Market Access CTR Summary

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1 Market Access CTR Summary Study No.: BEL Title: Efficacy of Belimumab Treatment in a Subpopulation of Systemic Lupus Erythematosus (SLE) Patients: A Pooled Analysis of the HGS1006-C1056 (BLISS-52) and HGS1006-C1057 (BLISS-76) Studies (Belimumab IV for Market Access) Rationale: The Phase III belimumab clinical studies HGS1006-C1056 (C1056, BLISS-52) and HGS1006-C1057 (C1057, BLISS-76) were conducted in subjects with active, autoantibody positive systemic lupus erythematosus (SLE). Subpopulations of subjects from these trials with more severe disease were studied further in an effort to see how these individuals respond to belimumab therapy. This information may be of interest to healthcare payers/insurance companies. Phase: III Study Period: The study period covering C1056 and C1057 was 08 February 2007 (1 st subject randomized) to 22 September 2009 (last subject completed 8 week follow-up of 52 week period). This pooled analysis was initiated on 01 July 2009 (analysis plan complete) and completed on 20 August 2010 (study report complete). Study Design: This Market Access report is based on pooled analyses of subpopulations of subjects from the Modified Intent-to-Treat (MITT) Population that was used in the Phase III belimumab clinical studies C1056 and C Week 52 analysis of each of these two studies individually formed the basis for the Biologics License Application (BLA) and Marketing Authorisation Application (MAA) regulatory dossiers submitted in June The analyses for this report were pre-specified and the analysis plan was finalized prior to the database lock of both Phase III studies. The Phase III pivotal safety and efficacy trials were conducted in subjects with active, autoantibody positive SLE. Belimumab was administered in addition to SLE standard of care (SOC) medications. By Week 24 of the trials, restrictions on SOC medications were completely implemented. Centres: Both studies were multicenter. C1056 had 92 centers (41 Asia Pacific; 40 Latin America; 11 Europe). C1057 had 136 centers (62 Europe; 65 North America; 9 Latin America). Indication: SLE Treatment: Subjects were randomly assigned to 1 of 3 treatment groups. The treatment groups consisted of 2 active treatment arms (belimumab 1 and ) and a placebo arm, plus SOC therapy. Belimumab or placebo was administered by intravenous infusion over a 1 hour period. All subjects were to be dosed on Days 0, 14, and 28, then every 28 days. Objectives: Primary objective - Evaluate impact of belimumab treatment on a subpopulation of subjects with severe SLE, including those with critical organ system involvement, to aid payers in making decisions regarding reimbursement and market access. Secondary objective - Evaluate the impact of belimumab treatment on exploratory subpopulations which represent SLE subjects that may be of interest to payers. Primary Outcome/Efficacy Variable: The primary market access endpoint was the response rate at Week 52, consistent with the primary efficacy endpoint for the belimumab Phase III clinical trials. A response was defined as: 4 point reduction from baseline in SELENA SLEDAI 2 score, AND No worsening (increase of AND 0.30 points from baseline) in Physician s Global Assessment (PGA) of Disease, No new BILAG 3 A organ domain score or two new BILAG B organ domain scores compared with baseline at the time of assessment (i.e., at Week 52). 1 Pooled analyses were of efficacy variables only. No safety analyses were conducted. Each study reported safety findings separately. 2 Safety of Estrogens in Lupus Erythematosus: National Assessment (SELENA) version of the Systemic Lupus Erythematosus Disease Activity Index (SLEDAI) 3 British Isles Lupus Assessment Group Page 1

2 Secondary Outcome/Efficacy Variable(s): Percent of subjects with 4 point reduction from baseline in SELENA SLEDAI score at Week 52 Mean change in SF-36 Physical Component Summary (PCS) score at Week 24 Time to first SLE flare after 24 weeks by modified SLE Flare Index (SFI). Statistical Methods: The primary comparisons of interest were the pairwise comparisons of each of the belimumab doses ( and ) plus standard of care versus placebo plus standard of care. All statistical testing was two-sided with significance interpreted at the =0.05 significance level. The primary market access endpoint was analyzed using a logistic regression model. Secondary market access endpoints were analyzed using a logistic regression model, analysis of covariance (ANCOVA), or a Cox proportional hazard model, as appropriate. Study Population: The Primary Market Access (PMA) Population is a subpopulation of the modified Intent-to-Treat (MITT) Population that was used for the belimumab regulatory submissions. The MITT Population had to have a clinical diagnosis of SLE according to the American College of Rheumatology (ACR) criteria and have active SLE disease (defined as a SELENA SLEDAI score of 6 at screening and be positive for autoantibodies, defined as an antinuclear antibodies (ANA) titer of 1:80 and/or anti-dsdna 30 IU/mL at two timepoints prior to randomization). In addition to these criteria, the subpopulation selected for this Market Access report (the PMA Population) had to have renal, neurological, haematological, or cardiovascular/respiratory organ domain involvement (as defined by a BILAG domain score of A, B or C in at least one of the domains) at baseline and at least one of the following: anti-dsdna positive ( 30 IU/mL) at baseline, OR low C3 (<90 mg/dl) and/or C4 (<16 mg/dl) complement relative to the normal range at baseline. MITT population PMA population (% of MITT population) 327 (58.2%) 342 (61.2%) 347 (61.6%) PMA population completed Wk 52, n (% PMA population) 242 (74.0%) 278 (81.3%) 273 (78.7%) Total number PMA population subjects withdrawn, N (%) 85 (26.0%) 64 (18.7%) 74 (21.3%) Withdrawn due to adverse events n (%) 25 (7.6%) 20 (5.8%) 25 (7.2%) Withdrawn due to lack of efficacy n (%) 20 (6.1%) 17 (5.0%) 20 (5.8%) Withdrawn for other reasons n (%) 40 (12.2%) 27 (7.9%) 29 (8.4%) Page 2

3 Demographics PMA population Females: Males 299 (91.4%): 28 (8.6%) 322 (94.2%): 20 (5.8%) 333 (96.0%): 14 (4.0%) Mean Age, years + SD Race 4 White/Caucasian, n (%) 146 (44.6%) 142 (41.5%) 150 (43.2%) European heritage, n (%) 136 (41.7%) 136 (39.8%) 137 (39.5%) Middle Eastern/North African heritage, n (%) 10 (3.1%) 6 (1.8%) 13 (3.7%) Asian, n (%) 83 (25.4%) 83 (24.3%) 98 (28.2%) East Asian heritage, n (%) 53 (16.3%) 52 (15.2%) 58 (16.7%) Southeast Asian heritage, n (%) 19 (5.8%) 15 (4.4%) 25 (7.2%) Central Asian heritage, n (%) (0.3%) South Asian (Indian subcontinent) heritage, n (%) 10 (3.1%) 15 (4.4%) 15 (4.3%) Japanese heritage, n (%) 1 (0.3%) 1 (0,3%) 0 Black/African American, n (%) 33 (10.1%) 28 (8.2%) 34 (9.8%) Alaska Native or American Indian from 64 (19.6%) 89 (26.0%) 65 (18.7%) North/Central/South American, n (%) Native Hawaiian or Other Pacific Islander 1 (0.3%) 0 0 Multiracial, n (%) 1 (0.3%) 2 (0.6%) 2 (0.6%) Hispanic or Latino origin, n (%) 108 (33.0%) 134 (39.2%) 103 (29.7%) Weight in kg, mean + SD PMA Population Baseline Characteristics Disease Activity BILAG Organ Domain Category 5 alphabetic score At least 1A or 2B, n (%) 213 (65.1%) 202 (59.1%) 202 (58.2%) At least 1A, n (%) 53 (16.2%) 61 (17.8%) 44 (12.7%) At least 1A or 1B, n (%) 301 (92.0%) 301 (88.0%) 317 (91.4%) BILAG Category 3 by Organ Domain Renal A - n (%)/B - n(%)/c - n (%) A 1 (0.3%) B 46 (14.1%) C -137 (41.9%) Neurological A - n (%)/B - n(%)/c - n (%) A 0 B 3 (0.9%) C 40 (12.2%) Hematology A - n (%)/B - n(%)/c - n (%) A 1 (0.3%) B 78 (23.9%) C 123 (37.6%) Cardiovascular & Respiratory A - n (%)/B - n(%)/c - n (%) A 3 (0.9%) B 14 (4.3%) C 56 (17.1%) A -6 (1.8%) B 49 (14.3%) C 126 (36.8%) B 4 (1.2%) C 45 (13.2%) B 88 (25.7%) C 122 (35.7%) A 5 (1.5%) B 11 (3.2%) C 53 (15.5%) B 50 (14.4%) C 128 (36.9%) A 1 (0.3%) B 4 (1.2%) C 56 (16.1%) A 3 (0.9%) B 79 (22.8%) C 141 (40.6%) B 15 (4.3%) C 58 (16.7%) SELENA SLEDAI Score Mean + SD < 9, n (%) 116 (35.5%) 140 (40.9%) 145 (41.8%) >10, n (%) 211 (64.5%) 202 (59.1%) 202 (58.2%) PGA Score Mean + SD Subjects with more than one racial sub-category were counted in each sub-category 5 BILAG Organ Domain Categories: A = requires disease modifying treatment, B= mild reversible problems requiring only symptomatic therapy, C= stable mild disease, D= previously affected but currently inactive, E=system never involved (Note Categories D and E assessed but not included here) Page 3

4 PMA Population Baseline Characteristics, contd. Disease Activity, contd. SLE Flare Index At least 1 flare 6, n (%) 86 (26.3%) 68 (19.9%) 70 (20.2%) Proteinuria level (g/24 hr) Mean + SD Serological Activity ANA positive (> 80 titer), n (%) 304 (93.0%) 329 (96.2%) 321 (92.5%) Anti-dsDNA positive (> 30 IU/mL), n (%) 292 (89.3%) 308 (90.1%) 306 (88.2%) Low C3 (<90 mg/dl), n (%) 188 (57.5%) 199 (58.2%) 214 (61.7%) Low C4 (<16 mg/dl), n (%) 229 (70.0%) 246 (71.9%) 252 (72.6%) Primary Efficacy Results: Response Rate at Week 52 Response, n (%) 110 (33.6%) 157 (45.9%) 172 (49.6%) Observed difference vs. (%) % 15.9% Odds Ratio (95% Confidence Interval [CI]) 7 vs (1.3, 2.5) 2.2 (1.6, 3.1) p-value < Odds ratio (95% CI) and p-value were from logistic regression for the comparison between each belimumab dose and placebo with covariates, including baseline SELENA SLEDAI (< 9 vs > 10), baseline proteinuria level (< 2 g/24 h vs > 2 g/24 h equivalent), race (African descent or indigenous-american descent vs. other) and study (HGS1006-C1056 vs. HGS1006-C1057) Secondary Outcome Variable(s): Major Secondary: Percent of subjects with 4 point reduction from baseline in SELENA SLEDAI score at Week 52 Response, n (%) 117 (35.8%) 161 (47.1%) 176 (50.7%) Observed difference vs. (%) % 14.9% Odds Ratio (95% CI) 8 vs (1.3, 2.4) 2.1 (1.5, 2.9) 8 Odds ratio (95% CI) was from logistic regression for the comparison between each belimumab dose and placebo with covariates, including baseline SELENA SLEDAI (< 9 vs > 10), baseline proteinuria level (< 2 g/24 h vs > 2 g/24 h equivalent), race (African descent or indigenous-american descent vs. other) and study (HGS1006-C1056 vs. HGS1006-C1057) 6 Flares occurring between screening and randomization; maximum of 35 days Page 4

5 Secondary Outcome Variable(s), contd. Major Secondary: Mean change in SF-36 Health Survey PCS score from Baseline at Week 24 (Last Observation Carried Forward) N Mean + SE Median (Min, Max) 3.06 (-27.48, 23.88) 3.00 (-22.72, 33.80) 3.24 (-24.41, 30.24) Least Square Mean (LSM) + SE Treatment differences (95% CI) 9 vs placebo (-0.36, 1.76) 0.60 (-0.45, 1.65) 9 All statistics, including the difference in LSM, were from ANCOVA model for the comparison between each belimumab dose and placebo, adjusted for baseline PCS score, baseline SELENA SLEDAI (< 9 vs > 10), baseline proteinuria level (< 2 g/24 h vs > 2 g/24 h equivalent), race (African descent or indigenous-american descent vs. other) and study (HGS1006-C1056 vs. HGS1006-C1057) as covariates. Major Secondary: Time to first SLE flare after 24 weeks by modified SLE flare index n (%) (72.2) 169 (55.4) 186 (60.0) Median days (Min, Max) 93 (1, 218) 149 (1, 207) 112 (2, 204) Hazard ratio (95% CI) vs (0.54, 0.81) 0.74 (0.60, 0.90) 10 Number (%) of subjects with a flare between Week 24 - Week 52 among subjects with at least 1 visit after Week From Cox proportional hazards model for the comparison between each belimumab dose and placebo, adjusted for baseline SELENA SLEDAI score (< 9 vs > 10), baseline proteinuria level (< 2 g/24 h vs > 2 g/24 h equivalent), race (African descent or indigenous-american descent vs. other) and study (HGS1006-C1056 vs. HGS1006-C1057) Conclusion: The Primary Market Access (PMA) Population is a subpopulation of the modified Intent-to-Treat (MITT) Population that was used for the belimumab regulatory submissions. The MITT Population had a clinical diagnosis of SLE according to the American College of Rheumatology (ACR) criteria and active SLE disease (screening SELENA SLEDAI score of 6 and autoantibody positive [antinuclear antibody (ANA) titer of 1:80 and/or anti-dsdna 30 IU/mL at two timepoints prior to randomization]). In addition to these criteria, the PMA Population had renal, neurological, haematological, or cardiovascular/respiratory organ domain involvement (BILAG domain score of A, B or C in at least one of the domains) at baseline and at least one of the following: anti-dsdna positive ( 30 IU/mL) at baseline, OR low C3 (<90 mg/dl) and/or C4 (<16 mg/dl) complement relative to the normal range at baseline With respect to the findings summarized above for the PMA population: Belimumab demonstrated substantial evidence of efficacy. Belimumab 1 and (plus standard of care) achieved a significantly greater response (primary endpoint) compared with placebo (plus standard of care) at Week 52. A significantly greater percentage of subjects treated with belimumab had a 4 point reduction in SELENA SLEDAI score over baseline compared with placebo at Week 52. This is clinically beneficial since a 4 point reduction in SELENA SLEDAI score represents elimination of a sign of symptom of SLE and/or normalization of a clinically important laboratory abnormality. Significant improvements in SF-36 PCS score were not achieved at Week 24 for either belimumab dose compared with placebo. Belimumab had significant beneficial effects on delaying time to first SLE flare after 24 weeks by the modified SLE flare index compared with placebo. Time to SLE flare is an important surrogate marker for SLE disease control. Page 5