A Phase 3b, Randomized, Double-blind, Placebo-controlled Study to Evaluate the Efficacy and Safety of TRC101 in Delaying Chronic Kidney Disease Progression in Subjects with Metabolic Acidosis - VALOR-CKD

Start Date06 Mar 2019

Sponsor / Collaborator

Tricida, Inc.

NCT03710291 / TerminatedPhase 3

A Phase 3b, Randomized, Double-blind, Placebo-controlled Study to Evaluate the Efficacy and Safety of TRC101 in Delaying Chronic Kidney Disease Progression in Subjects With Metabolic Acidosis

The purpose of this study is to evaluate the effect of TRC101 on the progression of chronic kidney disease (CKD) and to evaluate the safety profile of TRC101 in CKD patients with metabolic acidosis.

Start Date20 Nov 2018

Sponsor / Collaborator

Tricida, Inc.

EUCTR2018-001303-36-BG / Unknown statusPhase 3

Start Date14 Nov 2018

Sponsor / Collaborator

Tricida, Inc.

100 Clinical Results associated with Veverimer

100 Translational Medicine associated with Veverimer

100 Patents (Medical) associated with Veverimer

Literatures (Medical) associated with Veverimer

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

VALOR-CKD: A Multicenter, Randomized, Double-Blind Placebo-Controlled Trial Evaluating Veverimer in Slowing Progression of CKD in Patients with Metabolic Acidosis

Article

Author: Perkovic, Vlado ; Wheeler, David C ; Wesson, Donald E ; Bushinsky, David A ; Stasiv, Yuri ; Parsell, Dawn ; Li, Elizabeth ; Mathur, Vandana S ; Tangri, Navdeep ; Inker, Lesley A ; Walker, Michael ; Klaerner, Gerrit

Significance Statement:

Metabolic acidosis is a common complication of CKD and is associated with more rapid decline of kidney function, but well-powered controlled randomized trials testing the effect of treating metabolic acidosis on slowing CKD progression have not been conducted. The VALOR-CKD study randomized 1480 individuals with CKD and metabolic acidosis, across 320 sites to placebo or veverimer (a novel hydrochloric acid binder). The findings did not demonstrate the efficacy of veverimer in slowing CKD progression, but the difference in serum bicarbonate between placebo and drug arms was only approximately 1 mEq/L. Veverimer was safe and well tolerated.

Background:

Metabolic acidosis is common in CKD, but whether its treatment slows CKD progression is unknown. Veverimer, a novel hydrochloric acid binder that removes acid from the gastrointestinal tract, leads to an increase in serum bicarbonate.

Methods:

In a phase 3, double-blind, placebo-controlled trial, patients with CKD (eGFR of 20–40 ml/min per 1.73 m2) and metabolic acidosis (serum bicarbonate of 12–20 mEq/L) from 35 countries were randomized to veverimer or placebo. The primary outcome was the composite end point of CKD progression, defined as the development of ESKD (kidney transplantation or maintenance dialysis), a sustained decline in eGFR of ≥40% from baseline, or death due to kidney failure.

Results:

The mean (±SD) baseline eGFR was 29.2±6.3 ml/min per 1.73 m2, and serum bicarbonate was 17.5±1.4 mEq/L; this increased to 23.4±2.0 mEq/L after the active treatment run-in. After randomized withdrawal, the mean serum bicarbonate was 22.0±3.0 mEq/L and 20.9±3.3 mEq/L in the veverimer and placebo groups at month 3, and this approximately 1 mEq/L difference remained stable for the first 24 months. A primary end point event occurred in 149/741 and 148/739 patients in the veverimer and placebo groups, respectively (hazard ratio, 0.99; 95% confidence interval, 0.8 to 1.2; P = 0.90). Serious and overall adverse event incidence did not differ between the groups.

Conclusions:

Among patients with CKD and metabolic acidosis, treatment with veverimer did not slow CKD progression. The lower than expected bicarbonate separation may have hindered the ability to test the hypothesis.

Clinical Trial registry name and registration number:

VALOR-CKD, NCT03710291.

01 Dec 2023·Journal of cachexia, sarcopenia and muscle

Effects of correcting metabolic acidosis on muscle mass and functionality in chronic kidney disease: a systematic review and meta‐analysis

Review

Author: Hoorn, Ewout J. ; Visser, Wesley J. ; van der Burgh, Anna C. ; de Roos, Nicole M. ; Severs, David ; van de Braak, Elma E.M. ; van der Hoef, Iris ; de Mik ‐ van Egmond, Anneke M.E. ; Olieman, Joanne F. ; Jans, Inez

Abstract:

Metabolic acidosis unfavourably influences the nutritional status of patients with non‐dialysis dependent chronic kidney disease (CKD) including the loss of muscle mass and functionality, but the benefits of correction are uncertain. We investigated the effects of correcting metabolic acidosis on nutritional status in patients with CKD in a systematic review and meta‐analysis. A search was conducted in MEDLINE and the Cochrane Library from inception to June 2023. Study selection, bias assessment, and data extraction were independently performed by two reviewers. The Cochrane risk of bias tool was used to assess the quality of individual studies. We applied random effects meta‐analysis to obtain pooled standardized mean difference (SMD) and 95% confidence intervals (CIs). We retrieved data from 12 intervention studies including 1995 patients, with a mean age of 63.7 ± 11.7 years, a mean estimated glomerular filtration rate of 29.8 ± 8.8 mL/min per 1.73 m2, and 58% were male. Eleven studies performed an intervention with oral sodium bicarbonate compared with either placebo or with standard care and one study compared veverimer, an oral HCl‐binding polymer, with placebo. The mean change in serum bicarbonate was +3.6 mEq/L in the intervention group and +0.4 mEq/L in the control group. Correcting metabolic acidosis significantly improved muscle mass assessed by mid‐arm muscle circumference (SMD 0.35 [95% CI 0.16 to 0.54], P < 0.001) and functionality assessed with the sit‐to‐stand test (SMD −0.31 [95% CI −0.52 to 0.11], P = 0.003). We found no statistically significant effects on dietary protein intake, handgrip strength, serum albumin and prealbumin concentrations, and blood urea nitrogen. Correcting metabolic acidosis in patients with CKD improves muscle mass and physical function. Correction of metabolic acidosis should be considered as part of the nutritional care for patients with CKD.

31 May 2023·Nephrology, dialysis, transplantation : official publication of the European Dialysis and Transplant Association - European Renal Association

Design and population of the VALOR-CKD study: a multicenter, randomized, double-blind, placebo-controlled trial evaluating the efficacy and safety of veverimer in slowing progression of chronic kidney disease in patients with metabolic acidosis

Article

Author: Bushinsky, David A ; Wheeler, David C ; Perkovic, Vlado ; Wesson, Donald E ; Parsell, Dawn ; Stasiv, Yuri ; Walker, Michael ; Tangri, Navdeep ; Li, Elizabeth ; Inker, Lesley ; Mathur, Vandana S ; Klaerner, Gerrit

ABSTRACT:

Background:

Whether treating metabolic acidosis slows progression of chronic kidney disease (CKD) has not been established. Veverimer is a novel hydrochloric acid binder that removes acid from the gastrointestinal tract leading to an increase in serum bicarbonate; it is being developed to treat metabolic acidosis with the goal of slowing progression of CKD.

Methods:

The VALOR-CKD trial is an international, randomized, multicenter, double-blind, placebo-controlled study designed to evaluate the effect of once-daily veverimer on kidney disease progression in patients with metabolic acidosis and CKD. Eligibility criteria include a serum bicarbonate in the range of 12–20 mmol/L and an estimated glomerular filtration rate (eGFR) of 20–40 mL/min/1.73 m2. The primary outcome is kidney disease progression defined as the development of end-stage kidney disease, a sustained decline in eGFR of >40% from baseline or death due to kidney failure. Key secondary endpoints include effects on physical function.

Results:

Between December 2018 and December 2021, 1480 participants were randomized. The mean age at baseline was 65.1 years and 42% of the patients were female. The mean baseline eGFR was 29.1 mL/min/1.73 m2 and mean serum bicarbonate was 17.5 mmol/L. The median urine albumin-to-creatinine ratio at screening was 201 mg/g and the median 5-year predicted risk of kidney failure was 32%. Diabetes and hypertension were present in 56% and 98% of participants, respectively.

Conclusions:

VALOR-CKD has recruited a large population of people with metabolic acidosis at high risk for CKD progression to determine the effects of veverimer on the risk of progressive loss of kidney function.

News (Medical) associated with Veverimer

26 Apr 2024

·www.prnewswire.com

Renibus Therapeutics Announces Oral Presentations on RBT-1 at AATS and SCA Medical Conferences

SOUTHLAKE, Texas, April 26, 2024 /PRNewswire/ -- Renibus Therapeutics® ("Renibus"), a clinical-stage biopharmaceutical company focusing on the prevention and treatment of cardio, renal and metabolic diseases, today announced its participation at two prestigious medical conferences: the American Association for Thoracic Surgery (AATS) 104th Annual Meeting and the Society of Cardiovascular Anesthesiologists (SCA) 46th Annual Meeting, both taking place in Toronto, Canada, April 27-30, 2024. "We are pleased to present additional clinical data on RBT-1 at the AATS and SCA meetings in collaboration with key opinion leaders in our field, Drs. Charles Mack and Andrew Shaw," stated Jeffrey Keyser, RPh, JD, PhD, President and CEO of Renibus. "These presentations are critical to advancing the understanding of our preconditioning approach with RBT-1, and we thank the meeting organizers and principal investigators for their partnership. Our Phase 3 PROTECT study is enrolling well and we remain on track to report top-line data in the third quarter of 2025." RBT-1 (stannic protoporfin / iron sucrose) is a single dose, multi-organ, preconditioning agent that is administered intravenously 24-48 hours prior to patients undergoing cardiac surgery.Renibus Therapeutics is actively enrolling its PROTECT Phase 3 pivotal trial evaluating RBT-1's potential to reduce the risk of post operative complications and improve outcomes following cardiothoracic surgery. RBT-1 has received both FDA Breakthrough and Fast Track Designations. Details of the oral presentations at AATS: Title: RBT-1 Reduces Incidence of Blood Product Utilization in Patients Undergoing Non-Emergent Coronary Artery Bypass Grafting and/or Valve Surgery Date and Time: Sunday, April 28th at 9:44 am ET Location: Room 714 Presenter: Charles A. Mack, MD, FACS, Associate Professor of Cardiothoracic Surgery, New York-Presbyterian Hospital, Weill Cornell Medicine Title: RBT-1 Reduces the Number of Post-Operative Complications Associated with Cardiac Surgery Date and Time: Sunday, April 28th at 4:03 pm ET Location: Theater 2, Exhibit Hall Presenter: Bhupinder Singh, MD, Chief Medical Officer, Renibus Details of the oral presentation at SCA: Title: RBT-1 Improves Clinical Outcomes in Patients Requiring Prolonged Intensive Care Unit Stay Following Non-Emergent Cardiac Surgery Date and Time: Sunday, April 28th at 3:00 pm ET Session: Best of Meeting Oral Presenter: Andrew Shaw, MD, FRCA, FCCM, FFICM, Professor and Chair, Department of Intensive Care and Resuscitation, Cleveland Clinic About RBT-1 RBT-1 (stannic protoporfin/iron sucrose) is a potent inducer of anti-inflammatory andantioxidant pathways currently in Phase 3 [NCT # 06021457] for its lead indication to reduce post-operative complications following cardiothoracic surgery. Renibus completed the Phase 2 study of RBT-1 (NCT04564833) in February 2023 and announced positive final results from this study in May 2023. In October 2023, Renibus initiated enrollment and administration of RBT-1 in its PROTECT Phase 3 pivotal study. RBT-1 was granted Breakthrough Therapy designation status from the U.S. FDA to reduce the risk of complications in patients undergoing cardiothoracic surgery. About Renibus Therapeutics Renibus is a clinical stage biopharmaceutical company dedicated to treating, improving, and extending patients' lives by developing products to prevent disease progression, improve outcomes and protect against organ damage associated with cardio, renal and metabolic diseases. Renibus' first-in-a-new class lead program is RBT-1 (stannic protoporfin / iron sucrose), a single dose IV drug that is given over 1-2 hours, 24-48 hours prior to patients undergoing elective cardiac and/or valve surgery. It is in a Phase 3 pivotal trial to reduce the risk of post operative complications and improve outcomes following cardiothoracic surgery. The drug has received FDA Breakthrough and Fast Track Designations. Veverimer is an oral, non-absorbed hydrochloric acid binder that was acquired from Tricida. We are currently evaluating veverimer in preclinical models and analyzing historical data to further our understanding of its clinical profile with a goal of identifying an indication for evaluation in clinical trials. Renibus has three additional assets at earlier stages of development. For more information, please visit the Company's website at and engage with us on LinkedIn. Investor and Media Contact: Amy Conrad Juniper Point [email protected] 858-914-1962 Business Development Contact Jamie Donadio CFO, Renibus [email protected] SOURCE Renibus Therapeutics

Phase 3Fast TrackPhase 2Breakthrough Therapy

18 Apr 2024

·www.prnewswire.com

Renibus Therapeutics Announces Oral Presentation on RBT-1 at the European Association for Cardio-Thoracic Surgery (EACTS) 2nd Innovation Summit

SOUTHLAKE, Texas, April 18, 2024 /PRNewswire/ -- Renibus Therapeutics® ("Renibus"), a clinical-stage biopharmaceutical company focusing on the prevention and treatment of cardio, renal and metabolic diseases, today announced an oral presentation on RBT-1 at the prestigious, invitation only, European Association for Cardio-Thoracic Surgery (EACTS) 2nd Innovation Summit, taking place in Paris, France, April 18-20, 2024. Charles A. Mack, MD, FACS, Associate Professor of Cardiothoracic Surgery and Vice Chairman of Quality and Patient Safety, New York-Presbyterian Hospital, Weill Cornell Medicine, will be presenting on behalf of Renibus. RBT-1 (stannic protoporfin / iron sucrose) is a single dose, multi-organ, preconditioning agent that is administered intravenously 24-48 hours prior to patients undergoing elective cardiac surgery. RBT-1 is actively enrolling in a Phase 3 pivotal trial to reduce the risk of post operative complications and improve outcomes following cardiothoracic surgery. RBT-1 has received FDA Breakthrough and Fast Track Designations. "Presenting at EACTS enables Renibus to share our promising RBT-1 results with the global cardiothoracic surgery community," stated Jeffrey Keyser, RPh, JD, PhD, President and CEO of Renibus. "In a completed Phase 2 clinical trial, RBT-1 demonstrated the potential to improve outcomes in the post-cardiac surgery setting, including reductions in 30-day hospital readmission rates, time in the ICU, as well as time on ventilator. We continue to advance RBT-1 through the Phase 3 PROTECT study, with top-line data expected in the third quarter of 2025." Charles A. Mack, MD, FACS, Associate Professor of Cardiothoracic Surgery, New York-Presbyterian Hospital, Weill Cornell Medicine, added, "RBT-1 is an exciting pre-conditioning agent and I am honored to showcase its results at EACTS. While RBT-1 has demonstrated its potential benefit across multiple cardiac surgery types in its Phase 2 clinical trial, I look forward to presenting data demonstrating RBT-1's potential to have a greater impact on patients undergoing more complex procedures combining both CABG and valve surgeries where the risk of post-operative complications is greatest." Details of the oral presentation at EACTS 2nd Innovation Summit: Title: RBT-1: A Pharmacologic Approach to Reducing the Risk of Post-Operative Complications in Patients Workshop Group: Future of Extracorporeal circulation. Hypothermia in CT surgery Date and Time: Friday, April 19, 2024, 15:55 Presenter: Charles A. Mack, MD, FACS, Associate Professor of Cardiothoracic Surgery, New York-Presbyterian Hospital, Weill Cornell Medicine About RBT-1 RBT-1 (stannic protoporfin/iron sucrose) is a potent inducer of anti-inflammatory and antioxidant pathways currently in Phase 3 [NCT # 06021457] for its lead indication to reduce post-operative complications following cardiothoracic surgery. Renibus completed the Phase 2 study of RBT-1 (NCT04564833) in February 2023 and announced positive final results from this study in May 2023. In October 2023, Renibus initiated enrollment and administration of RBT-1 in its PROTECT Phase 3 pivotal study. RBT-1 was granted Breakthrough Therapy designation status from the U.S. FDA to reduce the risk of complications in patients undergoing cardiothoracic surgery. About Renibus Therapeutics Renibus is a clinical stage biopharmaceutical company dedicated to treating, improving, and extending patients' lives by developing products to prevent disease progression, improve outcomes and protect against organ damage associated with cardio, renal and metabolic diseases. Renibus' first-in-a-new class lead program is RBT-1 (stannic protoporfin / iron sucrose), a single dose IV drug that is given over 1-2 hours, 24-48 hours prior to patients undergoing elective cardiac and/or valve surgery. It is in a Phase 3 pivotal trial to reduce the risk of post operative complications and improve outcomes following cardiothoracic surgery. The drug has received FDA Breakthrough and Fast Track Designations. Veverimer is an oral, non-absorbed hydrochloric acid binder that was acquired from Tricida. We are currently evaluating veverimer in preclinical models and analyzing historical data to further our understanding of its clinical profile with a goal of identifying an indication for evaluation in clinical trials. Renibus has three additional assets at earlier stages of development. For more information, please visit the Company's website at and engage with us on LinkedIn. Investor and Media Contact: Amy Conrad Juniper Point [email protected] 858-914-1962 Business Development Contact Jamie Donadio CFO, Renibus [email protected] SOURCE Renibus Therapeutics

Phase 2Phase 3Fast TrackBreakthrough Therapy

02 Apr 2024

·www.prnewswire.com

Renibus Announces Participation at the 23rd Annual Needham Virtual Healthcare Conference

SOUTHLAKE, Texas, April 2, 2024 /PRNewswire/ -- Renibus Therapeutics® ("Renibus"), a clinical-stage biopharmaceutical company focusing on the prevention and treatment of cardio-renal and metabolic diseases, today announced its participation in the 23rd Annual Needham Virtual Healthcare Conference, being held in a virtual format, April 8-11, 2024. Company management will meet with investors in one-on-one meetings during the conference. About Renibus Therapeutics Renibus is a clinical stage biopharmaceutical company dedicated to treating, improving, and extending patients' lives by developing products to prevent disease progression, improve outcomes and protect against organ damage associated with cardio, renal and metabolic diseases. Renibus' first-in-a-new class lead program is RBT-1 (stannic protoporfin / iron sucrose), a single dose IV drug that is given over 1-2 hours, 24-48 hours prior to patients undergoing elective cardiac and/or valve surgery. It is in a Phase 3 pivotal trial to reduce the risk of post operative complications and improve outcomes following cardiothoracic surgery. The drug has received FDA Breakthrough and Fast Track Designations. Veverimer is an oral, non-absorbed hydrochloric acid binder that was acquired from Tricida. We are currently evaluating veverimer in preclinical models and analyzing historical data to further our understanding of its clinical profile with a goal of identifying an indication for evaluation in clinical trials. Renibus has three additional assets at earlier stages of development. For more information, please visit the Company's website at and engage with us on LinkedIn. Investor and Media Contact: Amy Conrad Juniper Point [email protected] 858-914-1962 Business Development Contact Jamie Donadio CFO, Renibus [email protected] SOURCE Renibus Therapeutics

Phase 3Fast Track

100 Deals associated with Veverimer

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Indication	Highest Phase	Country/Location	Organization	Date
Acidosis	NDA/BLA	US	Tricida, Inc.	04 Sep 2019
Chronic Kidney Diseases	Phase 3	US	Tricida, Inc.	26 Sep 2017
Chronic Kidney Diseases	Phase 3	BG	Tricida, Inc.	26 Sep 2017
Chronic Kidney Diseases	Phase 3	HR	Tricida, Inc.	26 Sep 2017
Chronic Kidney Diseases	Phase 3	HU	Tricida, Inc.	26 Sep 2017
Chronic Kidney Diseases	Phase 3	RS	Tricida, Inc.	26 Sep 2017
Chronic Kidney Diseases	Phase 3	SI	Tricida, Inc.	26 Sep 2017
Chronic Kidney Diseases	Phase 3	UA	Tricida, Inc.	26 Sep 2017

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Study	Phase	Population	Analyzed Enrollment	Group	Results	Evaluation	Publication Date


NCT03390842 (Pubmed) Manual	Phase 3	Acidosis \| Chronic Kidney Diseases	77	Veverimer	yswgdyplre(rqbtpdwfyv): P-Value = 0.0002 View more	Positive	25 Feb 2022
				Placebo
NCT03390842 (CTgov)	Phase 3	Chronic Kidney Diseases	196	TRC101 (TRC101 Treatment Arm)	xfhgmzgbme(cxvlxpoglo) = eiztfdltes hwbhdpzdld (pvvmuorepb, ecqxhwylpk - voqagzfqaq) View more	-	22 Oct 2021
				Placebo (Placebo Treatment Arm)	xfhgmzgbme(cxvlxpoglo) = dwxnlqjwtc hwbhdpzdld (pvvmuorepb, dvvbunsakg - tixtsqrjhk) View more
NCT03317444 (CTgov)	Phase 3	Chronic Kidney Diseases	217	TRC101 (TRC101 Treatment Arm)	mfozhdojsb(dheqaehwcf): Treatment difference in % of subjects = 36.7 (95% CI, 23.5 - 48.9), P-Value = < 0.0001; Treatment difference in % of subjects = 34.5 (95% CI, 21.2 - 46.8), P-Value = < 0.0001; Treatment difference in % of subjects = 33.1 (95% CI, 19.7 - 45.6), P-Value = < 0.0001 View more	-	26 Apr 2021
				Placebo (Placebo Treatment Arm)
ASN2020	Phase 3	Chronic Kidney Diseases	196	Veverimer	avdqbbfxvy(dmvflptwzu) = significantly improved in the veverimer group (+12.5 v +0.3, P <0.001) cdescaduic (bicrwvbozu )	Positive	19 Oct 2020
ASN2020	Phase 3	-	193	Veverimer	hyyhbkmctx(oluashjjiz) = ehxqjkxphn qbuhnevlck (equenrndzv )	Positive	19 Oct 2020
ASN2020	Not Applicable	-	-	Veverimer	mtvhwqashh(rwczotfbau) = ijlgfqtjoz zikattmepb (hycradgfga )	Positive	19 Oct 2020
ASN2020	Phase 3	-	217	Veverimer	mgjjmedhpg(gbymxdksyk) = improved both KDQOL-PFD scores and RCS time oljnrtkcnz (hincghyhor ) View more	Positive	19 Oct 2020
Phase 3 randomized, blinded, placebo-controlled trials (ASN2020)	Phase 3	Chronic Kidney Diseases	217	Veverimer	elycbzuzhd(nazmdcsgcn) = oorjmclvbw nutveniozd (iezzqtnafv )	Positive	19 Oct 2020
ASN2020	Phase 1	-	46	Veverimer	iwstwurban(drgbclagxt) = nrezsscueq kfnzwltgad (wwdlxuklvb )	Positive	19 Oct 2020
				Omeprazole	iwstwurban(drgbclagxt) = plpxafunce kfnzwltgad (wwdlxuklvb )
ERA2020	Phase 3	Chronic Kidney Diseases	196	Veverimer	esgscdhvip(vxblgjuqcr) = rzcpzzhfnu zdjleplret (tvmxeknfuz ) View more	Positive	06 Jun 2020
				Placebo	esgscdhvip(vxblgjuqcr) = yfydjyqazk zdjleplret (tvmxeknfuz )

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