Marcelo E. Bigal, MD,
`PhD
`David W. Dodick, MD
`Abouch V.
`Krymchantowski, MD,
`PhD
`Juliana H. VanderPluym,
`MD
`Stewart J. Tepper, MD
`Ernesto Aycardi, MD
`Pippa S. Loupe, PhD
`Yuju Ma, MS
`Peter J. Goadsby, MD
`
`Correspondence to
`Dr. Bigal:
`marcelo.bigal@tevapharm.com
`
`TEV-48 i 25 for the preventive treatment
`of chronic migraine
`Efficacy at early time points
`OPEN A
`
`ABSTRACT
`Objective: To evaluate the onset of efficacy of TEV- 48125, a monoclonal antibody against calci-
`tonin gene -related peptide, recently shown to be effective for the preventive treatment of chronic
`migraine (CM) and high- frequency episodic migraine.
`Methods: A randomized placebo -controlled study tested once -monthly injections of TEV -48125
`675/225 mg or 900 mg vs placebo. Headache information was captured daily using an electronic
`headache diary. The primary endpoint was change from baseline in the number of headache hours
`in month 3. Herein, we assess the efficacy of each dose at earlier time points.
`Results: The sample consisted of 261 patients. For headache hours, the 675/225 -mg dose sep-
`arated from placebo on day 7 and the 900 -mg dose separated from placebo after 3 days of ther-
`apy (p = 0.048 and p = 0.033, respectively). For both the 675/225 -mg and 900 -mg doses, the
`improvement was sustained through the second (p = 0.004 and p < 0.001) and third (p = 0.025
`and p < 0.001) weeks of therapy and throughout the study (month 3, p = 0.0386 and p =
`0.0057). For change in weekly headache days of at least moderate intensity, both doses were
`superior to placebo at week 2 (p = 0.031 and p = 0.005).
`Conclusions: TEV -48125 demonstrated a significant improvement within 1 week of therapy ini-
`tiation in patients with CM.
`Classification of evidence: This study provides Class II evidence that for patients with CM,
`TEV -48125 significantly decreases the number of headache hours within 3 to 7 days of
`injection. Neurology© 2016;87:41 -48
`
`GLOSSARY
`CGRP = calcitonin gene -related peptide; CI = confidence interval; CM = chronic migraine; LSM = least square mean; NNT =
`number needed to treat; TNC = trigeminal nucleus caudalis.
`
`Chronic migraine (CM) is characterized by headaches occurring on at least 15 days per month,
`with at least 8 days of migraine per month.' It affects approximately 1% of the adult popula-
`tion2'3 and is the most frequently seen headache syndrome at major headache clinics and
`neurology specialty centers.45 On the basis of ictal disability alone, migraine was ranked sixth
`highest among specific causes of disability globally.6'7 Migraine -related disability is classified by
`the World Health Organization as more burdensome than paraplegia, deafness, or angina, and at
`the same level as psychosis and quadriplegia.8 Furthermore, relative to individuals with episodic
`migraine or without headaches, those with CM are significantly more likely to be unemployed
`or employable but not actively working for pay.' Individuals with CM are also significantly more
`likely to be divorced and to have psychological comorbidities.9
`Despite its enormous burden, CM is undertreated. Effective treatment, at a minimum, re-
`quires consultation with a physician, an accurate diagnosis, and receiving appropriate treatment.
`
`From Teva Pharmaceuticals (M.E.B., E.A., P.S.L., Y.M.); Mayo Clinic (D.W.D., J.H.V.P.), Phoenix, AZ; The Headache Center of Rio (A.V.K.);
`American Headache Society (A.V.K.); Dartmouth Medical School (S.J.T.), Hanover, NH; and NIHR- Wellcome Trust King's Clinical Research
`Facility (P.J.G.), King's College London, UK.
`Go to Neurology.org for full disclosures. Funding information and disclosures deemed relevant by the authors, if any, are provided at the end of the anide.
`The Article Processing Charge was paid by Teva Pharmaceuticals Industries.
`This is an open access article distributed under the terms of the Creative Commons Attribution- NonCommercial- NoDerivatives License 4.0 (CC
`BY- NC -ND), which permits downloading and sharing the work provided it is properly cited. The work cannot be changed in any way or used
`Lilly Exhibit 1331
`commercially.
`Eli Lilly & Co. v. Teva
`© 2416 American Academy of Neurology Pharms. In$'{ GMBH
`2016 American Academy of Neurology. Unauthorized reproduction of this article is prohibited.
`
`

`

`In the United States, less than 5% of persons
`with CM are able to traverse all 3 of these hur-
`dles, and only a third of those with CM receive
`preventive medications.10 Furthermore, 1 -year
`adherence to labeled or off -label migraine pre-
`ventive medication among individuals with
`CM occurs in less than 20% of patients. The
`most important reasons for discontinuation of
`individuals
`preventive medications among
`with CM appear to be incomplete efficacy,
`as well as slow time to reach meaningful effi-
`cacy, and poor tolerability.10°" It has been sug-
`gested that fast onset of efficacy of migraine
`drugs may have significant implications for
`patients, since it would favor compliance and
`improve long -term outcomes :2
`TEV -48125 is a fully humanized monoclo-
`nal antibody that potently and selectively binds
`to calcitonin gene -related peptide (CGRP).13
`Its efficacy in the preventive treatment of CM
`was demonstrated in a large phase 2b study,
`where both tested doses separated from placebo
`after 1 month of therapy for primary, second-
`ary, and exploratory endpoints.14 Since statisti-
`cally significant effects were seen very early in
`that trial, herein we conducted post hoc analy-
`ses to evaluate the efficacy of 2 doses of sub-
`cutaneous TEV -48125 within the first few
`weeks of therapy in patients with CM.
`
`METHODS Study design and patients. The current study
`represents post hoc analyses conducted as part of a phase 2b trial
`assessing the efficacy of TEV -48125 in the preventive treatment
`in adults." The randomized, double -blind, placebo -
`of CM
`the
`controlled, phase 2b study was conducted at 62 sites
`in
`United States (headache centers, neurology clinics, and primary
`care facilities) and an independent clinical research organization,
`NCGS, monitored the study, assessing for appropriate patient
`eligibility, protocol adherence, and completeness and accuracy of
`case report entries. Eligible study participants were men or women
`aged 18 to 65 years with a history of CM as per the International
`Classification of Headache Disorders, 3rd edition (beta version).'
`frequencies were confirmed during
`Headache and migraine
`a prospective 28 days run -in period. Participants could continue
`to use up to 2 different standard migraine preventive medications,
`if on stable doses for at least 3 months before study onset. They were
`allowed to treat their acute migraine attacks as usual and had to show
`higher than 80% compliance in completing the electronic headache
`diary during the 28 -day run -in phase to participate in this study.
`Patients were excluded if they had received onabotulinumtoxinA
`during the 6 months before study entry or if 3 or more preventive
`medications failed because of lack of efficacy.
`
`Standard protocol approvals, registrations, and patient
`consents. The study was conducted in accordance with the prin-
`ciples of Good Clinical Practice and the US Food and Drug
`Administration guidelines for safety monitoring. All patients
`
`informed consent before enrollment. The
`provided written
`study protocol was approved by the institutional review boards
`is registered at clinicaltrials.gov
`for each site, and the trial
`(NCT02021773).
`
`Randomization and treatment procedures. After the run -in
`period, participants were randomized (1:1:1) via an electronic
`interactive web response system, which was accessible through
`the eClinical Operating System Portal. Randomization was
`stratified independently by sex and preventive medication use.
`The randomization sequence was developed centrally by staff at
`NCGS who had no further role in the study. Study sites had
`2 blinded study coordinators at clinic visits, one for clinical
`administration,
`and
`treatment
`assessments and one
`for
`participants were masked to treatment allocations. Participants
`randomized to the 900 -mg arm received 4 active injections of
`225 mg /1.5 mL once monthly. Those in the 675/225 -mg arm
`received an initial loading dose of 675 mg (3 active injections
`of 225 mg and one placebo injection), followed by maintenance
`doses of 225 mg (one active and 3 placebo injections) for the
`second and third monthly treatments. Patients receiving placebo
`received 4 placebo injections monthly. Adverse events, laboratory
`findings, ECG, and concomitant drugs were captured monthly at
`every visit.
`
`Outcomes. As described previously,' the primary endpoint
`for the study was the mean change from baseline in the num-
`ber of headache hours of any severity during the 28 -day
`posttreatment period ending with month 3. The secondary
`endpoint was the mean change from baseline in the number of
`headache days of at least moderate severity during month 3. Here,
`we analyzed the weekly cumulative headache hours and headache
`days of at least moderate severity in the first month by week and
`further analyzed accumulative headache hours in the first 7 days
`after the first dose of study medication.
`
`Statistical analyses. Similar to the analyses conducted for the
`primary and secondary endpoints, the mixed -effects model
`repeated measurement analysis method was used for the post
`hoc analyses reported herein of the weekly change -from-
`the number of headache hours and
`baseline values
`for
`moderate /severe headache days
`in first 4 weeks. We used
`analysis of covariance for the post hoc intraweekly assessments.
`For each given period (e.g., first week after treatment, or 3
`days after treatment), baseline values were calculated using the
`original monthly baseline value multiplied by a factor
`to
`match the time period (in the examples given above, first week
`the original monthly
`or first 3 days, baseline value was
`baseline multiplied by 7/28, or 3/28). In additional post hoc
`analyses, we calculated the absolute risk reduction and the
`number needed to treat (NNT) in the proportion of patients
`with at least a 50% reduction from baseline headache hours
`and moderate /severe headache days in the first few weeks.
`All statistical tests were 2 -sided at a level of 0.05. All effi-
`cacy variables were analyzed by the intent -to -treat principle,
`which included all randomized participants who received at
`least one dose of study drug and provided at least one endpoint
`measurement. Overall compliance for baseline and first month
`posttreatment was 92 %. For the analyses presented herein, all
`p values presented are nominal without multiplicity adjustment.
`Analyses were conducted with SAS version 9.2 (SAS Institute,
`Cary, NC).
`
`RESULTS Eligibility screening for the phase 2 study
`last patient visit
`began in January 2014 and the
`
`42
`
`Neurology 87 July 5, 2016
`2016 American Academy of Neurology. Unauthorized reproduction of this article is prohibited.
`
`

`

`occurred in December 2014. The sample consisted of
`261 patients randomized to receive placebo (n = 89),
`675/225 mg (n = 87), or 900 mg (n = 85) (figure 1).
`Demographics and clinical disease characteristics were
`similar across groups and are described in table 1.
`Mean overall age was 41 years, 86% of participants
`were women, 83% were white, and 40% of partici-
`pants used preventive medications at the time of the
`study.
`
`Planned analyses recap. A priori analyses have been
`published.14 In brief, at baseline, participants had
`a mean of 162 headache hours per month and a mean
`of 22 headache days and 17 migraine days per month.
`For the primary endpoint, least square mean (LSM)
`change from baseline to month 3 in the number of
`headache hours was -37.1 (SE 8.4) for placebo,
`-59.8 (8.6) for 675/225 mg (p = 0.039, LSM dif-
`ference -22.7, and 95% confidence interval [CI]:
`
`-44.28 to -1.21), and -67.5 (8.6) for 900 mg (p
`= 0.006, LSM difference -30.4, and 95% CI:
`-51.88 to -8.95). At 1 month of therapy, the num-
`ber of headache hours decreased from baseline for
`placebo was -18.1 (7.1), 675/225 mg = -44.1
`(7.3; p = 0.003); 900 mg = -56.82 (7.3; p <
`0.001). At 2 months of therapy, the number of hours
`decreased from baseline for placebo was -34.1 (8.0),
`675/225 mg = -58.3 (8.1;p = 0.018); and 900 mg
`= -66.2 (8.1; p = 0.002).
`
`Early time points: Headache hours. There were signifi-
`cant decreases in the mean number of headache hours
`after 1 week of therapy for both treatment doses rel-
`ative to placebo. The LSM change from baseline to 1
`week was -2.85 (2.21) hours for placebo, -9.08
`(2.25) for 675/225 mg (p = 0.031, LSM difference
`-6.22, and 95% CI: -11.86 to -0.59), and
`-11.37 (2.26) for 900 mg
`(p = 0.003, LSM
`
`Figure 1
`
`Patient disposition
`
`1
`
`Screened
`(N =950)
`
`Randomized
`(n =264)
`
`Assigned to TEV-48125
`675/225 mg
`(n=88)
`
`/ Excluded* (n =686):
`Fewer than 15 days of headache per month (243)
`Did not qualify for headache criteria (98)
`Did not qualify for inclusion /exclusion criteria (111)
`Nondiary compliant (137)
`Site enrollment closed (45)
`Subject withdrawal (33)
`Lost to follow -up or other (19)
`
`\
`
`Assigned to TEV -
`48125 900 mg
`(n =87)
`
`Assigned to
`placebo
`(n =89)
`
`f Did not complete (n =12; 13.5 %):
`Lack of efficacy (2)
`Lost to follow -up (1)
`Nonfatal AE (1)
`Protocol deviation (2)
`Withdrew consent (3)
`Other (3)
`
`Did not complete (n =16; 18.2 %):
`Lack of efficacy (2)
`Lost to follow -up (3)
`Nonfatal AE (4)
`Protocol deviation (3)
`Withdrew consent (4)
`
`-4
`
`Did not complete (n =11; 12.6%):
`Lack of efficacy (2)
`Nonfatal AE (3)
`Protocol deviation (1)
`Withdrew consent (5)
`
`l Analyzed intent -to -treat
`-}
`
`(n =89)
`In safety analysis
`(n =89)
`
`V
`Completed
`(n =77; 87 %)
`
`Analyzed intent -to -treat
`(n =87)
`In safety analysis
`(n =88)
`
`3
`
`Analyzed intent -to -treat
`(n =85)
`In safety analysis
`(n =86)
`
`Completed
`(n =76; 87 %)
`
`,
`
`Completed
`(n =72; 82 %)
`
`*Patients were considered screen failures for the chronic migraine study if they (1) had fewer than 15 days of headaches per month for 3 months before
`screening, (2) they had at least 15 days of headache per month for 3 months before screening but did not have 15 days of headaches or evidence of
`migraines during the 28 -day run -in period, (3) they met the headache criteria but did not qualify for one or more of the other inclusion /exclusion criteria, (4)
`they were less than 80% compliant with diary entry during the 28 -day run -in period and other miscellaneous reasons such as site closure, subject withdraws
`consent, and the subject was lost to follow -up. AE = adverse event. Modified from Lancet Neurol, 14, Bigal ME, Edvinsson L, Rapoport AM, et al., Safety,
`tolerability, and efficacy of TEV -48125 for preventive treatment of chronic migraine: a multicentre, randomised, double -blind, placebo -controlled, phase 2b
`study, 1081 -1090, 2015, with permission from Elsevier.14
`
`Neurology 87 July 5, 2016
`43
`2016 American Academy of Neurology. Unauthorized reproduction of this article is prohibited.
`
`

`

`rTable 1
`
`Patient characteristics
`
`Characteristic
`
`Age, y
`
`Height, cm
`
`Body weight, kg
`
`Body mass index, kg /cm2
`
`Sex
`
`Male
`
`Female
`
`Ethnic origin
`
`White
`
`Black /African American
`
`Asian
`
`Other
`
`Placebo (n = 89)
`
`TEV-48125, 675/225 mg (n = 88)
`
`TEV-48125, 900 mg (n = 86)
`
`1
`
`40.7 (11.5) 20 -63
`
`40.0 (11.6) 18 -63
`
`166.4 (8.1) 153 -188
`
`165.4 (8.3) 146 -187
`
`71.3 (13.1) 46 -107
`
`74.2 (17.0) 50 -119
`
`25.7 (4.5) 18-37
`
`27.0 (5.2) 18 -37
`
`41.5 (12.9) 18 -65
`
`165.7 (7.6) 152 -185
`
`73.0 (15.6) 50 -118
`
`26.6 (5.3) 18 -38
`
`13 (14.6)
`
`76 (85.4)
`
`76 (85.4)
`
`9 (10.1)
`
`1'(1.1)
`
`3 (3.4)
`
`12 (13.6)
`
`76 (864)
`
`70 (79.6)
`
`12 (13.6)
`
`0 (0)
`
`6 (6.8)
`
`12 (13.8)
`
`75 (86.2)
`
`73 (83.9)
`
`9 (10.3)
`
`0 (0)
`
`5 (5.8)
`
`Hours of headaches of any severity per month
`
`169.1 (13.9) 42 -672
`
`159.1 (9.73) 29 -431
`
`157.7 (11.73) 37 -672
`
`Headache days of at least moderate severity per month
`
`13.9 (5.6) 1 -28
`
`13.8 (6.3) 1 -28
`
`Days of acute medication use
`
`Years of migraines
`
`Preventive medicine use
`
`Yes
`
`No
`
`15.7 (6.2) 0 -28
`
`15.1 (7.0) 0 -28
`
`20.4 (13.1) 1 -58
`
`15.8 (11.2) 1 -45
`
`38 (42.7)
`
`51 (57.3)
`
`35 (39.7)
`
`53 (60.2)
`
`13.1 (5.9) 2 -28
`
`16.2 (6.7) 0 -28
`
`18.8 (12.2) 0 -48
`
`33 (37.9)
`
`54 (62.1)
`
`Data are mean (SD) minimum -maximum, or n ( %).
`Modified from Lancet Neurol, 14, Bigal ME, Edvinsson L, Rapoport AM, et al., Safety, tolerability, and efficacy of TEV -48125 for preventive treatment of
`chronic migraine: a multicentre, randomised, double- blind, placebo -controlled, phase 2b study, 1081 -1090, 2015, with permission from Elsevier.14
`
`difference -8.52, and 95% CI: -14.27 to -2.87),
`a benefit that was extended through the second and
`third weeks of therapy (figure 2A). The 900 -mg dose
`first separated from placebo after 3 days of therapy
`(-3.08 hours vs +0.36. for placebo, p = 0.0331).
`The lower dose separated from placebo on day 7
`(placebo = -1.59 hours, 675/225 mg = -7.28, p =
`0.0486, 900 mg = - 9.76, p = 0.0048) (figure 2B).
`As shown in table 2, the percent of patients with
`a 50% reduction from baseline in the number of
`headache hours increased in the TEV -48125 groups
`relative to the placebo group in weeks 1 to 3, although
`the NNTs at these early time points were high.
`
`Early time points: Moderate to severe headache days. For
`moderate to severe headache days, the lower dose,
`675/225 mg, nonsignificantly reduced the number
`of days with moderate severity headaches in week 1
`and week 3 (LSM change from baseline -1.12 vs
`placebo -0.77, p = 0.167 for week 1, and -1.13
`vs -0.74, p = 0.142 for week 3). The 900 mg
`showed separation after 1 week ( -1.26 vs -0.77
`for placebo, p < 0.054). Both doses separated from
`placebo after 2 weeks' LSM change from baseline
`(SE): -0.79 (0.19) for placebo, -1.34 (0.20) for
`675/225 mg (p = 0.031, LSM difference -0.55,
`and 95% CI: -1.06 to -0.05), and -1.51 (0.20)
`
`for 900 mg (p = 0.005, LSM difference 0.73, and
`95% CI: -1.23 to -0.22) (p = 0.005) (figure 3).
`The 900 -mg dose continued to separate from the
`( -1.39 vs -0.74, p =
`placebo group in week 3
`0.016).
`The percent of patients with a 50% reduction
`from baseline in the number of moderate to severe
`headache days also increased in the TEV -48125
`groups during weeks 1 to 3, although the NNTs, as
`seen for headache hours, were also high (table 2).
`
`DISCUSSION It has been previously demonstrated
`that both doses of TEV -48125 were superior to
`treatment of CM,
`the preventive
`placebo
`in
`validating for the first time CGRP as a therapeutic
`target in this disease. Since benefit was seen as early
`1 month after starting therapy, we explored the
`as
`earliest time point at which efficacy began. The new
`analysis demonstrated a significant decrease in the
`number of headache hours starting as soon as
`3 days after the highest dose (900 mg) was given,
`and 7 days after the lower dose (675/225 mg) was
`given. For moderate or severe headache days,
`a significant decrease was seen during the second
`week of treatment for the 675/225 -mg and 900 -mg
`doses. These data offer a glimpse of how quickly
`
`44
`
`Neurology 87 July 5, 2016
`2016 American Academy of Neurology. Unauthorized reproduction of this article is prohibited.
`
`

`

`r
`
`Figure 2
`
`Effect of TEV -48125 at early time points
`
`1
`
`A
`
`Baseline
`
`Week 1
`
`Week 2
`
`Week 3
`
`0
`
`-5
`
`-10
`
`-15
`
`-20
`
`-25
`
`-30
`
`-35
`
`-40
`
`-45
`
`**
`
`* **
`
`-o-Placebo
`
`--E-675/225 mg
`
`900 mg
`
`***
`
`B
`
`Baseline Day 1
`2
`
`Day 2
`
`Day 3
`
`Day 4
`
`Day 5
`
`Day 6
`
`Day 7
`
`-2 -
`
`-4
`
`-
`
`-6 -
`
`-8 -
`
`-10
`
`-
`
`-12 -
`
`**
`
`**
`
`**
`
`(A) Change in number of headache hours in the first 3 weeks of TEV -48125 treatment. (B) Change in headache hours in the
`first 7 days of TEV -48125 treatment. *p < 0.05, * *p < 0.01, * * *p < 0.001.
`
`preventive treatment effects may occur for CGRP
`monoclonal antibodies in CM.
`The new analysis of the data demonstrates that
`TEV -48125 can have an effect in some patients
`within a week of therapy initiation. Regarding clinical
`meaningfulness, it is not the purpose of summary
`measures to provide such information, but rather to
`offer the insight that some patients may benefit rela-
`tively rapidly from a new therapy. The early onset of
`effect is certainly of interest for at least 2 reasons.
`First, perceived early efficacy may be a reinforcing fac-
`tor for compliance to therapy, especially in the con-
`text of well -tolerated medications. Second,
`the
`timing of the onset of action provides important
`
`insights on the relevance of CGRP in the pathophys-
`iology of migraine.
`Fast onset of headache improvement is a highly
`desirable attribute for migraine medications.t5 Oral
`preventive medications must be titrated over weeks
`to effective doses, and then administered daily for
`to establish efficacy.'."
`approximately 3 months
`Although some patients respond quickly to onabotuli-
`numtoxinA, the only approved CM preventive treat-
`ment, response is often delayed.' 8 Clinical experience
`also suggests that in many cases, adverse events with
`migraine preventive medications are perceived nearly
`immediately while efficacy requires time to be noticed.
`Early onset of efficacy may provide positive
`
`Neurology 87 July 5, 2016
`45
`2016 American Academy of Neurology. Unauthorized reproduction of this article is prohibited.
`
`

`

`Table 2
`
`l
`
`Percent of patients with 50% reduction from baseline in headache
`hours and moderate to severe headache days in the first few weeks of
`TEV -48125 treatment
`
`1
`
`No ( %) patients
`
`ARR, % (NNT)
`
`Placebo
`(n = 89)
`
`TEV- 48125,
`675/225 mg
`(n = 87)
`
`TEV-48125,
`900 mg
`(n = 85)
`
`TEV- 48125,
`675/225 mg
`vs placebo
`
`TEV- 48125,
`900 mg
`vs placebo
`
`Patients with 250% reduction in headache hours from baseline
`
`Week 1
`
`Week 2
`
`Week 3
`
`27 (30)
`
`28
`
`(32)
`
`18 (20)
`
`37
`
`(43)
`
`27 (30)
`
`33
`
`(38)
`
`33 (39)
`
`41 (48)
`
`40 (47)
`
`2 (50)
`
`23 (4.3)
`
`8 (12.5)
`
`9 (11.1)
`
`28 (3.6)
`
`17 (5.9)
`
`Patients with z50% reduction in moderate to severe headache days from baseline
`
`Week 1
`
`Week 2
`
`Week 3
`
`34 (38)
`
`41 (47)
`
`33 (37)
`
`42 (48)
`
`36 (40)
`
`44 (51)
`
`40 (47)
`
`50 (59)
`
`45 (53)
`
`9 (11)
`
`11 (9.1)
`
`11 (9.1)
`
`9 (11.1)
`
`22 (4.5)
`
`13 (7.7)
`
`Abbreviations: ARR = absolute risk reduction; NNT = number needed to treat.
`
`reinforcement for migraineurs and increase adherence
`to therapy.
`Other CGRP monoclonal antibodies when stud-
`ied in episodic migraine have shown fast onset of effi-
`cacy.1920 It is known that circulating CGRP levels are
`increased in CM relative to episodic migraine and in
`to controls.21 CGRP-
`episodic migraine relative
`containing peripheral nerve cells in the trigeminal
`ganglion act as polymodal nociceptors, innervating
`peripheral tissues and in response to stimuli, release
`CGRP sending primary afferent sensory transmis-
`sions to neurons in dorsal horn of the spinal cord,
`the trigeminal nucleus caudalis (TNC), and the
`nucleus of the solitary tract. These neurons in turn
`project sensory inputs to the amygdala, hypothala-
`mus, brainstem, and thalamus, which relay these in-
`puts to the insular cortex.22 -25 Monoclonal antibodies
`large molecules that mostly do not cross the
`are
`
`Figure 3
`
`Change from baseline in the number of headache days of at least
`moderate severity
`
`1
`
`l
`
`Baseline
`0.0
`
`Week 1
`
`Week 2
`
`Week 3
`
`-0.5 -
`
`-1.0 -
`
`-1.5 =
`
`-2.0 -
`
`-2.5 -
`
`-3.0 -
`
`-3.5 -
`
`-4.0 -
`
`-4.5 -
`
`-Placebo
`-675/225 mg
`900 mg
`
`*p < 0.05, **p < 0.01.
`
`blood -brain barrier with immunoglobulin G plasma
`to CSF ratio of 0.1%.26 As a result, it has been sug-
`gested that modulation of CGRP outside the blood -
`brain barrier induces nearly immediate modulation of
`central pathways. This probable mechanism is sup-
`ported by previous work suggesting that in humans,
`IV administration of CGRP, which does not cross the
`blood -brain barrier, induces migraine attacks in in-
`dividuals with migraine.27 Antibodies could bind to
`the CGRP released at trigeminal nerve endings,
`thereby avoiding the peripheral events of migraine
`transmission
`to central
`and consequent sensory
`second -order neurons in the TNC, thus avoiding
`that would
`the secondary central sensitization
`input
`into
`central
`follow.28 Reduced afferent
`second -order neurons within the TNC could modu-
`late neuronal activity and subsequent central trigem-
`inal sensory transmission.
`The study has important limitations that should
`be considered. First, the analyses reported in this arti-
`cle had not been a priori defined. Nonetheless, post
`hoc analyses have an important role in further defin-
`ing the benefits of any drug, including subsets of pa-
`tients experiencing particular benefit2930 or, as in our
`case, providing preliminary evidence for future rigor-
`ous assessments. Second, and most important, we
`have not interviewed patients to check whether the
`effect size at early time points was clinically meaning-
`ful, and we do not suggest that they were for the early
`time points, although they certainly are for what is
`seen after 1 month of therapy, as the therapeutic gain
`(placebo- subtracted difference) seems to suggest so.
`In the pooled analyses of the onabotulinumtoxinA
`pivotal trials, the therapeutic gain for moderate or
`severe headache days after 6 months of therapy was
`-1.9.3' In the present study, after 1 month of ther-
`apy, 900 -mg and 675/225 -mg doses yielded a thera-
`peutic gain of values of respectively -2.8 and -2.0
`days. Since clinical benefit may be a function of abso-
`lute response rather than placebo- adjusted response,
`future studies should incorporate patients' subjective
`assessment of improvement.
`
`AUTHOR CONTRIBUTIONS
`M.E.B. designed the study, interpreted data, and drafted, edited, and
`final article. D.W.D., A.V.K., J.H.V.P., S.J.T., E.A.,
`submitted the
`and P.J.G. contributed to overseeing the data, discussed contents of
`the article, and participated in the writing of the article. Y.M. created
`the statistical analysis plan for the study and analyzed data. P.S.L. inter-
`preted data, prepared tables and figures, and participated in writing and
`editing of the article.
`
`STUDY FUNDING
`The protocol was designed and the study was conducted by the funder
`with input from all authors. The funder was responsible for data collec-
`tion, data analysis, data interpretation, and writing the article. All authors
`had full access to all the data in the study and the corresponding author
`had final responsibility for the decision to submit for publication.
`
`*
`
`46
`
`Neurology 87 July 5, 2016
`2016 American Academy of Neurology. Unauthorized reproduction of this article is prohibited.
`
`

`

`DISCLOSURE
`M. Bigal is an employee of Teva Pharmaceuticals Research and Develop-
`ment team. D. Dodick within the past 3 years has served on advisory
`boards and /or has consulted
`for Allergan, Amgen, Alder, Alcobra,
`Arteaus, Pfizer, CoLucid, Merck, ENeura, NuPathe, Eli Lilly and Com-
`pany, Autonomic Technologies, Ethicon J &J, Zogenix, Supernus,
`Labrys, Boston Scientific, MAP, Novartis, Tonix, Teva, and Trigemina
`and has received funding for travel, speaking, editorial activities or royalty
`payments from IntraMed, SAGE Publishing, Sun Pharma, Allergan,
`Oxford University Press, HealthLogiX, Universal Meeting Management,
`WebMD, UpToDate, Starr Clinical, Decision Resources, and Synergy.
`A. Krymchantowski and J. VanderPluym report no disclosures relevant to
`the manuscript. S. Tepper received grants /research support from Alder,
`Allergan, Amgen, ATI, ElectroCore, eNeuro, GSK, Teva, Pernix, and
`OptiNose /Avanir /Otsuka. These grants do not go to him personally. S.T.
`has served as a consultant for Acorda, Allergan, Amgen, ATI, Avanir,
`Depomed, ElectroCore, Impax, Pfizer, Scion Neurostim, Teva, and
`the speakers bureau for Allergan, Depomed,
`Zosana and has been on
`Impax, Pernix, and Teva. In the last 12 months, he served on advisory
`boards for Allergan, Amgen, ATI, Avanir, Dr. Reddy's, Merck, Pfizer,
`and Teva. He is editor -in -chief of Headache Currents, American Head-
`receives royalties for books published by University of
`ache Society,
`
`Comment:
`Monoclonal antibodies in chronic migraine -Are early effects
`meaningful?
`Chronic migraine affects approximately 1% of the adult population and is
`-.15 d /mo with ?8 days of migraine -type headache. Since
`defined as headache on
`treatment often remains frustrating for both the patient and physician, new treat-
`ment strategies are highly,welcome.
`No doubt, monoclonal antibodies (mAbs) against calcitonin gene -related
`peptide (CGRP) for the preventive treatment of episodic and chronic migraine
`deserve to be called a breakthrough -not because they cure headache, but rather
`because they are effective for relatively refractory headaches and were developed
`based on the pathophysiologic concept that the trigeminovascular system and
`CGRP have a key role in the development of migraine pain; this was not a seren-
`dipitous discovery.
`the authors presented convincing evidence that TEV -48125
`Recently,
`reduced headache hours over 9 to 12 weeks.' Here, they present data on early
`effects, suggesting a reduction of headache hours within the first few weeks.2 But
`statistical significance notwithstanding -how clinically meaningful is a reduction
`of a few headache hours per week? A valid answer to this question is not given here
`and would require multiple measurements and evidence to determine the benefit
`for patients' lives.
`Are these data still important? Most definitely: first, there is a biological
`effect with relatively quick onset, whether clinically meaningful or not. Second,
`unlike with many established drugs, we do not see the early onset of adverse events
`and later onset of clinical benefit, which often challenges patient adherence. Third,
`mAbs do not cross the blood -brain barrier, hence the critical therapeutic target is,
`rather, located peripherally and not in the brain.3 This reasoning, together with the
`demonstrated rapid onset, strongly supports an important concept toward
`improved understanding of migraine mechanisms and guidance of future drug
`discovery. Finally, this study reinvigorates an attractive objective, namely, to treat
`other chronic -refractory craniofacial pain syndromes with CGRP- neutralizing
`mAbs, such as trigeminal neuropathic pain, chronic temporomandibular joint
`pain, and, certainly, cluster headaches.
`
`1. Bigal ME, Edvinsson L, Rapoport AM, et al. Safety, tolerability, and efficacy of
`TEV -48125 for preventive treatment of chronic migraine: a multicentre, randomised,
`double -blind, placebo -controlled, phase 2b study. Lancet Neurol 2015;14:1091 -1100.
`2. Bigal ME, Dodick DW, Krymchantowski AV, et al. TEV -48125 for the preventive
`treatment of chronic migraine: efficacy at early time points. Neurology 2016;87:41 -48.
`3. Pietrobon D, Moskowitz MA. Pathophysiology of migraine. Annu Rev Physiol 2013;
`75:365 -391.
`
`Volker Limmroth, MD, PhD
`
`From the Klinik für Neurologic and Palliativmedizin Köln -Merheim, Cologne, Germany.
`Study funding: No targeted funding reported.
`Disclosure: The author reports no relevant disclosures. Go to Neurology.org for full disclosures.
`
`Mississippi Press and Springer, and has stock options in ATI. E. Aycardi
`is an employee of Teva Pharmaceuticals Research and Development
`team. P. Loupe is an employee of Teva Pharmaceuticals Research and
`is an employee of Teva Pharmaceuticals
`Development team. Y. Ma
`Research and Development team. P. Goadsby reports grants and personal
`fees from Allergan, eNeura, Autonomic Technologies Inc., Amgen, and
`personal fees from AlderBio, Pfizer, Dr. Reddy's, Zosano, CoLucid, Eli
`Lilly, Avanir, Gore, Heptanes, NuPathe, Teva, Cipla, Ajinomoto, Akita,
`Wells Fargo, Ethicon, EMKinetics, Promius, Medico -Legal, UpToDate,
`and Journal Watch. In addition, Dr. Goadsby has a patent magnetic
`for headache pending. Go
`to Neurology.org
`stimulation
`for
`full
`disclosures.
`
`Received October 9, 2015. Accepted in final form March 9, 2016
`
`4.
`
`6.
`
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