Jardiance-based CKD combo strategy hits setback

Additional clinical benefit compared with vicadrostat deemed unlikely

Remaining EASi Phase III trials, including heart failure studies, to continue

SGLT-2 inhibitor ‘Jardiance’

A combination strategy built around Jardiance has hit a setback in chronic kidney disease (CKD).

After evaluating whether adding the aldosterone synthase inhibitor vicadrostat (BI 690517) to Jardiance (empagliflozin) could further reduce kidney disease progression and cardiovascular risk in CKD, Boehringer Ingelheim concluded that the accumulated clinical data were unlikely to demonstrate meaningful additional clinical benefit.

Development of vicadrostat itself, however, has not been discontinued. The remaining Phase III trials in the EASi program, including studies in heart failure, will continue as planned following reviews by independent data monitoring committees (DMCs).

According to industry sources on the 16th, Boehringer Ingelheim recently decided to discontinue its Phase III EASi-KIDNEY trial.

Boehringer Ingelheim conducted EASi-KIDNEY in collaboration with the University of Oxford. The study compared vicadrostat plus Jardiance with Jardiance alone in patients with CKD to determine whether the combination could further slow kidney disease progression and reduce cardiovascular risk.

Jardiance is an SGLT-2 inhibitor originally developed for type 2 diabetes that subsequently expanded into heart failure and CKD. It is currently used to reduce the risk of cardiovascular death and hospitalization in patients with heart failure, as well as the risks of kidney function decline, end-stage kidney disease, cardiovascular death, and hospitalization in patients with CKD at risk of progression.

In CKD, the large-scale EMPA-KIDNEY trial demonstrated that Jardiance reduced the risk of kidney disease progression or cardiovascular death, establishing the drug as a cornerstone of kidney-protective therapy.

Against this backdrop, EASi-KIDNEY was designed to determine whether adding vicadrostat to baseline Jardiance could further reduce residual renal and cardiovascular risk in patients with CKD.

Low likelihood of additional clinical benefit…CKD Phase 3 discontinued

Vicadrostat is an oral investigational therapy that inhibits aldosterone synthase, thereby reducing aldosterone production.

Aldosterone plays a role in regulating fluid balance and blood pressure, but excessive activation can contribute to renal and cardiovascular damage. The development strategy for vicadrostat therefore centers on directly suppressing aldosterone production further to reduce residual renal and cardiovascular risk despite existing therapy.

Earlier clinical data had shown promise. In a Phase II study in patients with CKD, adding vicadrostat to Jardiance produced an additional reduction in albuminuria, suggesting potential kidney-protective effects.

However, in the Phase III trial assessing actual kidney disease progression and cardiovascular events, the likelihood that this potential would translate into meaningful clinical benefit diminished.

Based on a comprehensive assessment of EASi-KIDNEY data accumulated to date, Boehringer Ingelheim concluded that a clinically meaningful benefit on the primary composite endpoint was unlikely in patients with CKD.

Specific clinical results, including hazard ratios and event rates, were not disclosed in the announcement. The company said further analyses are underway and that the decision to discontinue the study was based on the totality of information currently available.

No new safety signal was cited as the direct reason for stopping the trial. Boehringer Ingelheim said it determined that discontinuation was appropriate after considering the efficacy and safety data available to date, patient safety and scientific rigor.

The decision is separate from the established efficacy of Jardiance itself in CKD. Boehringer Ingelheim said the EASi-KIDNEY findings do not change Jardiance’s approved indications or its established benefit-risk profile.

Remaining EASi Phase III Trials, including heart failure studies, to continue

The decision is limited to EASi-KIDNEY.

The late-stage EASi development program for vicadrostat includes three other phase 3 trials: EASi-HF Preserved, EASi-HF Reduced, and EASi-PROTKT.

EASi-HF Preserved and EASi-HF Reduced are evaluating the addition of vicadrostat to Jardiance in patients with heart failure with preserved or reduced ejection fraction, respectively.

After separately reviewing the data available to date, the DMCs for the respective studies recommended that all three remaining trials continue without modification. Thus, while the CKD arm of the development program has been discontinued, late-stage development of vicadrostat in heart failure and other patient populations will continue.

Vicadrostat remains an investigational therapy and has not been approved in any country.

Lykke Hinsch Gylvin, Chief Medical Officer and head of Global Medicine at Boehringer Ingelheim, said, “There are millions of people around the world living with interconnected cardiovascular, renal and metabolic conditions, and the need for better treatment options remains significant,” reaffirming the company’s commitment to developing new therapeutic approaches in these areas.

Will Herrington, professor at the University of Oxford and lead investigator of EASi-KIDNEY, also expressed disappointment with the outcome while emphasizing that substantial unmet medical need remains in this patient population.