From June 12 to June 15, 2024, the EULAR conference, one of the most prominent in the worldwide rheumatology and immunology community, was held in Vienna, Austria's capital. During the conference, rheumatoid arthritis remains a significant focus among rheumatological indications. Rheumatoid arthritis is among the highly investigated autoimmune diseases. The market is dominated by anti-TNF, interleukin inhibitors, and JAK inhibitors. Among the currently approved advanced classes, growth of anti-TNF, T-cell inhibitors and B-cell inhibitors are expected to be relatively flat, mainly due to the entry of biosimilars, which ultimately leads to erosion of sales value and lack of potential emerging candidates from these classes. There is a need for a better treatment alternative/new classes to treat Rheumatoid Arthritis. At the EULAR 2024 conference, several companies presented their data. We have highlighted some of the most important abstracts.

1. Emergence of Bispecific Antibodies: A Promising Frontier in Therapeutic Innovation

One notable development in the Rheumatoid Arthritis space is AstraZeneca's bispecific antibody for rheumatoid arthritis, AZD1163 (PAD2/4 bispecific antibody), which is currently in the pipeline. Although no bispecific antibody has been approved for rheumatoid arthritis yet, the approval of AZD1163 could be a game-changer. However, it is still early to predict outcomes as the company presented preclinical data at the conference in OP0110 abstract, with the first human trial data expected in healthy volunteers in 2025.

In the preclinical data, AZD1163 has shown efficacy in inhibiting PAD activity in neutrophils without causing activation. Its favorable pharmacokinetic and pharmacodynamic profile in these studies suggests potential clinical utility. Anti-citrullinated autoantigens are produced by PAD enzymes, primarily released by neutrophils. Inhibiting PAD activity is a potential therapeutic strategy, leading to the development of the PAD2/4 bispecific antibody. Although still in its early stages, AZD1163 has demonstrated promising results in inhibiting PAD activity in the serum and synovial fluid of rheumatoid arthritis patients, marking a significant advancement in potential treatments for the disease. The proof of concept for this compound indicates it could be a valuable addition to the rheumatoid arthritis therapeutic landscape, warranting further attention as it progresses through preclinical development.

It is worth noting that in addition to AstraZeneca, IGM Biosciences is also conducting a Phase Ib clinical study (NCT06087406; Recruiting) to evaluate their bispecific antibody, Imvotamab (CD20 x CD3 bispecific antibody T cell engager [TCE]) for the treatment of Rheumatoid arthritis. It will be fascinating to watch how the bispecific antibody space evolves in rheumatoid arthritis.

2. Olokizumab showed Long-term Remission in Patients Transitioning from IL-6 Receptor Inhibitors

The next abstract, OP0052, presented on June 12, 2024, at EULAR, focuses on enhancing IL-6 inhibition through the long-term efficacy and safety of transitioning to Olokizumab. 

For the treatment of rheumatoid arthritis, R-Pharm has been granted market authorization for olokizumab (ARTLEGIA) in many countries (Russia, Kazakhstan, Belarus, Kyrgyzstan and Azerbaijan).  Currently approved IL-6 receptor antagonists, such as tocilizumab and sarilumab, have significantly improved clinical outcomes for rheumatoid arthritis. The favorable efficacy and safety profile of tocilizumab has accelerated the development of biosimilars and new potent IL-6 receptor inhibitors.

Olokizumab has demonstrated promising efficacy in Phase III trials, with its safety profile supported by open-label extensions. This suggests that direct IL-6 inhibitors could play a critical role alongside existing treatments for managing rheumatoid arthritis. Clinical improvements with olokizumab were notable, with 74.8% and 84.0% of patients achieving remission or low disease activity based on DAS28-CRP scores at 6 and 12 months, respectively. Similar improvements were observed using DAS28-ESR scores, with 70.5% at 6 months and 81.0% at 12 months. These results position olokizumab as a viable alternative with a promising efficacy and safety profile for managing rheumatoid arthritis.

3. Kiniksa’s Abiprubart Provided Promising Implications of Targeting CD40/CD154 Costimulatory Interaction in Autoimmune Disease, including Sjogren's disease

Abiprubart shows promise in refractory rheumatoid arthritis with a significant reduction in DAS28-CRP in the OP0036 abstract presented at the conference. Treatment with abiprubart (anti-CD40 monoclonal antibody), led to a statistically significant reduction in DAS28-CRP at Week 12 for patients with refractory rheumatoid arthritis in the 5 mg/kg weekly subcutaneous dosing group compared to placebo. Sustained administration of abiprubart was well tolerated and exhibited a pharmacokinetic profile suitable for practical chronic subcutaneous dosing. 

However, Kiniksa has prioritized abiprubart clinical development in Sjogren's disease. The company believes that these Phase II results show abiprubart to be a potentially effective and well-tolerated treatment option for a number of autoimmune diseases, including Sjogren's disease. The comparable magnitude of reduction in Rheumatoid Factor observed across weekly, biweekly, and monthly dosing and supportive post-hoc analysis of pooled efficacy data reinforce confidence that abiprubart is highly active. 

4. Sequential treatment with RTX/ABA did not eliminate auto-antibody production and attenuated disease activity

The Phase II open-label study investigating rituximab followed by abatacept in anti-citrullinated protein antibodies (ACPA)-positive rheumatoid arthritis patients aimed to induce humoral immune tolerance and achieve a "deep" immunological remission presented in OP0069 abstract in EULAR 2024. Patients who received rituximab treatment followed by randomization into two groups (rituximab/abatacept and control), it was found that none of the participants experienced seroconversion, indicating no significant impact on autoantibody production. The rituximab/abatacept group showed higher anti-CCP2 antibody levels at 52 weeks compared to the control group, with no significant difference after adjusting for baseline levels. Disease activity, measured by DAS-28 ESR, did not significantly differ between the groups at 52 weeks.

The study's findings do not provide much optimism for the rituximab/abatacept sequence because they are not significantly positive.

5. In head-to-head comparison with tocilizumab, VDJ-001 showed impressive data

Last but not least is data from Phase II study of VDJ-001 was also presented at EULAR 2024 (Abstract ID #OP0079). VDJ-001, which is a novel humanized IgG1 monoclonal antibody engineered to improve upon the therapeutic index of tocilizumab. Both doses of 6mg/kg and 4mg/kg of VDJ-001 were found to be safe and well-tolerated, with most experiencing mild adverse reactions (grade I-II). Their safety profile was similar to that of the group treated with tocilizumab. Compared to a placebo group with less than 60% responders, patients treated with either a dose of VDJ-001 or Tocilizumab showed significantly improved efficacy (p <0.05) in achieving an ACR20 response (over 80% responders). 

The study's findings that VDJ-001 is both safe and effective in rheumatoid arthritis patients, coupled with a notable ACR70 response rate of 33.3%, highlight its potential as a best-in-class treatment. Currently, approved medications have a relatively low ACR70, and improving the ACR70 response rate is a particular issue in patients with moderate to severe Rheumatoid Arthritis who do not respond well to methotrexate or DMARDS. This positions VDJ-001 as a promising option for patients seeking more effective rheumatoid arthritis management, marking a noteworthy step forward in autoimmune disease therapy.