Clinical Review
`Ronald Farkas, MD, PhD
`N21-926
`MT400/Trexima
`
`Table 29: Nausea Efficacy, Study 302, 0-4 hrs.
`POZEN, Inc.
`
`_
`_
`>
`Table 14.2.53},
`Nausea by Time Post‘éfiose
`All ~Sdb§ie¢ts in the Innenbtofiifireatfi Popui‘atibn' J
`
`- Stufly..i§lfimber- M’Mfia-iofir
`"
`_
`-- m
`
`4
`
`-
`
`Treatniengrflm‘oup'
`syinptgini
`" *
`Tr‘éX-ima (M364)
`fitment
`mesa:
`
`'
`
`95:0 '8‘ T” " 13,0. S 8»
`. TayéixI-R s
`
`eu~weg~w~g~m~w
`one: ~~. “n“fiv-“W‘fi-“Hfi”"‘7‘",
`
`1.0.
`.;‘
`-
`‘
`.210» g
`3.0.
`4.9
`0.0.,
`, 7’
`'
`188:1:
`..
`V
`
`176 g {13%)
`
`"21251
`5.29,?”
`
`285.
`'79.
`
`( 7.8%} , 295 l 8,33)
`( 22%;
`69 ( 19%)-
`
`'
`
`Sumatri tan {N=361)
`Absent
`‘-
`’
`Present:
`
`.‘
`
`,
`
`,
`j
`-
`
`Naproxen 01:356.
`Absent,
`,
`‘
`‘
`yrasen‘c
`Piace’l'acfs, (M350)
`Await
`»
`Meant“
`j
`
`~
`'
`
`.
`
`.‘
`
`>
`i 54%)
`19.3
`1.63.; 46%}
`
`.
`
`.
`‘
`182 i 51%)
`17¢ l 49%)
`.‘
`x
`_
`.211 'f 59$»).
`> 149'
`" 41%)-
`
`.
`
`l
`.
`6.6%;32
`(_
`s( 34%;),
`
`.-
`.260.
`«1-91
`
`{ 72%}
`( 23%)
`
`--
`I 71%)
`25.7.
`104 (29%),
`
`,
`.
`V.
`H
`24.9 ( 7034‘)
`< 79%)
`( 30%) 167 ( 3(1)?)
`,
`
`’
`
`_ V
`.,
`2401/6715)
`116 l 339;}
`
`(- @521 2;? c 69%}. 1'99 4 «552A
`{..35%)‘
`1153‘:
`K 46%)
`1'51"
`( 4’53)
`
` P—ya;u駔
`
`_
`‘
`Trexima ‘vs. Placebjd.‘
`Trexima ys. Sumatriptgp
`
`
`
`
`
` 4, ’P-Vjalues are irom the -Coctiianétfiantel-‘S-Iaenszel test-W
`
`1 ~P'~Ya1ues are from Legistic Regression, withrgpole‘d
`
`Appears This Way
`on Original
`
`42
`
`

`

`Clinical Review
`Ronald Farkas, MD, PhD
`N21-926
`MT400/Trexima
`
`Photophobia
`
`Trexima was statistically superior to placebo for photophobia at 2 hours in both study 301 (50% photobia—free vs.
`32% for placebo)(Table 30), and study 302 (58% photophobia-free, versus 36% for placebo)(Table 31).
`
`Table 30: Photophobia, 0-4 hrs, study 301
`
`WWW
`
`i
`Tablg_.lé.2.13.l
`p
`
`Photophobia by Timé.Post-Dose
`All Subjects in the Intefitéte—Treat Populaeiom
`
`
`“NJ WWW W "W “”7
`
`:Exgatment Group
`—«a ~~~~~~~~~w~~9»wkwwwwwwwwwwwww,Mwav~~——efimmmmmmmmmmmmmmmmm
`[Symptom
`.
`-0.9
`1.0
`2.0
`_
`350
`£;0
`
`
`meme <N=362>
`\Abéent
`Ezesent
`
`.
`62 t 17%)
`3G0 ( 83%)
`
`.
`.
`91 i 25%)
`271 t 75%)
`
`,
`,
`:
`150 Q 56%)- 239‘( 64%)
`182 f 50%}' 132:1 36%)
`
`'
`
`248 ( 69%)
`.114 ( 31%)
`
`'Svma‘éfifitan (51:35-62)
`
`an. n:
`wanna
`
`60 < 332%) M9;
`302 ( 83M 27.;
`
`V.
`.
`.
`,,
`.
`‘
`20g { 55%}
`_§ 25%; my? (- 225%)
`r 75%) we: i: 3%), mg,
`g 45%,)
`
`.
`
`.
`.
`2:3 ( 59a); ‘
`1‘39 ( 41%).
`
`v
`
`'
`
`'
`
`fiaproxefi 1N=36§)
`Absent
`Eneser‘st
`éiacebo.(fl@38§l
`315mm:
`:?tégest
`
`,
`63 ( 17.35)
`301 ( 83%);
`
`8:61 24%;)
`:2'7;21(316-%§.1
`
`V
`2481 41%)
`2161 59%“);
`
`"1'12 i 4%?)
`192 r 33%;
`
`’,
`185 .(w
`17.9 (g,
`
`
`
`'
`
`11.33%),
`(
`3:2.
`f318 (”81%)
`
`(372.2%)
`'89;
`299 g 78%)
`
`( 3.2%}
`122'
`260 ( 68%)
`
`14o (
`
`242 ( "
`
`‘< 38%)
`(V62%)
`
`‘
`' E’IT‘QWM‘
`‘Ijxexima vs“ Placehd
`‘ VTregima vst~8um§tui§tan
`
`<-.001;g
`0.220:
`
`4.961
`
`0_§Gé
`
`‘ P~Values ate fzbm the Cochrag-Mantei'fiaénszel test, wifih'pobled investigacorxéitm'asithé strata.
`
`Table 31: Photophobia, 0-4 hrs, Study 302
`EOZBR;
`Inc.
`>
`.
`"
`
`,
`,
`Table 1412.3.1
`‘
`Phonophobia by Time Peat-Edge ’1‘
`V
`vAll Subjects in the:1ntentrtowr$eat §0§ulacibn
`
`
`:.
`
`Study Number Mfdookfiflz
`*
`‘
`-
`
`Treatment Group Symz‘ztm
`
`Trexima (3:364).
`Absent;
`Present
`
`>$umacrippan (Ng361)
`Absént
`'
`Present
`Naproxen {5:256}
`Absent
`Preach:
`
`76 t 21%;
`288 1 79%)
`
`1'
`2‘11 ("58%)
`195 t 29%;.
`25,53
`(_ 271%,}; 153 l 42%)
`
`'
`
`251;, r 70%)
`1-1:);(«30m
`
`(271 £ 74%)
`93 { 2am
`
`65 ( 18%)
`296'
`(_ 32%)
`
`>
`.
`.
`102 C 25%;
`25:9 1 72%}
`.
`63 c 19%) no, 1 2.22%)
`287 1 81%)
`’256 t 72%)
`
`.
`
`J73 (f48%)
`188 ("152.2%
`;
`.
`use .1 47953
`130 l 53%}
`
`.
`
`/
`210 i 58%)
`151.1 42%)
`
`g 53%)
`159.
`167 l 47%)
`
`22; { §l%l
`14's
`4 39%)
`.
`’
`202 if 57%)
`156 E $§§l
`
`Placebo (R236§l
`Absent
`,
`Present
`.
`VP”V&1§BSI
`p.061
`«.001
`Trexima v5. Placebo
`
`
`6.307--Trexima vs. Sumatriptan= <rool
`
`74 l 21%}
`286 l 79%)
`
`_'
`$9 ( 25%i
`2?1 (175%)
`
`v
`.
`N
`l3l‘l_3§¥3
`.2?9 i 64%}
`
`_
`I}; ('36?)
`22E 1 64%}
`
`137 l 38%)
`223 f 62%)
`
`_
`
`'
`
`I fi-Values axe from the Cochran~Mantel~Haenszel cast, wick pooled inveShigator site as the strata.
`
`43
`
`

`

`Clinical Review
`
`Ronald Farkas, MD, PhD
`N21-926
`MT400/Trexima
`
`o
`
`Phonophobia
`
`Trexima was statistically superior to placebo for phonophobia in study 301 (56% phonophobia—free, vs. 34% for
`placebo)(Table 32), and in study 302 (61% phonophobia—free, vs. 38% for placebo)(Tablc 33).
`
`Table 32: Phonophobia, 0-4 hrs, Study 301
`
`........ , m..-
`
`
`
`
`
`
`
`
`
`
`mtéatihen‘t
`“ (_.‘;-‘.V..\-.;.._~‘;._‘ ~
`
`‘Sympfioma'
`"
`'
`
` ‘ 1'15 a» ,
`
`g
`7.4? ‘r 6.931%)
`
`
`
`
`’Vii;
`
`(31%;), I
`"‘ n25;
`
`69%)
`
`
`
`
`
`0n Original
`
`44
`
`

`

`Clinical Review
`Ronald Farkas, MD, PhD
`N21-926
`MT400/Trexima
`
`Table 33: Phonophobia, 0-4 hrs, Study 302
`
`902m, Inc.
`
`
`Study xmmbaxr’wmooaoz -
`
`
`
`v
`‘
`Vrab’le’ 14:2‘41.‘
`
`
`.
`1,
`,
`{.phonophobia by Time .Eésp-mae
`
`All Subjaéztijsniiz the Enteritlt Arman 20'
`-;a_
`dri-
`
`
`
`
`- Treatmeg’itx Grbup i
`Symgt‘c’m‘
`
`
`
`”7.5
`
`“528:6
`
`..}iaprcxgn. {112356;}
`
`‘- Absent,
`‘.
`191- g
`Pxe'§§éfi
`‘
`'
`7965. x
`
`Piagelp’o ’lfiwékii’il
`
`.‘ Absent
`‘
`‘
`
`i'iTréxjma' Riv-«3645)
`’
`’ Absent
`: Present
`
`,Sfiwtxiptan magma:
`~ Absent
`¥
`- Present; ‘
`.
`
`.
`
`,
`
`.
`
`45
`
`

`

`Clinical Review
`Ronald Farkas, MD, PhD
`N21-926
`MT400/Trexima
`
`Fri/720:2 elzdgoz'm; 24%0511” lime gain!
`Trexima claims efficacy as a combination product of sumatriptan and naproxen, and was
`therefore required to show that the combination is statistically superior to the individual
`components for at least one clinically meaningfiil endpoint. The endpoint agreed to with the
`Division was sustained efficacy against migraine, termed ‘sustained pain-free 2-24 hours.’
`(choice of endpoint discussed in section 6.1.2, Geyem/Dzkcwyz’wz off/240012215). Trexima was
`not required to show superiority versus its components for associated migraine symptoms, but
`was expected to be no worse.
`I
`
`Sustained pain—free 2—24 hours
`o
`In both study 301 and 302, Trexima was statistically superior for this endpoint to its components,
`sumatriptan and naproxen, and to placebo (Table 34). The margin of superiority was clinically
`significant: patients taking Trexima who were pain free at 2 hours had a z25% chance of being
`pain free through 24 hours, while for sumatriptan (85 mg RT), Naproxen (500 mg), and placebo,
`this chance was, respectively, 315%, z10%, and 28% (average results from the two studies).
`
`Note that the percentage of patients that were pain free at 24 hours is probably ‘artificially’ low
`because only those patients pain free at 2 hours were measured for the “pain free between 2 and
`24 hour” time point. In actual clinical practice, many patients probably experience long-lasting
`relief, but with initial onset of relief later than 2 hours, or experience some residual pain, but
`relief appears adequate, at least insofar as rescue medication is not taken (presumably because it
`is not subjectively necessary)(see Figure 7: Percent Taking Rescue Medication, All Treatments).
`
`Table 34: Sustained pain-free 2-24 hours, 301, 302
`
`S
`
`Naproxen
`t
`t .
`“m “P a“ _ Sodium 500
`85 mg
`m
`I
`0
`
`16% (59/361)
`
`(13077356)
`
`Placebo
`
`0
`
`0
`
`.
`Trexima
`
`i
`
`25% (90/364)
`
`MT400-302
`
`MT400-301
`
`33/360) o
`
`23%: (83/362)
`
`14% 51/362)
`
`(£77,364)
`
`(72/5/382)
`
`+p<0.001 versus placebo, sumatriptan and naproxen sodium
`xp<0.001 versus placebo and naproxen sodium; p=0.009 versus sumatriptan.
`
`Appears This Way
`On Original
`
`46
`
`

`

`Clinical Review
`Ronald Farkas, MD, PhD
`N21—926
`MT400/Trexima
`
`Photophobia, phonophobia, nausea-free
`0
`For the migraine—associated symptoms of photophobia and phonophobia, Trexima was
`statistically superior to its components in both study 301 (Table 35) and 302 (Table 36). For
`nausea, Trexima was statistically superior only in study 302, while in study 301, Trexima was
`numerically but not statistically superior (48% sustained nausea-free for Trexima, versus 44%,
`41%, and 28% for sumatriptan, naproxen, and placebo, respectively).
`
`Table 35: Associated symptoms, sustained-relief, Study 301
`
`'
`
`"
`
`,,
`
`
`
`'
`'
`,
`Tame 14,2.3
`Sustained>Symptomefireefinuring 2%24 acute Pésé-noso
`Adjusted fox: Resette
`>
`_>
`>
`»
`All Subjects in thev‘i-nténtflio-Treat
`14o fixation
`
`Treatment Gran? V
`Symptom
`V_
`
`Suet‘ainefl
`.
`“
`»
`a
`V.
`'Susnained,
`‘
`Sustained
`
`Phetophobiawrfl‘ree ‘Naus‘eawf‘ree‘ Phonophobia-Eree’ *
`
`
`
`
`Trexima (N=362_) _
`bio
`Yes
`
`.
`
`snmatripnan (Na-1362')
`m
`'
`\Yes
`
`_
`
`-
`
`.
`
`’
`
`.
`V.
`
`'
`
`223
`l 63%)
`134‘( 32%)
`
`,
`.252,
`1520
`
`r 702;)
`( 30%)
`
`’
`
`‘
`
`'
`
`.
`
`:213' «my
`V
`149 '(‘4V§i%)
`
`,
`
`V
`
`_
`V
`,-
`67%“)
`‘243 .r
`.119 («33%)
`
`4
`
`'
`
`,
`
`.
`
`.
`
`a
`
`.
`
`’nag’roxen (#364)
`3%
`.
`"lives
`
`>
`29851. “23%)
`99 g 27%)
`
`.
`t 71%)
`“c 29%)
`
`183‘
`1‘74
`
`52a)"
`1.
`{ 48%")
`,
`
`' 3'
`
`V
`2.93 < 55%)
`2594/ 442;)
`
`,
`
`1
`.
`‘
`. 214 t 59%)
`15;):
`q «13%)
`
`mag-m (@382)
`' No , I
`'
`Yes
`‘
`‘
`, P—‘v’aailuies1
`
`4.001
`p.
`<.001 _
`\
`<.,0in
`Txeiéima vs. 913369
`Tgmxima vs. Surnatriptan , 0.203» , 0.05.0 , 0.014 / ’ »
`
`
`
`
`..
`'
`
`y
`
`,
`
`'
`322 (. 84%)
`6:)
`( 16%)
`
`
`Q
`
`ii,
`331:4“(._.-ag%)
`6'8 (513%)
`
`‘
`
`.
`
`'
`V
`275 ‘( 72%}:.'
`1‘07
`(23%)-
`
`_
`
`
`
`
`
`
`
`
`
`=1: fiEVaiues are 13150er jibe CochrahffiéntekiiaenszeiErase, with pooled investigator;s,iée_'ae .tzhe strata,-
`
`Appeors This Way
`On Original
`
`47
`
`

`

`Clinical Review
`Ronald Farkas, MD, PhD
`N21—926
`MT400/Trexima
`
`Table 36: Associated symptoms, sustained -relief, Study 302
`
`‘
`Table; 14.2.3
`Sustained Symptom—Free During 2-24 Hours Post—Dose
`All Subjects in the Intentdto~Treat Population
`
`l’rr‘eaement: Group
`‘
`n
`Suseained
`Suscainedv
`> Sustained ,
`
`'
`f .5pr cm
`Pilotophobia- Free
`Phonophbbi a — Free
`Rausea 45338,,
`
`Erejiima‘ (§:36‘4)
`"
`No
`Yes:
`
`Sumatriptan “1:361)
`No
`.
`Yes.
`
`.
`
`.
`
`»
`
`,
`
`>
`
`.
`
`.
`196 (54%}
`- 168 (46%}.
`
`,
`v
`.
`.
`( 65%)
`' 2‘35
`. 126 { 35;)
`
`~
`
`'
`
`>
`
`,
`
`NaiprdXen (mass)
`so
`are;
`
`».
`
`'
`. g
`
`.
`.
`
`»-
`.
`
`,
`
`,
`
`.
`,
`l 69%)
`.246.
`.110 r 31%)
`
`Placebo (3:360)
`No
`:
`Yes
`’
`
`'1
`
`,
`
`.3
`
`"j
`
`..
`
`'
`
`,»
`
`f
`
`,,
`
`'
`
`'
`-
`» «285 ‘c 7.9%}
`. 75mm
`
`.
`‘
`Mame .
`-.
`‘2 »Eisximasvéw'Bl‘abébd
`
`’»C»T.r..a'x auvsézsmawiptan ,
`
`,
`
`,
`
`'
`
`’.
`v
`
`«
`
`.
`4:001.
`0,1292
`
`.
`
`,
`
`v
`
`.
`
`.
`
`V
`
`t 51%»)
`’18.?!
`180 ( 49%}
`
`232 (64%)
`2,29 ( 36%!
`
`»
`64%»).
`228 t
`1'28 ( 3695)
`
`'
`t 79%)
`283:
`77 i an)
`
`-
`
`;
`~
`. «W
`«00:
`
`.
`
`.
`
`>
`
`,
`
`.
`»
`‘ sent 44%}
`204 t 55%)
`
`,
`
`’
`‘
`
`.
`
`.
`
`..
`
`.
`
`*
`
`’
`
`.
`
`’
`i
`.
`>
`201 t, 56%}
`160 t 44%).
`
`.
`.
`. 199 were
`157),} 4233)
`
`.
`
`g
`
`.,
`o
`,
`>
`2439(“68aii.
`
`* an (1335}
`
`‘
`.
`.
`
`->
`«093"
`
`': _ .,.o,..oo;2_>=
`
`.
`
`.
`
`.
`
`‘v,%‘"‘?‘.-‘"ia-lue'e-Iare front theh'Cocliran—Mantel—Haenszel test, with peeled invest'igatef'siteas thewé'brate;
`
`Other analysis supportive of efficacy
`
`1176/7241ngpal)!flee flatware/7 2—24’ éazmr
`The endpoint ‘sustained pain free at 24 hours’ for this study was designed with the unintended
`effect that the number of patients counted at 24 hours is partially dependent on the percentage of
`patients with pain relief at 2 hours. In other words, the higher the number of subjects that are
`pain free at 2 hours, the higher the number that are likely to be pain free at 24 hours, since the
`number at 24 hours depends, in part, on the ‘gate-keeping’ function of ‘pain relief at 2 hours.’ A
`scenario could therefore be envisioned in which a) the combination drug is more effective than
`its components at 2 hours but, b) the chance of relapse between 2 and 24 is actually ézgéer for
`the combined drugs than for the individual components, but that c) the combined drug still has a
`higher number of patients with pain relief at 24 hours.
`I therefore also examined theproportion
`of patients, pain free at 2 hours who remain pain free at 24. For Trexima, I calculated the chance
`of remaining pain free at 24 hours, given pain relief at 2 hours: the proportion is higher for
`Trexima (38%) than for sumatriptan (28-29%) or naproxen (23%), indicating that symptom relief
`by Trexima is not weighted to early time points (Table 37).
`
`48
`
`

`

`Clinical Review
`Ronald Farkas, MD, PhD
`N2 1 -926
`MT400/Trexima
`
`Table 37: Probability of remaining pain-free at 24 hrs. given pain free at 2 hrs.
`
`number
`
`
`
`
`38%
`
`28%
`
`38%
`
`29%
`
`23 %
`
`23%
`
`
`
`
`
`Probability of remaining pain-free at 24 hrs. given pain free at 2 hrs is calculated from the percentage of patients
`positive for sustained pain free at 2-24 hours divided by percentage of patients with pain score of 0 or 1 at 2 hours
`
`- Rescue medication use through 24 hours
`The proposed label includes a figure showing percentage of study patients who used rescue
`medication for symptoms inadequately treated by the first dose of medication (Figure 7). This
`endpoint was included as a secondary outcome in the SAP, but did not reach statistical
`significance in the step—down procedure based on a preceding outcome that did not reach
`statistical significance. Despite this fact, I believe the figure can be included in labeling. The
`primary endpoint for approval of Trexima under the combination rule was “sustained pain free,
`2-24 hours.” This outcome understates numerically the apparent efficacy of the medication,
`because only those patients who are pain free at 2 hours are counted at the later 24 hour time
`point. In fact, a higher percentage of patients are arguably treated adequately over 24 hours, as
`documented by the high percentage of patients who do not take rescue medication through 24
`hours. This majority of patients is composed of those who either had complete pain relief but
`after the 2 hour cutoff point, or had incomplete but still clinically beneficial pain relief (so as not
`to take rescue medication) across time points. Thus, “sustained pain free, 2-24 hours,” while a
`useful and valid study endpoint, does not fully describe the clinical efficacy of the medication.
`Arguably, too, one of the most important characteristics of migraine therapy for patients is the
`likelihood of requiring rescue medication, such that it should be included in labeling despite the
`relative lack of statistical support.
`
`Appears This Way
`
`49
`
`

`

`Clinical Review
`
`Ronald Farkas, MD, PhD
`N21-926
`MT400/Trexima
`
`Figure 7: Percent Taking Rescue Medication, All Treatments
`
`(from proposed Trexima label)
`
`
`
`.'Ehrcentaga02Patientstaking3RescueMedicafim
`
`
`
`
`
`., 1
`,
`_
`» Q maxim;
`I. Shmakiptan-flSing
`t Hapmxefion mg ; ~
`+ Piac'eho.
`’
`
`_
`
`'
`
`’
`
`»
`
`'180
`.
`90
`
`3“»
`70
`
`so”
`
`50'
`
`2:0:
`
`39
`
`g
`
`'
`
`t 20
`
`to
`
`
`
`
`i4
`,2.
`go
`._f Hours Postma-
`
`16.
`
`” 3341.129
`
`22-
`
`214
`
`1 ) V./Ka§31§n‘M§i€r plot bas ‘
`’ afibtajifiédiifi.ttiéQualifiicalléwfmlIsdirizilaprovidifigfisgiicte'ncé _
`
`..figsadditidnaltreatmentscensbredto 221ihours;-,=Plot’sal‘so'
`'
`.,
`..
`ffieacygvvijthgpati’
`
`
`adynovvriesponse to the initial dose. Noxescue medica’tionwjas-‘allbwed
`‘ 1:1ncltgdesypfiit-ients w
`-w1th,in.;,22,hé;gzsyspospa, sé.;{$géction 2.5.4.53, Baggage. 2.5.4}
`
`56601252252 elm’goz'lz/J
`Secondary endpoints were analyzed based on a hierarchical stepdown procedure designed to
`preserve study type I error. Below, I examine each secondary endpoint both for statistical
`significance and for the degree of support it provides for the primary outcomes.
`
`/. Pat/1279163 alZéou/"Jfor [hank/m VJ’. placeéo
`This outcome was demonstrated statistically (Table 27). The Division required Trexima to
`be superior to placebo at 2 hours, so this endpoint is part of a primary outcome variable.
`
`2. Sum/412264741}? relief/0r flan/>724 VJ’. p/aceéo
`This outcome was demonstrated statistically (Table 34). The outcome differs only slightly
`from a component of the primary outcome variable, ‘sustained pain-m 2-24 hrs’ for
`Trexima vs. placebo. Pain relief is defined in this secondary endpoint as moderate or severe
`pain decreasing to mild or no pain.
`
`50
`
`

`

`Clinical Review
`
`Ronald Farkas, MD, PhD
`N21 -926
`MT400/Trexima
`
`3. Say/azkzedpm’lz re/Z'Zeffor flex/Ma VJ'. Jamal/gala}?
`This was demonstrated in both pivotal studies (Table 38, Table 39). This secondary outcome
`is very similar to the primary outcome, sustained pain—free 2—24 hours versus Trexima’s
`components (Table 34).
`
`- Table 38: Sustained Pain Relief at 24 hours, MT400-301
`
`Nessa
`
`4. Sui/albedJy/izplom-fl’ee (péo/opéaéz’a—fl’ee, péwzqaéoéz’a-fl’ee, or flawed-ff’ee/flr
`War/Ma VS, ill/72417431412
`This was achieved in one, but not in two studies, and thus is a failed secondary endpoint. A11
`3 components (photophobia, phonophobia, and nausea) were achieved for study 302, but in
`study 301, sustained nausea-free was 48% for Trexima vs. 44% percent for sumatriptan
`(p=.203).
`
`The secondary endpoints below I do n_ot consider statistically significant based on failure of
`the preceding endpoint to reach significance at ‘p = 0.05.’ However, I have addressed them
`as individual endpoints, at p = 0.05 uncorrected for multiplicity.
`
`i are afraid/e meditation/’01” fiat/fwd VJ’. Jamal/$1412
`This was a statistically significant endpoint (uncorrected for multiplicity). I believe this
`outcome is important for communicating the effectiveness of Trexima to the public, as
`discussed above in this section under “Other analysis supportive of efficacy”.
`
`51
`
`

`

`Clinical Review
`
`Ronald Farkas, MD, PhD
`N21-926
`MT400/Trexima
`
`722726 to rescue/0r [Peri/7m VJ’. J’Z/lflfll/ZD/fl/Z
`6.
`Pozen claims this as a statistically significant result (Table 40,Tab1e 41), but does not explain
`adequately how it was derived. It appears to be very similar to secondary endpoint #5, use of
`rescue medication for Trexima vs. sumatriptan.
`I find Figure 7 adequate to describe ‘time to
`rescue.’
`
`Table 40: Time to rescue medication use, MT400-301
`
`‘ 902m}, in?"
`
`
`
`seedy Number MEGS-‘36;
`
`
`
`-
`-,
`/
`-
`.
`#2231581“
`‘Tregfigna-
`Sumat‘zgiptan
`Napmgaan
`‘ gmgacebq.
`(Traxi-ma Us;
`
`(k362i
`.
`‘ (gr—3'62)»
`{2&3184);
`n-‘(kdésSZt
`s'umaieriptan):
`
`.
`
`.LiSeki.3éécue."§tédiéati§ri.
`'
`No
`1'
`~ " '
`
`‘
`279 (we)
`83 ( 23%}
`
`..
`622's).
`
`'{ 38kt}
`
`
`221 (“6193)
`143 l 39%).
`
`,
`( 43%)
`159‘
`'Q 3-fi{§8%?
`
`
`
`. ‘s/a '
`
`,
`
`4:12.93:
`
`{9.90:
`
`8.2 (' 4.8)
`‘5)
`Mean {std}?
`4
`‘ at"?
`V
`.,
`.
`.
`.
`i
`’
`V ,.
`‘
`«
`“Gdial‘
`
`
`
`. 39.5; V1..;.°.'~'.24_,.»_G/- Min;_- t-iax, 3..s —» 23.0
`
`
`
`
`
`Mag;
`'Eime to ‘Rescugjen-‘Subjécts:fin .kescued‘ i;
`
`
`
`Worn the $0g»8ah1z es
`
`
`\ n’céznte‘cv”
`E$C§¥§d at. 24: h‘
`
`
`test», ”with 990123
`'gaeg: site as tine
`
`
`
`
`"item the Kap'lé‘nkméiei‘ met oil.
`
`Supfieéfiis
`
`Appears This Way
`On Original
`
`52
`
`

`

`Clinical Review
`Ronald Farkas, MD, PhD
`N21-926
`MT400/Trexima
`
`Table 41: Time to rescue medication use, MT400-302
`
`POZEN,
`
`Inc}
`
`‘
`
`gammy Number: Muse-£302
`
`fires
`
`v
`
`.
`
`-
`
`a
`
`_
`
`‘
`
`-_
`
`»-
`
`x
`
`3.- .svéj'efiés
`. w
`
`,
`
` ,
`
`Time ea Ree:
`fiefiia’ '
`g
`9.5% cy.‘ ~
`
`'.-=si‘mj.e‘eeéywao Rescued:
`
`
`,
`Mean. raid)...
`'
`Mediar‘u '
`»
`34m r 145%:
`
`@rexirna"
`,tuasegé
`
`Sumatriptarz
`'
`{KL-«361) ”
`
`ass ,( 78%!
`315.22%)
`
`24's ( 68%),
`1151 32%)
`
`221'» {523),
`1354313531
`
`1:68" r 453;)
`132 (53%),
`
`. r "
`
`‘
`
`~ 281/3:
`
`(my:
`
`‘
`
`‘
`
`,
`KIA
`
`,
`
`1:154 »
`
`
`g
`.
`
`
`
`
`1,2‘
`5.8 (“
`,-
`«110,.
`‘250. 3 Q3149
`
`.
`
`_
`V
`‘
`,_
`mp
`
`and Time; no Rescue '
`aw'l‘naat Popul’a
`
`
`
`
`
`
`,Napre‘xen’
`
`IN=356§~
`
`
`V
`
`j
`
`»
`
`-
`'-
`
`‘
`
`g
`
`‘
`
`"
`
`/
`
`V
`sii
`19,0 ( 6.6}
`3.0
`’2:0~23:.o
`
`,
`13.5.
`A
`:15
`6:8.“ (' 5(0)
`33.1 t 6:2)
`5,0:
`5.0
`91.9 «14.0 32.0" ~. 2.3.1)
` ‘
`
`
`’
`
`*
`
`
`
`,n ream? time-end 1)
`'
`.~
`who did-"no take any rescue medication
`
`
`'ftglr‘aaeinmx Size-é
`' s54
`e‘ frog-Rank» T1593;
`
`7. Paziz—refi'efa/ 4’flay/15'fir Wart/>724 VJ’. Jamal/”gala”
`This was statistically significant in both study MT400-301 and MT100-302 (uncorrected for
`multiplicity). Four hours is a later time point than acute migraine studies generally examine,
`and I do not believe it adds significantly to study findings given that at 2 hours Trexima was
`shown to be superior to sumatriptan alone for pain-free.
`
`é?
`
`tfj/mptam—flree (pfloz‘apflaéz'aflee, péoizopflaéz'a-fl’ee, 0r ”mama—flew) a! iflw/I’Jfir
`flaw/72¢ VJ'. Jamal/pm};
`This was not a statistically significant result in two studies, based on failure to show ‘nausea—
`free’ at 4 hours in study MT400-301 (p-Value 0.140) (Table 42). It was statistically
`significant in study MT400—302 (Table 43). I find this endpoint provides little additional
`information regarding efficacy.
`
`53
`
`

`

`Clinical Review
`
`Ronald Farkas, MD, PhD
`N21—926
`MT400/Trexima
`
`Table 42: S m ntom-free, 4 hrs, MT400-301 (ITT Poulation
`
`Trexima
`N = 362
`
`Sumatripta‘n
`N = 362
`
`p-Value
`
`—___
`
`Table 43: Symptom-free, 4 hrs, MT400-302 (ITT Population)
`
`
`0.002
`
`Trexima N =
`364
`
`Sumatriptan N
`= 361
`
`p-Value
`
`285 (78)
`
`271 (74)
`
`274 (75)
`
`295 (81)
`
`240 (66)
`
`221 (61)
`
`226 (63)
`
`257 (71)
`
`< 0.001
`
`< 0.001
`
`< 0.001
`
`100/12 re/z'ey’d/Z flay/15’ flaw/7m VJ'. mama/rwtd/z
`9.
`This was statistically significant in both study MT400-301 and MT100-3 02 (uncorrected for
`multiplicity). Endpoints using pain re/z’efand painflee are closely correlated, such that there
`is little extra information contributed.
`
`[fl Q/MpMM-jfiee {pflolapéoézkz—fl’ee, pflwzopéoéz’a-fl'ee, 0r ”aayeaflee/ at .2 flat/111781”
`i’rexz'ma VJ’. pry/724116401412
`'
`This was not shown in either study, due to multiple non-significant p-values (nausea in both
`studies, and additionally photophobia—free and phonophobia-free in study MT400-301).
`
`6.1.5 Clinical Microbiology
`
`Not applicable.
`
`6.1.6 Efficacy Conclusions
`
`Based on efficacy, Trexima is approvable under the Combination Drug Rule.
`
`54
`
`

`

`Clinical Review
`
`V
`
`Ronald Farkas, MD, PhD
`N2l-926
`MT400/Trexima
`
`7
`
`INTEGRATED REVIEW OF SAFETY
`
`7.1 Methods and Findings
`
`Study Satefl Monitoring
`Throughout Trexima development, critical cardiovascular safety data was not collected.
`
`For the two initial Phase 1 studies (MT400-101 and MT400-103), the following assessments
`were performed at screening and following the final dose of study medication [Notez no
`assessments were performed proximate to dosing]:
`
`- medical history review (screening only)
`
`physical examination
`0
`0 ECG
`
`o
`
`0
`-
`
`0
`
`vital signs (heart rate and blood pressure)
`
`clinical laboratory tests (hematology and chemistry)
`urine pregnancy test
`
`adverse event assessment (assessed throughout all phases of the study).
`
`The other three Phase 1 studies had these safety assessments performed at screening only, with
`adverse events assessed throughout the study.
`
`In the proof of concept single-dose study (MT400-204) the subjects had the following at
`screening and follow up:
`
`0
`
`review of medical history
`
`physical examination
`
`vital signs (heart rate and blood pressure)
`
`clinical laboratory tests (hematology and chemistry)
`urine pregnancy test
`
`Adverse events were assessed following administration of study medication through the
`follow-up visit.
`
`In the two phase 3 pivotal studies (MT400-301 and MT400-302), the following assessments
`were performed at screening and, up to several days following a single dose of study medication,
`at the follow-up visit:
`0 Review of medical history (at screening only)
`
`0
`
`Physical examination
`
`0 ECG (post-dosing only if chest symptoms suggestive of cardiac abnormality occurred
`post dosing).
`
`o
`
`0
`
`0
`-
`
`vital signs (heart rate and blood pressure)
`
`clinical laboratory tests (hematology and chemistry)
`
`urine pregnancy test
`adverse events were reported through the follow-up visit
`
`55
`
`

`

`Clinical Review
`Ronald Farkas, MD, PhD
`N21-926
`MT400/Trexima
`
`During review of the application the sponsor was asked by the Agency:
`
`“We are interested in the cardiovascular effects of Trexima near peak drug levels. Where
`in the NDA submission is this addressed? Can you summarize the data you have on this
`issue? Do you have any additional cardiovascular safety data collected while Trexima’s
`components were present in circulation?”
`
`The sponsor responded:
`“There are no additional data other than that presented in the original NDA and the 120—
`Day safety update submitted on December 5, 2005 (Amendment 005).
`
`Five Phase 1 studies (MT400-101, MT400-102, MT400-103, MT400-104, and MT400-
`105) were conducted as pharmacokinetic studies and while these studies did not include
`direct evaluations of possible cardiovascular effects, subjects remained under observation
`in clinic for at least 24 hours after dosing. The respective study reports identified all
`adverse events with onset during these post—dosing periods. The data, from 140 subjects
`receiving doses of Trexima, did not suggest a risk of cardiovascular effects during the 24
`hours after dosing corresponding to the times of peak levels of the components (for
`convenience, tables from the study reports are presented in Appendix 1). Further, there is
`no evidence of increased incidence of cardiovascular events in subjects who received
`Trexima when compared to subjects who received comparators.
`
`The long-term safety study (MT400-303) included a presentation of all reported adverse
`events with onset within 24 hours of dosing with Trexima. This 24-hour period would
`include the times of the peak blood levels of both components of Trexima. The profile of
`adverse events in these subjects (Please see Tables 14.2.7.2.1, 14.2.7.2.2 and 14.2.7.2.3
`from the final report of the long term safety study MT400-303 submitted December 5,
`2005, Amendment #003, as part of the l20-Day Safety Update) was not remarkably
`different from subjects who received either Trexima or monotherapy with sumatriptan or
`naproxen in the controlled trials.
`
`Trexima is a formulation containing two drugs that are approved for marketing and have
`established pharmacokinetic (PK) and safety profiles. The results of the PK studies
`within this NDA [filed under the provisions of 505(b)(2)] are consistent with the
`previously demonstrated pharmacokinetic and cardiovascular safety data for both
`sumatriptan and naproxen.”
`
`The safety assessments for the long term, open label safety study (MT400-303) are listed in
`Table 44 and Table 45. Note that vital signs are measured only at screening.
`
`56
`
`

`

`Clinical Review
`
`Ronald Farkas, MD, PhD
`N21—926
`MT400/Trexima
`
`Table 44: Safety Assessments, Long-term safety study (MT400-303)
`
`23mm»-
`Foliow-up
`
`Miami:
`Follow-up
`
`D-MDDm',
`IFollowAnp
`
`12-Month-
`.
`smug).
`Foilmv-n‘p , Follow-up
`
`Informed Consent __-___-
`DiagnosisConfinnation _—————_
`
`
`
`:2
`
`.
`
`'
`
`—
`
`Clinicallab Tests
`Pregnancytest (females of
`childbearing potential)
`
`i'Sfucly Drug Dispensed [Drug
`Accountability’
`
`Satisfaction& Quality of Life
`Questionnairé5.
`' Adverse mm Assessment
`
`Return Diary_Card"
`Rayon! Concurrent
`Medications
`. Ifany chestsymptoms suggestive
`2Oniy subjects who bird treated at
`
`was With31de medicationin the previous 6 aii‘onlhs could continue-panicipaiionin the study
`:Oniy subjects who had treated51 least32m
`/
`Drug Accomuabilily only.
`'
`1’ lfih'csubject withdrew from the study priorto3or l2 months;(he qwsiionnflires were to be completedatthe final visit
`IAn ECG was required only if “chest symptoms suggestive of cardiac abnormality occurred post—dosing.”
`
`Appears This Way
`On Original
`
`57
`
`

`

`-
`‘
`Platelet Count
`Red Blood Cell (RBC) Count
`'
`'
`*
`RBC Morphology
`,
`Mean Corpuscuiar Volume(MCV)
`/
`'1
`.Mean Corpuscii‘lar Hemoglobin (MCH)
`Mean Corpuscu’lar Hemoglbbin Concentration
`(MCHC)
`.
`.
`V
`1:;
`-,
`‘
`WhiteBlood Cell(W.BC) Count?
`, Differential including:
`.
`Neutrophils
`Lymphocytes
`Basophfls
`MOROCWBS
`Eo‘sinophils ,
`Bands
`
`:
`
`V
`
`.
`
`‘
`. V
`
`.
`
`.'
`
`.
`
`l
`
`‘
`
`.
`
`‘
`
`~
`
`\
`.
`
`‘
`
`K
`
`,
`
`'
`
`.
`
`a
`
`,
`
`_.
`.
`
`/
`
`, Calcium
`Chloride
`'li‘hosphorous (inorganic)
`j Bicarbonate
`Glucose
`Total Pretein
`V Albumin
`. Creating Kinase (CK)
`Magnesium
`I TtileCerides
`I Globulin
`Total Cholesterol
`BloodUreaNitrogen (BUN)
`Creatimne
`Una; Acid
`.
`~
`Total Bili'rubin \
`‘iAilcalihe’Phogphatase
`,AspartateAminotransferase (AST)
`AlanineAmmotransferase (ALT)
`
`Clinical Review
`
`Ronald Farkas, MD, PhD
`N21-926
`MT400/Trexima
`
`Table 45: Laboratory Tests, Long-term Safety Study (MT400-303)
`
`Hemoglobin
`Hematocrit
`
`_
`
`.
`
`V
`
`Sodium
`’llotassium
`
`'
`
`,
`
`'
`
`A
`
`I
`
`
`
`'
`
`‘
`
`,
`
`’
`
`'
`
`7.1.1 Deaths
`
`Deaths, Controlled Trials
`
`There was a single death due to a gunshot wound to the chest from an assault that occurred in a
`subject in the Trexima arm of the study.
`
`0
`
`Subject 7235 / Site 351 / Fatal Gunshot Wound / Treatment Group: Trexima/ _
`—
`
`28-year old male
`Following a domestic altercation, the subject received a gunshot wound to the chest from a
`passing automobile. He died on that date at a local hospital. Efforts to determine if he had
`administered study drug prior to his death were unsuccessful.
`I find this death unrelated to
`Trexima.
`
`58
`
`

`

`Clinical Review
`Ronald Farkas, MD, PhD
`N21—926
`MT400/Trexima
`
`fled/fly, Opel; [doe/Sofia 527/sz
`
`None
`
`7.1.2 Other Serious Adverse Events
`
`Serious and severe adverse events, Controlled Trials
`
`I have examined both severe adverse events (immediately following) and serious adverse events.
`By separating severe adverse events from those of mildgor moderate intensity, I believe specific
`attention can be given to those that are potentially ‘close to’ serious adverse events. Given that
`both pivotal studies involved only a single dose of study drug, few serious adverse events related
`to drug were, or could have been detected.
`
`0 MT400-204 Severe Adverse Events
`
`There were 15 severe adverse events, and no serious adverse events in the phase II controlled
`trial MT400-204(Table 46). This trial tested a combination of a lower dose of sumatriptan (50
`mg non-RT) with sumatriptan than used in the final Trexima formulation (85 mg-RT). There
`was no discernable pattern of severe adverse events among treatment arms, but of note the single
`case of ‘chest pain’ was in the MT400/combination arm. This event was also associated with
`increased blood pressure (summarized below) (There was an additional adverse associated with
`increased blood pressure in a PK study, which is described under Section 7.13, Dropowfr (Md
`Offlel’ Selim/5' Adverse Eve/715).
`
`ears This WGV
`
`59
`
`

`

`Clinical Review
`
`Ronald Farkas, MD, PhD
`N21-926
`MT400/Trexima
`
`Table 46: Severe Adverse Events, MT400-204
`
`mags; Enei
`'
`
`.
`Table 15
`Severe Adverse Events
`,_By Body System (31253 rmfermd Tern:
`
`‘
`
`'
`
`7
`
`sway-Number MTéC-Qr254
`‘ H -'
`'
`'
`'
`'
`
`'Sub3eet Had at Least: Dee Severe Adverse Event
`K0
`:.
`3”.
`Yes
`‘
`'
`'
`
`2&6 (98%)
`5 ( 2R)
`
`'
`
`226 (99%)
`3 (
`1%)
`
`2&8 (99%)
`2 i 3%?
`
`-
`
`237 £98%¥
`S l 2%!
`
`
`
`SumaLLptan
`{N=22§)
`
`team-aka: Sodium
`(R=250}
`
`Rlaaebo '1
`.{NW2é2}
`
`'
`
`'
`
`3 ( 1%)
`7.
`(<1?)
`2
`((1%)
`‘1
`((1%)
`
`U
`i)
`6
`E)
`
`0 i
`Q
`8"
`{3.
`
`G
`0]
`G
`G
`
`fsenéral daserders and admin site eondiéiune.
`
`Chest. pain
`’
`£33:ng .
`'
`,
`E‘ee x-ng gittery
`»'
`
`3
`_.ar£§ers
`v-Eyet'pai’n V
`V -:-°230$ophobia
`
`,
`
`,
`
`.
`
`Nervaas Laystexfi disorders
`Tehsinn‘ headacizm
`Dizziness (excl iéertigm
`Sbnmole‘sice
`
`3
`
`.
`
`Eat and labyrirth alsoedars
`:
`ITineit.us ;,
`’
`
`.
`Mauses": aggravated ‘
`Vem‘ting aggravated
`
`
`
`
`
`
`-
`
`(<1?)
`:
`‘1 (41%)
`0‘
`i (<lel
`i
`(<13)
`
`i?
`C
`0'
`Q
`0
`
`(«1%)
`(<1fi)
`
`3
`1-
`0
`0
`
`Q
`O ‘
`"o
`9
`’0
`0
`O
`O
`
`1 {(1%)
`E)
`0
`1 «1%)
`
`i
`
`9
`’0'
`.2' r 1%) _,
`O
`_
`a
`1. (are)
`I
`((1%)
`a
`
`6
`Q
`43’
`B
`cv
`
`0
`(3
`0
`(I
`
`.
`
`.
`
`t<1%)£
`1
`((133
`1
`:i ' fairs;
`G'v'
`:
`{:3
`\
`,1 (412;)
`{i
`0
`
`{911%}
`1
`.
`i}
`l {fil-‘il
`G
`G
`
`.
`
`.
`
`=
`
`3'
`3
`l
`(3
`g
`2"
`1}.-
`
`TREATMENT GROUPS: K’I’Mm: "G mg sumatriptan plus 500 mg naproxen sedium. Sumatriptan
`.
`Ilapzexen Seéiuzné‘fim mg naproxen sodium.
`.
`‘
`'
`Note: Adverse Ewe-iris the”: accurrezi heft):e dosing date were excludes.
`
`'
`
`I50 mg" Same: 1: irate n3.
`
`Jewel? Adverse Eve/Its off/tiara); Mflflfl-Zfli
`
`‘ Subject 179/1562 / Chest pain, blood pressure increased / Treatment group: MT-400
`
`[Reviewer’s assessment: likely drug—related adverse event]
`
`25-year old female
`One hour after dosing of MTR-400, the subject experienced chest heaviness/pressure, for 55
`minutes. Her blood pressure was measured at her workplace by ambulance service, and was
`elevated for 135 minutes post-dose, with maximum of 154/100. No treatment was given.
`
`Significant medical history:
`Hypertension treated with Lotrel (amlodipine/benazepril)
`Screening blood pressure: 136/86
`Concurrent medications included: Celexa, Lotrel
`
`6O
`
`

`

`Clinical Review
`Ronald Farkas, MD, PhD
`N21-926
`MT400/Trexima
`
`o MT400-301 and MT400-302
`
`Severe Adverse Events, studies 3 01 and 302
`For studies 301 and 302 combined, there was a small excess of severe adverse events in the
`Trexima arms compared to the other arms (2.6% for Trexima vs. 1.9%, 0.8%, and 1.3% for
`sumatriptan, naproxen, and placebo, respectively (
`
`Table 47). Although the numbers are small, I think differences between groups are potentially
`informative, particularly for Trexima vs. sumatriptan. Close attention is especially warranted for
`differences in ‘cardiac disorders’ between arms, with 5 for Trexima and 1 for sumatriptan, of
`which ‘chest pain/discomfort’ accounted for 4 for Trexima and none for sumatriptan (in study
`MT400-204, ‘chest pain’ occurred once in the combination drug arm, and not in other arms).
`
`ears This Way
`Amati Original
`
`61
`
`

`

`Clinical Review
`
`Ronald Farkas, MD, PhD
`N21-926
`MT400/Trexima
`
`Table 47' Severe adverse events, combined MT400-301 and MT400-302
`
`Table 2.?.§.?.6.3
`:Severe ?reatment Emergent Adverae Events
`.
`By- {fiedflPfi System 02:91am“ Ciasa and Ereferred 'E‘erm
`
`lifififie
`vdgél
`én frbm‘StfidieS 30? and 302
`
`
`Study Number MT409~ISS
`
`
`
`
`sém'atréptéfii
`1:1 735)
`
`"31 a'ls’s‘i)
`
`
`‘cra;d:xgéa«xfi
`
`
`atxdfiu
`
`
`00
`
` 3 1 0.33%)"
`
`
`L .1 0.1%,,
`i
`1 0511211
`1 < 0.1%») 31
`
`
`
`
`
`11:110:
`
`62
`
`

`

`Clinical Review
`
`Ronald Farkas, MD, PhD
`N21-926
`MT400/Trexima
`
`Sert'ausda’verse Eve/its, studies 30] 41102372
`Six serious adverse events occu