A phase 1 study to assess the pharmacokinetics,safety,and tolerability of fremanezumab doses (225 mg,675 mg and 900 mg) in Japanese and Caucasian healthy subjects

Abstract

Objectives

The primary and secondary objectives of this phase 1 study were to evaluate the pharmacokinetic profile, safety, and immunogenicity of fremanezumab subcutaneous (sc) doses tested in phase 2 and 3 trials (225 mg, 675 mg and 900 mg) following single administration in Japanese (n = 32) and Caucasian (n = 32) healthy subjects.

Methods

Japanese and matched Caucasian healthy subjects were enrolled into one of four cohorts and were randomly assigned to one of four treatments: 225, 675, or 900 mg fremanezumab, or placebo. Pharmacokinetic and immunogenicity sampling, and safety and tolerability assessments occurred at one inpatient visit and 12 ambulatory visits during the 36-week study.

Results

Pharmacokinetic analyses included those randomized to fremanezumab (n = 24 for each ethnic group) and safety analyses included all subjects enrolled in the study (n = 32 for each ethnic group). Fremanezumab concentration-time profiles and pharmacokinetic parameters per dose were similar for Japanese and Caucasians at all dose levels. Geometric mean ratios (GMRs) for C_max for Japanese to Caucasian subjects were 0.91, 1.04 and 1.14 for the 225 mg, 675 mg and 900 mg fremanezumab doses. GMRs for AUC_0-inf were 0.96, 1.09, and 0.98, respectively. Median T_max (range 5–11 days) and mean half-lives (range 31–39 days) were similar across doses for both ethnicities. Most frequently occurring adverse events were injection site reactions, abdominal pain, headache, upper respiratory tract infection, constipation and nasopharyngitis. There was no development of anti-drug-antibodies and no clinically meaningful changes in laboratory findings.

Conclusion

The results of the pharmacokinetic exposure parameters and safety measures were similar for Japanese and Caucasians and support the once monthly and once quarterly sc injections of fremanezumab.

Keywords

Calcitonin-gene-related peptide CGRP fremanezumab preventive migraine treatments TEV-48125

Introduction

Currently, there are five FDA-approved medications for the preventive treatment of migraine. Four of them (two beta blockers, propranolol and timolol maleate, and two anti-epileptic drugs, divalproex sodium and topiramate) are FDA approved for migraine prevention and a fifth medication, onabotulinumtoxinA, is approved for the prevention of chronic migraine (1). None of these were developed originally for migraine and were approved initially for other purposes. Cumbersome dosing schedules, side effects and delayed or inadequate efficacy likely reduce long-term adherence and may prompt patients to discontinue these treatments (2).

Currently, calcitonin gene-related peptide (CGRP) is the most actively evaluated target in migraine drug research (3). CGRP, a 37 amino acid neuropeptide, is present at trigeminal nerve endings and the trigeminal ganglion (4,5). Release of CGRP at perivascular trigeminal nerve endings results in vasodilation and neurogenic inflammation, and within the CNS it acts as a neuromodulator (5). CGRP levels, which are elevated in peripheral blood of patients with chronic migraine (CM) and episodic migraine (EM), are higher in patients with CM relative to those with EM, suggesting that increasing levels may be a predisposing factor of progression from EM to CM (6).

The first drugs developed and tested against the CGRP pathway, small molecule CGRP receptor antagonists, (gepants) were found to be efficacious as acute and preventive migraine treatments (7 –12), but were not approved because of an increased risk of liver toxicity with chronic use (13). Drug development efforts for migraine prevention then turned to monoclonal antibodies that bind to either the CGRP ligand or the CGRP receptor. As monoclonal antibodies are not metabolized by the liver, there is low risk of drug-drug interactions and drug-associated liver enzyme elevations (14,15). This new class of drugs includes fremanezumab, erenumab, galcanezumab, and eptinezumab, which have been tested in multiple clinical studies as preventive treatments for episodic and chronic migraine (16).

Fremanezumab is a fully humanized IgG2Δa/kappa monoclonal antibody that selectively targets CGRP and prevents it from binding to the CGRP receptor (17). In phase 2 and phase 3 studies, fremanezumab has been shown to significantly reduce migraine days, days with headaches of any severity including moderate-to-severe, and to be well-tolerated as a preventive treatment for patients with episodic migraine and chronic migraine (18 –20). The present phase 1 study examined the pharmacokinetic profile, safety and tolerability in Japanese and Caucasian healthy subjects of three doses of fremanezumab (225 mg, 675 mg and 900 mg) shown to have clinically significant benefit in phase 2 and 3 trials.

Method

Study design

This was a randomized, double-blind, placebo-controlled, single ascending dose and single dose phase 1 study in Japanese and Caucasian men and women that was conducted from 24 February to 19 December 2016 at a clinical pharmacology unit in the United States (PAREXEL, Glendale, CA). Study duration was approximately 36 weeks, including a four-week screening period and a 32-week treatment evaluation period. The primary and secondary objectives of the study were to evaluate the pharmacokinetics, safety, tolerability, and immunogenicity of fremanezumab in Japanese and Caucasian healthy subjects after single doses of fremanezumab or placebo. Pharmacokinetic and immunogenicity sampling, and safety and tolerability assessments occurred during 13 clinic visits including one inpatient visit from day −1 to day 6 and 12 ambulatory visits between post treatment days 8–225.

The study was conducted in full accordance with the International Conference on Harmonisation (ICH) Good Clinical Practice (GCP), the Declaration of Helsinki, and any applicable national and local laws and regulations. Investigators obtained institutional review board approvals from the Aspire IRB Chair: Bonnie J Brookshire, BA, CIP (Santee, CA), and subjects provided written informed consent. The trial is registered at Clinicaltrials.gov with the identifier NCT02673567.

Participants

For this study, 32 healthy Japanese subjects and 32 healthy Caucasian subjects were enrolled into one of four cohorts (Figure 1). Key inclusion criteria included the following: Men and women, aged 18–55 years, body mass index (BMI) ranging from 17.5 to 28.0 kg/m² inclusive, able to read and speak English and/or Japanese languages and in good health. Additional inclusion criteria for Japanese subjects included that they had to be a non-naturalized Japanese citizen and hold a Japanese passport, have two Japanese parents and four Japanese grandparents who were all non-naturalized Japanese citizens, and have been living outside of Japan for no more than 10 years, as confirmed by interview. Additional inclusion criteria for Caucasian subjects included that they had to have two Caucasian parents and four Caucasian grandparents as confirmed by interview. Key exclusion criteria included pregnancy or lactation, known allergy or sensitivity to injected proteins including monoclonal antibodies, or that they were suffering from any medical condition that could interfere or confound the results of the study. Subjects with any prior exposure to a monoclonal antibody targeting the calcitonin gene-related peptide (CGRP) pathway were also excluded.

Figure 1.

Study scheme. Cohort 1 included 16 Japanese subjects in a single ascending dose scheme: Dose level 1 (six subjects were enrolled with a 2:1 allocation ratio to either 225 mg fremanezumab or placebo); dose level 2 (five subjects were enrolled with a 4:1 allocation ratio to either 675 mg fremanezumab or placebo); and dose level 3 (five subjects were enrolled with a 4:1 allocation ratio to either 900 mg fremanezumab or placebo). Cohort 2: 16 Caucasian subjects (single dose) were randomized with a 1:1:1:1 allocation ratio to one of the following four treatments: 225, 675, or 900 mg fremanezumab, or placebo (n = 4 per group). Cohort 3 included 16 Japanese subjects (single dose) who were randomized with a 1:1:1:1 allocation ratio to one of the following four treatments: 225, 675, or 900 mg fremanezumab, or placebo (n = 4 per group). Cohort 4 included 16 Caucasian subjects (single dose) who were randomized with a 1:1:1:1 allocation ratio to one of the following four treatments: 225, 675, or 900 mg fremanezumab, or placebo (n = 4 per group).

Treatments

In the first treatment cohort of 16 Japanese subjects, a dose escalation scheme (5–6 subjects for each dose level receiving either active or placebo treatments in a 4:1–2 ratio) was applied, where the active drug was not escalated to the next dose level unless the safety and tolerability of the previous doses were acceptable by the sponsor and clinical team (Figure 1). In cohorts 2, 3 and 4, subjects were randomly assigned to receive treatment with fremanezumab at a dosage of 225 mg, 675 mg, and 900 mg, and matching placebo, in a 1:1:1:1 allocation ratio. Subjects were randomized to treatment groups on day 1, prior to dosing. Every effort was made to match Caucasian subjects to the Japanese population based on sex, age (±10 years), and BMI (±20%). Matching occurred at the cohort level with a Japanese cohort preceding the matching Caucasian cohort (Cohorts 2 and 4 matching to Cohorts 1 and 3, respectively). The randomization code (using blocked method without stratification) was created and maintained by PRA Health Sciences (PRA). Subject randomization codes were maintained in a secure location within Teva, Clinical Supply Chain, and in a secure location with PRA. At the time of analyses, when treatment codes were revealed, the random code generator provided the randomization code to the statistician assigned to this study.

The only individuals with access to the randomization blinding scheme during the study were the pharmacy personnel designated by the investigational center, who were responsible for the preparation of the study drug, a separate sponsor monitor only for the pharmacy, the statistician who generated the randomization code (and was not involved in the study otherwise), the personnel performing the bioanalysis (placebo samples were not tested for fremanezumab concentration or immunogenicity), and the personnel responsible for the pharmacokinetics analysis. The personnel responsible for bioanalysis and pharmacokinetic data analysis did not have access to clinical safety data. The investigator, sponsor, a medical monitor, and a sponsor clinical monitor remained blinded throughout the study, unless safety concerns necessitated unblinding.

The syringes with fremanezumab and placebo treatments were similar in appearance. Fremanezumab syringes were supplied as pre-filled syringes with a 1.5 mL minimum deliverable volume containing 150 mg/mL concentration. Placebo syringes were supplied as pre-filled syringes with a 1.5 mL minimum deliverable volume of the same vehicle and excipients as those for active injections. Regardless of dose, all subjects received a total of four subcutaneous (sc) injections composed of either fremanezumab or placebo depending on their individual dose injected into four quadrants of the abdomen, to maintain blinding. All subjects fasted overnight prior to drug administration and until 1 hour after dosing.

Measures

Blood samples (4 mL) for pharmacokinetics and for immunogenicity (5 mL) were collected predose and at specified time points up to 225 days post-dose. Blood for Anti-Drug Antibody (ADA) assessment was also collected upon observation of any severe hypersensitivity reaction (e.g. anaphylaxis).

During the study, safety was assessed by evaluating adverse events, clinical laboratory test results (chemistry, hematology, coagulation and urinalysis), vital signs measurements (blood pressure, pulse, and oral body temperature), safety 12-lead ECG recordings, local tolerability at injection sites (erythema, induration, ecchymosis and pain), physical examinations, pregnancy testing, immunogenicity, prior and concomitant medication usage. The safety assessments were conducted throughout the study, with particular procedures identified for each study visit.

Statistical analyses

No formal statistical hypotheses were applied, hence a sample size of eight subjects per dose level per ethnic group was considered sufficient.

Pharmacokinetic parameters derived from plasma concentrations were summarized, using descriptive statistics, by fremanezumab treatment doses and ethnic groups (number of subjects [n], mean, standard deviation [SD], standard error [SE] of the mean, minimum, median, maximum, coefficient of variation, and geometric means [for AUC and C_max]). Within each ethnic group, dose proportionality was assessed in an exploratory manner for C_max and AUCs. A power model was fitted separately to describe the relationship between Y (C_max, AUCs) and X (dose) using the least-squares linear regression model [ln(Y) = α + β ln(X)]. From each model, the intercept of the regression line α and the slope of the regression line β were presented along with the 90% CI of the slope. The effect of body weight and sex on pharmacokinetic parameters was explored in a descriptive manner. Descriptive statistics were calculated for safety measures for all subjects who were randomized and received one dose of study treatment. All analyses were pre-planned and described in the study SAP.

Results

Subject disposition and demographics

A total of 123 healthy subjects were screened for enrollment into this study. Of the 64 subjects randomized (32 Japanese and 32 Caucasian), all received one dose of the study drug (fremanezumab or placebo) and were evaluated for safety in the study; 62 subjects (97%) completed the study. Two (3%) Japanese subjects (1 in the 225 mg and 1 in the 900 mg fremanezumab groups) withdrew consent after returning to Japan due to family emergencies. The Japanese and Caucasian groups were well matched with regards to demographic characteristics (Table 1) and baseline demographic characteristics were also similar across the treatment groups (placebo and fremanezumab doses).

Table 1.

Subject demographics.

Characteristic*	Japanese subjects					Caucasian subjects					Study Overall
Characteristic*	Placebo (n = 8)	Fremanezumab dose			Overall (n = 32)	Placebo (n = 8)	Fremanezumab dose			Overall (n = 32)	Study Overall
225 mg (n = 8)	675 mg (n = 8)	900 mg (n = 8)	225 mg (n = 8)	675 mg (n = 8)	900 mg (n = 8)
% Females	50%	63%	50%	75%	59%	75%	63%	50%	50%	59%	59%
Age (years)	45 (7)	35 (9)	30 (5)	37 (8)	37 (8)	34 (7)	40 (12)	36 (12)	35 (10)	36 (10)	37 (10)
Weight (kg)	63 (16)	65 (10)	61 (9)	58 (7)	62 (11)	64 (8)	69 (14)	69 (9)	71 (11)	68 (11)	65 (11)
BMI (kg/m²)	23 (3)	23 (2)	23 (3)	23 (3)	23 (2)	23 (2)	23 (2)	24 (2)	23 (1)	23 (2)	23 (2)

mean (SD) unless otherwise indicated.

Plasma concentrations

All subjects who received fremanezumab (24 Japanese and 24 Caucasians) were evaluable for pharmacokinetics. For the two Japanese subjects who withdrew from the study early, the fremanezumab plasma concentrations of their early termination samples were used in the calculation of pharmacokinetic parameters as appropriate.

For 42 out of 48 subjects, fremanezumab plasma concentrations were quantifiable at all time points up to the last collection on day 225, and for the remaining subjects until day 169 or 197. As shown in Figure 2, mean fremanezumab plasma concentrations increased with increasing dose levels and generally peaked between 5 to 7 days post-dose for all doses, with gradual decline thereafter. The time to attain these peak concentrations was not impacted by dose or ethnicity. For each dose level, the mean profiles of Japanese and Caucasians were similar (Figure 3). Fremanezumab plasma concentration-time profiles were overlapping for Japanese and Caucasians at all dose levels.

Figure 2.

Overall mean fremanezumab plasma concentration-time profiles for both groups by dose level on a linear (±SD) and semi-log scale.

Figure 3.

Mean (SD) fremanezumab plasma concentration-time profiles by dose level and ethnicity.

Pharmacokinetics

The median t_max was similar across all dose levels and ranged from 5–7 days for fremanezumab dose levels (225 mg, 675 mg and 900 mg) with both ethnic groups combined, (Supplemental Table 1). Peak (C_max) and overall (all AUCs) exposures increased with increasing dose. Mean t_½ values were similar across all dose levels, ranging from 32 to 36 days. Mean CL/F (0.08–0.09 mL/min) and V_z/F (5.71–6.43 L) values were also similar across all dose levels.

When the pharmacokinetic parameters were evaluated separately by fremanezumab dose level and by ethnic group (Table 2), the results were similar to the values for the dose levels with both ethnic groups combined. For the exposure parameters, the geometric mean ratios (GMRs) for Japanese to Caucasian subjects were C_max: 0.91, 1.04 and 1.14, and AUC_0-inf: 0.96, 1.09, and 0.98 for the 225 mg, 675 mg and 900 mg fremanezumab doses, respectively, demonstrating exposure similarity for Japanese and Caucasian subjects. These exposure parameters increased with increases in dose level (Supplemental Figure 1). The median t_max was similar for Japanese and Caucasian subjects at the 225 mg (7 days) and 675 mg (5 days) dose levels and comparable at the 900 mg dose level (11 and 7 days, respectively). Mean t_½ values ranged between 31.36 and 38.58 days, and were generally similar across all dose levels and ethnic groups (Japanese and Caucasians at 225 mg: 33.57 and 36.35 days, respectively; at 675 mg: 31.36 and 33.10 days; and at 900 mg: 33.37 and 38.58 days). The CL/F and V_z/F values were also similar across all dose levels and ethnic groups.

Table 2.

Plasma pharmacokinetic parameters of fremanezumab by treatment and ethnic group.

Parameter (unit)	Statistic	Japanese subjects			Caucasian subjects
Parameter (unit)	Statistic	Fremanezumab dose level			Fremanezumab dose level
225 mg (n = 8)	675 mg (n = 8)	900 mg (n = 8)	225 mg (n = 8)	675 mg (n = 8)	900 mg (n = 8)
t_max (day)	n	8	8	8	8	8	8
t_max (day)	Median	6.98	5.00	10.51	7.03	5.00	7.02
Min, max	4.50, 7.09	3.50, 10.99	4.50, 28.01	4.99, 27.90	3.50, 28.93	5.00, 28.03
C_max (µg/mL)	n	8	8	8	8	8	8
	GeoMean GMR	28.32 0.91	106.77 1.04	150.68 1.14	31.20	102.88	132.18
	SD	3.95	32.50	33.95	4.02	32.63	59.64
%CV	13.8	29.4	22.0	12.8	30.2	42.1
AUC_0-28d (h*µg/mL)	n	8	8	7	8	8	8
	GeoMean GMR	15821 1.02	54584 1.10	77865 1.08	15548	49486	72039
	SD	2500	14089	13504	2163	14989	32013
%CV	15.6	25.2	17.1	13.8	29.0	41.6
AUC_0-84d (h*µg/mL)	n	7	8	7	8	8	8
	GeoMean GMR	32392 0.96	113306 1.10	158702 1.04	33667	103317	153133
	SD	5065	32,134	23,632	5068	30,456	50,964
%CV	15.5	27.5	14.8	14.9	28.5	32.0
AUC_0-t (h*µg/mL)	n	7	8	7	8	8	8
	GeoMean GMR	39,949 0.94	137,415 1.10	192,932 0.98	42,678	125,400	196,009
	SD	7593	48,374	38,422	7313	39,100	63,734
%CV	18.7	33.6	19.6	16.9	30.0	31.3
AUC_0-inf (h*µg/mL)	n	8	8	7	8	8	8
	GeoMean GMR	41,680 0.96	138,850 1.09	195,171 0.98	43,347	127,050	199,683
	SD	8096	49,553	40,516	7452	39,996	64,298
%CV	19.1	34.0	20.4	17.0	30.3	31.1
t_½ (day)	n	8	8	7	8	8	8
	Mean	33.57	31.36	33.37	36.35	33.10	38.58
	SD	5.31	6.87	6.82	1.49	7.36	4.73
%CV	15.8	21.9	20.4	4.1	22.2	12.3
CL/F (mL/min)	n	8	8	7	8	8	8
	Mean	0.09	0.09	0.08	0.09	0.09	0.08
	SD	0.02	0.03	0.01	0.01	0.03	0.02
%CV	20.1	32.6	17.1	16.0	29.3	24.8
V_z/F (L)	n	8	8	7	8	8	8
V_z/F (L)	Mean	6.26	5.22	5.31	6.60	6.20	6.22
SD	0.81	0.86	0.96	1.00	2.00	1.78
	%CV	13.0	16.4	18.2	15.2	32.3	28.6

CV: coefficient of variation; GeoMean: geometric mean; GMR: geometric mean ratios Japanese to Caucasian; max: maximum; min: minimum; N: total number of subjects; n: number of subjects with evaluable data; SD: standard deviation.

Japanese subjects (one at 225 mg fremanezumab and one at 900 mg fremanezumab) were excluded from the summary of AUC_0-t due to early termination.

Dose-proportionality analysis

Dose-normalized fremanezumab plasma pharmacokinetic parameters by ethnic group are presented in Supplemental Table 2. For Japanese subjects, dose-normalized peak (C_max) and overall (all AUCs) exposures were similar at the 675 mg and 900 mg fremanezumab dose level, and slightly lower at the 225 mg dose level. For Caucasian subjects, overall exposures were similar at 225 mg and 675 mg, and slightly higher at 900 mg group, whereas peak exposures were similar across all three doses. Box plots illustrating these trends in exposures for both Japanese and Caucasian subjects are provided in Supplemental Figure 2.

The dose proportionality assessment using the power model was conducted as an exploratory analysis. For the majority of dose proportionality assessments, the corresponding slopes were slightly greater than 1 (Supplemental Table 3). The increase in exposures appeared to be slightly greater than dose proportional in both Japanese and Caucasian subjects.

Table 3.

Adverse events occurring in at least two (3%) subjects by MedDRA preferred term.

Number (%)	Japanese subjects					Caucasian subjects					Total (N = 64)
Number (%)	Placebo (n = 8)	Fremanezumab dose level			Overall (n = 32)	Placebo (n = 8)	Fremanezumab dose level			Overall (n = 32)	Total (N = 64)
225 mg (n = 8)	675 mg (n = 8)	900 mg (n = 8)	225 mg (n = 8)	675 mg (n = 8)	900 mg (n = 8)
Patients with at least 1 AE	5 (63)	8 (100)	6 (75)	7 (88)	26 (81)	4 (50)	7 (88)	5 (63)	8 (100)	24 (75)	50 (78)
Abdominal pain	1 (13)	0	0	1 (13)	2 (6)	0	0	0	1 (13)	1 (3)	3 (5)
Constipation	0	0	1 (13)	0	1 (3)	0	0	1 (13)	0	1 (3)	2 (3)
Injection site erythema	3 (38)	6 (75)	4 (50)	7 (88)	20 (63)	4 (50)	5 (63)	1 (13)	4 (50)	14 (44)	34 (53)
Injection site induration	3 (38)	3 (38)	3 (38)	3 (38)	12 (38)	1 (13)	1 (13)	0	4 (50)	6 (19)	18 (28)
Injection site hemorrhage	1 (13)	3 (38)	0	1 (13)	5 (16)	0	0	0	1 (13)	1 (3)	6 (9)
Injection site pain	2 (25)	0	2 (25)	2 (25)	6 (19)	0	1 (13)	1 (13)	0	2 (6)	8 (13)
Upper respiratory tract infection	1 (13)	0	1 (13)	0	2 (6)	1 (13)	0	0	0	1 (3)	3 (5)
Nasopharyngitis	0	0	0	0	0	2 (25)	0	0	0	2 (6)	2 (3)
Headache	0	1 (13)	0	0	1 (3)	0	0	0	2 (25)	2 (6)	3 (5)

The effect of body weight and sex on exposure

Japanese subjects generally had somewhat lower body weights, and the weight difference between males and females was less pronounced relative to Caucasian subjects. In both Japanese and Caucasian subjects, dose-normalized peak (C_max) exposure was not impacted by sex, while dose normalized AUC exposures were generally higher in females than in males as illustrated for AUC_0-t in Figure 4 (C_max and AUC_0-inf shown in Supplemental Figures 3 and 4).

Figure 4.

Plot of dose-normalized AUC_0-t versus body weight by treatment and ethnic group.

For both males and females, lower body weights were generally associated with higher peak and overall exposures; this effect was somewhat more pronounced in Japanese than in Caucasian subjects. It should be noted that the higher exposures observed in females was confounded by lower body weights.

Safety

No deaths or serious adverse events occurred during the study, and no subject withdrew due to an adverse event. The incidence of adverse events was comparable between active and placebo treatment, and there was no relation to the fremanezumab dose. The reporting of adverse events was also comparable between Japanese and Caucasian subjects. The majority of adverse events reported were of mild intensity, except for one moderate treatment-related event (injection site pain) and six moderate adverse events that were not treatment-related (dental caries, infected skin ulcer, hand fracture, influenza-like illness, skin abrasion, and wrist fracture).

The most frequently occurring AEs (≥2 subjects) were injection site reactions, abdominal pain, headache, upper respiratory tract infection, constipation and nasopharyngitis (Table 3). The most frequently reported treatment-related AEs were injection site-related AEs (injection site erythema, injection site induration, injection site pain, and injection site hemorrhage) which occurred in all four quadrants of the abdomen. The frequency of injection site reactions was comparable between fremanezumab and placebo treatment and there was no clear relationship with fremanezumab dose. Injection site reactions were reported slightly more often in Japanese subjects than in Caucasian subjects; however, it should be taken into account that this was an exploratory study with small group sizes.

Other safety assessments included clinical laboratory (clinical chemistry with alanine aminotransferase and aspartate aminotransferase, coagulation, hematology, and urinalysis) electrocardiogram, vital signs, and physical examinations, and these safety results were also comparable in Japanese and Caucasian subjects. There were no clinically meaningful trends in mean changes from baseline for any clinical laboratory variable. Shifts in clinical laboratory values from the normal range at baseline to outside the normal range at one or more time points during the study were incidental, and none of these shifts were considered to be clinically meaningful. Three Japanese subjects (one each in the placebo, 225 mg, and 900 mg fremanezumab dose groups) and one Caucasian subject (675 mg fremanezumab) had potentially clinically significant abnormal hematology values that were considered to be not clinically significant. No clinical laboratory value was identified as a clinically significant abnormality. No relevant differences were observed between placebo and fremanezumab treatment or between Japanese and Caucasian subjects.

For immunogenicity, a total of 236 samples from 48 subjects treated with fremanezumab were analyzed. None of the subjects developed ADAs after fremanezumab exposure.

Discussion

Fremanezumab, a monoclonal antibody that selectively targets the CGRP ligand preventing it from binding to the CGRP receptor, is being developed to provide a safe and effective preventive treatment for migraine. The primary outcome of this study was to assess the pharmacokinetic profile of fremanezumab in Japanese and Caucasian healthy subjects after single administrations at three different dose levels (225, 675, and 900 mg) as well as to assess the safety, tolerability, and immunogenicity.

In Japan, roughly 8.4 million people are estimated to be affected by migraine, and 74% are reported to have disability. However, there is lack of awareness about treatments for migraine, and only 2.7% of migraine sufferers seek medical consultation. Pharmacotherapies used to treat chronic migraine and chronic daily headache in Japan include antiepileptic drugs (gabapentin, valproic acid, topiramate, and levetiracetam), the antidepressant amitriptyline, and the central muscle relaxant tizanidine (21). Botulinum neurotoxin type A may be considered for chronic migraine when other treatments have failed.

In this study, following single-dose sc administration of fremanezumab, plasma concentration-time profiles overlapped for Japanese and Caucasian subjects at all dose levels. At each dose level, exposure parameters were similar for Japanese and Caucasian subjects. The half-life, t_max, CL/F, and V_z/F were generally not impacted by dose or ethnicity.

Mean t_½ values for the Japanese and Caucasian subjects were similar across all dose levels, ranging from 32 to 36 days, and could be considered reliable as plasma samples were collected over more than double the half-life range. A long half-life allows for longer dosing intervals, and may lead to improved treatment adherence among patients with migraine.

Following sc administration at dose levels of 225, 675, or 900 mg, fremanezumab pharmacokinetics were characterized by a very low apparent clearance (mean CL/F ranged from 0.08–0.09 mL/min) as compared to the human glomerulus filtration rate (125 mL/min) (22). The mean V_z/F ranged between 5.7 and 6.4 L. The observed V_z/F values were consistent with previously reported volumes of distribution for IgG antibodies, indicating a volume of distribution slightly greater than plasma volume, but less than the volume of extracellular fluid (22).

It is important to note that the exposure results of this study are limited, as subjects received only one administration of each of the fremanezumab doses; however, half-life, time to maximum concentrations, apparent clearance and volume of distribution were well characterized in this study in both ethnic groups. In the study, every effort was made to match Japanese BMI to Caucasians, and indeed average BMI levels were very similar between Japanese and Caucasians in all four treatment groups; thus, the average BMI of the Caucasians was lower than what would be expected in a standard Caucasian population (23). In general, Japanese subjects had somewhat lower body weights than Caucasian subjects (i.e. 62 kg vs. 65 kg, respectively). It was demonstrated that lower body weights in both Japanese and Caucasian subjects were associated with higher exposures.

Regarding safety, the adverse event profiles of Japanese and Caucasian subjects were comparable in this study, and subjects regardless of dose or ethnicity did not developed ADAs. No deaths or serious adverse events occurred in this study, and there were no discontinuations due to adverse events.

As CGRP is involved in many physiological processes in addition to migraine and is a part of the homeostatic responses that occur during pathophysiological conditions, it is important to look closely for unintended side effects that could occur with the blockade of CGRP (24). Thus, one of the primary purposes of this study was to determine safety for therapeutically relevant doses, and a dose escalation scheme was used for cohort 1, which included only Japanese subjects as this was the first time Japanese subjects were exposed to fremanezumab, where a few subjects were closely monitored and doses were not increased until the safety of the current dose was reviewed by the safety monitoring board.

Therefore, although the safety information from this study is limited as subjects received a single dose administration, there were no findings of clinical relevance in any of the clinical examinations and laboratory assessments (clinical chemistry, coagulation, hematology, and urinalysis; ECG; vital signs; and physical examination), and these results add to the reports from previous studies, which have not shown any unexpected adverse events with fremanezumab treatment (18 –20,24).

Conclusion

The present study provided the pharmacokinetic profile, safety and immunogenicity of fremanezumab subcutaneous doses that were tested in the phase 2 and 3 trials (225 mg, 675 mg and 900 mg), following single administration in healthy Japanese and Caucasian subjects. Fremanezumab concentration-time profiles and the exposure parameters were similar for Japanese and Caucasians at all dose levels. Fremanezumab exposures were generally higher with lower body weight. The increase in C_max and AUCs were slightly greater than dose proportional for both Japanese and Caucasian subjects for this dose range. The maximum plasma concentrations (T_max) and fremanezumab half-lives were not impacted by dose or ethnicity and the long half life support dose regimens of 225 mg once monthly or 675 mg once quarterly. Overall, single-dose sc administration of fremanezumab (225, 675, or 900 mg) in healthy Japanese and Caucasian volunteers was well tolerated, and the safety profile was as expected based on the pharmacology of fremanezumab.

Supplemental Material

Supplementary Figure 1 top panel -Supplemental material for A phase 1 study to assess the pharmacokinetics, safety, and tolerability of fremanezumab doses (225 mg, 675 mg and 900 mg) in Japanese and Caucasian healthy subjects

Supplemental material, Supplementary Figure 1 top panel for A phase 1 study to assess the pharmacokinetics, safety, and tolerability of fremanezumab doses (225 mg, 675 mg and 900 mg) in Japanese and Caucasian healthy subjects by Orit Cohen-Barak, Sivan Weiss, Michele Rasamoelisolo, Nicola Faulhaber, Paul P Yeung, Pippa S Loupe, Esther Yoon, Mohit D Gandhi, Ofer Spiegelstein and Ernesto Aycardi in Cephalalgia

Supplemental Material

Supplementary Figure 1 middle panel -Supplemental material for A phase 1 study to assess the pharmacokinetics, safety, and tolerability of fremanezumab doses (225 mg, 675 mg and 900 mg) in Japanese and Caucasian healthy subjects

Supplemental material, Supplementary Figure 1 middle panel for A phase 1 study to assess the pharmacokinetics, safety, and tolerability of fremanezumab doses (225 mg, 675 mg and 900 mg) in Japanese and Caucasian healthy subjects by Orit Cohen-Barak, Sivan Weiss, Michele Rasamoelisolo, Nicola Faulhaber, Paul P Yeung, Pippa S Loupe, Esther Yoon, Mohit D Gandhi, Ofer Spiegelstein and Ernesto Aycardi in Cephalalgia

Supplemental Material

Supplementary Figure 1 bottom panel -Supplemental material for A phase 1 study to assess the pharmacokinetics, safety, and tolerability of fremanezumab doses (225 mg, 675 mg and 900 mg) in Japanese and Caucasian healthy subjects

Supplemental material, Supplementary Figure 1 bottom panel for A phase 1 study to assess the pharmacokinetics, safety, and tolerability of fremanezumab doses (225 mg, 675 mg and 900 mg) in Japanese and Caucasian healthy subjects by Orit Cohen-Barak, Sivan Weiss, Michele Rasamoelisolo, Nicola Faulhaber, Paul P Yeung, Pippa S Loupe, Esther Yoon, Mohit D Gandhi, Ofer Spiegelstein and Ernesto Aycardi in Cephalalgia

Supplemental Material

Supplementary Figure 2 top panel -Supplemental material for A phase 1 study to assess the pharmacokinetics, safety, and tolerability of fremanezumab doses (225 mg, 675 mg and 900 mg) in Japanese and Caucasian healthy subjects

Supplemental material, Supplementary Figure 2 top panel for A phase 1 study to assess the pharmacokinetics, safety, and tolerability of fremanezumab doses (225 mg, 675 mg and 900 mg) in Japanese and Caucasian healthy subjects by Orit Cohen-Barak, Sivan Weiss, Michele Rasamoelisolo, Nicola Faulhaber, Paul P Yeung, Pippa S Loupe, Esther Yoon, Mohit D Gandhi, Ofer Spiegelstein and Ernesto Aycardi in Cephalalgia

Supplemental Material

Supplementary Figure 2 middle panel -Supplemental material for A phase 1 study to assess the pharmacokinetics, safety, and tolerability of fremanezumab doses (225 mg, 675 mg and 900 mg) in Japanese and Caucasian healthy subjects

Supplemental material, Supplementary Figure 2 middle panel for A phase 1 study to assess the pharmacokinetics, safety, and tolerability of fremanezumab doses (225 mg, 675 mg and 900 mg) in Japanese and Caucasian healthy subjects by Orit Cohen-Barak, Sivan Weiss, Michele Rasamoelisolo, Nicola Faulhaber, Paul P Yeung, Pippa S Loupe, Esther Yoon, Mohit D Gandhi, Ofer Spiegelstein and Ernesto Aycardi in Cephalalgia

Supplemental Material

Supplementary Figure 2 bottom panel -Supplemental material for A phase 1 study to assess the pharmacokinetics, safety, and tolerability of fremanezumab doses (225 mg, 675 mg and 900 mg) in Japanese and Caucasian healthy subjects

Supplemental material, Supplementary Figure 2 bottom panel for A phase 1 study to assess the pharmacokinetics, safety, and tolerability of fremanezumab doses (225 mg, 675 mg and 900 mg) in Japanese and Caucasian healthy subjects by Orit Cohen-Barak, Sivan Weiss, Michele Rasamoelisolo, Nicola Faulhaber, Paul P Yeung, Pippa S Loupe, Esther Yoon, Mohit D Gandhi, Ofer Spiegelstein and Ernesto Aycardi in Cephalalgia

Supplemental Material

Supplementary Figures 3 and 4 -Supplemental material for A phase 1 study to assess the pharmacokinetics, safety, and tolerability of fremanezumab doses (225 mg, 675 mg and 900 mg) in Japanese and Caucasian healthy subjects

Supplemental material, Supplementary Figures 3 and 4 for A phase 1 study to assess the pharmacokinetics, safety, and tolerability of fremanezumab doses (225 mg, 675 mg and 900 mg) in Japanese and Caucasian healthy subjects by Orit Cohen-Barak, Sivan Weiss, Michele Rasamoelisolo, Nicola Faulhaber, Paul P Yeung, Pippa S Loupe, Esther Yoon, Mohit D Gandhi, Ofer Spiegelstein and Ernesto Aycardi in Cephalalgia

Supplemental Material

Supplementary Tables -Supplemental material for A phase 1 study to assess the pharmacokinetics, safety, and tolerability of fremanezumab doses (225 mg, 675 mg and 900 mg) in Japanese and Caucasian healthy subjects

Supplemental material, Supplementary Tables for A phase 1 study to assess the pharmacokinetics, safety, and tolerability of fremanezumab doses (225 mg, 675 mg and 900 mg) in Japanese and Caucasian healthy subjects by Orit Cohen-Barak, Sivan Weiss, Michele Rasamoelisolo, Nicola Faulhaber, Paul P Yeung, Pippa S Loupe, Esther Yoon, Mohit D Gandhi, Ofer Spiegelstein and Ernesto Aycardi in Cephalalgia

Footnotes

Clinical implications

Following single-dose sc administration of fremanezumab, a fully humanized IgG2Δa/kappa monoclonal CGRP antibody, plasma concentration-time profiles overlapped for Japanese and Caucasian healthy subjects at all tested dose levels (225 mg, 675 mg and 900 mg).

At each fremanezumab dose level, pharmacokinetic parameters were similar for Japanese and Caucasians subjects. The half-life, t_max, CL/F, and V_z/F were generally not impacted by dose or ethnicity.

The study results of the pharmacokinetic exposure parameters and safety measures support the once monthly sc injections of 225 mg and once quarterly sc injections of 675 mg as fremanezumab treatment doses.

Acknowledgements

The authors appreciate the subjects who participated in the study and the statistical analyses performed by Xiaojun Hu (Global Research and Development Teva Pharmaceuticals).

Declaration of conflicting interests

The authors declared the following potential conflicts of interest with respect to the research, authorship, and/or publication of this article: OC-B, SW, MR, NF, PPY, PSL, OS and EA are employees of Teva Pharmaceuticals, Inc., the sponsor of the clinical development of fremanezumab for the treatment of migraine. EY is an employee of PAREXEL International and MG is an employee of PRA Health Sciences, companies funded by Teva to perform the study described herein.

Funding

The authors disclosed receipt of the following financial support for the research, authorship, and/or publication of this article: Global Research and Development Teva Pharmaceuticals funded the phase 1 study described in this article.

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