” Pangalos said. “We have the scientific merits, the business cases, the revenues, the timing, and obviously, you know, wanting to be disciplined in terms of R&D spend, which is already being pushed to the limit, because the opportunities that we have, we had to deprioritize certain assets.” Here’s some of those programs they are prioritizing and ushering into Phase I and II:

VaccineAntibodyAcquisition

23 Apr 2021

·www.biospace.com

Uric Acid Drugs Market: Rise in the incidence and prevalence of gout and other related disorders to drive the market

Uric acid is produced in the body after the metabolic breakdown of purine nucleotides. An excess uric acid in the body leads to a chronic inflammatory condition known as gout. An excess of uric acid leads to the formation of crystals in the body, which eventually leads to the deposition of uric acid crystals in joints, resulting in inflammation and pain. Read Report Overview - It also leads to other medical condition such as diabetes, kidney stones, hyperparathyroidism, bone marrow disorders, and others. Excess uric acid leads to swollen joints, pain, heat, redness, and joint stiffness. Symptoms start with the inflammation of the big toe. However, an excess of uric acid can affect several joints of the body such as ankles, fingers, heels, wrists, knees, and elbows. Symptoms are more prevalent in men compared to women. Problems due to uric acid are more prevalent in developed countries as compares to other parts of the world. In 2013, uric acid problems affected around 5.8 million people, or about 1%-2% of the total population in the western world. Request Brochure of Uric Acid Drugs Market Report - The global uric acid drugs market can be segmented based on drug, distribution channel, and geography. Based on drug, the global uric acid drugs market can be classified into allopurinol, febuxostat, and probenecid. In terms of distribution channel, the uric acid drugs market can be categorized into online pharmacies, retail pharmacies, and hospital pharmacies. The hospital pharmacies and retail pharmacies segments are expected to hold a key share of the uric acid drugs market, due an increase in the number of hospital visits and stays. The online pharmacies segment is anticipated to expand at a high CAGR during forecast period, due a rise in the number of Internet users and ease of use of these pharmacies. Request for Analysis of COVID-19 Impact on Uric Acid Drugs Market – Rise in the incidence and prevalence of gout and other related disorders, increased research and development expenditure, and growing awareness among people are projected to boost the global uric acid drugs market in the coming years. Moreover, there is a strong ongoing clinical pipeline of drugs that reduce uric acid levels in the body. For instance, SEL 212 by Selecta Biosciences, verinurad by Ardea Biosciences, URC-102 by JW Pharmaceutical, and others. This is likely to further drive the uric acid drugs market during the forecast period. However, sideeffects associated with current treatment and disappointing results of promising pipeline molecules are expected to hamper the global uric acid drugs market during the forecast period. Pre-book Uric Acid Drugs Market Report -

100 Deals associated with Verinurad

External Link

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D11129	-	-	DB11873

R&D Status

10 top R&D records.

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Indication	Highest Phase	Country/Location	Organization	Date
Heart failure with normal ejection fraction	Phase 2	US	AstraZeneca PLC	19 May 2020
Heart failure with normal ejection fraction	Phase 2	AR	AstraZeneca PLC	19 May 2020
Heart failure with normal ejection fraction	Phase 2	AU	AstraZeneca PLC	19 May 2020
Heart failure with normal ejection fraction	Phase 2	AT	AstraZeneca PLC	19 May 2020
Heart failure with normal ejection fraction	Phase 2	BG	AstraZeneca PLC	19 May 2020
Heart failure with normal ejection fraction	Phase 2	CA	AstraZeneca PLC	19 May 2020
Heart failure with normal ejection fraction	Phase 2	DE	AstraZeneca PLC	19 May 2020
Heart failure with normal ejection fraction	Phase 2	MX	AstraZeneca PLC	19 May 2020
Heart failure with normal ejection fraction	Phase 2	PL	AstraZeneca PLC	19 May 2020
Heart failure with normal ejection fraction	Phase 2	RU	AstraZeneca PLC	19 May 2020

Clinical Result

Indication

Phase

Evaluation

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Study	Phase	Population	Analyzed Enrollment	Group	Results	Evaluation	Publication Date


NCT04327024 (AMETHYST, Pubmed \| JAMA Cardiol) Manual	Phase 2	Heart failure with normal ejection fraction	159	Verinurad plus Allopurinol	bkyqzumqzr(fculniywvg) = lwaupnjswx vmeqbolkkm (mdjptxxkxn, -0.56 to 1.10) View more	Negative	14 Aug 2024
				Allopurinol	bkyqzumqzr(fculniywvg) = gxhycslnbb vmeqbolkkm (mdjptxxkxn, -1.03 to 0.69) View more
NCT04327024 (AMETHYST, CTgov)	Phase 2	Heart failure with normal ejection fraction	159	Placebo for verinurad	vaeumokluk(bwbjbovsdd) = apxisuuxqu hfnqengbvf (yyabbxilun, ieycnhrgql - vuyigwdreb) View more	-	29 Jun 2023
NCT04550234 (CTgov)	Phase 1	Chronic Kidney Diseases	25	Verinurad prolonged release HPMC capsule+Allopurinol Tablet (Treatment 1)	hlzxyxmfwb(nfmorvjofp) = jyrvgtnkbh xubdpdvnxz (syehaphljq, zqeiwyzagq - hweztyecfl) View more	-	10 May 2023
				Verinurad/Allopurinol FDC Capsule (Treatment 2)	hlzxyxmfwb(nfmorvjofp) = zikpvjowlo xubdpdvnxz (syehaphljq, jckmoemvzq - nzzmyysxbb) View more
NCT04532918 (CTgov)	Phase 1	Chronic Kidney Diseases	14	Verinurad+Allopurinol (Period 1: Verinurad + Allopurinol)	qbaxaluqwl(luygmynvmq) = nbtbonxamb flnehaptxa (kvchevgsmw, asdrubmscu - imoctgbxjc) View more	-	27 Mar 2023
				Verinurad+Cyclosporine+Allopurinol (Period 2: Verinurad + Allopurinol + Cyclosporine)	qbaxaluqwl(luygmynvmq) = clsjgnvzmz flnehaptxa (kvchevgsmw, yfjolbsxpu - naamjlkhep) View more
NCT04256629 (Pubmed \| Br J Clin Pharmacol)	Phase 1	Chronic Kidney Diseases	24	Verinurad 24 mg extended release + allopurinol 300 mg	ddqrcrxvyn(mjwikwnwep) = uifolutdks hhiaksxzib (stvynfxtut, -4.6, - 0.8)	-	12 Dec 2022
NCT04256629 (CTgov)	Phase 1	Chronic Kidney Diseases	24	ER8+verinurad+allopurinol (Treatment A)	ncpgnzmapn(tnmtxvljmr) = apcvtyvcqp ezvanifqel (ccgjcyzdlm, egwzlmhheq - tnleqvcwmu) View more	-	31 Jan 2022
				verinurad+allopurinol (Treatment B)	ncpgnzmapn(tnmtxvljmr) = pnvixzklvb ezvanifqel (ccgjcyzdlm, gqwryjtfui - kyuouxplhq) View more
NCT03316131 (Pubmed \| J Clin Endocrinol Metab) Manual	Phase 2	Hyperuricemia	36	verinurad+febuxostat+dapagliflozin	schozdsszh(znqfruqged) = xkgbzentar dyxtqqwjwy (odfoppjjxg, -21.0 to -4.7) View more	Positive	23 Apr 2021
				Placebo+verinurad+febuxostat	schozdsszh(znqfruqged) = kaibwyyrux dyxtqqwjwy (odfoppjjxg, -21.3 to -5.0) View more
NCT04024501 (CTgov)	Phase 1	Chronic Kidney Diseases	25	ER8 (Treatment 1: 1 x 12 mg ER8 Capsule Fasted)	ayqjgkyuux(mhormczhyi) = fynrglonxk dzhvagxble (utvcbybzxp, htgoywqcec - qatmqqxtfu) View more	-	21 Aug 2020
				verinurad A (Treatment 2: 2 x 6 mg A-capsule Fasted)	ayqjgkyuux(mhormczhyi) = dohflnzqjd dzhvagxble (utvcbybzxp, zkgrfdvmsr - zrsyjwvgst) View more
NCT03118739 (SP262 \| URATE-LOWERING THERAPY WITH VERINURAD AND FEBUXOSTAT, CTgov)	Phase 2	Hyperuricemia \| Diabetes Mellitus, Type 2 \| Albuminuria	60	Verinurad+Febuxostat (Verinurad 9 mg+Febuxostat 80 mg)	mokepurrsc(vtagpmjyko) = nscizbvfrw tksdckclak (emmhmitqoq, jvszhzxiku - nqkpnjxsfv) View more	-	10 Jan 2020
				Placebo (Placebo)	mokepurrsc(vtagpmjyko) = hnjwbseyre tksdckclak (emmhmitqoq, nualgtxjea - hhgjczylbo) View more
NCT02078219 (CTgov)	Phase 2	Hyperuricemia \| Gout	204	RDEA3170 (RDEA3170 Treatment Group 1)	iuicqlujpv(hyrrvzkwnn) = jncblezdyd jwgvolldfw (mjnrmialnj, ghpolqpbhx - ecvjavhdzs) View more	-	24 Sep 2019
				RDEA3170 (RDEA3170 Treatment Group 2)	iuicqlujpv(hyrrvzkwnn) = zdzbkwabtk jwgvolldfw (mjnrmialnj, vtjsxdjthi - bccnzpmyff) View more

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