Promise in Chronic Kidney Disease for 3 New Agents

Agents from three novel drug classes showed promising safety and efficacy in patients with varying severity of chronic kidney disease (CKD) in three phase 2 studies recently `presented at the European Renal Association Congress.

Eight weeks of treatment with runcaciguat (Bayer), a soluble guanylate cyclase activator, led to a greater than 40% reduction in albuminuria from both baseline and compared with placebo in people with type 2 diabetes, regardless of whether they also received background treatment with a sodium-glucose cotransporter 2 (SGLT2) inhibitor. This was a randomized 8-week study of 170 patients with CKD and an abnormally elevated urinary albumin-to-creatinine ratio (UACR).

A second study randomized 248 people with CKD and type 2 diabetes to treatment with cotadutide (AstraZeneca), a dual agonist to receptors for two nutrient-stimulated hormones, glucagon and glucagon-like peptide-1 (GLP-1), for 26 weeks and found that cotaditude safely led to average UACR reductions of 45%-51% compared with placebo.

The third study tested a novel antithrombotic agent osocimab (Bayer), an antibody that inactivates factor XIa from the intrinsic pathway of the coagulation cascade. In 704 randomized patients with end-stage kidney disease on hemodialysis, a monthly injection of osocimab for up to 12 months cut clotting risk by 29%-34% and reduced the incidence of major or clinically relevant non-major bleeding events.

Runcaciguat Restores Renoprotective cGMP Signaling

Runcaciguat, an oral agent taken daily, activates guanylate cyclase, which then restores cyclic GMP and the latter’s reno-protective effect against oxidative stress, explained Ronald T. Gansevoort, MD, PhD, a nephrologist and professor at University Medical Center, Groningen, The Netherlands.

The CONCORD phase 2 study randomized 170 adults who were at least 45 years old with an estimated glomerular filtration rate (eGFR) of 25-60 mL/min/1.73m2, a UACR of 30-3000 mg/g, established atherosclerotic cardiovascular disease or mild-to-moderate heart failure, and either type 2 diabetes or hypertension to runcaciguat or placebo. Patients receiving runcaciguat went through four weekly scheduled dose up-titrations to a maximum daily dose of 120 mg, followed by a 4-week maintenance phase. The primary endpoint was change in UACR from baseline in a morning spot void after 3, 4, and 8 weeks on treatment (average of the three time points).

Almost all patients were on a stable, maximally tolerated dose of an angiotensin-converting enzyme (ACE) inhibitor or angiotensin-receptor blocker (ARB).

Among 63 patients with type 2 diabetes not treated with an SGLT2 inhibitor, the 44 patients who received runcaciguat had an average drop from baseline in UACR of 41% after 3, 4, and 8 weeks on treatment compared with a 7% increase among the 19 patients who received placebo.

Runcaciguat Cut UACR by More Than 40% From Baseline

Among the 58 patients with type 2 diabetes receiving an SGLT2 inhibitor, the 45 patients taking runcaciguat had an average drop from baseline in UACR of 46% compared with a 4% average increase among the 13 controls. And among the 47 patients without type 2 diabetes, the 38 who received runcaciguat had an average drop from baseline in UACR of 45%, but the 11 controls had an even larger average drop in UACR of over 60%.

Gansevoort cautioned that the change among patients without diabetes who received placebo might have been a chance finding given the small number in this subgroup.

Treatment with runcaciguat also showed a modest reduction in systolic blood pressure (among all patients receiving active agent) — with an average drop of 3 mmHg from baseline — compared with an average 2 mmHg rise among controls; a small rise in average heart rate (3 vs 0.5 beats/min); a small reduction in average eGFR (-2 mL/min/1.73m2 vs 2 mL/min/1.73m2), and a modest decrease in A1c (-0.3 percentage points vs no change).

Runcaciguat was also “well-tolerated,” said Gansevoort, with 80% of patients taking runcaciguat able to titrate up to the highest daily dose, with mild or moderate treatment-emergent adverse effects occurring in 69% of patients receiving runcaciguat and 53% of controls. Serious adverse events occurred in 6.5% of those taking runcaciguat and 8.5% of controls. Overall, Gansevoort said the safety profile showed “no safety concerns.”

Cotadutide Works as a Dual Agonist

Cotadutide follows the path blazed by tirzepatide (Mounjaro), the first FDA-approved single molecule to act as a dual agonist to the receptor for two different nutrient-stimulated hormones. Like tirzepatide, cotadutide has an agonist effect on the GLP-1 receptor, but unlike tirzepatide the second hormone receptor is a glucagon receptor agonist. Because cotadutide has a 12-hour half-life, it is administered as a daily injection.

The study randomized 248 adults with type 2 diabetes and CKD with an eGFR of 20-90 mL/min/1.73m2 and a UACR > 50 mg/g. All patients were taking an ACE inhibitor or ARB, and more than 40% were taking an SGLT2 inhibitor. Patients received any one of three daily doses of cotadutide, or the GLP-1 agonist semaglutide (Ozempic) as a 1-mg/week injection, or placebo. Treatment continued for 26 weeks but the primary endpoint was change in UACR compared with baseline after 14 weeks.

Cotadutide reduced UACR after 14 weeks in a dose-dependent manner, ranging from about 25% with a 100-µg daily dose, to about 45% with a 300-µg daily dose, and to about 50% with a 600-µg daily dose, reported Viknesh Selvarajah, MBChB, PhD, medical director of AstraZeneca in Cambridge, UK. The average reduction in UACR was about 10% reduction from baseline with placebo. The two highest cotadutide doses maintained these levels of UACR reduction out to 26 weeks on treatment. Cotadutide treatment had little apparent effect on eGFR.

Adverse events leading to treatment discontinuation occurred in 4% of patients on each of the two lowest cotadutide doses, but in 21% of those on the highest dose, as well as in 8% of controls who received placebo and in 16% of those who received semaglutide. Most cotadutide adverse events were gastrointestinal in nature, particularly nausea and vomiting. Incidence rates among patients receiving the highest cotadutide dose were similar to rates in patients who received 1-mg semaglutide weekly.

Osocimabs Potential as a Safer Anticoagulant

Given the elevated risk for both thrombotic events and major bleeds among patients with end-stage kidney disease on hemodialysis, researchers are searching for new approaches to anticoagulation such as osocimab, which dampens intrinsic coagulation by inhibiting factor XIa.

The CONVERT phase 2b study randomized 704 stable adults on hemodialysis to receive a low loading and maintenance dose of osocimab, or a twofold higher dose, or placebo for at least 6 months and for an extended duration of up to an additional 6 months. Roughly 85% of patients continued for a full 12 months on treatment.

Participants’ median age was 61 years old, median duration of dialysis was about 4 years, and about 38% of randomized patients also had type 2 diabetes. Overall, 96% received heparin for anticoagulation, and 40% also received low-dose aspirin.

The primary safety outcome was the incidence of major or clinically relevant non-major bleeding events, which occurred in 6.9% of patients taking the low-dose regimen, 4.9% of those who received the higher osocimab dose, and in 7.8% of controls who received placebo, said Wolfgang C. Winkelmayer, MD, ScD, chief of the section of nephrology at Baylor College of Medicine in Houston, Texas. The incidence of serious treatment-emergent adverse events was similar across the three treatment groups.

Researchers assessed efficacy by the incidence of partial or complete clotting, which was reduced by 29% among patients in the low-dose group compared with placebo, and by 34% among patients in the high-dose group compared with placebo, both significant differences.

This and other exploratory efficacy findings “are consistent with osocimab providing antithrombotic effects beyond those of heparin,” Winkelmayer said.

So far, no final decisions have been made about the types of patients on hemodialysis who might be the focus of pivotal trials, said Winkelmayer.

“People on dialysis have so many different types of thromboembolic events that it may make sense to see whether it benefits patients with very high cardiovascular disease risk who are undergoing dialysis,” he concluded.

The CONCORD and CONVERT studies were funded by Bayer, the company developing runcaciguat and osocimab. The cotadutide study was funded by AstraZeneca. Selvarajah is an employee of AstraZeneca. Gansevoort has reported receiving research funding from AbbVie, Bayer, AstraZeneca, Galapagos, Otsuka, Roche, and Sanofi-Genzyme. Winkelmayer has reported receiving personal fees from Akebia, Ardelyx, AstraZeneca, Bayer, Boehringer Ingelheim, GlaxoSmithKline, Lilly, Merck, Unicycive, and Zydus.

European Renal Association Congress. Abstract 3000. Presented June 16 and 17, 2023.

Mitchel L. Zoler is a reporter for Medscape and MDedge based in the Philadelphia area. @mitchelzoler

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