DOC

disease-modifying

By Lawrence Turner,2014-08-27 10:18
14 views 0
disease-modifying

FDA Briefing Document

    March 4, 2003 meeting of Arthritis Advisory Committee

UPDATE ON THE TNF-; BLOCKING AGENTS

    I. INTRODUCTION

    The intent of this document is to summarize the efficacy data that resulted in the licensure of the three tumor necrosis factor (TNF) blocking agents and to provide a more comprehensive update on their safety. The three products, Etanercept (Enbrel), Infliximab (Remicade) and Adalimumab (Humira) are indicated for treatment of patients with RA. Clinical studies have shown the products to improve signs and symptoms, inhibit the progression of structural damage, and impact functional outcomes in patients with RA. The efficacy section will begin with a summary of Adalimumab, the newest of the TNF blocking therapies.

    While all these agents have demonstrated efficacy in patients with active RA despite treatment with other DMARDs (disease modifying anti-rheumatic drugs), they have also been associated with certain uncommon but serious adverse events. Most of these events have come to light through the post-marketing passive surveillance program. At the time of approval of the first two TNF blocking agents, the total numbers of patients treated and extent of exposure from controlled clinical trials and the open label extension studies were relatively limited. As will be summarized in the safety section of this document, the post market safety updates and data from controlled clinical trials in other settings have triggered several different FDA actions, including updates to the prescribing information in the package inserts, communications to health care providers (Dear Health Care Provider Letters) a safety update on August 17, 2001 to the AAC, as well as presentations at ACR and other national and international meetings and publications in journals. This safety update will summarize safety data from the randomized controlled trials contained in the Biologics License Application (BLA) of Adalimumab for RA, and provide an update on safety information for Remicade and Enbrel. One major focus of this safety update will be a more in-depth review of the cases of lymphomas that have developed in patients treated with TNF blocking therapy. We specifically seek the committee’s advice on issues regarding the association between these products and lymphoma and input regarding how to best transmit this information in prescribing information.

     1

FDA Briefing Document

    March 4, 2003 meeting of Arthritis Advisory Committee

    II. EFFICACY OF TNF BLOCKING AGENTS

    A. Humira

    Humira is a human-derived recombinant IgG1 monoclonal antibody engineered by gene technology. Humira binds to TNF- but not TNF- and has a half-life of approximately

    2 weeks. It was approved for use in patients with RA December 31, 2002. The paragraphs below summarize the major efficacy findings; the Humira safety summary is presented in Section III. Appendix A provides the full medical review of the BLA. The sponsor conducted four randomized, double-blind efficacy studies in patients age

    18 with active rheumatoid arthritis diagnosed according to American College of

    Rheumatology (ACR) criteria. Patients had at least 6 swollen and 9 tender joints. Adalimumab was administered subcutaneously in combination with MTX (12.5 to 25 mg, Studies I and III) or as monotherapy (Study II) or with other disease-modifying anti-rheumatic drugs (DMARDs) (Study IV).

    Study I (DE009) evaluated 271 patients who had failed therapy with at least one but no more than four DMARDs and had inadequate response to MTX. Doses of 20, 40 or 80 mg of HUMIRA or placebo were given every other week for 24 weeks.

    Study II (DE011) evaluated 544 patients who had failed therapy with at least one DMARD. Doses of placebo, 20 or 40 mg of HUMIRA were given as monotherapy every other week or weekly for 26 weeks.

    Study III (DE 019) evaluated 619 patients who had an inadequate response to MTX. Patients received placebo, 40 mg of HUMIRA every other week with placebo injections on alternate weeks, or 20 mg of HUMIRA weekly for up to 52 weeks. Study III had an additional primary endpoint at 52 weeks of inhibition of disease progression (as detected by X-ray results).

    Study IV (DE031) assessed safety in 636 patients who were either DMARD-naive or were permitted to remain on their pre-existing rheumatologic therapy provided that therapy was stable for a minimum of 28 days. Patients were randomized to 40 mg of HUMIRA or placebo every other week for 24 weeks.

     Table 1 summarizes the ACR 20, 50, and 70 findings.

     2

FDA Briefing Document

    March 4, 2003 meeting of Arthritis Advisory Committee

    Table 1 : Summary of Percentage of ACR20, ACR50, and ACR70 Responses for All Adalimumab Studies At 6 and 12 Months at the recommended dose

    Adalimumab Placebo/

    40 mg Q2w Comparator Study

    24 or 26 Weeks

    ACR20 67 13 I Dose ranging ACR50 54 7 + MTX ACR70 24 3

    ACR20 46 20

    II Monotherapy ACR50 22 8

    ACR70 12 2

    ACR20 63 30

    III (+ MTX) ACR50 39 10

    ACR70 21 3

    ACR20 53 35 IV (Added to Usual ACR50 29 11 Clinical Practice) ACR70 15 3

     52 Weeks

    III (+ MTX) ACR20 55 25

    ACR50 42 10

    ACR70 23 5

    ACR Responses in Placebo-Controlled Trials (Percent of Patients)

The results of the components of the ACR response criteria for Studies II and III are

    shown in the table below. Improvement was seen in all components and was maintained

    to week 52.

     3

FDA Briefing Document

    March 4, 2003 meeting of Arthritis Advisory Committee

    Components of ACR Response

     Study II Study III a aParameter (median) Placebo HUMIRA/MTX Placebo/MTX HUMIRA

    N=110 N=113 N=200 N=207

    Baseline Wk 26 Baseline Wk 26 Baseline Wk 24 Baseline Wk 24

     Number of tender joints (0-68)35 26 31 16* 26 15 248* Number of swollen joints (0-66)19 16 18 10* 17 11 18 5*

    Physician global assessme 7.0 6.1 6.6 3.7* 6.3 3.5 6.5 2.0* b ntb Patient global assessment7.5 6.3 7.5 4.5* 5.4 3.9 5.2 2.0* b Pain7.3 6.1 7.3 4.1* 6.0 3.8 5.8 2.1* c Disability index (HAQ)2.0 1.9 1.9 1.5* 1.5 1.3 1.5 0.8*

    CRP (mg/dL) 3.9 4.3 4.6 1.8* 1.0 0.9 1.0 0.4* a 40 mg HUMIRA administered every other week b Visual analogue scale; 0 = best, 10 = worst c2 Disability Index of the Health Assessment Questionnaire; 0 = best, 3 = worst, measures the patient’s ability to perform the following: dress/groom, arise, eat, walk, reach, grip, maintain hygiene, and maintain daily

    activity

    * p<0.001, HUMIRA vs. placebo, based on mean change from baseline

    The time course of ACR 20 response for Study III is shown in figure 1. In Study III, 85% of patients with ACR 20 responses at week 24 maintained the response

    at 52 weeks. The time course of ACR 20 response for Study I and Study II were similar.

    40 mg every other weekPlacebo

    70

    60

    50

    40

    30

    20

    10Percent ACR20 Responders

    0

    081624324048

    Time (Weeks)

    Figure 1: Study III ACR 20 Responses over 52 Weeks 4

FDA Briefing Document

    March 4, 2003 meeting of Arthritis Advisory Committee

    In Study III, structural joint damage was assessed radiographically and expressed as change in Total Sharp Score (TSS) and its components, the erosion score and Joint Space Narrowing (JSN) score, at month 12 compared to baseline. At baseline, the median TSS was approximately 55 in the placebo and 40 mg every other week groups. The results are shown in Table 3. HUMIRA/MTX treated patients demonstrated less radiographic progression than patients receiving MTX alone.

Table 3 Radiographic data - change in score compared to baseline

     Placebo/MTX HUMIRA/MTX Placebo/MTX-P-value**

    40 mg every other HUMIRA/MTX

    week (95% Confidence

    Interval*)

Total Sharp score 2.7 0.1 2.6 (1.4, 3.8) <0.001

Erosion score 1.6 0.0 1.6 (0.9, 2.2) <0.001

    JSN score 1.0 0.1 0.9 (0.3, 1.4) 0.002

    *95% confidence intervals for the differences in change scores between MTX and HUMIRA.

    **Based on rank analysis

    The optimal dose of adalimumab is 40 mg sc every other week when given in combination with MTX. Higher doses were not more effective. In study II, which did not include MTX, although adalimumab 40 mg every other week was effective (46% ACR20 responses at 6 months), 40 mg weekly was associated with higher response rates (53% ACR20 responses at 6 months). Comparisons across trials must be carried out with caution; however, the higher point estimates of the response rates in 6-month trials of adalimumab 40 mg every other week with MTX suggest that the addition of MTX to adalimumab is more effective.

    In all four studies, Humira showed significantly greater improvement than placebo in the disability index of Health Assessment Questionnaire (HAQ) from baseline to the end of study, and significantly greater improvement than placebo in the health-outcomes as assessed by The Short Form Health Survey (SF 36). Improvement was seen in both the Physical Component Summary (PCS) and the Mental Component Summary (MCS). However, the duration of the longest study (12 months) was not sufficient to permit a claim of Improvement in Physical Function as delineated in the RA Guidance. Most patients enrolled in the controlled trials of adalimumab were offered the opportunity to roll over into a long-term open-label extension study. To assess tolerability of adalimumab treatment over time, the data from clinical trials were analyzed to determine

     5

FDA Briefing Document

    March 4, 2003 meeting of Arthritis Advisory Committee

    what fractions of patients who were allowed to continue treatment for 1, 2, 3 or 4 years chose to do so. As shown in Table 4, 70% of patients who began treatment with adalimumab chose to continue for 2 years and approximately 60% chose to continue for 3 years.

    Table 4: Percent of Adalimumab-Treated Subjects Choosing to Remain on

    Treatment

    Years of exposure # exposed Total possible % choosing to remain on treatment

    <1 yr 2468 2468 100%

    1990 2444 81% 1 yr

    1258 1795 70% 2 yrs

    331 534 62% 3 yrs

    142 254 56% 4 yrs

    41 89 46% 5 yrs

B. Enbrel efficacy summary

    The efficacy of Enbrel for improvement in signs and symptoms of rheumatoid arthritis was established in 3 randomized controlled trials. One efficacy trial was a study of Enbrel or placebo added onto background therapy in patients who had failed one or more DMARDs (study I, Table 5). Approximately 60% of patients had an ACR20 response at 6 months compared to approximately 10% of add-on placebo-treated patients. Similar results were seen in a randomized controlled trial of Enbrel added to background methotrexate in patients with active disease despite methotrexate (study II). A median improvement of approximately 50-60% was seen in each of the components of the ACR20. Continued durable responses have been seen for up to 36 months in open-label extension treatment trials when patients received Enbrel without interruption. The third randomized trial was an active controlled trial that compared a rapid dose escalation of methotrexate to Enbrel in patients with early RA (see section VI for more details) Most patients enrolled in the controlled trials of etanercept were offered the opportunity to roll over into a long-term open-label extension study. To assess tolerability of etanercept treatment over time, the data from clinical trials were analyzed to determine what fractions of patients who were allowed to continue treatment for 1, 2, 3 or 4 years chose to do so. As shown in Table 6, 73% of patients who began treatment with etanercept chose to continue for 2 years and approximately 50% chose to continue on study receiving etanercept for 3 years. It should be noted that these figures provide a conservative estimate of the proportion of patients who elected to continue etanercept as some patients dropped out of the study and received etanercept by prescription once it once approved.

     6

FDA Briefing Document

    March 4, 2003 meeting of Arthritis Advisory Committee Radiographic findings at 1 and 2 year time-points are shown in Table 7. Effects were

    seen on erosion and the joint space narrowing components of the Sharp score. Etanercept

    is also approved for treatment of polyarticular-course juvenile rheumatoid arthritis and

    for patients with psoriatic arthritis.

    Table 5: ACR Responses in Placebo- and Active-Controlled Trials

    (Percent of Patients)

     Placebo Controlled Active Controlled

     Study I Study II Study III aaa Placebo ENBREL MTX/Placebo MTX/ENBREL MTX ENBREL

    Response N = 80 N = 78 N = 30 N = 59 N = 217 N = 207

     ACR 20

     bb Month 3 23% 62% 33% 66% 56% 62% bb Month 6 11% 59% 27% 71% 58% 65%

     Month 12 NA NA NA NA 65% 72%

     ACR 50

     bb Month 3 8% 41% 0% 42% 24% 29% bb Month 6 5% 40% 3% 39% 32% 40%

     Month 12 NA NA NA NA 43% 49%

     ACR 70

     bbc Month 3 4% 15% 0 15% 7% 13% bbc Month 6 1% 15% 0 15% 14% 21%

     Month 12 NA NA NA NA 22% 25%

    a. 25 mg ENBREL SC twice weekly.

    b. p < 0.01, ENBREL vs. placebo.

    c. p < 0.05, ENBREL vs. MTX.

    Table 6: Percent of Etanercept-Treated Subjects Choosing to Remain on Treatment

    Years of exposure Early RA Later RA Total Percent

    (N) (N) (N) (%)

    482 606 1088 81% 1 yr

    433 547 980 73% 2 yrs

    295 501 796 52% 3 yrs

    245 450 695 52% 4 yrs

     7

FDA Briefing Document

    March 4, 2003 meeting of Arthritis Advisory Committee

    Table 7: Mean Radiographic Change Over 6 and 12 Months in Study III

    25 mg MTX-ENBREL

     MTX ENBREL (95% Confidence Interval*) P-value

    12 Months Total Sharp score 1.59 1.00 0.59 (-0.12, 1.30) 0.110

     Erosion score 1.03 0.47 0.56 (0.11, 1.00) 0.002

     JSN score 0.56 0.52 0.04 (-0.39, 0.46) 0.529

6 Months Total Sharp score 1.06 0.57 0.49 (0.06, 0.91) 0.001

     Erosion score 0.68 0.30 0.38 (0.09, 0.66) 0.001

     JSN score 0.38 0.27 0.11 (-0.14, 0.35) 0.585

* 95% confidence intervals for the differences in change scores between MTX and ENBREL

C. Remicade Efficacy Summary

    The efficacy of Remicade in combination with MTX, for improving the signs and symptoms of rheumatoid arthritis and for inhibition of progression of structural damage, was established in the ATTRACT trial of patients with active rheumatoid arthritis despite treatment with methotrexate. As shown in Table 8, treatment with Remicade increased the proportion of patients with ACR20 at 6 and 12 months. Efficacy was seen with each of the 4 dosing regimens, ranging from 3 mg IV q8w to 10 mg IV q4w. Similar response rates were seen at 6 months with each of the dose regimens. However, for patients in the lowest dose group, there was a trend towards decreasing rates of ACR20 response between 6 months and 1 year. Higher rates of ACR 50 and 70 responses were also seen with Remicade.

    Remicade has also demonstrated efficacy for improvement in physical function in RA, based on 2-year data from the ATTRACT trial. The sponsor’s primary analysis was the 2-year weighted mean change in HAQ (Table 9). The means for the weighted mean change in HAQ increased from 0.3 u for patients receiving placebo to 0.4-0.5 for infliximab-treated patients. The median values for the weighted mean change in HAQ was 0.1 u in the placebo arm and 0.3-0.4 for the 4 infliximab-treated arms. Both the global differences between treatment arms and each of the pairwise comparisons between infliximab and placebo were highly statistically significant. Multiple other analyses of HAQ showed robust and consistent effects -- including a sustained improvement in HAQ of 0.3 u, a benefit that exceeds the level of 0.22 u that has been demonstrated to be clinically meaningful. (see Appendix B, Tables 26-28)

     8

FDA Briefing Document

    March 4, 2003 meeting of Arthritis Advisory Committee

    Table 8: PERCENTAGE OF PATIENTS WHO ACHIEVED AN ACR RESPONSE AT

    WEEKS 30 AND 54

     REMICADE + MTX

     a a 3 mg/kg 10 mg/kg

    Placebo

    Response + MTX q 8 wks q 4 wks q 8 wks q 4 wks

     (n=88) (n=86) (n=86) (n=87) (n=81)

    ACR 20

    Week 30 20% 50% 50% 52% 58%

    Week 54 17% 42% 48% 59% 59%

    ACR 50

    Week 30 5% 27% 29% 31% 26%

    Week 54 9% 21% 34% 40% 38%

    ACR 70

    Week 30 0% 8% 11% 18% 11%

    Week 54 2% 11% 18% 26% 19%

     a p < 0.05 for each outcome compared to placebo

    Table 9: Weighted Mean Change from Baseline in HAQ

     Infliximab

     3 mg/kg 3 mg/kg 10 mg/kg 10 mg/kg

     Placebo q 8 Wks q 4 Wks q 8 Wks q 4 Wks

    Pts randomized 88 86 86 87 81

    Change from baseline

    through week 102

    Pts evaluated 88 86 85 87 81

    Mean ? SD 0.3 ? 0.4 0.4 ? 0.3 0.5 ? 0.5 0.5 ? 0.5 0.4 ? 0.4

    Median 0.1 0.4 0.4 0.4 0.3

    IQ range (0.0, 0.4) (0.1, 0.6) (0.1, 0.7) (0.2, 0.9) (0.1, 0.5)

    Range (0.0, 1.6) (0.0, 1.5) (0.0, 1.7) (0.0, 1.7) (0.0, 2.2)

    p-value vs placebo 0.006 < 0.001 < 0.001 0.002

    In the ATTRACT trial, all patients were initially offered one year of treatment. Of the

    subjects randomized to receive infliximab, 79% (268 of 340) remained on treatment for

    the full year. Subjects who completed one year of treatment were then offered a second

    year of therapy. Of the 268 who completed the first year, 76% (203 patients) remained

     9

    FDA Briefing Document

    March 4, 2003 meeting of Arthritis Advisory Committee

    on therapy through the end of the second year. Thus of the 340 patients initially begun

    on infliximab, 60% remained on therapy for the full two years.

    The ATTRACT trial also assessed inhibition of progression of structural damage based

    on the 12-month change in the total Sharp score. As shown in Table 10, patients in the

    placebo arm (i.e. receiving background MTX) experienced a rate of progression of 4 u/yr,

    while patients in the 4 infliximab arms (receiving MTX plus infliximab) had rates of

    progression of between 0.5 and 0.5. The differences between infliximab and placebo

    were highly statistically significant. The rates of progression of both erosion scores and

    joint space narrowing scores (JSN) were also reduced in the infliximab arms.

    Table 10: RADIOGRAPHIC CHANGE FROM BASELINE TO WEEK 54

    REMICADE + MTX Median

    3 mg/kg 10 mg/kg (10, 90 Placebo apercentiles) + MTX q 8wks q 4 wks q 8 wks q 4 wks p-value

     (n=64) (n=71) (n=71) (n=77) (n=66)

    Total Score

    Baseline 55 57 45 56 43

    (14, 188) (15, 187) (8, 162) (6, 143) (7, 178)

Change from 4.0 0.5 0.1 0.5 -0.5

    baseline (-1.0, 19.0) (-3.0, 5.5) (-5.2, 9.0) (-4.8, 5.0) (-5.7, 4.0) p<0.001

    Erosion Score

    Baseline 25 29 22 22 26

    (8, 110) (9, 100) (3, 91) (3, 80) (4, 104)

Change from 2.0 0.0 -0.3 0.5 -0.5

    baseline (-1.0, 9.7) (-3.0, 4.3) (-3.1, 2.5) (-3.0, 2.5) (-2.7, 2.5) p<0.001

    JSN Score

    Baseline 26 (3, 88) 29 (4, 80) 20 (3, 83) 24 (1, 79) 25 (3, 77)

Change from 1.5 0.0 0.0 0.0 0.0

    baseline (-0.8, 8.0) (-2.5, 4.5) (-3.4, 5.0) (-3.0, 2.5) (-3.0, 3.5) p<0.001

     a For comparisons of each dose against placebo

    Infliximab is also approved for the treatment of Crohn’s Disease.

     10

Report this document

For any questions or suggestions please email
cust-service@docsford.com