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Clinical Trials

Date: 2015-11-08

Type of information: Presentation of results at a congress

phase: 3

Announcement: presentation of results at the Annual Meeting of the American College of Rheumatology (ACR)

Company: Sanofi (France) Regeneron Pharmaceuticals (USA - NY)

Product: sarilumab (REGN88/SAR153191)

Action mechanism: monoclonal antibody. Sarilumab (REGN88/SAR153191) is a fully human monoclonal antibody directed against the alpha subunit of the IL-6 receptor complex (IL-6R Alpha).  Sarilumab is a high-affinity, subcutaneously delivered inhibitor of IL-6 signaling.  It blocks the binding of IL-6 to its receptor and interrupts the resultant cytokine-mediated inflammatory signaling cascade.  Sarilumab was developed using Regeneron\'s VelocImmune® antibody technology.

Disease: rheumatoid arthritis

Therapeutic area: Autoimmune diseases – Inflammatory diseases - Rheumatic diseases

Country:

Trial details:

  • The SARIL-RA Phase 3 program consists of 5 studies and is targeted to enroll approximately 2,600 adults with moderate-to-severe rheumatoid arthritis who have not had sufficient results with other treatment regimens.  The goal of the program is to evaluate the safety and efficacy of sarilumab in combination with methotrexate (MTX) in reducing the signs and symptoms and inhibiting the radiographic progression of RA.
  • 1.The SARIL-RA MOBILITY trial (N=1197) is evaluating sarilumab in combination with MTX as treatment in adults with moderate-to-severe active RA with an inadequate response to MTX.  SARIL-RA MOBILITY is fully enrolled and results are anticipated in first-half 2014.
  • 2.The SARIL-RA TARGET trial (N=522) is evaluating sarilumab in combination with non-biologic, disease-modifying anti-rheumatic drugs (DMARDs) as treatment in adults with moderate-to-severe active RA who have had inadequate response to, or were intolerant of, one or more TNF-alpha inhibitors.
  • 3.The SARIL-RA COMPARE trial (N=700) is currently recruiting and is evaluating the strategy of using IL-6 inhibition with sarilumab + MTX in patients who have had an inadequate response to open-label adalimumab + MTX after 16 weeks of therapy.  Those patients identified as inadequate responders will then be randomized to a second TNF-alpha inhibitor (etanercept) + MTX or sarilumab (150mg or 200mg) + MTX. This trial is a multi-center, randomized, double-blind, active-control, Phase 3 trial evaluating the safety and efficacy of sarilumab plus MTX compared to etanercept (a TNF-alpha inhibitor) plus MTX in adult patients with moderate-to-severe RA who demonstrate an inadequate response to adalimumab as their first TNF-alpha inhibitor therapy. COMPARE is designed to evaluate whether sarilumab is superior to etanercept when used in combination with MTX in this patient population.  The primary endpoint of the study is the change in Disease Activity Score 28 based on C-reactive protein (DAS28-CRP) at 24 weeks.  COMPARE is an international trial that expects to include 700 patients at approximately 300 sites.
  • 4.The SARIL-RA ASCERTAIN trial (N=200) is currently recruiting and is evaluating sarilumab and tocilizumab in patients with RA who are inadequate responders to, or intolerant of, TNF-alpha inhibitors. This multi-center, randomized, double-blind, active-calibrator, Phase 3 trial of 24 weeks  will assess the safety and tolerability of sarilumab and tocilizumab, both in combination with MTX, in patients with RA who are inadequate responders to, or intolerant of, TNF-alpha inhibitors.  The primary endpoint of this study is safety.
  • 5.The SARIL-RA EXTEND trial (N=2100) is a long-term safety study of sarilumab; it is open to patients who complete the MOBILITY, TARGET or ASCERTAIN studies.

Latest news:

  • • On November 8, 2015, Regeneron Pharmaceuticals and Sanofi announced results from a pivotal Phase 3 study of sarilumab, an investigational, human antibody against the IL-6 receptor. The results of the study, SARIL-RA-TARGET, are being presented at an oral session during the American College of Rheumatology (ACR) Annual Meeting in San Francisco, California. The study met both its co-primary endpoints of improvements in signs and symptoms of rheumatoid arthritis (RA) and improvements in physical function, as well as secondaryefficacy endpoints. The SARIL-RA-TARGET trial enrolled 546 RA patients who were inadequate responders or intolerant of TNF-alpha inhibitors (TNF-IR). Patients were randomized to one of three treatment groups self-administered subcutaneously (SC) every other week (Q2W): sarilumab 200 milligrams (mg), sarilumab 150 mg, or placebo, in addition to non-biologic disease modifying antirheumaticdrugs (DMARD) therapy. Top-line results were previously announced in May 2015. Both sarilumab groups showed clinically relevant and statistically significant improvements compared to placebo in both coprimary endpoints:
  • - Improvement in physical function at week 12, as measured by mean change from baseline in the Health Assessment Questionnaire-Disability Index (HAQ-DI). The HAQ-DI measures patients'abilities to perform a standard set of daily physical activities. The change from baseline to week 12 in HAQ-DI was -0.49, -0.50, and -0.29 in the sarilumab 200 mg (p=0.0004), sarilumab 150 mg (p=0.0007), and placebo groups, respectively.
  • - Improvements in signs and symptoms of RA at week 24, as measured by the proportion of patients achieving an ACR20 response (ACR20) were 61 percent in the sarilumab 200 mg group; 56 percent in the sarilumab 150 mg group; and 34 percent in the placebo group, all in combination with DMARD therapy (p less than 0.0001).
  • Secondary efficacy endpoints that will be presented during the ACR oral session include the following:
  • - Proportion of patients achieving an ACR50 response at week 24 were 41 percent in the sarilumab 200 mg group, 37 percent in the sarilumab 150 mg group, and 18 percent in the placebo group (p less than 0.0001).
  • -Proportion of patients achieving an ACR70 response at week 24 were 16 percent in the sarilumab 200 mg group (p=0.0056), 20 percent in the sarilumab 150 mg group (p=0.0002), and 7 percent in the placebo group. The mean change from baseline to week 24 in disease activity score in 28 joints using C-reactive protein (DAS28-CRP), which -evaluates the disease activity of RA, were as follows: -2.82, -2.35 and -1.38 in the sarilumab 200 mg, sarilumab 150 mg, and placebo groups, respectively.
  • - The proportion of patients achieving DAS28-CRP less than 2.6 at week 24 were as follows: 29 percent, 25 percent, and 7 percent in the sarilumab 200 mg, sarilumab 150 mg, and placebo groups, respectively.
  • - The change from baseline to week 24 in clinical disease activity index (CDAI), which also evaluates the disease activity of RA, were as follows: -30.43, -27.14, and -23.9 in the sarilumab 200 mg, sarilumab 150 mg, and placebo groups, respectively.
  • - The change from baseline to week 24 in HAQ-DI were as follows: -0.58, -0.52 and -0.34 in the sarilumab 200 mg, sarilumab 150 mg, and placebo groups, respectively.
  • Treatment-emergent adverse events (TEAEs) were more frequent in the sarilumab groups (65 percent and 66 percent in sarilumab 200 mg and 150 mg vs 50 percent in placebo respectively). The incidence of serious adverse events (SAEs) was higher than placebo in the sarilumab 200 mg group (5 percent vs. 3 percent) and was similar to placebo in the 150 mg group (3 percent). Infection was the most frequently reported adverse event (30, 22 and 27 percent in the 200 mg, 150 mg and placebo groups respectively). Serious infections occurred in 2 patients in the sarilumab 200 mg group, 1 patient in the sarilumab 150 mg group and 2 patients on placebo. The most frequent events leading to treatment discontinuation were infection and neutropenia. Adverse events and laboratory changes were consistent with observations from the MOBILITY study and with the mechanism of action of sarilumab. Sanofi and Regeneron recently submitted a Biologics License Application (BLA) for sarilumab to the FDA.
  • * On May 21, 2015, Sanofi and Regeneron Pharmaceuticals announced that a Phase 3 study of sarilumab, an investigational, fully-human IL6 receptor antibody, met its co-primary efficacy endpoints of a greater improvement in signs and symptoms of rheumatoid arthritis at 24 weeks, and physical function at 12 weeks compared to placebo. The study, called SARIL-RA-TARGET, evaluated the efficacy and safety of two subcutaneous sarilumab doses versus placebo, added to non-biologic disease modifying anti-rheumatic drugs therapy in rheumatoid arthritis patients who were inadequate responders to or intolerant of TNF-alpha inhibitors. The SARIL-RA-TARGET trial enrolled 546 TNF-IR patients who were randomized to one of three treatment groups self-administered subcutaneously every other week : sarilumab 200 mg, sarilumab 150 mg, or placebo, in addition to DMARD therapy. Both sarilumab groups showed clinically relevant and statistically significant improvements compared to the placebo group in both co-primary endpoints (p < 0.001):
  • - Improvement in signs and symptoms of RA at 24 weeks, as measured by the American College of Rheumatology (ACR20) score of 20 percent improvement, were as follows: 61 percent in the sarilumab 200 mg group; 56 percent in the sarilumab 150 mg group; and 34 percent in the placebo group, all in combination with DMARD therapy.
  • - Improvement in physical function, as measured by change from baseline in the Health Assessment Question-Disability Index (HAQ-DI) at week 12.
  • The most frequently reported adverse events included infections (30, 22 and 27 percent in the 200 mg, 150 mg and placebo groups respectively) and injection site reactions (8, 7, 1 percent in the 200 mg, 150 mg and placebo groups respectively). Serious infections were uncommon (1, 0.6 and 1 percent in the 200 mg, 150 mg and placebo groups respectively). Reduction in neutrophil count was the most common lab abnormality. No unexpected safety findings were observed. Two additional trials from the Phase 3 program, SARIL-RA-EASY and SARIL-RA-ASCERTAIN, also met their primary endpoints:
  • SARIL-RA-EASY enrolled 217 patients and was designed to evaluate the technical performance and usability of the sarilumab autoinjector device. There were no product technical failures with the auto-injector, the primary endpoint of the study.
  • SARIL-RA-ASCERTAIN was a 202-patient safety calibrator study, designed to assess the safety of two subcutaneous doses of sarilumab and tocilizumab infusion in combination with DMARDs in patients with RA who were TNF-IR. There were no clinically meaningful differences between the treatment groups in serious adverse events and serious infections. Detailed results from all three SARIL-RA trials will be presented at future medical congresses.
  • • On June 12, 2014, Sanofi and Regeneron Pharmaceuticals have presented positive results from a phase 3 trial of sarilumab in rheumatoid arthritis patients who were inadequate responders to methotrexate therapy. New data presented at the meeting showed that sarilumab increased major clinical response rates defined as achieving an ACR70 for at least 24 consecutive weeks and showed sustained improvement in signs and symptoms of rheumatoid arthritis after 52 weeks, which were secondary endpoints of the trial. As previously announced, in this study, called SARIL-RA-MOBILITY, sarilumab met all three co-primary endpoints, demonstrating improvement in disease signs and symptoms at 24 weeks, physical function at 16 weeks and inhibition of joint damage progression at 52 weeks.
  • The SARIL-RA-MOBILITY Phase 3 trial enrolled 1,197 adult patients with active, moderate-to-severe rheumatoid arthritis, who were inadequate responders to MTX therapy. Patients were randomized to one of three treatment groups dosed subcutaneously every other week, sarilumab 150 milligrams (mg), sarilumab 200 mg, or placebo, all in combination with MTX. Both sarilumab groups showed statistically significant improvements compared to the placebo group in all three co-primary endpoints (p < 0.0001). Improvement in signs and symptoms of RA at 24 weeks, as measured by the American College of Rheumatology score of 20 percent improvement (ACR20). These results were 58 percent, 66 percent, and 33 percent in the sarilumab 150 mg, sarilumab 200 mg, and placebo groups respectively, all in combination with MTX.
  • Improvement in physical function at Week 16 as measured by Health Assessment Questionnaire - Disability Index (HAQ-DI). Newly presented HAQ-DI results were -0.53, -0.55, and -0.29 in the sarilumab 150 mg, sarilumab 200 mg, and placebo groups respectively, all in combination with MTX.
  • Inhibition of progression of structural damage at Week 52, as measured by change in the van der Heijde modified total Sharp score (mTSS). These results were 0.90, 0.25, and 2.78 in the sarilumab 150 mg, sarilumab 200 mg, and placebo groups respectively, all in combination with MTX. The group receiving the 200 mg dose of sarilumab + MTX had a reduction of approximately 90 percent in the radiographic progression assessed by the mTSS compared to the radiographic progression with placebo + MTX at week 52.
  • Also newly presented, both sarilumab groups also showed improvement on the major clinical response secondary endpoint: Sarilumab combined with MTX demonstrated statistically significantly greater effect than MTX alone in achieving a major clinical response, defined as reducing signs and symptoms of RA by 70% or more, as measured by improvement of the American College of Rheumatology score (ACR70 response), for at least 24 consecutive weeks. These results were 13 percent, 15 percent and 3 percent in the sarilumab 150 mg, sarilumab 200 mg, and placebo groups, respectively (p < 0.0001).
  • Both doses also demonstrated a sustained response in improvement of signs and symptoms of RA compared to placebo at 52 weeks as measured by the ACR20 response. These results were 54 percent, 59 percent, and 32 percent in the sarilumab 150 mg, sarilumab 200 mg, and placebo groups, respectively.
  • In the SARIL-RA-MOBILITY trial, there was a higher incidence of treatment-emergent adverse events leading to withdrawal in the sarilumab treatment groups compared to placebo (12.5 percent in 150 mg, 13.9 percent in 200 mg and 4.7 percent in placebo). Infections were the most frequently reported adverse events and were reported with a higher incidence in the sarilumab groups compared to placebo, all in combination with MTX (40.1 percent for 150 mg, 39.6 percent for the 200 mg group and 31.1 percent for placebo). The incidence of serious infections was 2.6 percent in the 150 mg + MTX group, 4.0 percent in the 200 mg + MTX group, and 2.3 percent in the placebo + MTX group. Among patients treated with sarilumab, a dose-dependent decrease in mean neutrophil counts was observed. Serious infections were not associated with grades 3 and 4 neutropenia in this study. Increases in mean LDL cholesterol, and transaminases were observed. These safety findings were consistent with those observed in prior investigational studies with sarilumab.
  • • On November 22, 2013, Sanofi and Regeneron Pharmaceuticals have announced that in the SARIL-RA-MOBILITY Phase 3 clinical trial in adult patients with active rheumatoid arthritis (RA) who were inadequate responders to methotrexate (MTX) therapy, sarilumab treatment in combination with MTX improved disease signs and symptoms as well as physical function, and inhibited progression of joint damage.
  • The 52 week SARIL-RA-MOBILITY Phase 3 trial enrolled approximately 1,200 patients with active, moderate-to-severe rheumatoid arthritis, and who were inadequate responders to MTX therapy. Patients were randomized to one of three subcutaneous treatment groups, all in combination with MTX and dosed every other week: sarilumab 200 milligrams (mg), sarilumab 150 mg, or placebo.
  • Both sarilumab groups showed clinically relevant and statistically significant improvements compared to the placebo group in all three co-primary endpoints (p < 0.0001).
  • - Improvement in signs and symptoms of RA at 24 weeks, as measured by the American College of Rheumatology score of 20 percent improvement (ACR20): 66 percent, 58 percent, and 33 percent in the sarilumab 200 mg, sarilumab 150 mg, and placebo groups respectively, all in combination with MTX.
  • - Improvement in physical function, as measured by change from baseline in the Health Assessment Question-Disability (HAQ-DI) at week 16.
  • - Inhibition of progression of structural damage at Week 52, as measured by the change in the modified Van der Heijde total Sharp score (mTSS): 0.25, 0.90, and 2.78 in the sarilumab 200 mg, sarilumab 150 mg, and placebo groups respectively, all in combination with MTX. The group receiving the 200 mg dose of sarilumab + MTX had a reduction of approximately 90 percent in the radiographic progression assessed by the mTSS compared to the radiographic progression with placebo + MTX at week 52.
  • ACR Results at week 24:
  • Treatment Group

    ACR20^

    (%)

    ACR50

    (%)

    ACR70

    (%)

    200 mg sarilumab + MTX

    66*

    46*

    25*

    150 mg sarilumab + MTX

    58*

    37*

    20*

    Placebo + MTX

    33

    17

    7

    ^Primary Endpoint *p < 0.0001 compared to placebo group In the SARIL-RA-MOBILITY trial, there was a higher incidence of treatment emergent adverse events leading to withdrawal in the sarilumab treatment groups compared to placebo (13.9 percent in 200 mg, 12.5 percent in 150 mg and 4.7 percent in placebo). Infections were the most frequently reported adverse events and were reported with a higher incidence in the sarilumab groups compared to placebo, all in combination with MTX (39.6 percent for 200 mg, 40.1 percent for the 150 mg group and 31.1 percent for placebo).  The incidence of serious infections was 4.0 percent in the 200 mg + MTX group, 2.6 percent in the 150 mg + MTX group, and 2.3 percent in the placebo + MTX group.  Among patients treated with sarilumab, a dose dependent decrease in mean neutrophil counts was observed. Serious infections were not associated with grades 3 and 4 neutropenia in this study.  Increases in mean LDL cholesterol, and transaminases were observed. These safety findings were consistent with those observed in prior investigational studies with sarilumab.Additional analyses of efficacy and safety data from the SARIL-RA-MOBILITY study will be presented at a future medical conference.
  • • On May 15, 2013, Sanofi and Regeneron Pharmaceuticals have announced that the COMPARE and ASCERTAIN trials of sarilumab, the first fully human monoclonal antibody directed against the IL-6 receptor, which is delivered by subcutaneous injection every other week, have enrolled their first patients.

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