Pharmacological properties : תכונות פרמקולוגיות

Pharmacodynamic Properties

5.1 Pharmacodynamic properties
Pharmacotherapeutic group: Immunosuppressants, selective immunosuppressants, ATC code: L04AA23

Pharmacodynamic effects

Natalizumab is a selective adhesion-molecule inhibitor and binds to the α4-subunit of human integrins, which is highly expressed on the surface of all leukocytes, with the exception of neutrophils.
Specifically, natalizumab binds to the α4β1 integrin, blocking the interaction with its cognate 14
receptor, vascular cell adhesion molecule-1 (VCAM-1), and ligands osteopontin, and an alternatively spliced domain of fibronectin, connecting segment-1 (CS-1). Natalizumab blocks the interaction of α4β7 integrin with the mucosal addressin cell adhesion molecule-1 (MadCAM-1). Disruption of these molecular interactions prevents transmigration of mononuclear leukocytes across the endothelium into inflamed parenchymal tissue. A further mechanism of action of natalizumab may be to suppress ongoing inflammatory reactions in diseased tissues by inhibiting the interaction of α4-expressing leukocytes with their ligands in the extracellular matrix and on parenchymal cells. As such, natalizumab may act to suppress inflammatory activity present at the disease site, and inhibit further recruitment of immune cells into inflamed tissues.

In MS, lesions are believed to occur when activated T-lymphocytes cross the blood-brain barrier (BBB). Leukocyte migration across the BBB involves interaction between adhesion molecules on inflammatory cells and endothelial cells of the vessel wall. The interaction between α4β1 and its targets is an important component of pathological inflammation in the brain and disruption of these interactions leads to reduced inflammation. Under normal conditions, VCAM-1 is not expressed in the brain parenchyma. However, in the presence of pro-inflammatory cytokines, VCAM-1 is upregulated on endothelial cells and possibly on glial cells near the sites of inflammation. In the setting of central nervous system (CNS) inflammation in MS, it is the interaction of α4β1 with VCAM-1, CS-1 and osteopontin that mediates the firm adhesion and transmigration of leukocytes into the brain parenchyma and may perpetuate the inflammatory cascade in CNS tissue. Blockade of the molecular interactions of α4β1 with its targets reduces inflammatory activity present in the brain in MS and inhibits further recruitment of immune cells into inflamed tissue, thus reducing the formation or enlargement of MS lesions.

Clinical efficacy

AFFIRM clinical study
Efficacy as monotherapy has been evaluated in one randomised, double-blind, placebo- controlled study lasting 2 years (AFFIRM study) in RRMS patients who had experienced at least 1 clinical relapse during the year prior to entry and had a Kurtzke Expanded Disability Status Scale (EDSS) score between 0 and 5. Median age was 37 years, with a median disease duration of 5 years. The patients were randomised with a 2:1 ratio to receive Tysabri 300 mg (n = 627) or placebo (n = 315) every 4 weeks for up to 30 infusions. Neurological evaluations were performed every 12 weeks and at times of suspected relapse. MRI evaluations for T1-weighted gadolinium (Gd)-enhancing lesions and T2-hyperintense lesions were performed annually.

Study features and results are presented in the Table 2.

Table 2. AFFIRM study: Main features and results
Monotherapy; randomised double-blind placebo-controlled
Design parallel-group trial for 120 weeks
Subjects                                               RRMS (McDonald criteria) Treatment                                    Placebo / Natalizumab 300 mg i.v. every 4 weeks One year endpoint                                                  Relapse rate Two year endpoint                                         Progression on EDSS Secondary endpoints         Relapse rate derived variables / MRI-derived variables Subjects                                         Placebo                         Natalizumab Randomised                                         315                               627 15
Completing 1 years                              296                              609 Completing 2 years                              285                              589 
Age yrs, median (range)                     37 (19-50)                        36 (18-50) MS-history yrs, median (range)              6.0 (0-33)                        5.0 (0-34) Time since diagnosis, yrs median
2.0 (0-23)                       2.0 (0-24)
(range)
Relapses in previous 12 months,
median (range)                               1.0 (0-5)                        1.0 (0-12) EDSS-baseline, median (range)                2 (0-6.0)                         2 (0-6.0) 
RESULTS
Annual relapse rate
After one year (primary endpoint)            0.805                             0.261 After two years           0.733                             0.235
One year             Rate ratio 0.33 CI95% 0.26 ; 0.41
Two years              Rate ratio 0.32 CI95% 0.26 ; 0.40
Relapse free
After one year           53%                               76%
After two years           41%                               67%

Disability
Proportion progressed1(12-week              29%                               17% confirmation; primary outcome)
Hazard ratio 0.58, CI95% 0.43; 0.73, p<0.001
Proportion progressed1(24-week
23%                               11% confirmation)
Hazard ratio 0.46, CI95% 0.33; 0.64, p<0.001
MRI (0-2 years)
Median % change in T2-                                            -9.4% (p<0.001) +8.8% hyperintense lesion volume
Mean number of new or newly-                                             1.9 (p<0.001) 11.0 enlarging T2-hyperintense lesions



16
Table 2. AFFIRM study: Main features and results
Mean number of T1-hypointense                                                      1.1 4.6 lesions                                                  (p<0.001
Mean number of Gd-enhancing                                                       0.1 )
1.2 lesions                                                  (p<0.001
)
1 Progression of disability was defined as at least a 1.0 point increase on the EDSS  from a baseline EDSS >=1.0 sustained for 12 or 24 weeks or at least a 1.5 point increase on the EDSS from a baseline EDSS =0 sustained for 12 or 24 weeks.


In the sub-group of patients indicated for treatment of rapidly evolving RRMS (patients with 2 or more relapses and 1 or more Gd+ lesion), the annualised relapse rate was 0.282 in the natalizumab-treated group (n = 148) and 1.455 in the placebo group (n = 61) (p <0.001).
Hazard ratio for disability progression was 0.36 (95% CI: 0.17, 0.76) p = 0.008. These results were obtained from a post hoc analysis and should be interpreted cautiously. No information on the severity of the relapses before inclusion of patients in the study is available.

Tysabri Observational Program (TOP)

Interim analysis of results (as of May 2015) from the ongoing Tysabri Observational Program (TOP), a phase 4, multicentre, single-arm study (n =5,770) demonstrated that patients switching from beta interferon (n = 3,255) or glatiramer acetate (n = 1,384) to Tysabri showed a sustained, significant decrease in annualised relapse rate (p < 0.0001).
Mean EDSS scores remained stable over 5 years.
Consistent with efficacy results observed for patients switching from beta interferon or glatiramer acetate to Tysabri, for patients switching from fingolimod (n = 147) to this medicinal product, a significant decrease in annualised relapse rate (ARR) was observed, which remained stable over 2 years, and mean EDSS scores remained similar from baseline to Year 2. The limited sample size and shorter duration of natalizumab exposure for this subgroup of patients should be considered when interpreting these data.

Paediatric population

A post-marketing meta-analysis was conducted using data from 621 paediatric MS patients treated with natalizumab (median age 17 years, range was 7 to 18 years, 91% aged ≥14 years). Within this analysis, a limited subset of patients with data available prior to treatment (158 of the 621 patients) demonstrated a reduction in ARR from 1.466 (95% CI 1.337, 1.604) prior to treatment to 0.110 (95%
CI 0.094, 0.128).

Extended interval dosing

In a pre-specified, retrospective analysis of US anti-JCV antibody positive Tysabri patients intravenously administered (TOUCH registry), the risk of PML was compared between patients treated with the approved dosing interval and patients treated with extended interval dosing as identified in the last 18 months of exposure (EID, average dosing intervals of approximately 6 weeks). The majority (85%) of patients dosed with EID had received the approved dosing for ≥1 year prior to switching to EID. The analysis showed a lower risk of PML in patients treated with EID (hazard ratio = 0.06, 95% CI of hazard ratio = 0.01 to 0.22).
Efficacy has been modelled for patients who switch to longer dosing after ≥1 year of approved dosing with this medicinal product under intravenous administration and who did not experience a relapse in the year prior to switching.
Currentpharmacokinetic/pharmacodynamic statistical modelling and simulation indicate that the risk of MS disease activity for patients switching to longer dosing intervals may be higher for patients with dosing intervals ≥7 weeks. No prospective clinical studies have been completed to validate these findings.

The efficacy of natalizumab when administered with EID has not been established; therefore, the benefit/risk balance of EID is unknown (see “Intravenous administration Q6W”).

Intravenous administration Q6W

Efficacy and safety were evaluated in a prospective, randomized, interventional, controlled, open- label, rater-blinded, international phase 3 study (NOVA, 101MS329), involving subjects with relapsing-remitting MS according to the 2017 McDonald criteria dosed intravenously every six weeks with natalizumab. The study was designed to estimate an efficacy difference between Q6W and Q4W dosing regimens.

The study randomized 499 subjects aged 18-60, with an EDSS score ≤ 5.5 at screening, who received at least 1 year of natalizumab treatment IV Q4W and were clinically stable (no relapse in the last 12 months, no gadolinium (Gd) enhancing T1 lesions at screening). In the study, subjects who switched to Q6W after at least one year of IV Q4W treatment with natalizumab were evaluated in relation to subjects who continued on IV Q4W treatment.

Baseline demographic subgroups of age, sex, duration of natalizumab exposure, country, body weight, anti-JCV status and number of relapses in the year prior to the first dose, number of relapses while on natalizumab, number of prior DMTs, and type of prior DMT were similar between the Q6W and Q4W dosing treatment arms.

Table 3. NOVA study: Main features and results
Monotherapy; phase 3b prospective, randomized,
Design                                       interventional, controlled, open-label, rater-blinded, international study
Subjects                                                  RRMS (McDonald criteria) Treatment administration (part 1)    Natalizumab Q4W               Natalizumab Q6W 300 mg I.V.                   300 mg I.V.
Randomized               248                           251
RESULTS mITTa population for part 1 at week 72              242                            247 New/newly enlarging (N/NE) T2 lesions from baseline to Week 72
Subjects with number of lesions = 0       189 (78.1%)                    202 (81.8%) =1          7 (3.6%)                       5 (2.0%)
=2          1 (0.5%)                       2 (0.8%)
=3              0                              0
=4              0                              0
≥5              0                         2* (0.8%) missing        45 (18.6%)                     36 (14.6%)
Adjusted mean N/NE T2-hyperintense lesions (primary endpoint)*                                   0.05                              0.20 95% CIb,c                     (0.01, 0.22)                      (0.07, 0.63) p = 0.0755
Proportion of subjects that developed
4.1%                               4.3%
N/NE T2 lesions
Proportion of subjects who developed
0.8%                              1.2%
T1-hypointense lesions
Proportion of subjects who developed
0.4%                              0.4%
Gd-enhancing lesions

Adjusted annualized relapse rate                            0.00010                           0.00013 
Proportion of subjects free of relapse**                     97.6%                             96.9% 
Proportion free of 24-week confirmed
92%                               90%
EDSS worsening a mITT population, which included all randomized participants who received at least 1 dose of study treatment (natalizumab SID or natalizumab EID) and had at least 1 postbaseline result from the following clinical efficacy assessments: MRI efficacy assessments, relapses, EDSS, HPT, T25FW, SDMT, TSQM, CGI scale.
b Estimated using negative binomial regression with treatment as classification and baseline body weight (≤ 80 vs 
>80 kg), duration of natalizumab exposure at baseline (≤ 3 vs > 3 years), and region (North America, the UK, Europe and Israel, and Australia) as covariates.
c Observed lesions are included for analysis regardless of intercurrent events, and missing values due to efficacy or  safety (6 subjects switched to Q4W dosing and 1 subject each on Q6W and Q4W dosing discontinued treatment) are imputed by the worst case of subjects on treatment at the same visit in the same treatment group or otherwise via multiple imputation.
* The numerical difference seen in the N/NE lesions between the two treatment groups was driven by a high number of lesions occurring in two subjects in the Q6W arm – one subject who developed lesions three months after treatment discontinuation and a second subject who was diagnosed with asymptomatic PML at week 72.
** Relapses – clinical relapses were assessed as defined by new or recurrent neurologic symptoms not associated with fever or infection having a minimum duration of 24 hours.

Pharmacokinetic Properties

5.2    Pharmacokinetic properties

Following the repeat intravenous administration of a 300 mg dose of natalizumab to MS patients, the mean maximum observed serum concentration was 110 ± 52 μg/mL. Mean average steady-state trough natalizumab concentrations over the dosing period ranged from 23 μg/mL to 29 μg/mL in Q4W dosing. At any time, mean trough concentrations for the Q6W regimen were approximately 60 to 70% lower than for the Q4W regimen. The predicted time to steady state was approximately 24 weeks.
Population pharmacokinetic analysis includes 12 studies and 1,781 subjects receiving doses ranging from 1 to 6 mg/kg and fixed doses of 150/300 mg.


Distribution
Median steady-state volume of distribution was 5.96 L (4.59-6.38 L, 95% confidence interval).

Elimination
Population median estimate for linear clearance was 6.1 mL/h (5.75-6.33 mL/h, 95% confidence interval) and the estimated median half-life was 28.2 days. The 95th percentile interval of the terminal half-life is from 11.6 to 46.2 days.

The population analysis of 1,781 patients explored the effects of selected covariates including body weight, age, gender, presence of anti-natalizumab antibodies and formulation on pharmacokinetics. Only body weight, the presence of anti-natalizumab antibodies and the formulation used in phase 2 studies were found to influence natalizumab disposition. Natalizumab clearance increased with body weight in a less-than-proportional manner, such that a +/-43% change in body weight resulted in only a -33% to 30% change in clearance. The presence of persistent anti-natalizumab antibodies increased natalizumab clearance approximately 2.45-fold, consistent with reduced serum natalizumab concentrations observed in persistently antibody-positive patients.


Special Populations
Paediatric population

The pharmacokinetics of natalizumab in paediatric MS patients has not been established.

Renal impairment
The pharmacokinetics of natalizumab in patients with renal insufficiency has not been studied.

Hepatic impairment

The pharmacokinetics of natalizumab in patients with hepatic insufficiency has not been studied.