Various presentations at the EULAR Congress in Paris focused on biological agents for the treatment of rheumatoid arthritis. Among these, the focus was on those biologics that do not act by inhibiting the proinflammatory cytokine TNF-α.
Results from the randomized controlled AVERT trial (phase IIIb), which evaluated the safety and efficacy of subcutaneous abatacept, a selective immunosuppressant, in patients with early rheumatoid arthritis (RA), were presented by Prof. Paul Emery, MD, Leeds. The sample consisted of patients without pretreatment methotrexate with active synovitis in ≥2 joints for ≥8 weeks, with a DAS28 score of >3.2, and with symptom onset exactly or less than two years ago. Combination (abatacept and methotrexate) and monotherapies (either abatacept or methotrexate) were compared. The question was to what extent clinical remission could be achieved after one year with the respective approach, and also whether this could be maintained after rapid discontinuation of all RA drugs.
Results: Patients who achieved a DAS28 below 3.2 after the twelve months of treatment began a twelve-month discontinuation period without treatment. The primary endpoints were achievement of a DAS28 of <2.6 at 12 or at 12 and 18 months.
- Of the total 351 patients, 60.9% in the combination group, 42.5% in the abatacept group, and 45.2% in the methotrexate group achieved a DAS28 of <2.6 at one year.
- After one year and after 18 months, 14.8, resp. 12.4 and 7.8% a DAS28 <2.6.
- The efficacy in terms of symptoms and signs of disease (including DAS28) in the abatacept group was intermediate between that of the combination and methotrexate groups for most of the time.
- Most patients (79.4%) discontinued as disease activity returned.
Conclusion: “Patients with highly active early RA (average initial DAS28 score was 5.4) and poor prognosis benefit significantly from combination therapy of abatacept and methotrexate compared to methotrexate monotherapy (p=0.01 at one year; p=0.045 at 12 and 18 months). In addition, abatacept monotherapy was largely more effective than methotrexate. A small but significantly larger group achieved sustained drug-free remission with the combination compared to methotrexate alone,” Prof. Emery concluded.
Itolizumab and sarilumab
Two other promising compounds currently being investigated in randomized controlled phase II and III trials are itolizumab (anti-CD6 antibody) and sarilumab (anti-IL6R antibody).
Itolizumab: Itolizumab is the first antibody of its class (anti-CD6). It was studied in a 24-week phase II trial together with methotrexate in patients with active RA and inadequate response to methotrexate alone. Arvind Chopra, MD, Pune, presented the results. A total of 70 participants were randomized to receive either itolizumab at three different doses: 0.2, 0.4, or 0.8 mg/kgKG weekly (along with oral methotrexate). Or they were taking methotrexate only. The ACR criteria and DAS28 score served as efficacy instruments.
- Itolizumab was well tolerated. Most side effects were mild to moderate and dose-dependent. Fever and cough were the most common.
- Itolizumab patients had higher ACR20 response rates at 12 weeks (50% at 0.2 mg, 60% at 0.4, and 40% at 0.8) compared with methotrexate monotherapy (30%). This was confirmed at 24 weeks (40, 50, 20% compared with 20% on methotrexate alone).
- An ACR50 response was achieved at 12 weeks of 5, 35, and 15% (itolizumab) compared with 0% in the methotrexate group.
- An ACR70 response was achieved at 12 weeks of 5, 15, and 0% (itolizumab) compared with 0% in the methotrexate group.
- At 12 weeks, 58.3% from the itolizumab group and 20% from the methotrexate group showed a moderate to good response according to DAS28 criteria, with 51.6% of itolizumab patients maintaining these levels through week 24.
“So for now, strong evidence shows that itolizumab can be used safely and effectively in combination with methotrexate. Patients with active RA and an inadequate response to methotrexate alone may benefit from this new therapeutic option,” the expert said.
Sarilumab: According to Mark C. Genovese, MD, Palo Alto, the IL-6R antibody sarilumab has already shown good efficacy and safety in phase II trials in RA patients who did not respond adequately to methotrexate. After the two-week dosing in particular was well tolerated, patients for phase III were now assigned to sarilumab 150, 200 mg (every two weeks) or placebo (always in combination with methotrexate). The primary endpoints were: Number of patients with ACR20 at week 24 and change in HAQ-DI score (physical impairment questionnaire) at 16 weeks and mTSS score (joint erosion and joint space narrowing) at week 52. The study acquired 1197 patients who were evaluated for efficacy aspects and 1282 who were evaluated for safety aspects. They had active, moderate to severe RA.
- Both doses of sarilumab produced significant improvements compared to placebo in all three primary endpoints, but also in important secondary endpoints such as major clinical response, ACR50 and ACR70 rates, and DAS28 reduction (Table 1).
40 serious adverse events (mostly infections) occurred in the placebo group and 62 and 68, respectively, in the two sarilumab groups. Seven patients died during the study (two of them in the placebo arm).
“Both doses showed good efficacy in patients with active RA and inadequate response to methotrexate. Clinical, radiographic and functional endpoints were met. The clinical response was sustained until week 52. The infections and altered laboratory values (lipid and transaminase increase and neutrophil decrease) under sarilumab are explained by IL-6 signaling blockade,” Genovese concluded his presentation.
Tocilizumab vs. anti-TNFs
Data from the Portuguese Rheumatism Registry, also presented at EULAR, also suggest that the IL-6 receptor blocker tocilizumab may be superior to anti-TNF agents in terms of remission. Included were 524 patients who had undergone treatment with adalimumab, etanercept, golimumab, infliximab, or tocilizumab for at least six months and whose DAS28 values were available at baseline and six months. The question was how many of the patients achieved remission after this period.
- After six months, more tocilizumab than anti-TNF patients were in DAS28 remission on a percentage basis: 102 of 429 patients (23.8%) achieved this status with anti-TNFs, 55 of 95 patients (57.9%) with tocilizumab.
- For patients who had never been treated with biologics, remission in DAS28 (and also in other remission criteria) was significantly higher with tocilizumab.
- Multivariate logistic regression on age, sex, number of prior biologic therapies, and disease activity at baseline confirmed the results.
Thus, tocilizumab was associated with higher DAS28 remission rates compared with anti-TNFs in this analysis. This was also true for patients who had not previously received biologics.
Source: “Novel non-TNF biologics treatment of RA,” session at EULAR Congress, June 11-14, 2014, Paris.
CONGRESS SPECIAL 2014; 5(2): 39-41
