Dosing begins in Phase 2 trial for AAV and serious kidney disease

Study of lixudebart enrolling adults with rapidly progressive glomerulonephritis

Lindsey Shapiro, PhD avatar

by Lindsey Shapiro, PhD |

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A first patient has been dosed in a Phase 2 clinical trial testing lixudebart, Alentis Therapeutics‘ investigational antibody therapy, in ANCA-associated vasculitis (AAV) patients with rapidly progressing glomerulonephritis (RPGN), a serious kidney disease.

The study, RENAL-F02 (NCT06047171), currently is recruiting up to 60 adults with AAV and RPGN at sites in six European countries.

It is testing lixudebart at low and high doses, against a placebo, for safety, tolerability, and early signs of efficacy in preserving kidney function. Enrolled patients will remain on standard disease treatments throughout the trial.

“With lixudebart … we explore a truly novel approach in ANCA-RPGN patients,” Luigi Manenti, MD, Alentis’ chief medical officer, said in a company press release.

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“Dosing the first patient … at our hospital brings us a step closer to understanding the potential of lixudebart … to treat patients with this very severe [kidney] disease,” said Per Ivarsen, MD, a professor and trial principal investigator at the Aarhus University Hospital in Denmark. “I am looking forward to the study progressing as more patients are enrolled, and to seeing the results.”

An autoimmune disease, AAV is caused by the production of self-reactive antibodies, called ANCAs, that lead to inflammation and damage small blood vessels. While this can affect multiple organs — AAV has a wide range of disease symptoms — the kidneys that house many small vessels are commonly affected and often severely.

Glomerulonephritis, a serious complication of AAV, is marked by inflammation and damage to the waste filtering units of the kidneys, called glomeruli. This can be accompanied by the buildup of scar tissue, or fibrosis, that further compromises kidney function.

For some, this rapidly leads to declines in kidney function and end-stage kidney disease, where patients require dialysis — a way of filtering the blood when the kidneys are failing — or a kidney transplant.

Existing AAV treatments aim to stabilize the disease’s underlying autoimmune attacks, but new medicines are needed to more quickly prevent kidney decline in patients with RPGN, according to Alentis.

Formerly known as ALE.F02, lixudebart is an antibody designed to target and block claudin-1 (CLDN1), a protein implicated in fibrosis. In fibrotic conditions affecting various organs, the protein is found to have an altered distribution pattern.

Treated patients will be given 13 infusions of lixudebart at a low or high dose

In people with glomerulonephritis, CLDN1 has been found to be increased in the kidneys, where it is believed to contribute to glomerular crescent formation, a type of inflammatory lesion that serves as an indicator of severe glomerular injury.

Alentis expects that by suppressing CLDN1, lixudebart can help to prevent organ damage in AAV-RPGN and other conditions marked by lung, liver, or kidney fibrosis.

Ascending doses of the investigational therapy was found to be well tolerated without serious safety concerns in healthy volunteers in a Phase 1 trial, the company reported. A Phase 1b trial (NCT05939947) to test lixudebart in adults with advanced liver fibrosis also opened this year.

The Phase 2 trial in AAV patients with RPGN “is an important study into the potential of lixudebart … to recover kidney function in patients with severe [kidney inflammation] due to ANCA-associated vasculitis,” said David Jayne, MD, a professor of clinical autoimmunity at Cambridge University in England.

“Chronic and end-stage kidney disease remain common outcomes for patients, and this study will give us our first indication on the safety and efficacy of lixudebart in this population,” Jayne added.

Trial participants will be randomly assigned to 13 infusions of either lixudebart (high or low dose) or a placebo over the course of 24 weeks, or about six months.

All will continue using their standard AAV medications to control kidney inflammation, including glucocorticoids, rituximab, cyclophosphamide, or other immunosuppressants.

The trial’s main goal is to assess the therapy’s safety, with a key secondary goal being changes in estimated glomerular filtration rates after six months. This is a measure of kidney function that assesses how well the kidneys are filtering waste.

Other measures of kidney function, the need for dialysis to support the kidneys, and required doses of other immunosuppressive treatments also will be evaluated. The study is expected to finish in 2025.

“The … trial is a steppingstone to develop lixudebart for other more common [kidney] indications that are characterized by high CLDN1 [levels] such as lupus nephritis​, IgA nephropathy​ and diabetic nephropathy,” Manenti said.