ACR CONVERGENCE 2020—At the annual meeting’s second Plenary Session, Saturday, Nov. 7, speakers highlighted phase 2 results of a potential new biologic for systemic lupus erythematosus (SLE), as well as data on remission maintenance in rheumatoid arthritis (RA) after withdrawal of etanercept or methotrexate.
Phase 2 Trial of Monoclonal Antibody for Lupus (LILAC)
Several converging lines of evidence suggest type I interferons play a key role in the pathogenesis of lupus, including recent trials demonstrating clinical effectiveness of anifrolumab, a monoclonal antibody that blocks the type I interferon receptor. Richard Furie, MD, chief of the Division of Rheumatology at Northwell Health, in Great Neck, N.Y., presented promising results from a phase II trial of a different monoclonal antibody, BIIBO59, which interfaces with the pathway through another mechanism.1
Plasmacytoid dendritic cells are responsible for the bulk of type I interferon production in lupus and are abundant in the skin of lupus patients. BIIBO59 is an antibody to a protein unique to these cells, blood dendritic cell antigen 2 (BDCA2). The binding and internalization of the antibody results in inhibition of type I interferon, but also of various cytokines and chemokines, such as IL-6 and TNF-α.
An earlier phase I study of 12 lupus patients with cutaneous disease had demonstrated inhibition of the interferon gene signature, downregulation of an interferon-regulated protein and clinical improvement in skin activity as measured by the Cutaneous Lupus Erythematosus Disease Area and Severity Index-Activity (CLASI-A).2
Participants in the LILAC trial met at least four of the 11 ACR classification criteria, with at least four tender and at least four swollen joints (via 28-joint assessment), active skin disease as defined by the Systemic Lupus Erythematosus Disease Activity Index 2000 (SLEDAI-2K) and positive serology. Sixty-four patients were randomized to receive BIIB059 mg, with another 56 receiving placebo. These were administered every four weeks for 20 weeks, with an additional dose at week two.
Dr. Furie noted the trial met its primary endpoint: “Receipt of BIIB059 was associated with significant reduction in the total active joint count.”
Moreover, the patient group receiving BIIB059 demonstrated a statistically significant improvement in their SLE Responder Index-4 (SRI-4) response rate. Dr. Furie observed, “Like most other [lupus] trials, the driver of the significant and robust SRI response was the four point reduction in SLEDAI.”
A higher number of patients in the BIIB059 group also achieved a 50% reduction in their CLASI-A score, although this did not reach statistical significance. Safety signals were similar between the placebo and treatment groups.
The therapy may also be promising for patients with cutaneous lupus erythematosus (CLE), for which no specifically targeted therapies have ever been developed. Results from part B of the study, which looked at responses in patients with cutaneous lupus erythematosus, were presented later that day in an abstract session by another collaborator, Victoria Werth, MD, a professor of dermatology at the Hospital of the University of Pennsylvania, Philadelphia. Doses of 50 mg, 150 mg and 450 mg BIIB059 given every four weeks for 16 weeks significantly reduced CLASI-A scores at week 16, with a significantly dose-responsive relationship. At week 16, a higher proportion of patients at the 450 mg dose achieved a seven point or greater reduction in CLASI-A compared with placebo.
Withdrawal of Etanercept or Methotrexate During RA Remission
Jeffrey R. Curtis, MD, MPH, a professor of medicine in the Division of Clinical Immunology and Rheumatology at the University of Alabama at Birmingham, spoke about results from the SEAM-RA trial (Study of Etanercept And Methotrexate in RA), which studied the effects of withdrawing methotrexate or etanercept in patients who had been in remission on a combination therapy.3
Dr. Curtis pointed out that for RA patients in sustained remission on a combination therapy, such as methotrexate combined with a TNF-inhibitor like etanercept, it’s not clear if both these therapies need to be used indefinitely. “For someone in their 40s or 50s, having to stay on both of these medicines for what might be decades is a bit of a daunting prospect,” he noted.
Both ACR and EULAR guidelines recommend considering tapering RA medications for patients in sustained remission. “Probably it’s not realistic to expect people to come off all [RA] therapies, but the idea that someone starting on two drugs, combination therapy, might be able to withdraw one of them—that probably would be quite attractive to many patients, as well as clinicians,” said Dr. Curtis. However, the optimal way to approach this has not been clear.
This is not the first RA trial to study the question of therapy withdrawal in patients in remission. Dr. Curtis noted that one aspect that sets this trial apart is the use of a very stringent definition of remission. Before trial screening, patients had been in remission for six months or more on combination therapy of etanercept and methotrexate. During a 24-week lead in period, participants were evaluated several times for remission status, to make sure that they were still in remission, as assessed by the Simplified Disease Activity Index (SDAI).
The 24-week lead-in period included 371 patients, 253 of whom were eventually approved to be in the trial due to their sustained remission status. These participants were randomized into the three trial arms: an etanercept-only arm, a methotrexate-only arm and a continued combination arm. Patient enrollment was a respective ratio of 2:2:1 during the 48-week double-blind phase. Patients with disease worsening, as assessed by specific SDAI values, received combination rescue therapy and were considered non-responders.
The primary endpoint was continued SDAI remission on a single therapy at week 48. Only 28.7% of patients in the methotrexate arm were able to maintain remission at week 48. In contrast, 49.5% of the patients in the etanercept arm had stayed in remission, as had 52.9% of patients on combination medication.
In patients with worsening disease who had needed combination rescue therapy, a high percentage were back in SDAI remission by the end of the one year study (71%, 75%, and 80% in the methotrexate, etanercept and combination arms respectively). Dr. Curtis noted that he found these numbers reassuring as a clinician, “Because the likelihood that you can regain where you were before is quite good.” Dr. Curtis also noted that if disease worsening occurs, it is most likely to happen between three to six months after therapy cessation, based on their data.
Dr. Curtis said, “Similar proportions of patients maintained remission with etanercept monotherapy as compared to continuing with [combination therapy], so the implication is that probably if you are doing that well on both treatments, you can continue etanercept, stop methotrexate, and the majority of those people are going to do just as well.”
Ruth Jessen Hickman, MD, is a graduate of the Indiana University School of Medicine. She is a freelance medical and science writer living in Bloomington, Ind.
- Werth V, Furie R, Romero-Díaz J, Navarra S, et al. BIIB059, a Humanized monoclonal antibody targeting blood dendritic cell antigen 2 on plasmacytoid dendritic cells, shows dose-related efficacy in a phase 2 study in participants with active cutaneous lupus erythematosus [abstract]. Arthritis Rheumatol. 2020 Oct;72(suppl 10).
- Furie R, Werth VP, Merola JF, et al. Monoclonal antibody targeting BDCA2 ameliorates skin lesions in systemic lupus erythematosus. J Clin Invest. 2019 Mar 1;129(3):1359–1371.
- Curtis J, Emery P, Karis E, et al. Maintenance of remission after withdrawal of etanercept or methotrexate in patients with rheumatoid arthritis in sustained remission on combination therapy: Results from a randomized, double-blind, controlled trial [abstract]. Arthritis Rheumatol. 2020 Oct;72(suppl 10).