Pharmacological properties : תכונות פרמקולוגיות

Pharmacodynamic Properties

Mechanism of action

The pathophysiology of MS is multifaceted and propagated through ongoing inflammatory and neurodegenerative stimuli, mediated at least in part by toxic oxidative stress. Due to the similarities between Vumerity and dimethyl fumarate, Vumerity is assumed to have the same effects on MS pathophysiology as dimethyl fumarate.


Preclinical studies indicate that the pharmacodynamic effects of dimethyl fumarate and its metabolite monomethyl fumarate appear to be primarily mediated through activation of the nuclear factor (erythroid-derived 2)-like 2 (Nrf2) transcriptional pathway, which is the cellular defence system for responding to a variety of potentially toxic stimuli, including inflammatory and oxidative stress. Dimethyl fumarate has been shown to up regulate Nrf2-dependent antioxidant genes in patients (e.g. NAD(P)H dehydrogenase, quinone 1; [NQO1], confirming clinical pharmacodynamic activity in humans.


Dimethyl fumarate reduces inflammatory responses in both peripheral and central cells, and promotes cytoprotection of central nervous system cells against toxic stressors, demonstrating beneficial effects on pathways known to exacerbate multiple sclerosis pathology. Vumerity and dimethyl fumarate undergo rapid hydrolysis prior to systemic circulation by esterases and are converted to the primary active metabolite, monomethyl fumarate.
However, the mechanism by which Vumerity and dimethyl fumarate exerts therapeutic effects in multiple sclerosis is not fully understood.

Pharmacodynamics

Activation of the Nuclear factor (erythroid-derived 2)-like 2 (Nrf2) Transcriptional Pathway The mechanism of action of Vumerity and dimethyl fumarate appears to be mediated, at least in part, through activation of the Nrf2 anti-oxidant transcriptional pathway. Biological response markers of Nrf2 activation (e.g. NAD(P)H dehydrogenase, quinone 1 [NQO1]) are detected at elevated levels in blood from patients with MS following 12 or 48 weeks of oral dosing with dimethyl fumarate. These clinical data appear to be consistent with preclinical studies demonstrating dimethyl fumarate-dependent up-regulation of Nrf2 antioxidant response genes in multiple tissue types. The relationships between blood NQO1 levels and the mechanism(s) by which dimethyl fumarate exerts its effects in MS are unknown.

Effects on the immune system

In preclinical and clinical studies, dimethyl fumarate demonstrates anti-inflammatory and immunomodulatory properties. Dimethyl fumarate and monomethyl fumarate, the primary metabolite of dimethyl fumarate, significantly reduce immune cell activation and subsequent release of pro-inflammatory cytokines in response to inflammatory stimuli in preclinical models, and moreover in clinical studies, affects lymphocyte phenotypes through a down-regulation of pro-inflammatory cytokine profiles (TH1, TH17), with a bias towards anti-inflammatory production (TH2). Dimethyl fumarate demonstrates therapeutic activity in multiple models of inflammatory and neuroinflammatory injury, and also appears to promote improvement in blood brain barrier integrity.
In Phase 3 studies, following 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. The anti-inflammatory and immune-modulatory effects appear consistent with the significant clinical activity of dimethyl fumarate in reducing brain lesions and relapses in multiple sclerosis patients.

Effects on the central nervous system

In preclinical studies, monomethyl fumarate is able to penetrate into the central nervous system where it promotes cyto- and neuro-protective responses. Dimethyl fumarate and monomethyl fumarate significantly improve cell viability after oxidative challenge in primary cultures of astrocytes and neurons, suggesting monomethyl fumarate and dimethyl fumarate directly prevent neurodegeneration in response to toxic stress. Acute neurotoxic injury models and genetic models of neurodegenerative disease confirm that dimethyl fumarate provides therapeutic benefit in reducing neuronal and functional damage resulting from various types of toxic stimuli and other forms of cellular stress inherent in neurodegenerative disease states.
These preclinical data combined with imaging and functional endpoints from clinical studies suggest dimethyl fumarate and Vumerity may promote a neuroprotective benefit in the central nervous system.
Effects on the Gastrointestinal System

In a double-blind clinical study comparing GI tolerability of Vumerity versus dimethyl fumarate, Vumerity demonstrated reduced incidence of GI adverse events, as well as GI adverse events leading to treatment discontinuation, compared to dimethyl fumarate (see section “Undesirable effects”).


Effect on the Cardiovascular System
In a double-blind, placebo- and active-controlled thorough QT study in healthy subjects, Vumerity up to 2× the recommended doses (924 mg BID) did not have a clinically relevant effect on QTc interval.


Effects of the metabolite HES
2-Hydroxyethyl succinimide (HES) is a major inactive metabolite of Vumerity. In in vitro studies,
HES demonstrated no biological activities at concentrations similar to or exceeding those seen clinically and was not shown to interfere with biological activity of monomethyl fumarate. To assess the potential impact of HES on efficacy in vivo, diroximel fumarate was tested compared to dimethyl fumarate in a standard rat model of MS and diroximel fumarate and dimethyl fumarate were found to have similar efficacy, demonstrating that HES does not interfere with efficacy in vivo. In the interim analysis of the ongoing, 96-week clinical study of Vumerity in patients with MS, HES did not appear to have any clinically relevant impact on the safety profile of Vumerity.

Clinical efficacy

Vumerity and dimethyl fumarate are rapidly metabolized by esterases before they reach the systemic circulation to the same active metabolite, monomethyl fumarate, following oral administration. The pharmacokinetics (PK) comparability of Vumerity to dimethyl fumarate through the analysis of monomethyl fumarate exposure has been demonstrated, thus their efficacy profiles are expected to be similar (see section “Pharmacokinetics”). The clinical studies described in the following sections were conducted using dimethyl fumarate.


Two, 2-year, randomised, double-blind, placebo controlled studies [DEFINE, 1’234 subjects and CONFIRM, 1’417 subjects] and an 8-year two phase extension study [ENDORSE, 1’736 subjects] of subjects with relapsing-remitting multiple sclerosis (RRMS) were performed.
Subjects with progressive forms of MS were not included in these studies. Efficacy (see table below) and safety was demonstrated in two of the three studies (DEFINE and CONFIRM) including subjects 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 who, within 6 weeks of randomisation, had a brain Magnetic Resonance Imaging (MRI) scan demonstrating at least 1 gadolinium-enhancing (Gd+) lesion.


In DEFINE and CONFIRM, dimethyl fumarate was investigated either at a dose of 240 mg twice a day or 240 mg three times a day (DEFINE: 410 patients twice and 416 patients three times a day; CONFIRM: 359 patients twice and 345 patients three times a day). The efficacy of both dosages was comparable: efficacy was no better with lower tolerance of the higher dosage.
CONFIRM contained a rater-blinded (i.e. study physician/investigator assessing the response to study treatment is blinded, but not the patient or treating physician) reference comparator of glatiramer acetate.


Median values for baseline characteristics in DEFINE: age 39 years, years since diagnosis 4.0 years and EDSS score at baseline 2.0. Median values for baseline characteristics in
CONFIRM: age 37 years, years since diagnosis 3.0 years and EDSS score at baseline 2.5.


Compared to placebo, patients treated with dimethyl fumarate had a statistically significant reduction in the primary endpoint in DEFINE (proportion of subjects who had had a relapse at 2 years) and the primary endpoint in CONFIRM (annualised relapse rate at 2 years).


Dimethyl fumarate only exhibited a statistically significant reduction in the progression of disability after 12 weeks in DEFINE, and not in CONFIRM. When considering progression of disability after 24 weeks, neither study revealed a statistically significant reduction.


Table 3: Clinical results of DEFINE and CONFIRM
DEFINE                        CONFIRM
Placebo       Dimethyl       Placebo        Dimethyl       Glatiramer fumarate                      fumarate       acetate
240 mg                        240 mg twice a day                   twice a day
Clinical   Endpointsa
DEFINE                   CONFIRM
Placebo    Dimethyl       Placebo   Dimethyl       Glatiramer fumarate                 fumarate       acetate
240 mg                   240 mg twice a day              twice a day
No. of subjects                       408        410            363       359            350 Annualised relapse rate               0.364      0.172***       0.401     0.224***       0.286* Rate ratio                                       0.47                     0.56           0.71 (95% CI)                                         (0.37, 0.61)             (0.42, 0.74)   (0.55, 0.93) Proportion of patients with one       0.461      0.270***       0.410     0.291**        0.321** relapse
Hazard ratio                                     0.51                     0.66           0.71 (95% CI)                                         (0.40, 0.66)             (0.51, 0.86)   (0.55, 0.92) Proportion of patients with 12-week   0.271      0.164**        0.169     0.128#         0.156# confirmed disability progression
Hazard ratio                                     0.62                     0.79           0.93 (95% CI)                                         (0.44, 0.87)             (0.52, 1.19)   (0.63, 1.37) Proportion of patients with 24-week   0.169      0.128#         0.125     0.078#         0.108# confirmed disability progression
Hazard ratio                                     0.77                     0.62           0.87 (95% CI)                                         (0.52, 1.14)             (0.37, 1.03)   (0.55, 1.38) MRI Endpointsb
No. of subjects                       165        152            144       147            161 Mean (median) number of new or        16.5       3.2            19.9      5.7            9.6 newly enlarging T2 lesions over       (7.0)      (1.0)***       (11.0)    (2.0)***       (3.0)*** 2 years
Lesion mean ratio                                0.15                     0.29           0.46 (95% CI)                                         (0.10, 0.23)             (0.21, 0.41)   (0.33, 0.63) Mean (median) number of Gd lesions    1.8        0.1            2.0       0.5            0.7 at 2 years                            (0)        (0)***         (0.0)     (0.0)***       (0.0)** Odds ratio                                       0.10                     0.26           0.39 (95% CI)                                         (0.05, 0.22)             (0.15, 0.46)   (0.24, 0.65) Mean (median) number of new T1        5.7        2.0            8.1       3.8            4.5 hypointense lesions over 2 years      (2.0)      (1.0)***       (4.0)     (1.0)***       (2.0)** Lesion mean ratio                                0.28                     0.43           0.59 (95% CI)                                         (0.20, 0.39)             (0.30, 0.61)   (0.42, 0.82) a
All analyses of clinical endpoints were intent-to-treat analyses;
b
MRI analysis used MRI cohort
*P-value < 0.05;
**P-value < 0.01;
***P-value < 0.0001;
#not statistically significant


ENDORSE enrolled eligible patients from DEFINE and CONFIRM into an 8-year two phase extension study of 1’736 patients with RRMS. The first phase was a multicenter, parallel group, randomized, dose blind, dose comparison study in which patients received dimethyl fumarate at a dose of 240 mg twice a day or 240 mg three times a day. The second phase was an open label study during which all patients received dimethyl fumarate at a dose of 240 mg twice a day. Eligible patients were enrolled at the Week 96 visit (Visit 24) of their previous study (DEFINE or CONFIRM), which served as the Baseline Visit for this extension study.


The primary objective of ENDORSE was to evaluate the long-term safety of dimethyl fumarate.
The secondary objectives were to evaluate the long-term efficacy of dimethyl fumarate using clinical endpoints (including relapse and ARR) and disability progression (EDSS) and in terms of MS brain lesions on MRI scans.
The median age of patients was 40.0 years. Most patients (945 participants, 54%) were in the study for 7 years or longer and the median time spent in the study (min, max) was 6.759 (0.04, 10.98) years.


In the first year of treatment with dimethyl fumarate twice daily in ENDORSE, the adjusted ARR (95% CI) ranged from 0.139 (0.105, 0.184) to 0.178 (0.108, 0.295), and remained low in the eighth year, ranging from 0.077 (0.039, 0.153) to 0.111 (0.053, 0.233) (see Table 3).
Table 3: Adjusted ARR at Year 1 and Year 8 for patients treated twice a day in the ENDORSE study
Overall population (N=868)
Clinical Endpoint     dimethyl fumarate BID dimethyl fumarate BID         dimethyl fumarate BID
(previously treated with)                 (dimethyl fumarate BID in
(placebo in DEFINE/             (GA in DEFINE/
DEFINE/
CONFIRM)                     CONFIRM)
CONFIRM)
N=249                        N=118
N=501
Adjusted ARR (95%               0.139                       0.171                         0.178 CI)                        (0.105, 0.184)               (0.119, 0.248)                (0.108, 0.295) Year 1a
Adjusted ARR (95%              0.110                        0.077                         0.111 CI)                        (0.073, 0.165)               (0.039, 0.153)                (0.053, 0.233) Year 8b n=261                        n=111                         n=55 a
From a negative binomial regression model, adjusted for baseline EDSS score (≤2.0 vs >2.0), baseline age (<40 vs ≥40), region and number of relapses in the 1 year prior to DEFINE/CONFIRM study entry.
b
From a Poisson regression model, adjusted for baseline EDSS score (≤2.0 vs >2.0), baseline age (<40 vs ≥40), region and number of relapses in the 1 year prior to DEFINE/CONFIRM study entry.


In the ENDORSE study, the mean (median) EDSS score at baseline in the twice a day group ranged from 2.42 (2.00) to 2.64 (2.0). The estimated proportion of patients with confirmed disability progression (95% CI) from the start of ENDORSE up to the eighth year of ENDORSE after treatment with dimethyl fumarate twice daily ranged from 0.326 (0.279, 0.380) to 0.343 (0.272, 0.427). Table 4 shows the EDSS at baseline and Week 384.


Table 4: Mean EDSS score at Baseline and Week 384 for patients treated twice a day in the ENDORSE study
Overall Population (N=868)
Clinical              dimethyl fumarate BID        dimethyl fumarate BID       dimethyl fumarate BID GA in Endpoint              dimethyl fumarate BID in       Placebo in DEFINE/                  DEFINE/ (previously treated          DEFINE/                      CONFIRM)                     CONFIRM) with)                       CONFIRM)                       N=249                          N=118 N=501
Mean EDSS score              2.42 (2.0)                   2.58 (2.5)                    2.64 (2.0) (Median)
Baseline
Mean EDSS score              2.64 (2.5)                   2.87 (2.5)                    3.03 (3.0) (Median)
Week 384                       n=230                       n=101                          n=45 


In the ENDORSE study, 752 patients (367 in the twice a day group) were included in an MRI cohort, which also included patients who had previously been included in the MRI cohort of DEFINE or CONFIRM. Due to sample size restrictions, MRI results are presented only through Year 6 of ENDORSE. The percentage of patients at Year 6 with no Gd+ lesions ranged from 90% to 100%. The mean number of new T1 hypointense lesions over 6 years, adjusted for region and baseline volume of T1 lesions (based on negative binomial regression), ranged from 1.060 (1.0) to 3.419 (2.0).

Pharmacokinetic Properties

Pharmacokinetics
Following oral administration Vumerity (diroximel fumarate) undergoes rapid presystemic hydrolysis by esterases and is converted into both its active primary metabolite, monomethyl fumarate, and an inactive metabolite, HES. Diroximel fumarate is not quantifiable in plasma following oral administration of Vumerity. Therefore, all pharmacokinetic analyses related to Vumerity were performed with plasma monomethyl fumarate concentrations.
Pharmacokinetic data were obtained in subjects with multiple sclerosis and healthy volunteers.

Absorption

The median T max of monomethyl fumarate is 2.5 to 3 hours. Following administration of Vumerity 462 mg twice a day in MS patients (A301), the mean C max of monomethyl fumarate was 2.11 mg/L. The mean steady state daily AUC (AUC ss ) of monomethyl fumarate was estimated to be 8.32 mg*hr/L in MS patients.

Food Effect

Administration of Vumerity together with a high-fat, high-calorie meal (up to 1050 kcal and 55 g fat) did not affect the AUC of monomethyl fumarate, but resulted in an approximately 44% reduction in C max compared to a fasting state. The monomethyl fumarate C max with low-fat (up to 400 kcal and 15 g fat) and medium-fat meals (up to 700 kcal and 30 g fat) was reduced by approximately 12% and 25%, respectively.

Alcohol Effect

Co-administration of Vumerity with 5% v/v and 40% v/v ethanol did not alter total monomethyl fumarate exposure relative to administration with water, demonstrating that the co-ingestion of ethanol does not induce dose dumping. The mean peak plasma monomethyl fumarate concentration for diroximel fumarate was decreased by 9% and 21%, when co-administered with 240 mL of 5% v/v and 40% v/v of ethanol, respectively.
Distribution

The apparent volume of distribution (Vd) for monomethyl fumarate is 72-83 L in healthy subjects after administration of Vumerity. Human plasma protein binding of monomethyl fumarate is 27- 45% and was not concentration dependent.

Metabolism

In humans, diroximel fumarate is extensively metabolized by esterases, which are ubiquitous in the gastrointestinal tract, blood, and tissues, before it reaches the systemic circulation. Esterase metabolism of diroximel fumarate produces both monomethyl fumarate, the active metabolite, and HES, an inactive metabolite.
Further metabolism of monomethyl fumarate occurs through esterases followed by the tricarboxylic acid (TCA) cycle, with no involvement of the cytochrome P450 (CYP) system.
Fumaric and citric acid, and glucose are the major metabolites of monomethyl fumarate in plasma.

Elimination

Monomethyl fumarate is mainly eliminated as carbon dioxide in expired air with only trace amounts recovered in urine. The terminal half-life (t 1/2 ) of monomethyl fumarate is approximately 1 hour, and no accumulation in monomethyl fumarate plasma exposures occurred with multiple doses of Vumerity. HES is mainly eliminated in urine (58-63% of the dose).
Linearity

Vumerity exposure increases in an approximately dose-proportional manner in the recommended daily dose range (462 mg to 924 mg).

Pharmacokinetics in special patient groups

Based on the results of Analysis of Variance (ANOVA), body weight is the main covariate of exposure (by C max and AUC) in relapsing-remitting multiple sclerosis (RRMS) subjects, but did not affect safety and efficacy measures evaluated in the clinical studies.
Gender and age did not have a clinically significant impact on the pharmacokinetics of dimethyl fumarate. The pharmacokinetics in patients aged 65 and over have not been studied.

Paediatric population

The pharmacokinetics in patients below the age of 18 have not been studied.
Patients with renal impairment
A single-dose clinical study investigating the effect of renal impairment on the PK of the Vumerity metabolites monomethyl fumarate and HES was conducted. The study included cohorts with mild, moderate, and severe renal impairment and a healthy cohort and found no clinically relevant changes in monomethyl fumarate exposure. HES exposure increased 1.3-, 1.8-, and 2.7-fold with mild, moderate, and severe renal impairment, respectively. There are no data available on long-term use of Vumerity in patients with moderate or severe renal impairment.

Patients with hepatic impairment

No studies have been carried out on the pharmacokinetics in individuals with hepatic impairment.

Preclinical data

Mutagenesis
Diroximel fumarate was not mutagenic in the in vitro bacterial reverse mutation assay. Diroximel fumarate was clastogenic in the in vitro chromosomal aberration assay in human peripheral blood lymphocytes, but not clastogenic/genotoxic in vivo in the rat micronucleus and comet assays.

Carcinogenicity

Oral administration of diroximel fumarate (0, 0, 30, 100, 300 or 1000 [females only] mg/kg/day) for 26 weeks to Tg.rasH2 mice resulted in no drug-related tumours. At the highest dose tested, plasma exposures for MMF and HES (the major circulating drug-related compound in humans) were 3-13 (MMF) and 1-4 (HES) times those in humans at the recommended human dose (RHD) of 924 mg/day.


Oral administration of diroximel fumarate (0, 0, 15, 50, or 150 mg/kg/day) to male and female rats resulted in an increase in tumours (Leydig cell adenomas of the testes) in males at the highest dose tested. At the higher dose (50 mg/kg/day) that was not associated with drug- related tumours, plasma exposures for MMF and HES were similar to (MMF) and less than (HES) those in humans at the recommended human dose (RHD) of 924 mg/day.