Dimethyl fumarate Teva GmbH

Pharmacotherapeutic group: Immunosuppressants, other immunosuppressants, ATC code: L04AX07 Mechanism of action The mechanism by which dimethyl fumarate exerts therapeutic effects in multiple sclerosis is not fully understood. Preclinical studies indicate that dimethyl fumarate pharmacodynamic responses appear to be primarily mediated through activation of the Nuclear factor (erythroid-derived 2)-like 2 (Nrf2) transcriptional pathway. Dimethyl fumarate has been shown to up regulate Nrf2-dependent antioxidant genes in patients (e.g. NAD(P)H dehydrogenase, quinone 1; [NQO1]). Pharmacodynamic effects Effects on the immune system In preclinical and clinical studies, dimethyl fumarate demonstrated anti-inflammatory and immunomodulatory properties. Dimethyl fumarate and monomethyl fumarate, the primary metabolite of dimethyl fumarate, significantly reduced immune cell activation and subsequent release of pro-inflammatory cytokines in response to inflammatory stimuli in preclinical models. In clinical studies with psoriasis patients, dimethyl fumarate affected lymphocyte phenotypes through a down-regulation of pro-inflammatory cytokine profiles (T H 1, T H 17), and biased towards anti-inflammatory production (T H 2). Dimethyl fumarate demonstrated therapeutic activity in multiple models of inflammatory and neuroinflammatory injury. In phase 3 studies in MS patients (DEFINE, CONFIRM and ENDORSE), upon treatment with dimethyl fumarate mean lymphocyte counts decreased on average by approximately 30% of their baseline value over the first year with a subsequent plateau. In these studies, patients who discontinued treatment with lymphocyte counts below the lower limit of normal (LLN, 0.9 × 10 9 /L) were monitored for recovery of lymphocyte counts to the LLN. Figure 1 shows the proportion of patients estimated to reach the LLN based on the Kaplan-Meier method without prolonged severe lymphopenia. The recovery baseline (RBL) was defined as the last on-treatment ALC prior to treatment discontinuation. The estimated proportion of patients recovering to LLN (ALC ≥ 0.9 x 10 9 /L) at Week 12 and Week 24, who had mild, moderate, or severe lymphopenia at RBL are presented in Table 1, Table 2, and Table 3 with 95% pointwise confidence intervals. The standard error of the Kaplan-Meier estimator of the survival function is computed using Greenwood's formula. Figure 1: Kaplan-Meier method; proportion of patients with recovery to ≥ 910 cells/mm 3 (0.9 × 10 9 /L) LLN from the recovery baseline (RBL) Note: 500 cells/mm 3 , 800 cells/mm 3 , 910 cells/mm 3 correspond to 0.5 × 10 9 /L, 0.8 × 10 9 /L and 0.9 × 10 9 /L respectively. Table 1: Kaplan-Meier method; proportion of patients estimated to reach LLN, mild lymphopenia at the recovery baseline (RBL), excluding patients with prolonged severe lymphopenia Number of patients with mild lymphopenia a at risk Baseline N=86 Week 12 N=12 Week 24 N=4 Proportion reaching LLN (95% CI) 0.81 (0.71, 0.89) 0.90 (0.81, 0.96) a Patients with ALC < 0.9 × 10 9 /L and ≥ 0.8 × 10 9 /L at RBL, excluding patients with prolonged severe lymphopenia. Table 2: Kaplan-Meier method; proportion of patients estimated to reach LLN, moderate lymphopenia at the recovery baseline (RBL), excluding patients with prolonged severe lymphopenia Number of patients with moderate lymphopeniaa at risk Baseline N=124 Week 12 N=33 Week 24 N=17 Proportion reaching LLN (95% CI) 0.57 (0.46, 0.67) 0.70 (0.60, 0.80) a Patients with ALC < 0.8 × 10 9 /L and ≥ 0.5 × 10 9 /L at RBL, excluding patients with prolonged severe lymphopenia. Table 3: Kaplan-Meier method; proportion of patients estimated to reach LLN, severe lymphopenia at the recovery baseline (RBL), excluding patients with prolonged severe lymphopenia Number of patients with severe lymphopeniaa at risk Baseline N=18 Week 12 N=6 Week 24 N=4 Proportion reaching LLN (95% CI) 0.43 (0.20, 0.75) 0.62 (0.35, 0.88) a Patients with ALC < 0.5 × 10 9 /L at RBL, excluding patients with prolonged severe lymphopenia. Clinical efficacy and safety Two, 2 year, randomised, double-blind, placebo-controlled studies (DEFINE with 1,234 patients and CONFIRM with 1,417 patients) of patients with RRMS were performed. Patients with progressive forms of MS were not included in these studies. Efficacy (see Table 4) and safety were demonstrated in patients with expanded disability status scale (EDSS) scores ranging from 0 to 5 inclusive, who had experienced at least 1 relapse during the year prior to randomisation, or, in the 6 weeks before randomisation had a brain MRI demonstrating at least one gadolinium-enhancing (Gd+) lesion. Study CONFIRM contained a rater-blinded (i.e. study physician/ investigator assessing the response to study treatment was blinded) reference comparator of glatiramer acetate. In DEFINE, patients had the following median baseline characteristics: age 39 years, disease duration 7.0 years, EDSS score 2.0. In addition, 16% of patients had an EDSS score > 3.5, 28% had ≥ 2 relapses in the prior year and 42% had previously received other approved MS treatments. In the MRI cohort 36% of patients entering the study had Gd+ lesions at baseline (mean number of Gd+ lesions 1.4). In CONFIRM, patients had the following median baseline characteristics: age 37 years, disease duration 6.0 years, EDSS score 2.5. In addition, 17% of patients had an EDSS score > 3.5, 32% had ≥2 relapses in the prior year and 30% had previously received other approved MS treatments. In the MRI cohort 45% of patients entering the study had Gd+ lesions at baseline (mean number of Gd+ lesions 2.4). Compared to placebo, patients treated with dimethyl fumarate had a clinically meaningful and statistically significant reduction on the primary endpoint in study DEFINE, proportion of patients relapsed at 2 years; and the primary endpoint in study CONFIRM, annualised relapse rate (ARR) at 2 years. Table 4: Clinical and MRI endpoints for studies DEFINE and CONFIRM DEFINE CONFIRM MEEM Placebo Dimethyl fumarate 240 mg twice a day Placebo Dimethyl fumarate 240 mg twice a day Glatiramer acetate Clinical endpoints a No. patients 408 410 363 359 350 Annualised relapse rate 0.364 0.172*** 0.401 0.224*** 0.286* Rate ratio (95% CI) 0.47 (0.37, 0.61) 0.56 (0.42, 0.74) 0.71 (0.55, 0.93) Proportion relapsed 0.461 0.270*** 0.410 0.291** 0.321** Hazard ratio (95% CI) 0.51 (0.40, 0.66) 0.66 (0.51, 0.86) 0.71 (0.55, 0.92) Proportion with 12-week confirmed disability progression 0.271 0.164** 0.169 0.128# 0.156# Hazard ratio (95% CI) 0.62 (0.44, 0.87) 0.79 (0.52, 1.19) 0.93 (0.63, 1.37) Proportion with 24 week confirmed disability progression 0.169 0.128# 0.125 0.078# 0.108# Hazard ratio (95% CI) 0.77 (0.52, 1.14) 0.62 (0.37, 1.03) 0.87 (0.55, 1.38) MRI Endpoints b No. patients 165 152 144 147 161 Mean (median) number of new or newly enlarging T2 lesions over 2 years 16.5 (7.0) 3.2 (1.0)*** 19.9 (11.0) 5.7 (2.0)*** 9.6 (3.0)*** Lesion mean ratio (95% CI) 0.15 (0.10, 0.23) 0.29 (0.21, 0.41) 0.46 (0.33, 0.63) Mean (median) number of Gd lesions at 2 years 1.8 (0) 0.1 (0)*** 2.0 (0.0) 0.5 (0.0)*** 0.7 (0.0)** Odds ratio (95% CI) 0.10 (0.05, 0.22) 0.26 (0.15, 0.46) 0.39 (0.24, 0.65) Mean (median) number of new T1 hypointense lesions over 2 years 5.7 (2.0) 2.0 (1.0)*** 8.1 (4.0) 3.8 (1.0)*** 4.5 (2.0)** Lesion mean ratio (95% CI) 0.28 (0.20, 0.39) 0.43 (0.30, 0.61) 0.59 (0.42, 0.82) a All analyses of clinical endpoints were intent-to-treat; bMRI analysis used MRI cohort *P-value < 0.05; **P-value < 0.01; ***P-value < 0.0001; #not statistically significant An open non-controlled 8-year extension study (ENDORSE) enrolled 1,736 eligible RRMS patients from the pivotal studies (DEFINE and CONFIRM). The primary objective of the study was to assess the long-term safety of dimethyl fumarate in patients with RRMS. Of the 1,736 patients, approximately half (909, 52%) were treated for 6 years or longer. 501 patients were continuously treated with dimethyl fumarate 240 mg twice daily across all 3 studies and 249 patients who were previously treated with placebo in studies DEFINE and CONFIRM received treatment 240 mg twice daily in study ENDORSE. Patients who received treatment twice daily continuously were treated for up to 12 years. During study ENDORSE, more than half of all patients treated with dimethyl fumarate 240 mg twice daily did not have a relapse. For patients continuously treated twice daily across all 3 studies, the adjusted ARR was 0.187 (95% CI: 0.156, 0.224) in studies DEFINE and CONFIRM and 0.141 (95% CI: 0.119, 0.167) in study ENDORSE. For patients previously treated with placebo, the adjusted ARR decreased from 0.330 (95% CI: 0.266, 0.408) in studies DEFINE and CONFIRM to 0.149 (95% CI: 0.116, 0.190) in study ENDORSE. In study ENDORSE, the majority of patients (> 75%) did not have confirmed disability progression (measured as 6-month sustained disability progression). Pooled results from the three studies demonstrated dimethyl fumarate treated patients had consistent and low rates of confirmed disability progression with slight increase in mean EDSS scores across ENDORSE. MRI assessments (up to year 6, including 752 patients who had previously been included in the MRI cohort of studies DEFINE and CONFIRM showed that the majority of patients (approximately 90%) had no Gd-enhancing lesions. Over the 6 years, the annual adjusted mean number of new or newly enlarging T2 and new T1 lesions remained low. Efficacy in patients with high disease activity: In studies DEFINE and CONFIRM, consistent treatment effect on relapses in a subgroup of patients with high disease activity was observed, whilst the effect on time to 3-month sustained disability progression was not clearly established. Due to the design of the studies, high disease activity was defined as follows: - Patients with 2 or more relapses in one year, and with one or more Gd-enhancing lesions on brain MRI (n=42 in DEFINE; n=51 in CONFIRM) or, - Patients who have failed to respond to a full and adequate course (at least one year of treatment) of beta-interferon, having had at least 1 relapse in the previous year while on therapy, and at least 9 T2-hyperintense lesions in cranial MRI or at least 1 Gd-enhancing lesion, or patients having an unchanged or increased relapse rate in the prior year as compared to the previous 2 years (n=177 in DEFINE; n=141 in CONFIRM). Paediatric population The safety and efficacy of dimethyl fumarate in paediatric RRMS was evaluated in a randomised, open-label, active-controlled (interferon beta-1a) parallel group study in patients with RRMS aged 10 to less than 18 years of age. One hundred and fifty patients were randomised to dimethyl fumarate (240 mg twice daily oral) or interferon beta-1a (30 µg IM once a week) for 96 weeks. The primary endpoint was the proportion of patients free of new or newly enlarging T2 hyperintense lesions on brain MRI scans at week 96. The main secondary endpoint was the number of new or newly enlarging T2 hyperintense lesions on brain MRI scans at week 96. Descriptive statistics are presented as no confirmatory hypothesis was pre-planned for the primary endpoint. The proportion of patients in the ITT population with no new or newly enlarging T2 MRI lesions at week 96 relative to baseline was 12.8% for dimethyl fumarate versus 2.8% in the interferon beta-1a group. The mean number of new or newly enlarging T2 lesions at week 96 relative to baseline, adjusted for baseline number of T2 lesions and age (ITT population excluding patients without MRI measurements) was 12.4 for dimethyl fumarate and 32.6 for interferon beta-1a. The probability for clinical relapse was 34% in the dimethyl fumarate group and 48% in the interferon beta-1a group by the end of the 96 week open-label study period. The safety profile in paediatric patients (aged 13 to less than 18 years of age) receiving dimethyl fumarate was qualitatively consistent with that previously observed in adult patients (see section 4.8).