NKF Roundup: Latest Data on Tolvaptan, Terlipressin, and Lumasiran

AUSTIN, Texas — Some of the latest research advancements in the field of nephrology presented at the National Kidney Foundation (NKF) Spring Clinical meeting included a newly approved non-immunosuppressive agent’s superior proteinuria reduction versus standard IgA nephropathy treatment, spironolactone’s effect on atherosclerosis in people with type 2 diabetes and chronic kidney disease (CKD), and year-long renal function during combination pegloticase (Krystexxa) and methotrexate treatment for gout.

Below are some more scientific highlights from this year’s meeting.

Liver Monitoring With Tolvaptan

No additional liver safety signals emerged during a 4-year post-marketing follow-up of patients prescribed tolvaptan (Jynarque) for autosomal dominant polycystic kidney disease (ADPKD), found Michael Lioudis, MD, of SUNY Upstate Medical University in Syracuse, New York, and colleagues.

Approved in 2018, tolvaptan — a selective vasopressin V2-receptor antagonist — carries a boxed warning on its label about potentially serious and potentially fatal liver injury. Because of this, all U.S-based patients prescribed this agent must enroll in an FDA-required risk evaluation and mitigation strategy (REMS) program to monitor liver safety.

In the REMS, the incidence of severe drug-induced liver injury (DILI) was significantly lower than that seen in clinical trials (0.78% vs 5.5%), for incidence rates of 0.64 and 1.57 per 100 patient-years, respectively (incidence rate ratio 0.408, 95% CI 0.307-0.542, P<0.0001). This lower event rate was most likely due to more frequent liver enzyme monitoring in the REMS, the researchers pointed out.

In the 69 patients (out of 10,737) who did develop possible severe DILI, a third fully recovered by 4 years, 3% were in the process of recovery, 12% didn’t recover, and data weren’t provided on recovery status for 42% of patients. Most DILI events occurred within the first year of treatment. There were no cases of liver transplants or fatalities due to tolvaptan reported.

“Regular liver enzyme monitoring as specified in the tolvaptan prescribing information and the REMS enables prompt detection of liver abnormalities and appropriate action, including repeat testing at greater frequency and potentially tolvaptan withdrawal, to reduce risk of severe outcomes in real-world clinical practice,” the group’s poster read.

Cost-Analysis of Terlipressin

When used in a non-ICU setting, terlipressin (Terlivaz) was found to be cost-effective compared with other treatments for hepatorenal syndrome (HRS).

The agent was approved in September 2022, marking the first drug to nab an indication for hepatorenal syndrome. It works as an injectable synthetic vasopressin analog dosed at 0.85 mg every 6 hours for up to 14 days.

Combination terlipressin plus albumin was significantly better at reversal HRS when compared with midodrine and octreotide plus albumin (55.56% vs 4.76%). That being said, upfront costs were higher for the combination treatment including terlipressin — coming in at $47,401 versus $22,267.

However, because patients treated with midodrine and octreotide plus albumin subsequently faced higher ICU and dialysis-related costs due to low efficacy of treatment, the total cost per response ended up being far lower for patients treated with terlipressin than with midodrine and octreotide plus albumin: $85,315 versus $467,794.

“Two patients need to be treated with terlipressin plus albumin to achieve one HRS reversal versus 21 patients who need to be treated with [midodrine and octreotide] plus albumin,” said Xingyue Huang, PhD, of Mallinckrodt Pharmaceuticals in Bridgewater, New Jersey, and colleagues on their poster.

A similar pattern was seen when terlipressin plus albumin was compared with norepinephrine plus albumin, with total cost per HRS reversal priced at $81,614 versus $139,324. Two patients needed to be treated with terlipressin and albumin to see one HRS reversal versus four treated with norepinephrine and albumin.

Lumasiran in Primary Hyperoxaluria Type 1

The RNA interference therapeutic lumasiran (Oxlumo) continued to reduce urinary oxalate (UOx) long-term in patients with primary hyperoxaluria type 1, according to 36-month findings of the phase III ILLUMINATE-A trial.

In this extension study, patients on lumasiran treated saw a 63% decline in average 24-h UOx from baseline. And for the patients initially treated with placebo during the 6-months double-blind period who then crossed over to lumasiran treatment during the extension phase, there was a 55% average 24-h UOx reduction over the course of their 30-month on-treatment time.

At month 26, 76% of the lumasiran-lumasiran patients and 92% of the placebo-lumasiran patients had a 24-h UOx excretion ≤1.5 times the upper limit of normal. Average drops in plasma oxalate from baseline to month 36 were 36% and 37% in the treatment groups, respectively.

Both groups also saw stable estimated glomerular filtration rates (eGFRs) and medullary nephrocalcinosis also either remained stable or improved, found Jeffrey Saland, MD, of Icahn School of Medicine at Mount Sinai in New York City, and colleagues.

All 39 patients from the two groups were at least age 6 years with genetically confirmed primary hyperoxaluria type 1 and an eGFR ≥30 mL/min/1.73 m².

The 24-month findings were presented at last year’s National Kidney Foundation Spring Clinical Meeting. The extension phase of the trial is slated to run for 54 months. Findings from the ILLUMINATE-C trial, which assessed the treatment in patients with stages 3B through 5 CKD, was presented at the American Society of Nephrology’s Kidney Week in 2021.

Approved in November 2020, lumasiran decreases hepatic oxalate production by inhibiting the production of glycolate oxidase. It is administered subcutaneously and is dosed based on weight with three monthly starting doses, then followed by ongoing monthly or quarterly doses. The most common lumasiran-related adverse event was mild injection site reaction, occurring in 49% of patients.