Rheumatoid arthritis

Insights on the long-term use of baricitinib and ixekizumab

Wednesday, 7 Apr 2021


A webcast showcasing long-term efficacy and safety data for both baricitinib and ixekizumab provided the opportunity for local rheumatologists to gain further insights into the data and discuss its relevance to clinical practice.

The webcast was sponsored by Eli Lilly, and the discussion was moderated by Professor Bruce Kirkham, Professor of Translational Rheumatology from Kings College London, and Consultant Rheumatologist and Guy’s & St Thomas’ NHS Foundation Trust, United Kingdom. Data was presented by leading European experts Professor Peter Taylor (Professor of Musculoskeletal Sciences, Botnar Research Centre at the University of Oxford, United Kingdom) and Associate Professor Lars Erik Vølund Kristensen (Chief Scientific Officer at the Parker Institute, University of Copenhagen, Denmark and Associate Professor at Lund University, Sweden).

The limbic spoke to Australian rheumatologist Doctor Anna Dorai Raj about her take-home messages from the webcast, particularly with respect to the data presented for baricitinib, a therapy she’s used in both the clinical trial setting and in her clinical practice.

The continued unmet need in rheumatoid arthritis

“One thing that stood out to me was the data showing the continuing unmet need in rheumatoid arthritis even though we have quite a lot of options, including the biologics,” said Doctor Dorai Raj. “There is still that gap for a certain number of patients, and that is where it’s useful to have options,” she said.

Professor Taylor was a lead investigator in the pivotal baricitinib RA-BEAM1 study and the extension study, RA-BEYOND.2 He noted that despite advances in the management of rheumatoid arthritis there is an unmet need for treatments that “exceed the standard of care and are associated with a rapid and sustained onset of action.” He noted that up to 40% of patients with rheumatoid arthritis do not respond or are unable to tolerate methotrexate (MTX) or alternative agents.3

RA-BEAM1: disease remission and structural preservation with baricitinib

Professor Taylor presented data from the RA-BEAM1 study that compared the efficacy of baricitinib and adalimumab (both in combination with MTX). RA-BEAM was a 52-week, phase 3, double-blind, placebo- and active-controlled trial. Patients with active RA (n=1307) who were receiving background MTX therapy were randomly assigned to either placebo (and switched to baricitinib after 24 weeks), baricitinib (4 mg once daily) or adalimumab (40 mg every second week).

Baricitinib plus MTX resulted in a superior increase in ACR20 response rate at week 12 versus adalimumab plus MTX (70% versus 61%; P=0.014. In addition, baricitinib was also superior to adalimumab according to the mean change in DAS28-CRP at week 12 (-2.24 for baricitinib versus -1.95 for adalimumab; P<0.001). The proportion of patients achieving disease remission with baricitinib plus MTX was similar to adalimumab plus MTX at week 12, week 24 and week 52.

Radiographic progression of structural joint damage, a major secondary end point in RA-BEAM, was found to be significantly reduced at weeks 24 and 52 for both baricitinib and adalimumab as compared with placebo.1

“The RA-BEAM study included patients with erosive disease,” noted Dr Dorai Raj. “These are quite difficult patients to treat. The data reinforced that even in severe disease, baricitinib has the potential to suppress progression,” she said.

RA-BEYOND: long-term baricitinib offers sustained response and stable safety profile

Professor Taylor presented the long-term extension data from RA-BEYOND, the open-label extension study of RA-BEAM in which patients continued on with baricitinib or switched to baricitinib from adalimumab at Week 52.2

Remission with baricitinib at one year was maintained for the additional two years of the extension study. Similarly, low disease activity (SDAI ≤11) and normalised physical function (HAQ-DI ≤0.5) at one year were both maintained out to three years.2 Most recently, data presented at the ACR Convergence Meeting 2020 that analysed long-term results from three phase 3 studies of baricitinib, including RA-BEAM, showed that treatment with baricitinib maintained low rates of radiographic progression for up to five years.4

There is now data on the safety and efficacy profile of baricitinib in more than 3770 patients treated up to 8.4 years,5 said Prof Taylor. He explained that the incidence rate of serious infections with baricitinib has remained stable over time. ‘There doesn’t appear to be any incremental effect of serious infections with cumulative exposure,’ he said.

“The availability of data out to 8 years is reassuring,” said Doctor Dorai Raj. When considering the clinical significance of the efficacy and safety data presented, she remarked, “I think it’s important not to take trial data and to apply it to what you would expect in individual patients but it does inform our decisions.”

Ixekizumab versus adalimumab for psoriatic arthritis

Associate Professor Lars Erik Vølund Kristensen presented the results of SPIRIT H2H study, a head-to-head study comparing ixekizumab and adalimumab in patients with active psoriatic arthritis (PsA).

The SPIRIT H2H study6,7 enrolled patients with active PsA who were naïve to biological disease modifying drugs. The study compared ixekizumab (80 mg four-weekly, with a 160 mg start dose) and adalimumab (40 mg twice weekly). The primary outcome was superiority of ixekizumab to adalimumab as measured by the proportion of patients simultaneously achieving ACR50 and PASI100 responses at week 24.

A significantly higher percentage of patients treated with ixekizumab versus adalimumab simultaneously achieved ACR50 and PASI100 (36% versus 28%, p<0.05), and PASI100 (60% versus 47%, p≤0.001) at Week 24. The difference was maintained through to week 52. Efficacy of ixekizumab versus adalimumab was similar at Week 52 for ACR20, ACR50 and ACR70 at week 52. Ixekizumab efficacy was found to be consistent irrespective of concomitant conventional synthetic disease-modifying anti-rheumatic (csDMARD) drug use.

 

“This is useful information,” said Dr Dorai Raj. “Patient quality of life is influenced by both joint and skin disease in psoriatic arthritis, so the superiority on both parameters is obviously positive. Both of these outcomes are relevant to the patient,” she said.

Prof Vølund Kristensen explained that improvements in both joint and skin disease are necessary to achieve optimal patient health-related quality of life (HR-QoL). He added that improvements in joint symptoms are pivotal to improving overall patient HR-QoL but the greatest improvements are achieved when patients experience both maximal joint and skin improvements.6,7

The overall safety profiles of both drugs were consistent with clinical trial data, but there were numerical differences between the treatment groups: although ixekizumab treatment resulted in more treatment emergent adverse events (TEAEs), the majority were classified as mild and moderate, while more severe TEAEs and serious AEs were observed in the adalimumab group. Injection site reactions were higher in the ixekizumab group, but the number of patients discontinuing due to an injection site reaction was similar between the groups. There was one confirmed case of Crohn’s disease in the ixekizumab treated group, which occurred in the week 0 – 24 period. There were no new cases reported from week 24 – 52.

Ixekizumab for PsA: Consistent responses with or without MTX

In a pre-specified subgroup analysis of the SPIRIT H2H, it was found that the response rates for ixekizumab monotherapy were consistent with those for ixekizumab plus csDMARD. In contrast, concomitant csDMARD with adalimumab resulted in higher response rates than with adalimumab monotherapy. The study authors say, “These observations can inform decision making when considering concomitant csDMARD to ixekizumab or adalimumab.”

“This data suggests that you can do without methotrexate when using ixekizumab if patients are methotrexate-intolerant,” said Dr Dorai Raj. “This is a useful option,” she added.

Adherence considerations in both rheumatoid arthritis and psoriatic arthritis

In the discussion following the presentations, Professor Taylor reinforced the importance of long-term adherence to therapy for rheumatoid arthritis, reminding clinicians that many patients are prone to discontinue therapy when their disease stabilises. He reminded the audience that relapses can be difficult to manage if treatment has been discontinued and then is subsequently reinitiated.

“I tell patients that achieving and maintaining a good level of remission or low disease activity is very important for long-term outcomes,” said Dr Dorai Raj. “It’s better to have this discussion early. If I get the feeling that a patient is starting to forget to take their regular medication, I explain that studies have shown that if you stop the drug you’re likely to relapse, but if you taper in a slightly slower way, you may be able to manage the level of control you’ve achieved,” she said. “Adherence is influenced in part by what the patient wants to do and in part by what we tell them,” she said. “We need to remind patients that the condition is chronic. Patients are often worried about side effects of long-term medication but I try to get them to also consider the long-term effects of the condition as well.”

 

This article was commissioned by Eli Lilly Australia Pty Ltd. The content is independent and based on studies and the authors opinion. The views expressed do not necessarily reflect the views of Eli Lilly. Before prescribing please review the Olumiant® (link) and Taltz® (link) full product information via the TGA website. Treatment decisions based on these data are the responsibility of the prescribing physician.

 

References

  1. Taylor PC et al. Baricitinib versus placebo or adalimumab in rheumatoid arthritis. N Engl J Med 2017; 376:652–662 https://www.nejm.org/doi/full/10.1056/nejmoa1608345
  2. Smolen JS et al. Efficacy of baricitinib in patients with moderate-to-severe rheumatoid arthritis with 3 years of treatment: results from a long-term study. Rheumatology 2020:00:1-11 (RA Beyond) https://pubmed.ncbi.nlm.nih.gov/33200220/
  3. Gabay C et al. Biological agents in monotherapy for the treatment of rheumatoid arthritis. Swiss Med Mkly 2014;144:w13950 https://pubmed.ncbi.nlm.nih.gov/24723273/
  4. Van der Heijde D et al. Radiographic progression of structural joint damage over 5 years of baricitinib treatment in patients with rheumatoid arthritis: results from RA-BEYOND. Poster presented at ACR Annual meeting 2020. https://acrabstracts.org/abstract/radiographic-progression-of-structural-joint-damage-over-5-years-of-baricitinib-treatment-in-patients-with-rheumatoid-arthritis-results-from-ra-beyond/
  5. Genovese MC et al. Safety profile of baricitinib for the treatment of rheumatoid arthritis up to 8.4 years: an updated integrated safety analysis. Poster presented at EULAR Annual meeting 2020. FRI0123. https://ard.bmj.com/content/79/Suppl_1/642.1
  6. Smolen et al. Multicentre, randomised, open-label, parallel-group study evaluating the efficacy and safety of ixekizumab versus adalimumab in patients with psoriatic arthritis naïve to biological disease-modifying antirheumatic drug: final results by week 52. Ann Rheum Dis 2020;79:1310-1319. https://ard.bmj.com/content/annrheumdis/79/10/1310.full.pdf
  7. Kavanaugh A et al. The contribution of joint and skin improvements to the health-related quality of life of patients with psoriatic arthritis: a post hoc analysis of two randomised controlled studies. Ann Rheum Dis. 2019;78(9):1215-9 https://ard.bmj.com/content/annrheumdis/78/9/1215.full.pdf

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