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Future Therapeutics for Rheumatoid Arthritis and Lessons Learned - RNL2021 Highlights

Mar 24, 2021 1:16 pm

In case you missed it, RheumNow Live 2021 delivers what it promises: a good consistent program pack with high energy interactive learning. In the Day 1 learning pods, the audience was given a tour of the new drugs in development for RA. Several noteworthy ones were highlighted by Dr. Roy Fleischmann as listed below:  

Interleukin receptor associated kinase 4 (IRAK4) inhibitors.  IRAK4 is a key signaling kinase for toll-like and IL-1 receptors. PF-06650833 (Pfizer) is a reversible IRAK4 inhibitor that demonstrated in a 12-week exploratory phase 2b study1 statistically significant dose dependent efficacy compared to placebo; ACR50 scores were 40-48% with 200 and 400 mg/day dosing; adverse events were comparable to placebo, but 3 cases of zoster was noted in the study drug.  

GM-CSF inhibitors. GM-CSF induces monocyte and macrophage survival, differentiation, polarization, and enhances the release of inflammatory cytokines within the joints. Elevated levels of GM-CSF and GM-CSF-R are found in inflamed synovial fluid and tissue of RA patients. Mouse models have shown that neutralization of GM-CSF/GM-CSF-R improves inflammatory arthritis. In a phase 2b study2 of RA patients who are methotrexate incomplete responders (MTX-IR), otilimab, a GM-CSF inhibitor that targets GM-CSF-chemokine (C-C motif) ligand 17 (CCL17), showed significant responses in clinical scores (ACR 20/50/70 and EULAR responses) as well as pain scores. 

Therapeutic nanoparticles. Despite their tiny sizes, nanoparticles are drawing excitement as they can exert enormous effects on the immune system.  A chitosan-hyaluronic acid nanoparticle has been developed with the ability to block antibodies to pathogenic citrullinated proteins and peptides (ACPAs) using neutrophil recruitment as a delivery mechanism to inflamed joints. First in its class, Cy5.5 aptamer-nanoparticle had >50% reduction of disease activity using only 1 nM drug every 48 hours in a collagen induced RA mouse model compared to placebo (N=30; p<0.001); it also reduced IL6 and TNFa levels in mice sera with effects confirmed in the serum transfer arthritis model. These effects were not inferior compared to tocilizumab treated controls3. Clinical studies in humans are anxiously awaited. 

Despite the excitement with new drug development, Dr. Fleischmann emphasized that it is unlikely a medication with a new mechanism of action will be approved this year or even next year.   

He also weighed in on the following treatment considerations:  

  1. RA guidelines might be outdated already. Both recent ACR and EULAR RA treatment guidelines recommended starting a biologic (bDMARD) or targeted synthetic DMARD (tsDMARD) after methotrexate (MTX) based on studies conducted prior to 2019. More recent studies have demonstrated better responses with starting a tsDMARD or using combination bDMARD with MTX. Monotherapy can be effective but in few patients; JAK inhibitor (JAKi) and tocilizumab (TCZ) would be preferable for monotherapy. Note that JAKi with MTX is at least effective as TNFi with MTX.   
  2. The recent FDA communication on tofacitinib should be balanced with historical data.   On February 4, 2021, the FDA issued a Drug Safety Communication that tofacitinib (TOFA) show an increased risk of serious heart-related problems and cancer compared to TNFi.  This communication was based on preliminary results from the Pfizer 1133 study.  Before we condemn TOFA, Dr. Fleischmann wanted us to consider historical data and sets up this argument: RA patients with active disease have greater risks for major adverse cardiovascular events (MACE) and veno-thrombotic events/pulmonary embolism (VTE/PE). The Pfizer 1133 study specifically recruited patients > 50 years old with at least 1 cardiovascular risk factor (e.g., history of coronary disease, smoker, obesity, etc).  In the study, the non-inferiority criterion for these events was not met for the combined TOFA doses compared to TNFi due to the upper limit of the 95% confidence interval (CI) of the incidence ratio exceeding the prespecified upper limit (e.g, TOFA upper limit of 95% CI was 1.94, prespecified study upper limit was 1.8). No lower limit of the confidence interval was prespecified, but in all TOFA doses, the confidence interval crossed 1.0 for MACE, VTE/PE, and malignancy. Most MACE were related to myocardial infarction (MI), and the most frequently reported malignancy was lung cancer. Not surprisingly, subjects with a higher prevalence of MACE risk factors and malignancy (e.g, older age, current smokers) have higher occurrences of events across all treatment groups.  When looking at historical controlled trials, long term extension data, and registry data, the risk for MACE, VTE/PE and malignancy were not higher for TOFA compared to bDMARD.  Additionally, Dr. Fleischmann noted that incidence of MACE, VTE/PE were lower with TNFi in the Pfizer 1133 study compared to historical data for this class of drug. So, is there a signal? The FDA noted that TOFA should be avoided in patients who may be at increased risk of thrombosis. Would you do this if this is the best drug for the patient? 


1. ACR 2019 Abstr#2909 

2. ACR 2019 Abstr#535 

3. ACR 2020 Abstr#1453 


The author has no conflicts of interest to disclose related to this subject

Rheumatologists’ Comments

Keshav Raj Sigdel

| Mar 24, 2021 10:46 pm

Great study , in my experience if used tofa in lower dose Rick of dyslipidemia, venous thromboembolism is lower . However, we need to keep consideration of the MACE and regularly monitor. Combination of TOFA with MTx is helpful to control the disease activity .

what is MACE

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