New Data on Terlipressin Presented at DDW 2025

When terlipressin was approved by the FDA in September 2022 to treat hepatorenal syndrome–acute kidney injury (HRS-AKI), it was not only the first medication approved for HRS-AKI but the first for any form of AKI. A synthetic vasopressin analog, terlipressin has been used in other parts of the world for years.

However, the approval was not universally applauded. Questions remained about the drug’s efficacy and adverse events, particularly respiratory failure, which occurred among patients in the CONFIRM trial. In addition, the complexity of the study population made even the trial’s positive findings difficult to interpret. Although CONFIRM met its primary efficacy end point, terlipressin failed to receive FDA approval in 2020, and post hoc analysis was required before the drug’s eventual approval. Notably, use is limited to patients with serum creatinine no greater than 5 mg/dL and the prescribing information includes a black box warning regarding the risk for respiratory failure. 

During Digestive Disease Week (DDW) 2025, which took place May 3-6 in San Diego, California, terlipressin was the subject of five research presentations. Two were post hoc analyses of CONFIRM data, and three focused on real-world data regarding terlipressin use. Nephrology Times spoke with Peter Richardson, BMedSci, BM, BS, MRCP, and George Wan, PhD, MPH, of Mallinckrodt Pharmaceuticals, which markets terlipressin under the brand name Terlivaz, about what the new data (particularly “Improving the Benefit-to-Risk Profile: Efficacy Outcomes in Patients With Hepatorenal Syndrome-Acute Kidney Injury When Selected According to the Terlipressin Prescribing Information” by Curry et al and “A Comparative Analysis of Real-World HRS-AKI Treatment and Outcomes in the UK and US: Raw Clinical Data and Propensity Score-Matched Evidence” by Gonzalez et al) added to the conversation about the drug.

Could you remind us of the CONFIRM data supporting approval of terlipressin for HRS-AKI?

The primary end point of the CONFIRM trial was verified hepatorenal syndrome reversal, which is defined as renal function improvement, the avoidance of renal replacement therapy, and short-term survival. Twenty-nine and one tenth percent of patients treated with Terlivaz, compared with 15.8% of patients receiving placebo, achieved this end point, with the statistically significant P value of 0.012.

To achieve verified hepatorenal syndrome reversal, patients had to have two consecutive creatinine values of less than 1.5 mg/dL at least 2 hours apart while on treatment by day 14 or prior to hospital discharge.

To be included in the primary efficacy end point analysis, patients had to be alive and without intervening renal replacement therapy—for example, dialysis—at least 10 days after achieving verified HRS reversal. In CONFIRM, terlipressin-treated subjects also achieved three out of four of the prespecified secondary end points.

What does the Curry research identifying a label-specific population add to our understanding of terlipressin?

Curry was a post hoc analysis of the CONFIRM trial. The importance of this is really focusing on the appropriate patient population. You mentioned in your question the label-specific population. With this large dataset, 300 patients, it allows us to be able to categorize the different patient subgroups into two. We [identified patients] in the on-label specific population, and we compared that with those that were not. They had to meet three different criteria. The first criterion is that they had to have an ACLF between 0 and 2. ACLF stands for acute-on-chronic liver failure. They also had to have serum creatinine levels under 5 mg/dL. In addition to that, they had to have a MELD score of less than 35, if listed for liver transplant. MELD stands for model for end-stage liver disease.

What we found here was that for patients in the on-label (label-specific) population, the rate of HRS reversal was higher, 44.7% compared to 19.4%. When we also looked at the proportion of patients that were alive without requiring renal replacement therapy, that was also higher at day 30 for terlipressin, at 77.8% versus 61.3%.

These findings emphasize the importance of identifying patients that are appropriate [candidates] for terlipressin to allow us to maximize the benefits while reducing the potential risks of those patients being treated, and ultimately, it reinforces terlipressin’s role in managing those patients with hepatorenal syndrome with rapid reduction in kidney function.

One of the things that we wanted to note as a limitation is, with post hoc analysis of clinical trial data, it’s very valuable when it comes to allowing us to generate research questions, which we could test formally in future research. Therefore, when it comes to the interpretation of results, we have to interpret those with caution, given that these analyses were not prespecified prior to the conduct of the CONFIRM trial.

Gonzalez looked at real-world data comparing terlipressin with standard of care. What does this contribute to the current outlook on terlipressin’s efficacy?

We conducted two separate chart review studies, one in the United Kingdom and one in the United States. In the chart review study of patients that were diagnosed with hepatorenal syndrome, most of those patients were treated with terlipressin—90% of those were treated with terlipressin. When we did the study in the United States—and this was prior to the approval of Terlivaz—we found that 90% of those patients were treated with midodrine and octreotide [M&O]. That allowed us to essentially pool the data using a methodological approach. We call that indirect treatment comparison. Given that there were no direct head-to-head data from clinical trials comparing terlipressin and M&O, by doing so, it allowed us to adjust for different characteristics. We used a technique called propensity score matching, and we matched on several factors, including baseline characteristics as well as baseline serum creatinine levels.

After adjustment, what we did find is that the patients that were treated with terlipressin had higher rates of complete response. We defined complete response as a serum creatinine level of less than or equal to 1.5 and with each of the thresholds it was based on at the end of the study. So, those rates were higher compared to the M&O-treated population. Then when we looked at another outcome measure of HRS reversal, defined as less than or equal to 1.5 in their serum creatinine levels at any time during the observation period, we saw very consistent results. For example, for those patients that achieved HRS reversal, we saw 54% of those patients on terlipressin compared to 24% on M&O. The findings really focus on the importance of terlipressin as an appropriate treatment option for patients with hepatorenal syndrome.

In addition to that, it also is very supportive of the controlled trial data that we saw from CONFIRM. By validating the work that we saw in the controlled clinical trial environment, we are also able to see similar trends in real-world settings. It’s also important to know that, with midodrine and octreotide, though it’s currently being used frequently in the United States, the efficacy and safety of this treatment are not established. It’s not approved for that indication by the US FDA.

It’s also important to note that there are also limitations for this particular analysis and that different clinical markers such as MELD scores, such as ACLF, were not available in the UK dataset. However, it was available in the US. So those specific factors we were not able to use for adjusting for some of the baseline characteristics between the two treatment groups.

Overall, what do the data presented at DDW add to the conversation about terlipressin’s efficacy and potential adverse effects?

The data on terlipressin presented at DDW do confirm what we saw in the pivotal CONFIRM study. Using terlipressin according to the label is important in providing the best results. It contributes to the ongoing conversation around the efficacy and safety of terlipressin in HRS-AKI by absolutely reinforcing the clinical utility while addressing the safety concerns— both in the real world and in the controlled clinical settings of a clinical study.

Overall, the DDW data underscore the importance of terlipressin in the management of HRS-AKI and support its use in appropriate patients. So, please do see the safety information, including the boxed warning in the prescribing information.