Today we discuss the group of BAFF/APRIL inhibitors, specifically the three TACI mAb constructs that are currently in development. They were tested in a broad gamut of B-cell indications but failed to show efficacy in many. So far, consistent clinical success has been seen only in IgA nephropathy (IgAN), with an average reduction in proteinuria by half. Alpine Immune Sciences’ povetacicept also had commercial success; it was acquired by Vertex for $4.9 billion in 2024.
The field of nephrology did not attract much attention by pharma companies for a long time, maybe because so many SLE and lupus nephritis trials failed. But things are changing. A better understanding of the pathophysiology of IgAN and MN and the demonstration that BAFF/APRIL inhibitors can block B-cell activation in a different manner from rituximab is intriguing enough. The fact that these drugs reduce IgA >> IgG levels in blood certainly rekindled interest in conditions related to IgA. While data convincingly show great improvement in proteinuria, there is still some debate as to whether or not BAFF/APRIL inhibitors can stop the decline in GFR. Phase 2 data indeed look promising, and Phase 3 studies are underway for all of these compounds.
FDA approval hinges on showing improved GFR in patients vs controls, an endpoint that is usually measured at 52 wks. Reduction in protein- or albuminuria is a surrogate 6-month endpoint that is a more sensitive marker and may serve as preliminary evidence of efficacy. This is how iptacopan first obtained interim, then full approval.
Drug development efforts often lead to a better understanding of the diseases under study. IgAN is certainly better understood now than 10 years ago when the first complement inhibitor and endothelin receptor antagonist trials were initiated.
IgAN studies are also a lot easier to conduct – and less risky – than SLE studies. In IgAN there are objective laboratory endpoints, a situation much more attractive than SLE or RA scores. Take the history of SLE studies: how many showed a benefit and how long did it take for approval? We only know of 2 ‘successes’, belimumab and anifrolumab. Both had quite a tortuous pathway to approval, and both barely made it.
The frustrating litany of drug failures in SLE has led to soul-searching by regulators and clinical investigators. Are we using the right outcome measures to assess drug effects? Which disease stage is best selected for study? Are LN patients a more homogeneous group of patients to study? [1]
By contrast, IgAN can claim several recent drug approvals (sparsentan, iptacopan, Nefecon). The regulatory pathway for companies to follow is straightforward and clear.
Improvement in proteinuria is a good thing, as it points to normalization of kidney function which should benefit eGFR. We have not seen a single study in which proteinuria was reduced while GFR worsened
As more data accumulates, FDA may make proteinuria, or UPCR, a surrogate endpoint for approval replacing eGFR
Still, the exact role of B-cells in IgAN is not totally understood. Rituximab, a CD20 mAb, failed in a mid-size IgAN PoC trial [3],[2]. However, its MoA is different from that of BAFF/APRIL inhibitors, which bind to a different receptor (TACI) and – unlike rituximab – suppress immunoglobulin production in long-lived plasma cells. Rituximab is not known to reduce IgA levels but BAFF/APRIL inhibitors (“TACIcepts”) do so consistently, decreasing blood levels by approx. 50%.
There are 3 “TACIcepts” in development: Atacicept, the grand-daddy of them all; telitacicept, the drug that was approved for SLE in China based on very little Phase 3 data, and povetacicept, the most recent player. All 3 compounds have changed hands a few times, which makes for a rather checkered development history. All are essentially similar constructs. We will deal with the purported differences in a later blog.
Atacicept was first tested in B-cell malignancies (multiple myeloma, B-cell lymphoma), and then in SLE and also in RRMS. It failed in all these indications. Almost as an afterthought, it was tested in IgAN as well. In a Phase 2 study of IgAN, the drug showed clear clinical efficacy reducing proteinuria, hematuria, and IgA levels while preserving GFR. Great – but what an Odyssey! It is now undergoing Phase 3 testing.
Telitacicept is already approved in China for SLE. It is now being studied in RA, RRMS, gMG, NMOSD, Sjögren’s and IgAN. In IgAN patients it produced significant reduction in proteinuria, but information for the other indications is sparse. Publications are often in the form of case reports. In pSS, results were discordant with only the lower dose being efficacious. Surprisingly, the only Phase 3 studies active in the US deal are for gMG and SLE. Other indications, including IgAN, are executed in Mainland China [2]
For Povetacicept the literature is still quite limited. Vertex reported an IA of the Phase 1b/2a RUBY-3 IgAN trial, but many details were not shared. In this trial 2 doses were being tested, but it remains unclear if there was a dose response; the lower dose was selected for Phase 3. Povetacicept is under investigation in many other autoimmune diseases as well (MN, LN, ANCA vasculitis, ITP, AIHA, and cold agglutinin disease).
As is often the case in biology, even when a receptor is successfully identified and blocked by an inhibitor, we are often still uncertain about its clinical use. Because animal models are so often misleading, companies start a clinical journey of exploration for the right indication. This leads to a basket trial approach and a series of PoC trials.
Our insufficient knowledge of disease pathology is at the core of these failures. In addition, the intertwined pathways in immunology and the redundancy built into the system still present formidable challenges. We need to get better at this!
We still have a lot to learn about the origins of IgAN
J. FLOEGE [3],[4]
ABBREVIATIONS
APRIL a proliferation-inducing ligand
ANCA anti-neutrophil cytoplasmic antibody
BAFF B-cell activating factor
BLyS B-lymphocyte stimulator (=BAFF)
GFR glomerular filtration rate
gMG generalized myasthenia gravis
IA interim analysis
IgAN IgA nephropathy
LN lupus nephritis
MoA mode of action
NMOSD neuromyelitis optica spectrum disease
PoC proof of concept
pSS primary Sjögren’s syndrome
RA rheumatoid arthritis
RRMS recurrent multiple sclerosis
SLE systemic lupus erythematosus
TACI transmembrane activator, calcium modulator and cyclophilin-ligand interactor
pMN primary membranous nephropathy
UPCR urinary protein/creatinine ratio
REFERENCES
[1] Dolgin E. Lupus in crisis: as failures pile up, clinicians call for new tools. Nature Biotechnol; 37:7, 2019
[2] Clinicaltrials.gov (accessed 5/29/25)
[3] Floege J. Glomerular disease: Rituximab therapy for IgA nephropathy Nat Rev Nephrol . 2017 Mar;13(3):138
[4] Lafayette R. A randomized, controlled trial of rituximab in IgA nephropathy with proteinuria and renal dysfunction. J Am Soc Nephrol. 2016; 28:1306
