Lefluniclo (Page 5 of 8)

13 NONCLINICAL TOXICOLOGY

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility

No evidence of carcinogenicity was observed in a 2-year bioassay in rats at oral doses of leflunomide up to the maximally tolerated dose of 6 mg/kg (approximately 1/40 the maximum human teriflunomide systemic exposure based on AUC). However, male mice in a 2-year bioassay exhibited an increased incidence in lymphoma at an oral dose of 15 mg/kg, the highest dose studied (1.7 times the human teriflunomide exposure based on AUC). Female mice, in the same study, exhibited a dose-related increased incidence of bronchoalveolar adenomas and carcinomas combined beginning at 1.5 mg/kg (approximately 1/10 the human teriflunomide exposure based on AUC). The significance of the findings in mice relative to the clinical use of leflunomide tablet is not known.

Leflunomide was not mutagenic in the Ames assay, the unscheduled DNA synthesis assay, or in the HGPRT gene mutation assay. In addition, leflunomide was not clastogenic in the in vivo mouse micronucleus assay or in the in vivo Chinese hamster bone marrow cell cytogenic test. However, 4-trifluoromethylaniline (TFMA), a minor metabolite of leflunomide, was mutagenic in the Ames assay and in the HGPRT gene mutation assay, and was clastogenic in the in vitro Chinese hamster cell chromosomal aberration assay. TFMA was not clastogenic in the in vivo mouse micronucleus assay or in the in vivo Chinese hamster bone marrow cell cytogenic test.

Leflunomide had no effect on fertility or reproductive performance in either male or female rats at oral doses up to 4.0 mg/kg (approximately 1/30 the human teriflunomide exposure based on AUC) [see Use in Specific Populations (8.1, 8.6)].

14 CLINICAL STUDIES

The efficacy of leflunomide tablets in the treatment of rheumatoid arthritis (RA) was demonstrated in three controlled trials showing reduction in signs and symptoms, and inhibition of structural damage. In two placebo controlled trials, efficacy was demonstrated for improvement in physical function. In these trials, efficacy was evaluated by:

1. Reduction of signs and symptoms

Relief of signs and symptoms was assessed using the American College of Rheumatology (ACR) 20 Responder Index, a composite of clinical, laboratory, and functional measures in rheumatoid arthritis. An “ACR20 Responder” is a patient who had ≥ 20% improvement in both tender and swollen joint counts and in 3 of the following 5 criteria: physician global assessment, patient global assessment, functional ability measure [Modified Health Assessment Questionnaire (MHAQ)], visual analog pain scale, and erythrocyte sedimentation rate or C-reactive protein. An “ACR20 Responder at Endpoint” is a patient who completed the study and was an ACR20 Responder at the completion of the study.

2. Inhibition of structural damage

Inhibition of structural damage compared to control was assessed using the Sharp Score, a composite score of X-ray erosions and joint space narrowing in hands/wrists and forefeet.

3. Improvement in physical function

Improvement in physical function was assessed using the Health Assessment Questionnaire (HAQ) and the Medical Outcomes Survey Short Form (SF-36).In all leflunomide tablets trials, participants of at least 18 years of age and in ARA functional class of I, II or III received an initial loading dosage of 100 mg leflunomide per day for three days, followed by 20 mg per day thereafter.

Exclusion criteria included patients with a history of hypersensitivity to the study medication; women who were pregnant or breast feeding and men or women of child bearing age and potential who had not received contraceptives for at least 4 weeks before entering the study and to be maintained throughout the study and for at least 6 months after discontinuing treatment; patients with a history of inflammatory disease, impaired renal function or liver impairment, cardiac failure, congenital or acquired immunodeficiency, impaired coagulation, or a history of recent major traumatic injury; patients taking intra-articular or systemic concomitant medications which could affect the safety and/or efficacy of the study medication.

Trial 1

Trial 1, a 2 year study, randomized 482 patients with active RA of at least 6 months duration to leflunomide 20 mg/day (n=182), methotrexate 7.5 mg/week increasing to 15 mg/week (n=182), or placebo (n=118). All patients received folate 1 mg BID. The primary analysis was at 52 weeks with blinded treatment to 104 weeks.

Overall, 235 of the 508 randomized treated patients (482 in primary data analysis and an additional 26 patients), continued into a second 12 months of double-blind treatment (98 leflunomide, 101 methotrexate, 36 placebo). Leflunomide dose continued at 20 mg/day and the methotrexate dose could be increased to a maximum of 20 mg/week. In total, 190 patients (83 leflunomide, 80 methotrexate, 27 placebo) completed 2 years of double-blind treatment.

Trial 2

Trial 2 randomized 358 patients with active RA to leflunomide 20 mg/day (n=133), sulfasalazine 2.0 g/day (n=133), or placebo (n=92). Treatment duration was 24 weeks. An extension of the study was an optional 6-month blinded continuation of Trial 2 without the placebo arm, resulting in a 12-month comparison of leflunomide and sulfasalazine.

Of the 168 patients who completed 12 months of treatment , 146 patients (87%) entered a 1-year extension study of double blind active treatment; (60 leflunomide, 60 sulfasalazine, 26 placebo/ sulfasalazine). Patients continued on the same daily dosage of leflunomide or sulfasalazine that they had been taking at the completion of Trial 2. A total of 121 patients (53 leflunomide, 47 sulfasalazine, 21 placebo/sulfasalazine) completed the 2 years of double-blind treatment.

Trial 3

Trial 3 randomized 999 patients with active RA to leflunomide 20 mg/day (n=501) or methotrexate at 7.5 mg/week increasing to 15 mg/week (n=498). Folate supplementation was used in 10% of patients. Treatment duration was 52 weeks.

Of the 736 patients who completed 52 weeks of treatment in study Trial 3, 612 (83%) entered the double-blind, 1-year extension study (292 leflunomide, 320 methotrexate). Patients continued on the same daily dosage of leflunomide or methotrexate that they had been taking at the completion of Trial 3. There were 533 patients (256 leflunomide, 277 methotrexate) who completed 2 years of double-blind treatment.

Clinical Trial Results

Clinical Response

The ACR20 Responder at Endpoint rates are shown in Figure 1. Leflunomide tablets was statistically significantly superior to placebo in reducing the signs and symptoms of RA by the primary efficacy analysis, ACR20 Responder at Endpoint, in study Trial 1 (at the primary 12 months endpoint) and Trial 2 (at 6 month endpoint). ACR20 Responder at Endpoint rates with leflunomide tablets treatment were consistent across the 6 and 12 month studies (41 to 49%). No consistent differences were demonstrated between leflunomide and methotrexate or between leflunomide and sulfasalazine. Leflunomide tablets treatment effect was evident by 1 month, stabilized by 3 to 6 months, and continued throughout the course of treatment as shown in Figure 1.

Figure 1. Percentage of ACR20 Responders at Endpoint in Patients with Active RA in Trials 1, 2, and 3

Image
(click image for full-size original)
Comparisons95%Confidence Intervalp Value
Trial 1Leflunomide tablets vs. Placebo(12, 32)<0.0001
Methotrexate vs. Placebo(8, 30)<0.0001
Leflunomide tablets vs. Methotrexate(-4, 16)NS
Trial 2Leflunomide tablets vs. Placebo(7, 33)0.0026
Sulfasalazine vs. Placebo(4, 29)0.0121
Leflunomide tablets vs. Sulfasalazine(-8, 16)NS
Trial 3Leflunomide tablets vs. Methotrexate(-19, -7)<0.0001

Figure 2. ACR20 Responders over Time in Patients with Active RA in Trial 1*

Image
(click image for full-size original)

ACR50 and ACR70 Responders are defined in an analogous manner to the ACR 20 Responder, but use improvements of 50% or 70%, respectively (Table 3). Mean change for the individual components of the ACR Responder Index are shown in Table 4.

Table 3. Summary of ACR Response Rates in Patients with Active RA in Trials 1,2, and 3*
Study and Treatment GroupACR20ACR50ACR70
Placebo-Controlled Studies
Trial 1 (12 months)
Leflunomide tablets (n=178) 52 34 20
Placebo (n=118) 2684
Methotrexate (n=180) 46239
Trial 2 (6 months)
Leflunomide tablets (n=130) 55 33 10§
Placebo (n=91) 29142
Sulfasalazine (n=132) 57308
Non-Placebo Active-Controlled Studies
Trial 3 (12 months)
Leflunomide tablets (n=495) 513110
Methotrexate (n=489) 654416
* Intent to treat (ITT) analysis using last observation carried forward (LOCF) technique for patients who discontinued early. † N is the number of ITT patients for whom adequate data were available to calculate the indicated rates. ‡ p<0.001 Leflunomide tablets vs placebo § p<0.02 Leflunomide tablets vs placebo

Table 4 shows the results of the components of the ACR response criteria for Trial 1, Trial 2 and Trial 3. Leflunomide tablets was significantly superior to placebo in all components of the ACR Response criteria in study Trial 1 and Trial 2. In addition, leflunomide tablets was significantly superior to placebo in improving morning stiffness, a measure of RA disease activity, not included in the ACR Response criteria. No consistent differences were demonstrated between leflunomide tablets and the active comparators.

Table 4. Mean Change in the Components of the ACR Responder Index in Patients with Active RA in Trials 1, 2, and 3*
ComponentsPlacebo-Controlled StudiesNon-placebo Controlled Study
Trial 1 (12 months)Trial 2 Non-US (6 months)Trial 3 Non-US (12 months)
Leflu nomideMetho trexatePlaceboLeflu nomideSulfa salazinePlaceboLeflunomideMethotrexate
Tender joint count1 -7.7-6.6-3.0-9.7-8.1-4.3-8.3-9.7
Swollen joint count1 -5.7-5.4-2.9-7.2-6.2-3.4-6.8-9.0
Patient global assessment2 -2.1-1.50.1-2.8-2.6-0.9-2.3-3.0
Physician global assessment2 -2.8-2.4-1.0-2.7-2.5-0.8-2.3-3.1
Physical function/disability (MHAQ/HAQ)-0.29-0.150.07-0.50-0.29-0.04-0.37-0.44
Pain intensity2 -2.2-1.7-0.5-2.7-2.0-0.9-2.1-2.9
Erythrocyte Sedimentation rate-6.26-6.482.56-7.48-16.563.44-10.12-22.18
C-reactive protein-0.62-0.500.47-2.26-1.190.16-1.86-2.45
Not included in the ACR Responder Index
Morning Stiffness (min)-101.4-88.714.7-93.0-42.4-6.8-63.7-86.6
* Last Observation Carried Forward; Negative Change Indicates Improvement 1 Based on 28 joint count 2 Visual Analog Scale — 0=Best; 10=Worst

Maintenance of effect

After completing 12 months of treatment, patients continuing on study treatment were evaluated for an additional 12 months of double-blind treatment (total treatment period of 2 years) ,. ACR Responder rates at 12 months were maintained over 2 years in most patients continuing a second year of treatment.

Improvement from baseline in the individual components of the ACR responder criteria was also sustained in most patients during the second year of leflunomide tablets treatment in all three trials.

Radiographic Response

The change from baseline to endpoint in progression of structural disease, as measured by the Sharp X-ray score, is displayed in Figure 3. Leflunomide tablets was statistically significantly superior to placebo in inhibiting the progression of disease by the Sharp Score. No consistent differences were demonstrated between leflunomide and methotrexate or between leflunomide and sulfasalazine.

Figure 3. Change in Sharp Score in Patients with Active RA in Trials 1, 2, and 3

Image
(click image for full-size original)
95% Confidence Interval p Value
Trial 1Leflunomide tablets vs. Placebo(-4.0, -1.1)0.0007
Methotrexate vs. Placebo(-2.6, -0.2)0.0196
Leflunomide tablets vs. Methotrexate(-2.3, 0.0)0.0499
Trial 2Leflunomide tablets vs. Placebo(-6.2, -1.8)0.0004
Sulfasalazine vs. Placebo(-6.9, 0.0)0.0484
Leflunomide tablets vs. Sulfasalazine(-3.3, 1.2)NS
Trial 3Leflunomide tablets vs. Methotrexate(-2.2, 7.4)NS

Physical Function Response

The Health Assessment Questionnaire (HAQ) assesses a patient’s physical function and degree of disability. The mean change from baseline in functional ability as measured by the HAQ Disability Index (HAQ DI) in the 6 and 12 month placebo and active controlled trials is shown in Figure 4. Leflunomide tablets was statistically significantly superior to placebo in improving physical function. Superiority to placebo was demonstrated consistently across all eight HAQ DI subscales (dressing, arising, eating, walking, hygiene, reach, grip and activities) in both placebo controlled studies.

The Medical Outcomes Survey Short Form 36 (SF-36), a generic health-related quality of life questionnaire, further addresses physical function. In Trial 1, at 12 months, leflunomide tablets provided statistically significant improvements compared to placebo in the Physical Component Summary (PCS) Score.

Figure 4. Change in Functional Ability Measure in Patients with Active RA in Trials 1, 2, and 3*

Image
(click image for full-size original)
Comparison95% Confidence Intervalp Value
Trial 1Leflunomide tablets vs. Placebo(-0.58, -0.29)0.0001
Leflunomide tablets vs. Methotrexate(-0.34, -0.07)0.0026
Trial 2Leflunomide tablets vs. Placebo(-0.67, -0.36)<0.0001
Leflunomide tablets vs. Sulfasalazine(-0.33, -0.03)0.0163
Trial 3Leflunomide tablets vs. Methotrexate(0.01, 0.16)0.0221

Maintenance of effect

The improvement in physical function demonstrated at 6 and 12 months was maintained over two years. In those patients continuing therapy for a second year, this improvement in physical function as measured by HAQ and SF-36 (PCS) was maintained.

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