Aritinercept

Aritinercept (AUR200) 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) (others 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 (others 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 the competitor dual BAFF/APRIL inhibitors.

Table comparing binding affinity (Kd in pM) of Aritinercept versus Atacicept and Telitacicept for BAFF and APRIL targets. Aritinercept, developed by Aurinia, has the highest binding affinity with Kd values of 117 pM for BAFF and 25 pM for APRIL. Atacicept (Vera) has Kd values of 919 pM for BAFF (7.9x lower affinity) and 67 pM for APRIL (2.7x lower affinity). Telitacicept (RemeGen) shows Kd values of 616 pM for BAFF (5.3x lower affinity) and 82 pM for APRIL (3.3x lower affinity).

^a Morales et al., ACR Convergence 2022

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

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

Two line graphs and a comparison table show the effect of Aritinercept, Atacicept, and Telitacicept on B cell proliferation in the presence of BAFF and APRIL. The graphs plot relative luminescence units (RLUs) against drug concentration in nanomolar (nM). Aritinercept (blue circles) shows the most potent inhibition of B cell proliferation compared to Atacicept (orange squares) and Telitacicept (purple triangles). The accompanying table shows Aritinercept has the lowest IC₅₀ values: 0.02 nM for BAFF and 0.37 nM for APRIL. In comparison, Atacicept shows 19x and 5.8x weaker inhibition, and Telitacicept shows 52.5x and 11.2x weaker inhibition for BAFF and APRIL, respectively.

^a Morales et al., ACR Convergence 2022

Aritinercept Reduced Immunoglobulins in Non-Human Primates

After 4 weekly doses, IgA, IgM and IgG were lowered by up to 76%, 67% and 43%, respectively. Aritinercept was well-tolerated with no adverse findings at any of the doses tested.

^a Morales et al., ACR Convergence 2022

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, there were no treatment‑related serious adverse events (SAEs) and there were no discontinuations due to treatment-related adverse events. Adverse events 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.

Aritinercept SAD Study: Pharmacokinetics Summary

A half-life of 6-8 days after a single dose in the target dose range was observed.

^a Geometric mean

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); Willen et al., Eur J Drug Metab Ph 2020 (atacicept); Xieet al., Clin Pharm Drug Dev 2022 (telitacicept); Zhang et al., ClinPharm Drug Dev 2023 (sibeprenlimab). 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

Aritinercept SAD Study: 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 at least two autoimmune diseases in the second half of 2025.