Safety, Tolerability, Pharmacokinetics, and Pharmacodynamics
臨床薬理 Jpn J Clin Pharmacol Ther 2017; 48(4): 131-139 131
ORIGINAL ARTICLE
Safety, Tolerability, Pharmacokinetics, and Pharmacodynamics of Galcanezumab, a Monoclonal Antibody to Calcitonin Gene-Related Peptide, in Healthy Japanese and Caucasian Subjects
Masako NAKANO＊1, Kazunori UENAKA＊1, William KIELBASA＊2, Yuri MATSUYAMA＊3, Akichika OZEKI＊1 and Mosun A. AYAN-OSHODI＊2
Abstract Introduction Galcanezumab, a humanized monoclonal calcitonin gene-related peptide(CGRP)antibody, is being developed for cluster head- Migraine is a disabling primary headache disorder that was ranked as the third most prevalent disorder and seventh highest ache and migraine prevention. This study evaluated galcanezu- 1) mab safety, tolerability, pharmacokinetics, and pharmacodynam- specific cause of disability worldwide. In Japan, a nationwide ʼ ics in healthy Japanese and Caucasian subjects. Galcanezumab or migraine survey found the country s overall migraine prevalence . ％2) placebo was administered as subcutaneous injections to 4 single- was 8 4 and a population-based survey of Daisen, a rural ( ) ( community in western Japan, reported a 6.0％ migraine dose cohorts 5, 50, 120, 300 mg and 1 multiple-dose cohort 3 3) consecutive, 300-mg doses, every 4 weeks). Safety measure- prevalence. Consistent with the high disability worldwide, ( ) 20.3％ of Japanese patients who have migraine had taken time ments included treatment-emergent adverse events TEAEs , 3) vital signs, electrocardiograms, clinical laboratory tests, and anti- off from work because of migraine over a 3-month period. drug antibodies(ADA). Blood samples were analyzed for serum Preventative treatment is indicated for patients with migraine refractory to acute medications or those with responsive but galcanezumab and plasma CGRP concentrations. 4) Twenty-five Japanese and twenty Caucasians, 22 to 63 years disabling frequent headache attacks. Approved prophylactic of age, were enrolled; 27 received a single dose(N＝6 to 8 per medications include valproic acid, propranolol, and lomerizine; dose level), 8 received multiple doses, and 10 received placebo however, these treatments were not originally developed for the (8 single dose, 2 multiple dose). Forty-one subjects completed prevention of migraine. In addition, a survey conducted in Japan ( ) showed that less than 10％ of migraine patients were medically the study 24 single dose, 7 multiple dose, 10 placebo . 3) Galcanezumab was well tolerated in Japanese and Caucasian treated on a regular basis, indicating the limitations of existing subjects. There were no apparent dose-related increases in prophylactic medications. There remains a great need for TEAEs or changes in vital signs, electrocardiogram parameters, effective and safe prophylactic migraine medications with fewer laboratory values, or treatment-emergent ADA. Following single side effects. and multiple doses, maximum galcanezumab concentrations Migraine is thought to be associated with trigeminovascular were observed approximately 5 to 9 days postdose and mean system activation, resulting in the release of pain-producing ( ) half-life was about 3 to 4 weeks. Increases in area under the substances. Calcitonin gene-related peptide CGRP is a neuro- peptide found throughout the trigeminovascular system and is concentration-time curve and maximum observed concentration 5) were dose proportional. Galcanezumab pharmacokinetics and released after system activation. CGRP is a potent vasodilator and has well established roles in neurogenic inflammation and pharmacodynamics were similar between Japanese and Caucasi- 6) an subjects. Plasma CGRP concentrations increased following nociception. The mechanism by which CGRP triggers migraine ( ) remains uncertain, but CGRP may play a role in enhancement of galcanezumab administration consistent with CGRP target 6) binding to galcanezumab(antibody). These data support further sensitivity to sensory input. Several lines of evidence support development of galcanezumab in Japanese patients. CGRP as a promising drug target for the acute and preventative treatment of migraine. CGRP has been temporally associated 7) Key words: galcanezumab, cluster headache, migraine, calcito- with the onset and duration of migraine, with increases in nin gene-related peptide(CGRP) jugular venous blood CGRP concentrations observed in spontaneous migraine attacks. Migraines have also been Jpn J Clin Pharmacol Ther. 2017; 48(4): 131-139 triggered using intravenous infusion of CGRP in susceptible subjects.8,9) Anti-CGRP antibodies are thought to bind to CGRP preventing CGRP-induced trigeminovascular system activation,
＊1 Eli Lilly Japan K.K., Kobe, Japan ＊2 Eli Lilly and Company, Indianapolis, Indiana, USA ＊3 Eli Lilly Japan K.K., Tokyo, Japan Address for correspondence：NAKANO M. Eli Lilly Japan K.K., 7-1-5 Isogamidori, Chuo-ku, Kobe 651-0086, Japan TEL：078-242- 9288 FAX：078-242-9828 E-mail：[email protected] Manuscript received December 20, 2016; revised May 8, 2017; accepted May 9, 2017 ISSN 0388-1601 Copyright: ©2017 the Japanese Society of Clinical Pharmacology and Therapeutics(JSCPT)
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resulting in decreased migraine frequency over time.5� Galcane- to a 5 : 1 ratio for Japanese subjects and a 3 : 1 ratio for zumab is a humanized monoclonal antibody that potently and Caucasian subjects, such that 8 subjects �5 Japanese and 3 selectively binds to CGRP and has been identified for cluster Caucasian�received galcanezumab and 2 subjects�1 Japanese headache and migraine prevention.10−12� In nonclinical testing and 1 Caucasian�received placebo in each cohort. This sample with rats and non-human primates, galcanezumab prevents size was considered adequate to meet study objectives. increases in capsaicin-induced dermal blood flow �DBF�;a Subjects in Cohorts 1 to 4 received galcanezumab or placebo response which is predominantly CGRP dependent.13� With non- as 1 SC injection�Cohorts 1 to 3�or 2 SC injections�Cohort 4� human primates, galcanezumab demonstrated inhibition of of up to 1.5 mL each into the abdomen on the morning of Day 1. capsaicin-induced DBF for 28 days after a single administra- Subjects returned to the clinical research unit �CRU� for tion.14� The effect of galcanezumab on the capsaicin-induced outpatient visits at regular intervals during a 20-week follow-up increase in DBF in healthy human subjects was measured as part period. Subjects in Cohort 5 received galcanezumab or placebo of a double-blind, placebo-controlled, single dose escalation as two 1.5-mL SC injections into the abdomen on the mornings and multiple-dose study �ClinicalTrials. gov identifier: of Days 1, 29, and 57. Subjects returned to the CRU for NCT01337596�. In that clinical study, galcanezumab demon- outpatient visits at regular intervals over approximately 28 strated dose-dependent inhibition of the capsaicin-induced weeks after the first dose. increase in DBF.14� In a randomized, double-blind, placebo-controlled Phase 2 Study participants proof-of-concept study�NCT01625988�, galcanezumab 150 mg The study protocol was approved by an institutional review administered as subcutaneous�SC�injections every 2 weeks for board and was conducted in accordance with the Declaration of 12 weeks significantly reduced the number of migraine headache Helsinki and Good Clinical Practice guidelines. All subjects days per 28-day period�least squares mean difference in change provided written informed consent prior to participating. The from baseline −1.2, 90％ confidence interval［CI]−1.9 to study was conducted at a single site. Eligible subjects included −0.6; P＝0.0030� compared to placebo.10� Galcanezumab healthy Japanese or Caucasian men and women 20 to 65 years of efficacy, pharmacokinetics�PK�, and pharmacodynamics�PD� age with a body mass index of 18.0 to 35.0 kg／m2. Use of over- were assessed in a Phase 2b, randomized, double-blind, placebo- the-counter or prescription medication was to be avoided within controlled study in patients with episodic migraine who were 7 days prior to dosing and during the study. treated with 5 mg, 50 mg, 120 mg, and 300 mg doses every 4 weeks �Q4W� for 12 weeks �NCT02163993�. Compared to Study assessments and analyses placebo, SC injections of galcanezumab 120 mg or 300 mg Safety assessment and analysis Q4W for 12 weeks significantly reduced the overall number of Safety and tolerability were assessed throughout the study by migraine headache days by 0.86 and 0.87 days, respectively physical examinations, monitoring of treatment-emergent ad- �P＝0.018 for both�.15� Galcanezumab PK were linear�galcane- verse events �TEAEs�, vital signs, electrocardiogram �ECG� zumab concentrations increased linearly with increasing dose�, parameters, clinical laboratory evaluations, and Columbia but the relationship between CGRP and galcanezumab concen- Suicide Severity Rating Scale�C-SSRS�. Safety analyses were trations was nonlinear.16� conducted for all enrolled subjects who received at least one dose The current study was the first clinical evaluation of of study drug, whether or not they completed all protocol galcanezumab in Japanese subjects and was conducted to assess requirements. The TEAE incidence for each treatment was the safety, tolerability, PK, and PD of single and multiple doses presented by severity and by association with study drug as of galcanezumab. These data were essential for further clinical judged by the investigator. Assessments of clinical laboratory development in Japan. Caucasian subjects were included in the safety parameters included hematology, urinalysis, and clinical study to compare the safety, tolerability, PK, and PD between chemistry panels. Japanese and Caucasian subjects. Over-read ECG data were obtained directly from the triplicate 12-lead ECG traces and were transmitted to a central laboratory Methods where a cardiologist conducted a full over-read on 1 of the Study design replicate ECGs. The mean QT interval corrected for heart rate This was a randomized, single and multiple-dose, subject- and using Fridericiaʼs formula �QTcF� was calculated from the investigator-blind, placebo-controlled study in Japanese and triplicate ECGs. Baseline was defined as Day 1 predose and the Caucasian healthy subjects �NCT02104765�. Galcanezumab 5 frequency of subjects with maximum increases of ＞30 msec mg, 50 mg, 120 mg, and 300 mg doses were assessed in 4 and ＞60 msec from baseline in QTcF interval was summarized single-dose cohorts �Cohorts 1 to 4, respectively� and a for each treatment. The frequency of subjects with QTcF galcanezumab 300 mg dose Q4W was assessed in a multiple- postdose values was also summarized as thresholds of ＞450 dose cohort�Cohort 5�. msec, ＞480 msec, and ＞500 msec. The QTcF change from Subjects in Cohorts 1, 2, and 3 were randomized to receive baseline versus serum galcanezumab concentrations where either galcanezumab or placebo �0.9％ sodium chloride for analyzed in a scatter plot where ECGs collected more than one injection�according to a 3 : 1 ratio within each population, such hour apart from the corresponding blood collection time were that 6 subjects�3 Japanese and 3 Caucasian�received galcanezu- omitted. mab and 2 subjects �1 Japanese and 1 Caucasian� received Immunogenicity assessment and analysis placebo in each cohort. Subjects in Cohorts 4 and 5 were Blood samples were collected for immunogenicity testing to randomized to receive either galcanezumab or placebo according detect anti-drug antibodies �ADA� against galcanezumab. For
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single-dose cohorts, samples were collected predose and 2, 8, Table 1 Subject demographics and baseline characteristics and 20 weeks postdose. For the multiple-dose cohort, samples (All cohorts) were collected before the first dose, 2 weeks after the second Japanese Caucasian All Subjects dose, and 4 and 20 weeks after the third dose. Immunogenicity (N＝25) (N＝20) (N＝45) was assessed using a validated enzyme-linked immunosorbent Age, years assay designed by Eli Lilly and Company to detect ADA in the Mean 40.7 39.1 40.0 presence of galcanezumab.17) Treatment-emergent ADA (TE- SD 12.4 9.2 11.0 ADA) was defined as an ADA-negative result at baseline Range 22-63 24-57 22-63 followed by an ADA-positive result post baseline with a titer B20(double the minimal required dilution of the assay), or an Sex, number ADA-positive result at baseline followed by an ADA-positive Male 12 14 26 result post baseline with a B4-fold increase in titer. The number Female 13 6 19 of subjects with TE-ADA was summarized by dose level. Weight, kg Pharmacokinetic and pharmacodynamic sample collection Mean 62.66 78.07 69.51 In Cohorts 1 to 4, blood samples were collected for SD 11.43 16.82 15.92 determination of galcanezumab serum concentration for PK Range 44.0-85.0 52.8-108.8 44.0-108.8 purposes and plasma CGRP concentration for PD purposes at Height, cm predose and at regular intervals from 8 hours to 20 weeks Mean 164.91 172.60 168.33 postdose. In Cohort 5, PK and PD blood samples were collected SD 8.59 8.45 9.27 predose and at regular intervals from 8 hours to 3 weeks after the Range 151.9-179.3 157.4-186.9 151.9-186.9 first dose; predose and at regular intervals from 48 hours to 2 2 weeks after the second dose; and predose and at regular intervals Body mass index, kg／m from 24 hours to 20 weeks hours after the final dose. Mean 22.89 26.07 24.30 Bioanalysis SD 2.70 4.64 3.98 Serum samples were analyzed for galcanezumab using a Range 18.5-28.3 18.9-35.0 18.5-35.0 validated enzyme-linked immunosorbent assay method. The Abbreviations：N＝number of subjects；SD＝standard deviation. lower limit of quantification was 0.75 ng／mL and the upper limit of quantification was 30.00 ng／mL. The interassay accuracy(relative error)during validation ranged from −10.5％ evaluated to delineate dose proportionality for the single-dose to −2.0％. The interassay precision(relative standard devia- cohorts over the 5-mg to 300-mg dose range. Log-transformed
tion) during validation ranged from 2.7％ to 5.2％. Freeze／ Cmax and AUC(0-∞)were evaluated using a power model to thaw stability was demonstrated for galcanezumab in human estimate ratios of dose-normalized geometric means and serum through 5 cycles. Room-temperature stability was corresponding 90％ CIs. The observed safety, PK, and PD data demonstrated for up to 17 hours. The long-term stability of across Japanese and Caucasian subjects were compared using galcanezumab in human serum was demonstrated up to 361 days tabular and graphical methods without any formal statistical in a freezer set to maintain −20℃. comparison due to the small number of subjects in each Plasma samples from all subjects who participated in the study population. (including those receiving placebo)were analyzed for plasma Pharmacodynamic analyses CGRP concentrations using an electrochemiluminescent immu- The time course of plasma CGRP concentrations plotted by dose noassay method. This assay measures the plasma CGRP level was evaluated by visual inspection. In addition, mean concentrations, which includes CGRP bound to galcanezumab as serum galcanezumab concentrations and mean plasma CGRP well as free CGRP. concentrations were evaluated graphically together. Pharmacokinetic analyses Results PK parameter estimates for galcanezumab were calculated using standard noncompartmental methods of analysis with WinNonlin Demographics and disposition version 6.2.1(Certara, Princeton, New Jersey, United States). Forty-five healthy subjects, 26 male and 19 female, between the For the single-dose cohorts, PK parameters for analysis ages of 22 and 63, entered this study and were randomly
included: maximum observed concentration(Cmax); time of Cmax assigned to treatment. Table 1 summarizes the demographic
(tmax); area under the concentration versus time curve(AUC) characteristics. Thirty-five subjects received at least 1 dose of from time 0 to infinity〔AUC(0-∞)〕; half-life associated with galcanezumab (27 subjects in the single-dose cohorts and 8
the terminal rate constant(lz)using noncompartmental analysis subjects in the multiple-dose cohort)and 10 received at least 1
(t1/ 2); apparent total body clearance of drug calculated after dose of placebo; 41 subjects completed the study. Of the 4 extravascular administration (CL／F); and apparent volume of subjects who did not complete the study, 1 Caucasian subject in distribution during the terminal phase after extravascular Cohort 2 was lost to follow-up 18 days after receiving
administration(Vz／F). The multiple-dose cohort PK parameters galcanezumab 50 mg, 1 Japanese subject in Cohort 3 withdrew for analysis were: AUC over a dosing interval〔AUC(0-t)〕; for personal reasons 19 days after receiving galcanezumab 120
Cmax,tmax,t1/ 2, and accumulation ratio(RA)based on AUC(0-t). mg, 1 Caucasian subject in Cohort 4 withdrew due to personal Galcanezumab serum concentration-time profiles were plotted reasons 43 days after receiving galcanezumab 300 mg, and 1 by dose level and population. The PK parameter estimates were Caucasian subject in Cohort 5 was discontinued due to a positive
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Table 2 Summary of treatment-emergent adverse events considered by the investigator to be related to study drug for healthy Japanese and Caucasian subjects following single galcanezumab doses up to 300 mg or three 300 mg galcanezumab doses Q4W
Number of adverse events (Number of subjects with adverse events／ Total number of subjects) Single dose(Cohorts 1 to 4) Japanese Caucasian All Subjects All adverse events Placebo 2(2／4) 5(3／4) 7(5／8) 5 mg galcanezumab 2(2／3) 3(3／3) 5(5／6) 50 mg galcanezumab 2(2／3) 3(3／3) 5(5／6) 120 mg galcanezumab 2(2／4) 1(1／3) 3(3／7) 300 mg galcanezumab 8(4／5) 4(2／3) 12(6／8) All galcanezumab 14(10／15) 11(9／12) 25(19／27) Injection site erythema Placebo 1(1／4) 3(2／4) 4(3／8) 5 mg galcanezumab 2(2／3) 3(3／3) 5(5／6) 50 mg galcanezumab 1(1／3) 3(3／3) 4(4／6) 120 mg galcanezumab 1(1／4) 1(1／3) 2(2／7) 300 mg galcanezumab 7(4／5) 4(2／3) 11(6／8) All galcanezumab 11(8／15) 11(9／12) 22(17／27) Injection site reaction Placebo 1(1／4) 1(1／4) 2(2／8) 5 mg galcanezumab ― ― ― 50 mg galcanezumab 1(1／3) ― 1(1／6) 120 mg galcanezumab 1(1／4) ― 1(1／7) 300 mg galcanezumab 1(1／5) ― 1(1／8) All galcanezumab 3(3／15) 0(0／12) 3(3／27) Headache Placebo ― 1(1／4) 1(1／8) 5 mg galcanezumab ― ― ― 50 mg galcanezumab ― ― ― 120 mg galcanezumab ― ― ― 300 mg galcanezumab ― ― ― All galcanezumab 0(0／15) 0(0／12) 0(0／27) Multiple dose(Cohort 5) Japanese Caucasian All Subjects All adverse events Placebo Q4W 3(1／1) 3(1／1) 6(2／2) 300 mg galcanezumab Q4W 13(4／5) 5(3／3) 18(7／8) Injection site erythema Placebo Q4W 2(1／1) 3(1／1) 5(2／2) 300 mg galcanezumab Q4W 4(3／5) 4(2／3) 8(5／8) Injection site reaction Placebo Q4W ― ― ― 300 mg galcanezumab Q4W 8(4／5) 1(1／3) 9(5／8) Injection site hemorrhage Placebo Q4W 1(1／1) ― 1(1／2) 300 mg galcanezumab Q4W ― ― ― Injection site pain Placebo Q4W ― ― ― 300 mg galcanezumab Q4W 1(1／5) ― 1(1／8) Abbreviations：Q4W＝every 4 weeks.
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30
Japanese Caucasian 20
10
0
－10 QTcF Change from baseline（msec） －20
－30 0 25000 50000 75000 100000 125000 150000 Serum LY2951742 concentration（ng/mL） Model: Delta_QTcF＝0.32＋0.000029＊Concentration 90％ CI and p－value for slope:（－.000006，0.000063）［0.171］ Figure 1 Scatter plot of changes from baseline QTcF in healthy Japanese(filled circles)and Caucasian (open circles)subjects administered three 300 mg galcanezumab every 4 weeks
drug test 27 days after the second galcanezumab 300 mg dose. 66.7％ administered galcanezumab reported injection site The Japanese subject who withdrew from Cohort 3 was replaced erythema or injection site reaction. Of Japanese subjects to ensure that complete data would be available from at least 3 receiving multiple doses of study drug, the 1 subject Japanese subjects in Cohort 3. administered placebo reported injection site hemorrhage and 4 out of 5 administered galcanezumab reported injection site Safety and tolerability erythema, injection site reaction, or injection site pain(Table 2). Single galcanezumab doses up to 300 mg and three 300 mg Safety assessments revealed no clinically important or dose- galcanezumab doses Q4W were well tolerated in Japanese and related changes in vital signs or in chemistry, hematology, or Caucasian subjects. Of the 35 subjects who received a single urinalysis laboratory values for the single- and multiple-dose dose of study drug, 24 subjects receiving galcanezumab reported cohorts. No suicidal ideation or behavior was reported using the a total of 37 TEAEs, and 6 subjects receiving placebo reported a C-SSRS. There were no clear dose-related changes in ECG total of 18 TEAEs. Of these, 25 TEAEs reported by 19(70.4％) parameters. A total of 2 Japanese and 1 Caucasian subject subjects receiving galcanezumab and 7 TEAEs reported by 5 administered a single galcanezumab dose and 1 Caucasian (62.5％) subjects receiving placebo were judged by the subject administered multiple galcanezumab doses had a investigator to be related to study drug (Table 2). Of the 15 maximum increase in QTcF ＞30 msec and no subjects had an Japanese subjects who received a single galcanezumab dose, 10 increase ＞60 msec. A total of 3 Japanese subjects administered (66.7％)subjects reported TEAEs considered by the investiga- a single galcanezumab dose, 2 Japanese subject administered tor to be related to study drug. Of the 10 subjects who received multiple galcanezumab doses, and 1 Japanese subject adminis- multiple doses of study drug, 7 subjects receiving multiple doses tered multiple placebo doses had a QTcF interval ＞450 and no of galcanezumab reported a total of 35 TEAEs and 2 subjects subjects had intervals ＞480 msec or ＞500 msec. Analysis of receiving multiple doses of placebo reported a total of 8 TEAEs. QTcF change from baseline versus serum galcanezumab Of these, 18 TEAEs reported by 7(87.5％)subjects receiving concentrations identified no obvious trend in QT prolongation in multiple doses of galcanezumab and 6 TEAEs reported by 2 Japanese or Caucasian subjects administered multiple galcanezu- (100％) subjects receiving multiple doses of placebo were mab doses(Figure 1). judged by the investigator to be related to study drug(Table 2). Four (80％) the 5 Japanese subjects who received multiple Immunogenicity galcanezumab doses reported 13 TEAEs considered by the A total of 3 out of 34 subjects developed TE-ADA following investigator to be related to study drug. All TEAEs considered by single or multiple galcanezumab doses. One Japanese subject the investigator to be related to single or multiple doses of study who received a single 5-mg galcanezumab dose had a positive drug were mild in severity. ADA titer(1:20)at baseline that increased by Day 57(titer 1: The most common TEAEs reported during this study were 80)and returned to baseline levels by the end of study visit on related to administration site conditions, including injection site Day 141. This subject reported injection site erythema after erythema, injection site reaction, injection site hemorrhage, and dosing on Day 1 that was considered related to study drug. One injection site pain. Of Japanese subjects receiving a single dose Japanese subject who received 3 doses of 300 mg galcanezumab of study drug, 50.0％ of subjects administered placebo and Q4W had a negative ADA titer at baseline and positive ADA
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Table 3 Pharmacokinetic parameter estimates following single galcanezumab doses up to 300 mg in healthy Japanese and Caucasian subjects
Geometric mean(CV％) Parameters 5 mg 50 mg 120 mg 300 mg Japanese Caucasian Japanese Caucasian Japanese Caucasian Japanese Caucasian N 3 3 3 2 4 3 5 3
c Cmax(ng／mL) 914 657 4480 6466，2457 19500 16200 44400 36800 (11) (28) (63) (9) (31) (19) (7)
a c tmax(day) 6.26 7 9 9，5 4.62 7 5 5 (4-7) (7-7) (9-11) (4-9) (5-9.15) (4-5) (4-5)
b c d t1/ 2(day) 22.8 27.0 22.6 23.2，23.5 28.7 26.8 29.5 24.0 (17.0-29.4) (24.3-30.1) (18.6-27.7) (24.8-32.8) (21.1-30.9) (21.8-47.9) (21.0-29.2) AUC(0-∞) 27900 28800 180000 288000，103000c 829000d 700000 1870000 1440000 (ng・day／mL) (19) (36) (48) (4) (65) (28) (5) CL／F(mL／day) 179 174 277 174，486c 145d 171 160 209 (19) (36) (48) (4) (65) (28) (5)
c d VZ／F(mL) 5890 6750 9020 5830，16500 5990 6620 6810 7220 (12) (25) (28) (12) (40) (20) (14)
Abbreviations：AUC(0-∞)＝area under the concentration-time curve from time 0 to infinity；CL／F＝apparent clearance；Cmax ＝maximum serum
concentration；CV＝coefficient of variation；N＝number of subjects；t1/ 2＝half-life time；tmax＝time of maximum observed serum concentration；VZ／F＝ apparent volume of distribution during the terminal phase. a Median(range). b Geometric mean(range). c Individual subject parameter. d N＝3.
titers on Day 43(titer 1 : 80), Day 85(titer 1 : 40), and the end tration-time profiles following 300 mg galcanezumab Q4W of study visit on Day 197(titer 1 : 160). This subject reported dosing (Cohort 5) on Days 1, 29, and 57 for Japanese and injection site reactions on Day 29(second dose)and on Day 57 Caucasian subjects. The PK following multiple doses of (third dose)as well as injection site erythema on Day 58, all of galcanezumab was comparable between Japanese and Caucasian
which were considered related to study drug. One Caucasian subjects. Galcanezumab tmax was approximately 4 to 9 days
subject who received 3 doses of 300 mg galcanezumab Q4W following administration of 300 mg Q4W and was similar to tmax
had a negative ADA titer until the end of study visit on Day 197 after a single dose(Table 4). The geometric mean t1/ 2 following (titer 1 : 20). This subject reported an injection site reaction on 300 mg galcanezumab Q4W on Day 57(third dose)was 32.3
Day 1 and injection site pain on Day 57, both of which were days and was similar to t1/ 2 reported following a single dose. considered related to study drug. The specific values reported Galcanezumab geometric mean RA based on AUC (0-t) was here are only relevant for this study assay and should not be 1.77. compared to other reported values due to differences in assay Single-dose and multiple-dose pharmacodynamics characteristics. Mean plasma CGRP concentration-time profiles in Japanese and Caucasian subjects following single and multiple doses of Pharmacokinetics and pharmacodynamics galcanezumab are shown in Figure 2 C and D. Visual inspection Single-dose and multiple-dose pharmacokinetics of mean plasma CGRP concentration-time profiles following Figure 2 A shows the mean concentration-time profiles of single single and multiple doses of galcanezumab suggests there was no galcanezumab doses up to 300 mg(Cohorts 1 to 4)for Japanese difference between Japanese and Caucasian subjects. Following and Caucasian subjects. The PK after single galcanezumab doses single doses of galcanezumab 5 mg to 300 mg, plasma CGRP was similar between Japanese and Caucasian subjects. Following concentrations increased over time, reached a maximum, and single SC dosing, serum concentrations increased with median then declined(Figure 2 C). In the multiple-dose cohort, mean
tmax of approximately 5 to 9 days postdose(Table 3). Following plasma CGRP concentrations increased after dosing on Days 1,
Cmax, serum galcanezumab concentrations appeared to decline in 29, and 57, reached a maximum concentration between Days 78
an apparent monophasic manner. The AUC(0-∞)and Cmax were and 85(approximately 3 to 4 weeks after the third dose), and similar between Japanese and Caucasian subjects and the mean then declined (Figure 2 D). The plasma CGRP concentration
t1/ 2 was approximately 3 to 4 weeks across all dose levels(Table continued to increase after each dose of the 3 galcanezumab 3). Results of a dose proportionality analysis showed a dose doses.
proportional increase in AUC(0-∞)and Cmax over the galcane- The time courses of plasma CGRP concentration and serum zumab single dose range of 5 mg to 300 mg. The ratios of the galcanezumab concentration were evaluated graphically togeth- dose-normalized geometric means for the highest to lowest dose er. The CGRP and galcanezumab concentration-time profiles level (300 mg versus 5 mg) were 1.07 (90％ CI: 0.751 to following a single SC injection of 300 mg galcanezumab and 1.51) for AUC (0-∞) and 0.948 (90％ CI: 0.684 to 1.31) after the third SC injection of 300 mg galcanezumab on Day 57
for Cmax. were similar between Japanese and Caucasian subjects. Profiles Figure 2B shows the mean serum galcanezumab concen- for the overall study population are shown in Figure 2 E. These
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Figure 2 Serum galcanezumab and total plasma CGRP concentration-time profiles in healthy Japanese and Caucasian subjects following single subcutaneous injection of 5 to 300 mg galcanezumab or three 300 mg galcanezumab every 4 weeks(Q4W) Panel A：single dose arithmetic mean serum galcanezumab concentration-time profiles. Panel B：multiple dose arithmetic mean serum galcanezumab concentration-time profiles. Panel C：single dose arithmetic mean(±standard deviation)total plasma CGRP concentration-time profiles. Panel D：multiple dose arithmetic mean(±standard deviation)total plasma CGRP concentration-time profiles. Panel E：arithmetic mean serum galcanezumab and total plasma CGRP concentration-time profiles following the first and third subcutaneous injections of 300 mg galcanezumab Q4W.
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Table 4 Pharmacokinetic parameter estimates following three 300 mg galcanezumab Q4W in healthy Japanese and Caucasian subjects
Geometric mean(CV％) 300 mg Day 1 300 mg Day 29 300 mg Day 57 Parameters (First dose) (Second dose) (Third dose) Japanese Caucasian Japanese Caucasian Japanese Caucasian N 5 3 5 3 5 2
c Cmax(ng／mL) 38000 33700 64100 54000 67100 51798，46238 (49) (38) (58) (70) (66)
a c tmax(day) 5 4 9 4 4 5，5 (5-9) (4-5) (4-28) (4-9.01) (3.23-7)
b c t1/ 2(day) NA NA NA NA 34.7 24.9, 29.6 (21.9-48.2) AUC(0-t) 808000 679000 1310000 785000，725000c,d 1410000 1080000，955000c (ng・day／mL) (44) (42) (59) (54) RA NA NA NA NA 1.74 1.71，2.01c (10)
Abbreviations：AUC(0-t)＝area under the concentration-time curve during 1 dosing interval；Cmax＝maximum serum concentration；CV＝coefficient variation；N＝number of subjects；NA＝not applicable；Q4W＝every 4 weeks；RA＝
accumulation ratio；t1/ 2＝half-life time；tmax＝time of maximum observed serum concentration. a Median (range). b Geometric mean (range). c Individual subject parameter. d One Caucasian subject withdrew from the study after administration of the second galcanezumab dose and there was insufficient data to reliably determine the parameter.
profile figures illustrate the serum galcanezumab tmax at5to9 were reported. Immunogenicity was analyzed by measuring
days postdose is followed by plasma CGRP tmax. formation of TE-ADA against galcanezumab. The development of TE-ADA was detected in 8.8％ of Japanese and Caucasian Discussion subjects and titers were low, ranging from 1 : 20 to 1 : 160. The Galcanezumab is a humanized monoclonal antibody that potently 3 subjects who had TE-ADA also reported mild injection site and selectively binds to CGRP and has been identified for cluster erythema, injection site reaction, and injection site pain; headache and migraine prevention. This study was the first however, subjects without TE-ADA also experienced these clinical evaluation of the safety, tolerability, PK, and PD of injection site-related TEAEs. These findings are consistent with single and multiple galcanezumab doses in Japanese subjects. those reported for the Phase 2b study(NCT02163993)in which This study included Caucasian subjects in order to compare 30 patients(11.4％)administered galcanezumab had TE-ADA, Japanese and Caucasian subjects within the same study and all with low titers and no effect on efficacy, safety, PK, or clinical setting. antibody target-mediated binding.19) Single doses of galcanezumab up to 300 mg and three 300 mg This was the first study to compare galcanezumab PK and PD galcanezumab Q4W doses were well tolerated in Japanese and between Japanese and Caucasian subjects. Following both single Caucasian subjects. No safety signals were identified and there and multiple doses, galcanezumab PK were similar between were no differences in TEAEs between Japanese and Caucasian Japanese and Caucasian subjects. There were dose proportional
subjects in this study. There were no apparent dose-related increases in AUC(0-∞)and Cmax over the galcanezumab single TEAEs and no clear pattern for TEAEs with repeated dosing. dose range of 5 mg to 300 mg. This is similar to the These results are consistent with findings in the first-in-human galcanezumab first-in-human report of linear PK and dose study, where galcanezumab was well tolerated as single doses up proportionality over single doses of 1 to 600 mg.18) Despite the to 600 mg and as 4 consecutive doses of 150 mg／week. In that difference in body weight between Japanese and Caucasian study, there were no dose-dependent differences in either type or subjects, we concluded the dose adjustment would not be needed frequency of TEAEs.18) for Japanese patients in future studies because of the consistent The most common TEAEs in this study were injection site- PK and PD profiles. related and were reported by Japanese and Caucasian subjects We showed an increase in plasma CGRP concentrations after who received single and multiple doses of study drug. Injection galcanezumab administration, and that this result was similar in site reactions are not uncommon after SC administration of Japanese and Caucasian subjects. When galcanezumab is monoclonal antibodies, so it was not surprising that subjects in administered, the premise is that CGRP will bind to galcanezu- this study reported injection site-related TEAEs after galcanezu- mab and the amount of free CGRP that is available to interact mab administration. Injection site-related TEAEs were also with the CGRP receptor will be reduced, owing to its potential as reported by subjects administered single and multiple doses of a treatment for migraine and cluster headache. The assay used to placebo. All the injection site-related TEAEs in this study were measure CGRP detects both galcanezumab-bound CGRP and considered mild and no allergic or hypersensitivity reactions free CGRP(bound CGRP＋free CGRP＝total CGRP). In the
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presence of galcanezumab when administered at the dose levels Olesen J. CGRP may play a causative role in migraine. Cephalalgia. in this study, the majority of the CGRP is in the bound form, 2002; 22(1): 54-61. doi: 10.1046／j.1468-2982.2002.00310.x since the amount of CGRP in plasma is much lower compared to 9) Hansen JM, Hauge AW, Olesen J, Ashina M. Calcitonin gene-related the amount of galcanezumab. Since the clearance of the peptide triggers migraine-like attacks in patients with migraine with galcanezumab-bound CGRP is much slower than the clearance aura. Cephalalgia. 2010; 30(10): 1179-86. doi: 10.1177／033310241 of free CGRP, the concentration of the measured plasma total 0368444. ) CGRP increases following galcanezumab treatment. It is well 10 Dodick DW, Goadsby PJ, Spierings EL, Scherer JC, Sweeney SP, Grayzel DS. Safety and efficacy of LY2951742, a monoclonal antibody documented that ligand - antibody complexes often take on the to calcitonin gene-related peptide, for the prevention of migraine: a disposition characteristics of the antibody.20) In the absence of an phase 2, randomised, double-blind, placebo-controlled study. Lancet assay to measure plasma free CGRP, the increase in plasma total Neurol. 2014; 13(9): 885-92. doi: 10.1016／S1474-4422(14)70128- CGRP indicates that CGRP is bound to galcanezumab. 0. Conclusion 11) Benschop RJ, Gehlert DR, Merchant KM, Shanafelt AB, inventors; Eli Lilly and Company assignee. Treatment of migraine with anti-CGRP In conclusion, single and multiple galcanezumab doses were well antibodies. Patent WO2007076336. 2007. tolerated in Japanese and Caucasian subjects and there were no 12) Benschop RJ, Collins EC, Darling RJ, Allan BW, Leung D, Conner differences in PK and PD between these populations. Data from EM, et al. Development of a novel antibody to calcitonin gene-related this study support further development of galcanezumab in peptide for the treatment of osteoarthritis-related pain. Osteoarthritis Japanese patients with migraine and cluster headache. Cartilage. 2014; 22(4): 578-85. doi: 10.1016／j.joca.2014.01.009. 13) de Hoon JN, Pickkers P, Smits P, Struijker-Boudier HA, Van Bortel Disclosure of funding sources LM. Calcitonin gene-related peptide: exploring its vasodilating This study was funded by Eli Lilly Japan K.K. mechanism of action in humans. Clin Pharmacol Ther. 2003; 73(4): 312-21. Conflicts of interest 14) Vermeersch S, Benschop RJ, Van Hecken A, Monteith D, Wroblewski This study was sponsored by Eli Lilly Japan K.K. Authors MN, KU, VJ, Grayzel D, et al. Translational pharmacodynamics of calcitonin YM, and AO are employees of Eli Lilly Japan K.K. Authors WK gene-related peptide monoclonal antibody LY2951742 in a Capsaicin- and MA are employees of Eli Lilly and Company. Induced Dermal Blood Flow Model. J Pharmacol Exp Ther. 2015; 354 (3): 350-7. doi: 10.1124／jpet.115.224212. Acknowledgments 15) Oakes T, Zhang Q, Ferguson M, Skljarevski V, Martinez JM, Johnson The authors wish to acknowledge the investigators and subjects who KW, et al. Efficacy and safety of LY2951742 in a randomized, double- participated in this study; David Coutant, PhD, of Eli Lilly and blind, placebo-controlled, dose-ranging study in patients with migraine. ® Company(Indianapolis, Indiana, USA)for scientific support and In: Program Abstracts: American Headache Society 58th Annual review; and Amanda Hodgson, PhD, of Covance Inc.(Madison, Scientific Meeting. Headache. 2016; 56 (Suppl 1): PS42. doi: Wisconsin, USA)for providing writing assistance. 10.1111／head.12832. 16) Kielbasa W, Quinlan T, Bell R, Miller B, Skljarevski V. Pharmacoki- netic and pharmacodynamic modeling of LY2951742, a calcitonin References gene-related peptide antibody, in migraine patients. 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