Intact natalizumab pharmacokinetics is impacted by endogenous IgG4 concentration.

BACKGROUND: Natalizumab (NAT) pharmacokinetics and pharmacodynamics are complicated by arm exchange with endogenous IgG4, resulting in a mixture of a more potent intact, bivalent form and a less potent, functionally monovalent form. Total NAT and endogenous IgG4 concentrations vary considerably across patients. This study assessed the concentration of intact NAT, and how it relates to total NAT and endogenous IgG4 levels in blood and saliva. METHODS: Paired serum and saliva samples from a small cohort of relapsing-remitting multiple sclerosis patients were measured for levels of intact NAT, total NAT, IgG and IgG4. RESULTS: Intact NAT concentration was dependent on both total NAT and endogenous IgG4 levels. Low endogenous IgG4 led to a higher ratio of intact NAT to total NAT, while the opposite was observed in subjects with high endogenous IgG4. Serum and saliva measurements show good concordance. CONCLUSIONS: Intact NAT concentration is influenced by both NAT pharmacokinetics and endogenous IgG4 levels. Patients with low IgG4 levels can have high concentrations of intact NAT even with lower levels of total NAT, which may explain cases of NAT-associated progressive multifocal leukoencephalopathy (PML) in such patients. Monitoring both forms of NAT could better guide dosing, maximizing drug efficacy and safety.

Drug and Neurofilament Levels in Serum and Breastmilk of Women With Multiple Sclerosis Exposed to Natalizumab During Pregnancy and Lactation.

Objective: To determine the transfer of the monoclonal antibody natalizumab into breastmilk and to evaluate drug and serum neurofilament light chain ((s)NfL) levels in natalizumab exposed pregnancies and lactation periods. Methods: Eleven women with relapsing remitting multiple sclerosis treated with natalizumab during pregnancy and lactation were included in this study. Breastmilk samples were collected up to 302 days after delivery and analyzed for natalizumab concentration and NfL. Additionally, maternal drug levels and sNfL were determined preconceptually, in each trimester, at delivery and postpartum. Clinical and radiological disease activity was systemically assessed across pregnancy and postpartum period. Results: The mean average natalizumab concentration in breast milk was low at 0.06 µg/ml [standard deviation (SD) 0.05] in the eight patients who provided serial breastmilk samples with an estimated mean absolute infant dose of 0.007 mg/kg/d (SD 0.005). The relative infant dose (RID), a metric comparing the infant with maternal drug exposure was low as well with a mean of 0.04% (SD=0.03). Most patients had a maximum concentration in breast milk at one to eight days after infusion. Pregnancy was associated with a non-significant decline of the median natalizumab serum concentration. All patients exposed to natalizumab prior (n=10) and during pregnancy (n=11) kept free of disease activity during gestation. While pregnancy was associated with low sNfL levels in patients treated with natalizumab prior and during pregnancy, the postpartum period was linked to a transient sNfL increase in some patients without any evidence of clinical or radiological disease activity. NfL was detectable in the majority of breastmilk samples with a median concentration of 1.7 pg/ml (range 0.004-18.1). Conclusion: We determined transfer of natalizumab into breastmilk with an RID far below the threshold of concern of 10%. Studies including childhood development assessment are needed in order to gain safety data about natalizumab-exposed breastfeeding. SNfL assessment might be a useful adjunct to monitor silent disease activity and therapeutic response during pregnancy and postpartum period. However, further investigations regarding transient postpartum sNfL increases are required to determine its association to parturition per se or to a silent disease activity in people with multiple sclerosis.

Wearing-off at the end of natalizumab dosing intervals is associated with low receptor occupancy.

OBJECTIVE: We aimed to investigate whether wearing-off symptoms at the end of the natalizumab dosing interval were associated with clinical and demographic patient characteristics or natalizumab receptor occupancy (RO) on leukocytes. METHODS: In this cross-sectional study of 40 patients with relapsing-remitting MS (RRMS) receiving natalizumab at the Department of Neurology, Haukeland University Hospital, we recorded clinical and demographic data including age, body mass index (BMI), working status, smoking habits, disease characteristics, treatment duration, vitamin D levels, and wearing-off symptoms. We quantified neurofilament light chain in serum and measured natalizumab RO in leukocyte subtypes by high-parameter mass cytometry. Associations with wearing-off symptoms were analyzed. RESULTS: Eight (20.0%) patients who reported regular occurrence of wearing-off symptoms, 9 (22.5%) who sometimes had wearing-off symptoms, and 23 (57.5%) who did not have wearing-off symptoms were evaluated. Patients who regularly had wearing-off symptoms had lower natalizumab RO than patients who reported having such symptoms sometimes or never. The former group also had higher BMI and higher frequency of sick leave. High BMI was associated with low RO. No other demographic or disease characteristics were associated with the phenomenon. CONCLUSIONS: Low RO may explain the wearing-off phenomenon observed in some patients with RRMS treated with natalizumab, and high BMI may be the underlying cause.

Pharmacodynamics of natalizumab extended interval dosing in MS.

OBJECTIVE: To determine if the concentration and saturation of natalizumab (NTZ) administration at extended interval dosing (EID; every 5-8 weeks) over 18 months is able to be maintained in the range considered adequate to sustain the clinical efficacy of NTZ. METHODS: In a cross-sectional assessment of patients with multiple sclerosis (MS) who received standard interval dosing (every 4 weeks) or EID, serum NTZ concentrations were measured using ELISA, and α4-integrin receptor saturations were analyzed via cytometry, in blood samples obtained at trough timepoints. RESULTS: Trough serum concentration was above the "therapeutic" concentration of 2.0 µg/mL in 72% of EID patients. Trough saturation was above the "therapeutic" 50% threshold in 79% of EID-treated patients. Our model predicted that at least 9 NTZ infusions/year are required to maintain adequate trough saturation and concentration levels. Higher body mass index (BMI) was a predictor of suboptimal trough saturation on EID NTZ. CONCLUSIONS: Trough α4-integrin receptor saturation >50% correlated with high clinical efficacy of NTZ in previous studies. A continual treatment with EID maintains receptor saturation and concentration that are in the "therapeutic range" for most patients. This finding provides biological plausibility for the clinical efficacy of NTZ EID. Patients with higher BMI may require closer clinical and MRI follow-up.

The natalizumab wearing-off effect: End of natalizumab cycle, recurrence of MS symptoms.

OBJECTIVE: Natalizumab is effective in treating relapsing-remitting multiple sclerosis (RRMS). However, many patients report an increase of multiple sclerosis symptoms at the end of the natalizumab cycle: a wearing-off effect. The objective of this study was to evaluate the prevalence of the wearing-off effect in patients with standard and extended intervals and to study possible associations with pharmacokinetic/dynamic measurements and patient characteristics in a prospective, monocenter, cross-sectional cohort study. METHODS: Patients with RRMS, with a minimum of 6 natalizumab infusions, were asked to complete 3 questionnaires: the Multiple Sclerosis Impact Scale, the 36-Item Short Form Health Survey, and a general questionnaire regarding the wearing-off effect. Natalizumab concentration and α4-integrin receptor saturation were measured before redosing. RESULTS: Ninety-three patients were included. A total of 54% experienced a wearing-off effect during natalizumab treatment and 32% experienced a current wearing-off effect at time of measurement. The self-reported wearing-off effect was not associated with natalizumab concentration nor with α4-integrin receptor saturation. The wearing-off effect was more frequently reported in the standard interval group (39%) than in the extended interval group (19%); the duration of symptoms was comparable between both groups. The wearing-off effect was not associated with number of infusions, disease duration, age, or sex. CONCLUSION: The wearing-off effect is a frequently reported phenomenon but is unlikely to reflect a nonoptimal pharmacokinetic/dynamic state. We did not find risk factors predicting the wearing-off effect.

Pharmacokinetics and pharmacodynamics of natalizumab in pediatric patients with RRMS.

Objective: This phase I study investigated pharmacokinetic (PK) and pharmacodynamic (PD) profiles of natalizumab in pediatric patients with relapsing-remitting MS (RRMS). Methods: Pediatric patients with RRMS who were prescribed natalizumab 300 mg IV every 4 weeks were enrolled. Blood samples were collected on days 1, 2, 8, 15, and 22 and at weeks 4, 8, 12, and 16 to estimate PK parameters; PD properties were evaluated by measuring α4-integrin saturation and lymphocyte counts over time. Natalizumab's safety profile was also evaluated. Results: PK parameters were similar to those reported in adult patients; natalizumab concentrations peaked approximately 1 day after infusion in most of the participants (Cmax 142.9 µg/mL, AUClast 47389.4 hr*µg/mL), followed by a biphasic decline with a rapid distribution phase and a slow elimination phase, with a terminal half-life of 215.1 hours. In terms of PD, both time course and magnitude of α4-integrin saturation and increase in lymphocyte counts were similar to those observed in adults. During the 16-week study follow-up, 3 adverse events attributed to natalizumab were observed; no unexpected safety events occurred. Conclusions: PK profile, α4-integrin saturation, lymphocyte counts, and safety observed in these pediatric patients are comparable to those reported in adults. Classification of evidence: This study provides Class I evidence that natalizumab PK/PD parameters and safety profile are similar in adults and pediatric patients in the short term. Longer studies, also including a larger number of younger subjects (aged 10-12 years), are required to further inform about long-term PK and PD parameters in pediatric patients with MS.

Evaluation of natalizumab pharmacokinetics and pharmacodynamics with standard and extended interval dosing.

BACKGOUND: Natalizumab (NTZ) is a highly efficacious therapeutic for multiple sclerosis (MS), but treatment is associated with an increased risk of progressive multifocal leukoencephalopathy (PML). Extended interval dosing (EID) of NTZ has been proposed as an alternative dosing strategy to reduce PML risk. Pharmacokinetic (PK) and pharmacodynamic (PD) profiles of standard interval dosing (SID) and EID under real-world circumstances remain poorly characterized. OBJECTIVE: To evaluate PK and PD parameters of NTZ for SID and EID in the context of patient and treatment characteristics. METHODS: An observational cohort study was conducted to measure NTZ serum concentrations in MS patients at SID and EID nadir timepoints. NTZ occupancy of α4-integrin receptor sites, and cell surface expression of α4-integrin, was also measured. Patient body weight, age, and treatment exposure metrics were collected. RESULTS: NTZ serum concentrations were lower for EID than SID (mean = 18.2 versus 35.7 µg/ml, respectively; p < 0.001). Patient body weight, age, and treatment duration impacted concentrations with SID, though their influences were reduced or absent with EID. α4-integrin receptor occupancy by NTZ was lower for EID than SID (mean = 78.2 versus 87.4%, respectively; p < 0.001). Body weight impacted α4-integrin receptor occupancy differentially for EID versus SID. α4-integrin cell surface expression was modestly higher for EID than SID (267.2 versus 238.1 MFI, respectively; p < 0.001). CONCLUSIONS: EID of NTZ reduces nadir serum drug levels and α4-integrin receptor occupancy, as well as increases α4-integrin cell surface expression. The resulting increase in the number of open α4-intregrin receptors may enhance immune surveillance of JCV and prevention of PML. Body weight plays a significant role in the pharmacokinetic and pharmacodynamic responses to NTZ treatment. Further research is warranted to help establish pharmacological thresholds of NTZ efficacy and safety, which could help guide decision-making for dosing of NTZ.

An experimental study to evaluate safety/toxicity of intravitreal natalizumab.

PURPOSE: The purpose of this prospective experimental study was to evaluate the safety/toxicity of α4ß1 integrin blockade in rabbit retina using its monoclonal antibody (Natalizumab). METHODS: Twelve New Zealand albino rabbits were divided into three groups (n = 4). Unilateral intravitreal injections of three different concentrations of natalizumab were performed in every rabbit of each group (Group A: 0.625 mg, Group B: 1.25 mg, and Group C: 2.5 mg). Baseline electroretinogram (ERG) and fundus photography were performed prior to injection. At days 1, 7, and 21 postinjection, ERG and fundus photography of each eye were performed. At last follow-up, Group C animals with highest drug concentration were sacrificed and the enucleated eyes were evaluated for retinal toxicity using transmission electron microscopy (TEM). RESULTS: No difference in ERG responses was observed in eyes injected with low and intermediate concentration of natalizumab between day 0 and day 21. Furthermore, rabbits injected intravitreally with highest dose showed reduction in amplitude of "a" wave (P = 0.0017) and a reduction in amplitude of "b" wave of ERG at day 21 (P = 0.0117). TEM revealed changes in the outer plexiform layer and inner nuclear layer, suggestive of toxicity primarily to the photoreceptor synaptic terminals and bipolar cells. CONCLUSION: Low-dose (0.625 mg) and intermediate-dose (1.25 mg) intravitreal injection of natalizumab appears safe for rabbit retina. However, functional and anatomical changes were observed in rabbit retina following a high-dose (2.5 mg) intravitreal injection of a monoclonal antibody blocking α4ß1 integrin.

Alemtuzumab for the treatment of multiple sclerosis.

INTRODUCTION: Alemtuzumab is a monoclonal antibody that targets for the destruction CD52+ cells, particularly B and T cells. Alemtuzumab is approved in more than 50 countries around the world for the treatment of adult patients with relapsing remitting multiple sclerosis (MS). Areas covered: In this review, the authors summarize biological, clinical and safety data related to the use of alemtuzumab in patients with MS. The authors then provide their expert opinion on alemtuzumab and the field as of whole before providing their perspectives for the future. Expert opinion: Alemtuzumab is highly efficacious; more so than first line treatments but comparable to natalizumab. Treatment schedule makes alemtuzumab administration easy and attractive to patients. However, its safety profile makes it a choice for a very limited number of patients, in a specific disease window. As of now, a cure for MS remains elusive and there is an unmet need for a safe and highly potent agent at the level of and beyond the blood brain barrier.

Population Pharmacokinetics and Target Engagement of Natalizumab in Patients With Multiple Sclerosis.

Natalizumab (humanized immunoglobulin G4 antibody targeting alpha-4 integrins) is a highly efficacious treatment for relapsing-remitting multiple sclerosis (RRMS) that has been in clinical use since 2006. However, natalizumab pharmacokinetic (PK) characteristics and concentration alpha-4 integrin saturation relationships have not been well described in the scientific literature. Therefore, clinical data from 11 studies were pooled and analyzed to characterize the PK and pharmacodynamic (PD) properties of natalizumab in RRMS subjects. Natalizumab PK was best described using a 2-compartment model with linear first-order and Michaelis-Menten elimination. Subcutaneous absorption of natalizumab was characterized using first-order absorption with lag time. The relationship between natalizumab concentration and alpha-4 integrin saturation (PD) was best described by a direct response model with a sigmoidal effect on alpha-4 integrin saturation mediated by a maximum effect relationship with natalizumab concentrations. Covariate analysis showed that body weight, product formulations, and the presence of antinatalizumab antibodies were the main covariates affecting natalizumab PK, whereas age and formulations affected PD. The use of simulations based on a pharmacokinetic-pharmacodynamic model showed that covariates, although statistically significant, are not expected to have any clinical impact at the approved clinical dosing regimen of natalizumab (300 mg once every 4 weeks).

Exposure-disease response analysis of natalizumab in subjects with multiple sclerosis.

Natalizumab, a human immunoglobulin monoclonal antibody that targets α4ß1/α4ß7 integrin, is an effective therapy approved for the treatment of multiple sclerosis (MS). The objective of this analysis was to develop a population exposure-response model utilizing gadolinium-enhancing (Gd) lesion count data from four clinical studies and annualized relapse rate (ARR) data from three clinical studies. The natalizumab exposures were derived for the individuals using a population pharmacokinetic model. A log-linear exposure effect on Gd lesion count and ARR adequately characterized the relationship between exposure and disease response. In the case of the Gd lesion count model, a bimodal model that distributed subjects into two subpopulations based on low or high baseline Gd lesion count provided a superior goodness of fit. The mean (95% confidence interval) slopes from the exposure-Gd lesion count model and exposure-ARR model are -0.0903 (-0.100, -0.081) and -0.0222 (-0.026, -0.015) (mg/L)-1, respectively. From these slopes, it can be inferred that both Gd lesion count and ARR decrease with increasing exposure to natalizumab in MS subjects. Model-based simulations demonstrated that although reductions in Gd lesion count and ARR were observed with lower doses (75, 150, or 200 mg), only the dose of 300 mg every 4 weeks (q4w) was associated with an ARR ≤0.25 and was considered clinically effective. The results from the exposure-Gd lesion count and exposure-ARR models thus support the appropriateness of the approved natalizumab dose (300 mg q4w) in MS subjects.

Efficacy, safety, and pharmacokinetics of natalizumab in Japanese multiple sclerosis patients: A double-blind, randomized controlled trial and open-label pharmacokinetic study.

BACKGROUND: Natalizumab, an anti-α4 integrin monoclonal antibody, has demonstrated efficacy in phase 2 and 3 studies of predominantly Caucasian patients with relapsing-remitting multiple sclerosis (RRMS). OBJECTIVE: To evaluate the efficacy, safety, pharmacokinetics (PK), and pharmacodynamics (PD) of natalizumab in Japanese RRMS patients. METHODS: This multicenter, phase 2 study included an open-label PK/PD study in 12 patients (part A) and a double-blind, placebo-controlled, randomized (computer-generated sequence) study in 94 patients (part B). For part B, patients received intravenous natalizumab 300mg (n=47) or placebo (n=47) every 4 weeks. The primary efficacy endpoint was the rate of development of new active lesions (gadolinium-enhancing or new/enlarging T2 lesions) over 24 weeks. Clinical relapses and safety were also assessed. RESULTS: New active lesions developed at a significantly lower mean rate in natalizumab-treated patients (0.06 lesions/24 weeks) than in placebo-treated patients (0.35 lesions/24 weeks) (p<0.001). The annualized relapse rate was 0.53 for natalizumab and 1.73 for placebo (p<0.001). Twice as many natalizumab-treated patients (79%) as placebo-treated patients (38%) were relapse-free (p<0.001). The safety, PK, and PD profiles of natalizumab in this study were consistent with data in Caucasian RRMS patients. CONCLUSIONS: In Japanese RRMS patients, natalizumab treatment every 4 weeks for 24 weeks was well tolerated and reduced the development of new brain lesions and relapses (Funded by Biogen; ClinicalTrials.gov identifier: NCT01440101).

Use of natalizumab in multiple sclerosis: current perspectives.

INTRODUCTION: Natalizumab is an efficacious monoclonal antibody approved for use in relapsing-remitting multiple sclerosis (RRMS). Multiple studies have demonstrated reduced relapse rate, decreased disability progression and prolonged disease-free intervals with natalizumab use. However, natalizumab is associated with an increased risk of progressive multifocal leukoencephalopathy (PML), thus restricting its widespread use with populations at high risk for developing PML. Recently, the effect of natalizumab in secondary-progressive (SPMS) population has been explored. AREAS COVERED: This review highlights the pathophysiology behind disease progression in MS and summarizes various attributes of natalizumab including: its pharmacological properties and global economic impact, results of clinical efficacy studies, its role in SPMS, pregnancy and its adverse events profile including PML and discontinuation protocols. EXPERT OPINION: Despite an established role in reducing RRMS disease activity, natalizumab has found limited use in SPMS due to insufficient evidence of efficacy. Current disease-modifying therapies exert modest overall benefit in SPMS owing to its complex pathophysiology, higher prevalence of comorbidities and increased PML risk with age and lack of reliable outcome measures. Finding more appropriate MRI and clinical outcome measures is quintessential for designing future randomized trials and possibly exploring primary neuroprotective agents for treating SPMS.

A Randomized Trial Evaluating Various Administration Routes of Natalizumab in Multiple Sclerosis.

The study's primary objective was to compare the pharmacokinetics (PK) and pharmacodynamics (PD) of single subcutaneous (SC) or intramuscular (IM) 300-mg doses of natalizumab with IV 300-mg doses of natalizumab in patients with multiple sclerosis (MS). Secondary objectives included investigation of the safety, tolerability, and immunogenicity of repeated SC and IM natalizumab doses. DELIVER was a 32-week, open-label, multicenter study of natalizumab-naive patients with relapsing-remitting MS (RRMS) or secondary progressive MS (SPMS) randomized to receive 300 mg natalizumab by SC injection, IM injection, or IV infusion. PK and PD were evaluated over 8 weeks after the first natalizumab treatment (Part 1) and over 24 weeks with repeated dosing every 4 weeks, beginning at week 8 (Part 2). Seventy-six patients (24 with RRMS and 52 with SPMS) were enrolled in DELIVER. Following SC or IM administration of natalizumab, peak serum concentrations were approximately 40% of those observed with IV administration and showed no major differences in elimination characteristics. Mean bioavailability relative to IV administration was 57.1% to 71.3% with SC administration and 48.7% with IM administration; mean trough serum concentrations were similar with SC or IV administration and lower with IM administration. Following single or multiple doses of natalizumab, PD response was comparable across administration routes and disease stages. No meaningful differences were observed across administration groups in the incidence or nature of overall adverse events, serious adverse events, administration site reactions, hypersensitivity reactions, or antinatalizumab antibodies. These findings support the comparability of PD measures of natalizumab administered IV, SC, or IM.

Transfer of natalizumab into breast milk in a mother with multiple sclerosis.

Natalizumab (Tysabri) is a recombinant humanized antibody to α4-integrin that is approved by the Food and Drug Administration for the treatment of multiple sclerosis (MS) and Crohn disease. This is a case report of a 28-year-old woman with MS who was taking natalizumab (300 mg intravenously infused over 1 hour every 4 weeks) while breastfeeding her 11.5-month-old daughter 3 times a day. Breast milk samples were collected over a 50-day period after the patient's first drug infusion. The average concentration of natalizumab was 0.93 µg/mL/d, and the relative infant dose was 1.74% of the weight-adjusted maternal dose. Transfer of natalizumab into human milk increased over time and with subsequent injections, with the highest concentration of 2.83 µg/mL at day 50 with a relative infant dose of 5.3%. Because these data suggest continued accumulation of natalizumab in milk, and because we cannot provide an accurate assessment of levels of this drug at 24 weeks (steady state), we are unable to determine safety at this time.