New monoclonal antibodies targeting IL-6

RATE

New monoclonal antibodies that target interleukin-6 (IL-6) or the IL-6 receptor and are currently in advanced stages of development include agents sarilumab, sirukumab, and BMS-945429.1-3

 

Emerging monoclonal antibodies that target IL-6

Agent
Sponsor
Target
Phase
Sarilumab (REGN88/SAR153191)
Sanofi / Regeneron
IL-6 receptor
Phase III
Sirukumab (CNTO 136)
Janssen
IL-6
Phase III
BMS-945429 (formerly ALD518)
Bristol-Myers Squibb
IL-6
Phase II

 

Sarilumab. Sarilumab (REGN88/SAR153191) is an IL-6 receptor antibody being developed jointly by Sanofi and Regeneron. It is formulated for subcutaneous (SC) administration. It is also a fully human monoclonal antibody. The significance of this is that, unlike monoclonal antibodies that are derived from animals such as mice, fully human antibodies have less risk for certain side effects.4

The sarilumab development program includes five large studies. The Phase 2 stage of the ongoing Phase 2/3 MOBILITY study tested sarilumab in 306 patients with moderate to severe RA who had had an inadequate response to methotrexate. At week 12, sarilumab (given in combination with methotrexate) resulted in significantly greater rates of ACR20 responses than placebo, with the highest responses shown for the 150- and 200-mg doses given once every two weeks. These doses are being studied in the Phase 3 stage of MOBILITY (results are due to be announced in 2014) and four other Phase 3 studies (including one long-term safety study) in which sarilumab is being given in combination with methotrexate and other conventional and biologic disease-modifying anti-rheumatic drugs (DMARDs). The studies are focusing on populations of RA patients who have had an inadequate response to conventional and biologic DMARD therapy, including tunor necrosis factor-alpha (TNF-α) inhibitor therapy.5

 

Phase 3 RA program for sarilumab

Trial
Number of patients
Description
Status
MOBILITY
1197
  • Sarilumab + MTX as treatment in patients with inadequate response to MTX
Ongoing
TARGET
522
  • Sarilumab + non-biologic DMARDs in patients with inadequate response to, or were intolerant of, one or more TNF-α inhibitors
Recruiting
COMPARE
700
  • Sarilumab + MTX in patients with inadequate response to open-label adalimumab + MTX after 16 weeks of therapy
  • Inadequate responders randomized to a second TNF-α inhibitor (etanercept) + MTX or sarilumab + MTX
Recruiting
ASCERTAIN
200
  • Sarilumab + tocilizumab in patients with inadequate response, or intolerant of, TNF-α inhibitors
Recruiting
EXTEND
2100
  • Long-term safety study of sarilumab, open to patients who complete MOBILITY, TARGET, or ASCERTAIN

 

Sirukumab. Sirukumab (CNTO 136) is a fully human monoclonal antibody that targets IL-6. It is being developed by Janssen in cooperation with GlaxoSmithKline. Sirukumab is formulated for SC dosing. Interim results (reported in 2011) from a Phase 2 study comparing sirukumab given in combination with methotrexate to placebo + methotrexate showed significantly greater reductions in Disease Activity Score 28 (DAS28) C-reactive protein (CRP) levels at week 12 compared with placebo. Among patients who received sirukumab, 82% had good or moderate DAS28 CRP reductions compared with 32% of patients who received placebo and methotrexate (P = 0.015). ACR20 responses at week 12 were achieved by 75% of patients treated with sirukumab + methotrexate versus 21% of patients receiving placebo + MTX (P = 0.002).1,6

Sirukumab is currently being evaluated in two ongoing Phase 3 studies, the SIRROUND-T and -D studies. SIRROUND-T is a randomized, controlled trial evaluating sirukumab in RA patients who have had an inadequate response to (or who are intolerant of) TNF-α therapy. SIRROUND-D is a randomized, controlled trial evaluating sirukumab in RA patients who have had an inadequate response to conventional DMARD therapy.7

 

BMS-945429. BMS-945429 (formerly ALD518) is a humanized (this means that it was derived from a non-human antibody, but modified to fit inside a human antibody) monoclonal antibody being developed by Bristol-Myers Squibb. Results from a Phase 2 study of BMS-945429 conducted in RA patients who had an inadequate response to methotrexate found that BMS-945429 resulted in significant and rapid improvements in disease activity and quality of life. At week 12, BMS-945429 resulted in ACR20 response rates ranging from 71% to 81% in different dosing groups versus 27% for placebo + methotrexate (P<0.0005). In the highest dosing group (320 mg), 44% of patients achieved DAS28 remission by week 16.8

 

Another Phase 2 study of BMS-945429 is currently ongoing.2

view references
1. Reichert JM. Which are the antibodies to watch in 2013? MAbs 2013;5:1-4. 2. Clinicaltrials.gov. 3. Buch MH, Emery P. New therapies in the management of rheumatoid arthritis. Curr Opin Rheumatol 2011;23:245-51. 4. Woodrick RS, Ruderman EM. IL-6 inhibition for the treatment of rheumatoid arthritis and other conditions. Bull NYU Hosp Jt Dis 2012;70:195-9. 5. Sanofi and Regeneron announce patient enrollment in two Phase 3 trials with sarilumab in rheumatoid arthritis (RA). Regeneron press release; May 15, 2013. 6. Interleukin-6 inhibitor sirukumab (CNTO 136) phase 2 data show promise in the treatment of active rheumatoid arthritis. Medical News Today. May 25, 2011. 7. Janssen announces initiation of phase 3 development program for sirukumab in rheumatoid arthritis. Janssen Research & Development, LLC Press Release; August 23, 2012. 8. Mease P, Strand V, Shalamberidze L, et al. A phase II, double-blind, randomised, placebo-controlled study of BMS945429 (ALD518) in patients with rheumatoid arthritis with an inadequate response to methotrexate. Annals of the Rheumatic Diseases 2012;71:1183-9.
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