Targeted Drug First to Show Real Promise in IgA Nephropathy

Pam Harrison

June 12, 2020

Atacicept (Merck Serono) is showing promise as a targeted treatment for patients with IgA nephropathy and persistent proteinuria, interim results from a small phase 2 efficacy and safety trial show.

IgA nephropathy "is a slowly progressive disease that affects young adults, with the likelihood that they will end up needing dialysis or transplantation in their 40s or early 50s, so the disease has a significant impact," said Jonathan Barratt, MD, PhD, honorary consultant nephrologist, John Walls Renal Unit, Leicester General Hospital, United Kingdom.

"Our standard treatment is to control blood pressure and reduce proteinuria with the ACE inhibitors and the ARBs, but then it's very controversial whether anything else works in IgA nephropathy that is safe," he told Medscape Medical News.

Atacicept, an investigational drug that inhibits B-cell activation and the production of immunoglobulin (Ig)G, at least in vitro, is the first drug of any kind to directly interfere with the pathology that gives rise to the disease.

It "is hitting the tap essentially at the very beginning of the cascade," Barratt explained during his presentation at the virtual European Renal Association–European Dialysis and Transplant Association 57th Congress.

In this small study, "I think the signal is strong enough to get excited and want to take this further," he added.

Interim Analysis

The interim analysis looked at 24-week results in the 16 study participants who had IgA nephropathy and persistent proteinuria, defined as a 24-hour urine protein to creatinine ratio of at least 1 mg/mg despite maximal standard-of-care therapy.

The main study goal was to evaluate the ability of atacicept to reduce pathogenic galactosylated polymeric IgA1 (Gd-IgA1) levels and its safety.

An excess of Gd-IgA1 in the circulation is the primary substrate for the formation of immune complexes. Circulating IgA-containing immune complexes are deposited in the kidneys where they trigger glomerular inflammation and tubulointerstitial scarring.

The primary study end point was change in persistent proteinuria from baseline to week 48. Six patients were randomly assigned to a once-weekly subcutaneous injection of atacicept 25 mg, five to atacicept 75 mg, and five to placebo.

"Notably, all patients had a recent kidney biopsy and, as expected, all were taking either an ACE inhibitor or an ARB, and one-quarter had been previously treated with systemic corticosteroids," Barratt reported.

Baseline estimated glomerular filtration rates (eGFR) were similar in the three treatment groups. Levels of serum immunoglobulin and of Gd-IgA1 were, as expected, elevated in all study participants.

At 24 weeks, there was a dose-dependent response in proteinuria from baseline: an 18.7% reduction in the 25 mg atacicept group, a 25.3% reduction in the 75 mg group, and a 0.1% increase in the placebo group.

"There was also a consistent, dose-dependent reduction in serum immunoglobulins," Barratt said.

For example, in the 75 mg group, the median reduction from baseline in IgA levels was about 50%, in IgG levels was about 30%, and in IgM levels was close to 70%.

"Particularly striking," though, was the dose-dependent 60% reduction in median Gd-IgA1 levels, "suggesting that atacicept is capable of substantially reducing the major precursor for immune complex formation in IgA nephropathy," Barratt said.

This supports the idea that atacicept could be most useful at diagnosis, when it could "switch the tap off" for Gd-IgA1 production and the consequent immune complex formation, and reduce subsequent scarring of the kidneys, he said.

No severe treatment-related adverse effects were seen at 24 weeks, and no safety signals were identified.

These findings "provide an early proof-of-concept for atacicept in the potential treatment of patients with IgA nephropathy and persistent proteinuria," Barratt concluded.

Debate Over Immunosuppressive Therapy

There has been a long debate over whether immunosuppressive therapy is effective in IgA nephropathy, but immunosuppressive therapy has been shown to reduce proteinuria and prevent progression to end-stage renal disease, said Lucia Del Vecchio, MD, from Alessandro Manzoni Hospital in Lecco, Italy.

"Steroids have also been found effective in several studies and are recommended in KDIGO guidelines in patients at risk for progression," she told Medscape Medical News.

Disappointingly, rituximab, which targets the CD20 found on virtually all B-cells, has not been shown to be effective in IgA nephropathy, she said.

The reduction in proteinuria seen at 24 weeks in this study suggests that atacicept might well be effective in IgA nephropathy, but Del Vecchio cautioned that the sample size is "definitely too small" to draw any conclusions from the data.

Still, the "sharp and dose-dependent" reduction in Gd-IgA1 levels seen in response to atacicept is the most interesting finding from the study, she said.

The study was sponsored by Merck and Darmstadt Germany. Barratt reports having served as a consultant for Aduro Biotech, Novartis, Calliditas, Visterra, Omeros, Alnylam, Retrophin, Astellas, and EMD Serono, and having received research grants from Retrophin, Aduro Biotech, Visterra, and Novartis. Del Vecchio has served on advisory boards for DOC, Roche, Astellas, and GlaxoSmithKline, and has served as a speaker for meetings supported by DOC, Roche, Astellas, and Vifor Pharma.

European Renal Association–European Dialysis and Transplant Association (ERA-EDTA) 57th Congress: Abstract MO039. Presented June 8, 2020.

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