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Terlivaz (Terlipressin) to Improve Kidney Function in Adults with Hepatorenal Syndrome

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Disease Burden and Clinical Landscape

Hepatorenal syndrome (HRS) is an extreme manifestation of progressive kidney function deterioration in patients with advanced liver disease. This is most common in those with advanced cirrhosis and ascites.1 HRS is further subdivided into several types that are generally differentiated by disease course i.e. HRS Type 1 (HRS-1), known more recently as HRS-acute kidney injury (HRS-AKI), or HRS Type 2 (HRS-2), which is further divided into HRS-acute kidney disease (HRS-AKD) and HRS-chronic kidney disease (HRS-CKD).2,3 

  • HRS-1 or HRS-AKI is characterized by an abrupt deterioration of renal function whereby serum creatinine doubles or rises by at least 0.3 mg/dl within 48 hours and/ or urine output of fewer than 0.5 ml/kg of body weight is observed over at least 6 hours.2
  • HRS-AKD and HRS-CKD are associated with more gradual impairment in renal function and refractory ascites resistant to diuretics. Classification is based on the estimated glomerular filtration rate (eGFR) rather than serum creatinine.2

The diagnosis of HRS-1 confers a relatively short survival period. Literature indicates mortality rates range from 36% to 100%, with the risk increasing if there are delays in therapy.4,5 While the only curative therapy is a liver transplant, which corrects both liver disease and associated impaired renal function, timely diagnosis and early effective management of HRS-1 is critical as pharmacological treatment can improve short-term outcomes and bridge time to liver transplantation. 

The pathophysiology of HRS relates, in part, to the splanchnic vasodilation characteristic of cirrhosis with portal hypertension, leading to systemic hemodynamic effects that manifest as vasoconstriction of the renal arterial system, renal hypoperfusion and a decrease in glomerular filtration rate.6 The rationale for use of vasoconstrictors in HRS is thus an attempt at reverting splanchnic vasodilation and its consequences. In clinical practice today, vasoconstrictors employed in the management of HRS include terlipressin, noradrenaline and the combination of midodrine and octreotide. Terlipressin represents the most used and tested drug in the therapeutic algorithm and is considered first-line pharmacological therapy for HRS whenever available, and in the absence of contraindications.7–9 Noradrenaline, although less costly, remains limited by its requirement for administration in an intensive care setting. Midodrine and octreotide are observed to be inferior to terlipressin regarding HRS reversal10, and their use is not well supported by high-quality evidence.11

In Singapore, Glypressin® (terlipressin acetate) is routinely employed in clinical practice and is approved for use by the Health Sciences Authority (HSA) for the treatment of ‘bleeding oesophageal varies and the ‘treatment of patients with HRS-1 who are actively being considered for liver transplant’.12

US FDA approval and the Phase III CONFIRM trial 

For decades, however, terlipressin firmly eluded market authorisation in the United States despite its routine use in Europe and Asia to treat HRS-1. The drug has also been recommended by the American Association for the Study of Liver Diseases (AASLD) and the American College of Gastroenterology (ACG) as a treatment option for people with HRS. In September 2022 following a fast-track priority review, the US FDA approved its first terlipressin molecule, Terlivaz, to improve kidney function in adults with HRS with a rapid reduction in kidney function.13 The therapeutic has received an orphan drug designation and expands the historically limited treatment armamentarium in the United States.

US FDA approval was attained, in part, based on results from the Phase III CONFIRM trial, the largest-ever prospective study (n=300) conducted to assess the safety and efficacy of terlipressin in patients with HRS-1 in the US and Canada.14 The CONFIRM trial met its primary endpoint of Verified HRS Reversal, defined as renal function improvement, avoidance of dialysis and short-term survival. Further, the efficacy of terlipressin, compared with placebo, in reversing HRS-1 was observed to be more pronounced among the subgroup of patients with systemic inflammatory response syndrome. A summary of the study is presented in the table below. 

In terms of safety, however, terlipressin is associated with serious adverse events (AEs). More AEs, including abdominal pain, nausea, diarrhoea, and respiratory failure, occurred with terlipressin than with a placebo. An excess of early respiratory failure contributed to poor outcomes in the terlipressin arm, and pooled analysis with previous trials indicated that patients with entry serum creatinine levels ≥ 5 mg/dL were particularly likely to experience harm with terlipressin treatment.15 In addition, death within 90 days due to respiratory disorders occurred in 11% of patients in the terlipressin group, as compared with 2% of patients in the placebo group. Although terlipressin improves kidney function, patients with advanced liver disease may nonetheless continue to have other complications of decompensated cirrhosis unrelated to HRS-1 and die from these complications.

Population Intervention/ Comparator Efficacy Outcomes Safety Outcomes
N=300
A trial was conducted between Jul 13, 2016, and July 24, 2019, at 60 sites in the US and Canada
Average age: 54yMean serum creatinine level: 3.5 mg/dl
Randomized 2:1 to receive 0.85mg of terlipressin (N=199) or placebo (N=101) every 6 hours as an intravenous injection for up to 14 days
Concomitant use of albumin was strongly recommended in both groups (83% in the terlipressin group and 91% in the placebo group) 
Primary endpoint

  • Verified reversal of HRS: 63 patients (32%) in the terlipressin group and 17 patients (17%) in the placebo group (p=0.006)

Secondary endpoints

  • HRS reversal: 78 patients (39%) in the terlipressin group and 18 (18%) in the placebo group (p<0.001)
  • HRS reversal among patients with systemic inflammatory response syndrome: in 31 of 84 (37%) patients in the terlipressin group and 3 of 48 patients (6%) in the placebo group (p=0.001)
  • Verified reversal of HRS without recurrence by day 30: 52 (26%) of patients in the terlipressin group and 17 (17%) of patients in the placebo group (p=0.08)
  • At day 90, liver transplantation was performed in 46 (23%) of patients in the terlipressin group and 29 (29%) of patients in the placebo group
  • The most commonly observed adverse reactions in at least 4 per cent of patients treated with Terlivaz compared to placebo were abdominal pain (19.5% vs. 6.1%), nausea (16% vs. 10.1%), respiratory failure (15.5% vs. 7.1%), diarrhoea (13% vs. 7.1%) and dyspnoea (12.5% vs. 5.1%).
  • Death within 90 days due to respiratory disorders occurred in 22 patients (11%) in the terlipressin group and 2 patients (2%) in the placebo group

Untreated HRS-1 is often fatal, with a median duration of survival of weeks to months. Vasoconstrictors play an essential role in the current management of HRS and the landmark US FDA regulatory approval provides access to physicians and critically ill patients in the United States who historically have had limited treatment interventions. Notwithstanding important advances, nearly half of treated patients do not recover and further developments are still needed in this field of research.

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