Is there a new trend in the journal world: publication of interim analysis (IA) results?
The NEJM recently published two articles back to back, both highlighting 9 month ‘interim’ data from Phase 3 pivotal trials in IgAN. The primary efficacy endpoint used in either study was UPCR at 9 months, a de-facto surrogate for eGFR stabilization [1],[2]. We are talking about sibeprenlimab and atacicept, of course, an APRIL and BAFF/APRIL inhibitor, respectively.
Such interim demonstration of efficacy was acceptable to Regulators in the past as they gave conditional approval to iptacopan / Fabhalta based on 9-mo UPCR data; a recent press release claims that iptacopan also had positive effects on eGFR after 2 yrs of treatment [3]. This was the path also taken by sibeprenlimab / Voyxact which obtained conditional approval in Nov 2025; for this drug, long-term 2-yr GFR data are still pending. Going back further, the same pattern is seen with the approvals for budesonide / Tarpeyo and sparsentan / Filpari, in both cases UPCR was the trigger for submission and conditional approval.
FDA always reserves the option to revoke an approval if the eGFR data do not show a benefit over placebo. This is reasonable: why would we expose patients to drugs that just lower proteinuria but otherwise have no impact on kidney function. For regulators, UPCR is just an ‘interim’ step, albeit an important one. For them, the primary endpoint remains eGFR even if sponsor protocols list UPCR as primary efficacy endpoints.
Does this twisted nomenclature make sense? We usually associate an IA with decision-making before enrollment is complete. The question usually asked at the time of an IA: is there a need for sample size adjustment? Should a trial be stopped for futility? Here, however, we use the term IA like an interim endpoint for a co-primary result. The terms ‘interim’ and ‘primary’ take on a slightly different meaning from the traditional way we use those terms.
What is the chance that a positive early UPCR signal may be followed by a negative late GFR read-out? We believe this risk is small but not negligible. Consider the following:
- for budesonide and sparsentan, the Kaplan-Meier graphs for UPCR show in both cases show impressive improvements in albuminuria/proteinuria. However, neither drug has much of an impact on eGFR decline (see sparsentan graph below)
- we are dealing with 2 assumptions in series, in a nested concatenation: First, we assume that eGFR decline over 2-yrs is an early predictor of kidney failure, and second, that ΔUPCR at 9-mos is a useful surrogate for eGFR decline after 2-yrs.
- UPCR and eGFR are not tightly correlated. In their press release Novartis did not provide the new iptacopan 2-yr eGFR data from the APPLAUSE-IgAN study [3]. We interpret this as a sign that the results are anything but stellar!
Nonetheless, UPCR is a useful predictor for eGFR decline according to various Expert Panels that reviewed the existing trial data. However, it is a weak relationship: In a recent review by Heerspink (48 studies of 85,681 patients!), the correlation coefficient (or R2) was only 0.68.[5] This is not exactly a tight corrrelation as can easily be seen in the graph below (showing the relationship between change in albuminuria and ‘clinical endpoint’). However, ttreatments that reduce UACR by at least 25% have “a high probability of reducing the risk for the clinical endpoint”.
For Sponsors, positive data on UPCR data are the ticket for submiission and key to early market access. Of course, companies recognize the residual risk – perceived as small – that a study may fail at the 2-yr timepoint.
Now the tacicepts have their turn, submitting their ‘interim’ results for FDA review in quick succession. All 3 of them were able to reduce UPCR after 6 months by >25%, usually by 40-55%. Therefore, the chance of approval looks good, indeed, good right now, barring any surprises.
APRIL or BAFF / APRIL inhibitors have consistently shown potent IgA lowering. These drugs do not stop the decline in kidney function; they do change the downhill trajectory. Expect a flatter slope, a moderate improvement but not a reversal of damage already done.
In the world of available interventions for IgAN, the next battle will be among the BAFF/APRIL inhibitors. Timing is key: The IA data for atacicept look good; the PDUFA date is July 26, 2026. Povetacicept has BTD status and – with good data and a rolling submission – its PDUFA date should be in mid-2026 too. In contrast, telitacicept does not show up on the FDA’s 2026 PDUFA list.
There is fierce competition at work here; the IgAN market is new territory and underserved. We sense the spirit of yet another Olympic style race. Citius, altius, fortius, taciceptius! For sponsors, the interim UPCR data are most important in the marketing battle now, and GFR benefit 2 years later is assumed.
Does this sound mockingly cynical to you? It should not. We are now leaving the clinical arena behind entering Wall Street territory. We become spectators to the high stakes game played by sponsors and investors.
There are a few secondary beneficiaries of this Olympic spectacle too: publishers vying for breaking news, academics adding a NEJM article to their CVs. Guidelines for IgAN will be rewritten by experts at the ASN and other societies; advertising campaigns will test marketing concepts getting ready for the launch.
The enthusiasm is palpable; a new era is dawning for CKD patients. We chime in with more Greek and Olympic hyperbole calling it a time for dithyrambic* bacchanalian drunkenness. Make this: Dionysian!
Such euphoria is understandable, but let’s not forget the bigger picture and what really matters. How big actually is the benefit provided by BAFF/APRIL inhibitors when administered on top of optimized ACE/ARB/SGLT2 therapy? Neither paper presented 9-month GFR data although available. Why FDA asked that this information to be withheld from being published is not clear to us. The data is already unblinded as the UPCR read-out already happened.
Ultimately, we want to know whether these drugs can delay the need for dialysis. On this key information, the jury is still out. The excellent editorial by Tonelli in the NEJM comes to a similar conclusion [4]. Next, are these drugs worth the exorbitant price (sibeprenlimab is about USD 390k / year)?
Just as we were about to post this blog, yet another NEJM article was published on IgAN and today’s topic. In the large Phase 3 APPLAUSE-IgAN study, iptacopan, a complement Factor B inhibitor, showed improvement in eGFR over placebo at the 2-yr mark, with a delta compared to placebo of 3.02 mL per minute per 1.73 m2 per year.[6]
While statistically significant (p<0.001), we are not terribly impressed with the effect size. As a reminder, the 9-mo UPCR reduction with iptacopan was only 26.4% better than the placebo control, much less than seen with any of the BAFF/APRIL inhibitors. A slightly higher number of (serious) infections was observed, as to be expected with a complement inhibitor.
Not sure, how long the applause will last…
* dithyrambic = exuberant
** supposedly per FDA request
ABBREVIATIONS
ACE angiotensin-converting enzyme
APRIL a proliferation-inducing ligand
ARB angiotensin-receptor blocker
ASN American Society of Nephrology
BAFF B-cell activating factor
BTD break-through designation
CKD chronic kidney disease
eGFR estimated glomerular filtation rate
IA interim analysis
IgAN IgA nephropathy
PDUFA prescription drug user fee amendment
PI package insert / label
SGLT2 sodium-glucose transport 2 inhibitor
UACR urinary albumin to creatinine ratio
UPCR urinary protein to creatinine ratio
REFERENCES
[1] Lafayette R. A Phase 3 Trial of Atacicept in Patients with IgA Nephropathy. N Engl J Med 2026;394: 647
[2] Perkovic V. Sibeprenlimab in IgA Nephropathy — Interim Analysis of a Phase 3 Trial. N Engl J Med 2026;394: 635
[3] https://www.novartis.com/news/media-releases/novartis-fabhalta-iptacopan-meets-phase-iii-primary-endpoint-slows-kidney-function-decline-patients-iga-nephropathy-igan
[4] Tonelli A. Targeting the Pathogenesis of IgA Nephropathy — A New Treatment Approach? N Engl J Med 2026; 394:712
[5] Heerspink H. A meta-analysis of albuminuria as a surrogate endpoint for kidney failure. Nature Medicine 32, 2026: 281
[6] Barratt N. Iptacopan in IgA Nephropathy —Final 24-Month Data. NEJM 2026, DOI: 10.1056/NEJMoa2600743
