dm+d

Unassigned

New Medicines

Metabolic acidosis in patients with chronic kidney disease

Information

New molecular entity
Tricida
Tricida

Development and Regulatory status

Phase III Clinical Trials
Phase III Clinical Trials
Not approved
Feb 21Company receives an Appeal Denied Letter (ADL) from the Office of New Drugs (OND) of the FDA in response to its FDRR [10]
Dec 20Company presentation suggests that if the FDA rejects the FDRR, VALOR-CKD data are unlikely to support re-submission before mid-2022 (probability of trial stopping at first interim analysis <5%). No information given on intentions outside the US [9].
Dec 20The company have submitted a Formal Dispute Resolution Request (FDRR) to the FDA, requesting that the surrogate measure used in the TRCA-301 and TRCA-301E trials is found to be reasonably likely to predict clinical benefit and can therefore serve as a basis for accelerated approval. They expect an answer during Q1 2021. If the request is refused, an application would be made on the basis of results from the VALOR-CKD trial [7].
Aug 20The US FDA have issued a complete response letter seeking additional data beyond the TRCA-301 and TRCA-301E trials regarding the magnitude and durability of veverimer on serum bicarbonate levels and and the applicability of the treatment effect to the US population. They expressed concern as to whether the demonstrated effect size would be reasonably likely to predict clinical benefit. There were no safety or clinical issues identified. Tricida plans to request a Type A meeting with the FDA, expected to take place in Q4 2020 after which the company will provide an update on next steps and estimated timing of a potential resubmission of the NDA.[6]
Nov 19Tricida announce FDA acceptance of NDA for veverimer to treat metabolic acidosis in patients with CKD. FDA have assigned a PDUFA date of 22/8/20 [5].
Mar 19Tricida plans to submit a New Drug Application (NDA) in the second half of 2019 [1], (no info about Europe).

Category

Non-absorbed, orally-administered polymer
Metabolic acidosis becomes more common with advancing stages of CKD. The prevalence of a serum bicarbonate concentration of <22 mEq/L, for example, is <5% in CKD stages 1 and 2 and increases linearly to approximately 25% in patients with non-dialysis dependent CKD stage G5 [2].
Metabolic acidosis in patients with chronic kidney disease
Oral

Trial or other data

Aug 19PIII extension study (NCT03390842; n=196) is published; the authors report that compared with placebo, fewer patients on veverimer discontinued treatment prematurely (3% vs 10%, respectively), and no patients on veverimer discontinued because of an adverse effect [4]. In a related commentary, authors highlight that in the parent 12-week randomised, blinded, placebo-controlled trial of patients with chronic kidney disease and metabolic acidosis, veverimer significantly increased serum bicarbonate concentration, with minimal side-effects. Authors state these extension study results confirm veverimer safely and effectively corrected metabolic acidosis and improved subjective and objective measures of physical function.
Jul 19PIII RCT (NCT03390842RCT; n=196) reports at week 52, more patients on veverimer vs placebo had an increase in bicarbonate (≥4 mmol/L or normalisation, 63% vs 38%, p=0.0015) and higher bicarbonate concentrations were observed at all time-points starting at week 1 (p<0.001) [3].
Mar 19PIII TRCA-301 clinical trial (NCT03390842) achieved both its prespecified primary and secondary endpoints. After 12 weeks of treatment, the primary endpoint, the proportion of patients achieving a ≥4 mEq/L increase from baseline in blood bicarbonate at Week 12 or a blood bicarbonate in the normal range, was met by 59.2% of patients in the TRC101-treated group compared to 22.5% of patients in the placebo group (p<0.0001) [1].

Evidence based evaluations