How 72-Week Data Informs Nephrologists on Potential of Atacicept in IgA Nephropathy, with Richard Lafayette, MD

Richard Lafayette, MD
Credit: Stanford Healthcare

After years of watchful waiting as kidney function deteriorated, the last half decade has seen an explosion in the pipeline of potential treatment options for IgA nephropathy.

In late 2021, the nephrology community witnessed the first approval of an agent for management of the rare glomerular disorder when the US Food and Drug Administration awarded an accelerated approval to oral budesonide (Tarpeyo). Then, in late 2023, oral budesonide made history once, becoming the first agent to receive full approval for reducing the loss of kidney function in adults with primary IgA nephropathy.

In the background, multiple additional agents have been progressing through clinical programs, such as sparsentan (Filspari), atrasentan, sibeprenlimab, iptacopan, atacicept, and others.

Now, less than a month into 2024, the community is once again celebrating positive data—this time, the 72-week open label extension data from atacicept in the phase 2b ORIGIN trial. Announced by Vera Therapeutics on January 25, 2024, results from the OLE portion of the trial complement data from the 36-week blinded treatment period, which indicated 80% of those receiving atacicept 150 mg experienced hematuria resolution compared to 5% of the placebo group and 82% of those using atacicept 150 mg reduced serum Gd-IgA1 to the lowest risk quartile.

“The demonstration of stable eGFR well beyond a year in participants receiving atacicept represents an important potential advancement for IgAN patients and has potential implications for the future treatment paradigm in this disease," said phase 2b ORIGIN's lead investigator Richard Lafayette, MD, professor of medicine and director of the Stanford Glomerular Disease Center at Stanford University Medical Center.

In their release highlight open-label extension data, Vera Therapeutics suggested those treated with atacicept for 72 weeks experienced a 62% reduction in Gd-IgA1, a reduction in the percentage of participants with hematuria to 19%, and a 48% reduction in UPCR in the per-protocol analysis. Further analysis suggested those who switched from placebo to atacicept after 36 weeks experienced a 59% reduction in Gd-IgA1, a reduction in the percentage of participants with hematuria to 41%, and a 47% reduction in UPCR during the open-label extension period in the per-protocol analysis.

To learn more about how the 72-week data further informs nephrologists on the potential effects of atacicept in patients with IgA nephropathy while the community awaits data from the phase 3 ORIGIN 3 trial, HCPLive Nephrology sat down with Lafayette and that conversation is the subject of the Q&A found below.

Richard Lafayette, MD, on Interpreting 72-Week ORIGIN OLE Data

HCPLive: Although the data was positive, there appeared to be mixed reaction to the 72-week OLE data from the phase 2b ORIGIN trial. What was your reaction to the data and why does this mean for patients?

Lafayette: So, I would just start by saying that data is tremendously exciting. What the 72-week data gives us is several things. First, the 36-week data had shown pretty clearly that the drug had the potential to be antiproteinuric, to be disease-modifying (in that it lowers galactose deficient IGA very efficiently) and can reduce hematuria in line and in association with that reduction of galactose deficient IGA. So, that was all great at 36 weeks, but really the sweetest thing at 36 weeks was the absolute stability of the kidney function. While the control group was progressing, as had been seen in other phase 3 and phase 2 programs with patients with significant kidney risk where patients were losing about 6 to 8 mLs per minute per year of kidney function. So, the 36-week data, that was super exciting.

Now, in these next 36 weeks, what we see is that patients who stay on the drug do really, really well, first, and maybe most importantly, they stay in the program. So, we don't see dropouts, patients are able to tolerate the weekly injections, and there were not any adverse events that were out of proportion to what we would expect with patients with chronic kidney disease. So ,the drug does not seem to be causing issues that are unexpected and does not cause infections, which is all really nice.

Secondly, we see that the antiproteinuric effect is maintained and somewhat intensified, going from reductions of nearly 40% to reductions of nearly 50%, which is also great. We see more patients resolving hematuria, we see the galactose deficient IGA levels down, which is what's expected, and again, most importantly, now we're out to a year and a half and patients have the same kidney function that they started with—really, really wonderful. Now we've lost the control group, because they all went out to active drug among those who stayed in study, but we have another handful of patients demonstrating that the drug reduces their proteinuria by about 40%. Even their GFR, which was allowed in the first nine months to go down further than baseline, it absolutely stabilizes with a trendline going back up and recovering what they had lost in those 9 months.

So again, now you have another small group of phase 2 patients, showing the drugs effective at reducing proteinuria hematuria and stabilizing kidney function. Obviously, we'll look for the 2-year data to show continued stability of all those measures and that's only six months away. So, hopefully it will achieve that.

I think it compares favorably to short term use of oral budesonide. In that the proteinuria can be kept down and continue going down while on drug. Oral budesonide, according to the label, has to stop after 9 months, but people will try extending oral budesonide. Compared to other phase 2 programs of B-cell modulation, this is the first drug with data a year and a half out. So, it is the best and boldest, which is very exciting.

There is still an open issue, whether the idea of dual BAFF and APRIL will outperform APRIL alone, butas the first to show long-term complete stabilization of GFR, this is as exciting as it can be. I will be surprised if I don't have people clamoring to join this study, and to sort of get compassionate use of the drug because, again, it's as good as it gets. So, it's really exciting.

HCPLive: Does the full approval of oral budesonide raise the bar for new therapies in terms of burden of proof?

Lafayette: I would say more that it sets the bar that you need to show a prolonged improvement in GFR progression rate. There is still a little uncertainty for IgA nephropathy development, whether or not, with a fully approved drug which does stabilize GFR, whether or not the FDA will still give early approval on the basis of data that suggests a robust progeria reduction. I suspect they will, because that's where they've gotten to so far with the two approved drugs for oral budesonide and sparsentan, but I know there is lots of uncertainty in the community about whether or not they really want to see that GFR signal to be sure. At least with this program with the B-cell modifying drug, combined BAFF and APRIL, we do see an early and, now, sustained signal of GFR preservation. Again, that's what the bar will be for full approval for sure and the fact that this extension study now takes these patients all the way to 72 weeks and takes another group of brand-new patients that show stabilization of GFR out to nine months, it just makes the risk very, very much lower, that phase 3 won't work. So, I think it is really exciting.

HCPLive: How exciting, after so many years with limited options, to see so much progress in the pharmacotherapies for IgA nephropathy?

Lafayette: It's super exciting and when you combine that with the aspect of complement blockers being available soon, and maybe at a price we can afford, as a way to really dampen down acute inflammation, you really do have this belief that in a year and a half, maybe 2 years, we'll have lots of tools. Then, we can really individualize the therapy and we can really push the community to identify these patients early and well and then risk stratify them and start treatment. The profound hope is that we really can slow progression of kidney disease and, with agents that actually completely flatlined progression, maybe patients can have the option of never developing kidney failure. It's very, very exciting.

Relevant disclosures for Lafayette include Aurinia, Callidatas, Complexa, Mallinckrodt, Omeros, Pfizer, and others.

References:

1. Brooks A. FDA awards full approval to Budesonide (Tarpeyo) in treatment of IGA nephropathy. HCP Live. December 20, 2023. Accessed February 1, 2024. https://www.hcplive.com/view/fda-awards-full-approval-to-budesonide-tarpeyo-in-treatment-of-iga-nephropathy.
2. Campbell P. 72-week phase 2B origin data highlight potential benefit of ATACICEPT in IGA nephropathy. HCP Live. January 25, 2024. Accessed February 1, 2024. https://www.hcplive.com/view/72-week-phase-2b-origin-data-highlight-potential-benefit-of-atacicept-in-iga-nephropathy.