Aritinercept

Aritinercept Is a Dual BAFF/APRIL Inhibitor for the Potential Treatment of Autoimmune Diseases

Aritinercept contains a B cell maturation antigen (BCMA)-engineered extracellular binding domain optimized for superior affinity to B cell-activating factor (BAFF) and a proliferation-inducing ligand (APRIL) (other dual BAFF/APRIL inhibitors use transmembrane activator and CAML interactor [TACI]-engineered extracellular binding domain). BCMA has a stronger natural affinity for APRIL than TACI. ^a

Aritinercept contains an immunoglobulin (Ig) G4 fragment crystallizable region (Fc) domain with no appreciable effector function (other dual BAFF/APRIL inhibitors use IgG1 Fc domain). IgG4 is considered the least inflammatory across the IgG subclasses, in part because it poorly activates the complement system. ^b

^a Mathur et al., J Clin Med 2023
^b Oskam et al., Front Immun 2023

3D molecular diagram illustrating the structure of Aritinercept, a fusion protein.

Role of BAFF and APRIL

BAFF and APRIL are important cytokines that regulate B cell survival and differentiation, whose targets are expressed on B cells at different stages of B cell development. ^a Targeting both BAFF and APRIL depletes a broader set of B cells, including plasma cells, than targeting a single cytokine. Aritinercept may prevent the activation of autoreactive B cells and reduce their numbers and associated immunoglobulins (antibodies) in the body, thereby reducing important drivers of B cell-mediated autoimmune diseases.

Diagram titled “B Cell Maturation” showing the progression of B cell development from hematopoietic stem cells (HSCs) in the bone marrow to differentiated B cells in the periphery and back into the bone marrow.

The antigen-independent phase occurs in the bone marrow and includes:

HSC → Pro B cell → Large Pre B cell (with surrogate light chain and Igα/Igβ) → Small Pre B cell → Immature B cell
The antigen-dependent phase occurs in the periphery and bone marrow and includes:

Immature B cell → Mature native B cell → Memory B cell or Plasma cell
BAFF Dependency is indicated beneath the progression from immature B cell to memory B cell.
APRIL Dependency is indicated beneath the differentiation into plasma cells.
Plasma cell development is described as “Antigen/T cell dependent.”

Antibodies (Y-shaped symbols) are shown on the surface of cells or secreted by plasma cells to indicate immune function.

^a Mathur et al., J Clin Med 2023
‍^b Schrezenmeier et al., J Am Soc Nephrol 2018

Aritinercept Is a High Affinity Dual BAFF/APRIL Inhibitor

Aritinercept has high binding affinity for both BAFF and APRIL as compared to other dual BAFF/APRIL inhibitors.

^a Data on file

Aritinercept Potently Inhibits BAFF- and APRIL-Mediated B Cell Proliferation

Aritinercept potently inhibits both BAFF- and APRIL-mediated B cell proliferation as compared to other dual BAFF/APRIL inhibitors.

^a Data on file

Aritinercept Single Ascending Dose (SAD) Study: Design

The study investigated aritinercept doses of 5 mg, 25 mg, 75 mg, 150 mg, 225 mg and 300 mg and placebo, administered by subcutaneous injection, in 61 healthy subjects.

Screening (up to 5 weeks), In-Clinic Phase (1 week) and Out-Patient Visits (13 weeks)

SC=subcutaneous

Aritinercept SAD Study: Safety Summary

Aritinercept was well tolerated at all dose levels tested. There were no treatment-related Grade ≥3 adverse events (AEs), there were no treatment‑related serious adverse events (SAEs) and there were no discontinuations due to treatment-related AEs. There was 1 Grade ≥3 AE and 1 SAE (same event) of concussion due to motor vehicle accident reported as not treatment related. AEs that occurred in more than one subject included injection site reactions (24% aritinercept, 13% placebo), headache (11% aritinercept, 7% placebo), upper respiratory tract infection (7% aritinercept, 0% placebo) and back pain (4% aritinercept, 0% placebo). All injection site reactions were Grade 1.

Anti‑drug antibodies (ADAs) were detected in the majority of subjects at dose levels of 25 mg and higher. The presence of ADAs was not associated with any changes in safety, pharmacokinetic or pharmacodynamic parameters.

Aritinercept SAD Study: Single Doses of Aritinercept Led to Robust and Long-Lasting Reductions in Immunoglobulins in Humans

Single doses of aritinercept led to robust and long-lasting reductions in immunoglobulins (antibodies). Specifically, mean reductions from baseline to Day 28 of up to 48%, 55% and 20% were observed for IgA, IgM and IgG, respectively. Pharmacodynamic effects are supportive of once-monthly dosing.

Effect of a Single Dose of BAFF/APRIL Inhibitors on IgA, IgM and IgG

Below are comparative results of the reduction in immunoglobulins IgA, IgM and IgG, respectively, between aritinercept and other BAFF/APRIL inhibitors.

^aThe figures and tables above represent cross-trial comparisons of SAD studies. No head-to-head clinical studies have been conducted. Adapted from Davies et al., Clin Trans Sci 2024 (povetacicept); Zhang et al., ClinPharm Drug Dev 2023 (sibeprenlimab); Willen et al., Eur J Drug Metab Ph 2020 (atacicept); Xie et al., Clin Pharm Drug Dev 2022 (telitacicept). Dose levels for povetacicept, sibeprenlimab, atacicept and telitacicept represent dose levels selected by respective sponsors for Phase 3 development.
^b There was no apparent reduction in serum IgG levels following single-dose atacicept at any of the tested doses

Summary and Next Steps

Aritinercept was well tolerated at all dose levels tested. Single doses of aritinercept led to robust and long-lasting reductions in immunoglobulins supportive of once-monthly dosing. Aurinia plans to initiate clinical studies of aritinercept in two autoimmune diseases by the end of 2025.