Frontier Therapeutics Exhibit 1019
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`Page 1 of 5
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`

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`
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`0
`RheumatoidArthritis
`
`zero
`'
`I
`
`Functional capacity
`Full activity
`Most activities
`Light activities
`Mainly chair and bed
`AHA = American Rheumatism Association.
`
`"
`
`in}
`None
`17
`45
`16
`
`two to three months The
`sessments usuail has been eve
`following il'lfDl'i"I‘la);iOF| has beengoorcieciatmostvisits (1)
`durationofmorningstiffness; (2)painrelativetoactivity (3)
`numberofpainfui ioints, (4)numberandseverityofswollen
`joints, (5) functional capacity {6} estimate of severity of
`
`disease activity by th
`
`TABLE II‘
`
`Nu
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`count (including platelet estimate), urinalysis, SMA 12i'60.
`'
`baseline complete blood
`erythrocyte seciimentatio
`,
`‘
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`A total of 12 patients have died, none as a known
`consequence of methotrexate thera
`
`.
`
`were In “"5 group The other rm-awed of mficellaneous
`causes’that'5,’cerebralVaswhhs(Oneanew’ Odom"
`told compression of brain stem (one patient) terminal
`WE‘-"-'”‘°”'3 355°C"3t5'd “""" 59”"?de'"3"t''3 3'“Qmeral
`dfibimi-' “W0 DEWBWTEJ
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`died during therapy
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`Marked
`14
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`is
`3
`
`4
`
`1
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`
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`mtiers of Patients Showing Various Degrees of improvement in Grade with Therapy
`ParametersMeasured
`None
`iid
`oderaie
`Morningstiffness
`»
`25
`Activity producing pain
`3
`5
`everity of disease activity
`a
`25
`36
`Functional capacity
`11
`36
`27
`
`Elia
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`e
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`l
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`as
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`29
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`as
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`‘
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`Page 2 of 5
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`ORAL GOLD SYMPOSlUM—-HDFFMEISTEFI
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`TABLE 111
`M
`
`Reasons for stopping Melhetrexalg
`Permanently
`
`Reason
`Complete remission
`Lost effect
`inadequate response
`Uncooperstlve
`Excess alcohol intake
`Moved away
`Toxicity
`Died
`
`Patients
`15
`4
`10
`1
`1
`3
`7
`3
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`
`
`
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`
`
`be related to methotrexate therapy; however, the fi-
`brosis was present prior to therapy. in none was the
`pneumonitis of the type attributed to methotrexate
`toxicity present [10].
`Sixty-tour of the patients were receiving up to 10 mg
`1 of prednisone daily. Forty-six of these have been able
`_ to reduce their dosage. No patient continues to take
`more than 5 mg of prednisone daily.
`1
`improvement should be apparent after three to six
`months of therapy. Therefore. we have compared the
`initial erythrocyte sedimentation rate values with one
`obtained after at least three months. Because erythro-
`cyte sedimentation rate studies were not carried out on
`
`28 mm per hour.
`Similarly. we have determined change in count of
`active joints after four to six months of therapy. The
`average initial joint count of 18 fell dramatically to four.
`in only six of the 78 patients did the joint count not de-
`crease.
`
`An estimate of overall improvement was made based
`on all the data presented plus the patients’ own as-
`sessment (Table iv]. Little or no improvement was
`noted in 14 patients. as opposed to marked improve-
`ment in 45. Of the latter group, 23 were judged to be in
`complete remission. Our criteria for complete remission -
`are morning stiffness lasting less than 30 minutes. lack
`of active synovitis on examination, pain related only to
`old damage rather than active disease. and a normal
`erythrocyte sedimentation rate. in 15 of the 23 patients
`it has not been possible to maintain remission without
`therapy.
`Toxicity. A total of 67 liver biopsy specimens have
`been obtained from 34 patients. Twenty—tour of these
`were from patients who had been receiving therapy for
`
`x to 15 years after the continuous use
`of methotrexate. Twenty-one patients have undergone
`between two and five biopsies. Each specimen was
`stained with three different stains, that is. hematoxyiin
`and eosin. periodic acid—Schiff, and a reticulum stain.
`Fifty biopsy specimens were normal. The remaining
`
`TABLE IV _
`
`Overall Improvement
`
`‘
`
`31: 4%}
`None
`11 [1496]
`Mud
`19 (24 9'9)
`Moderate
`45 (53%)
`Marked
`—.—j:-
`
`December 3|), 1983 The American Journal oi‘ Medicine
`
`71
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`NUMBEROFPATIENTSMto4:onon-4on
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`
`
`:1 451513 2110111213
`2
`1
`
`vanes necelvrrue METHOTREXATE
`Figure 2'. e Duration oftherapyin 44patients before stopping
`
`methotrexate therapy.
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`Page 3 of 5
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`slonaliyrequiring a reduction in dosage
`that was usually temporary. Onepatient hascomplained
`of thinning hair, and one of increased frequency of
`
`especraliy when c
`_
`rords, but has not been observed with the low doses
`used in this study.
`
`r-«:--1-=----4-—
`
`
`
`peared to have obtained
`maximal effect with intra-
`muscular therapy. in 10 of
`these. their condition dete—
`riorated but improved pro
`mptly when returned to in-
`tramusoular therapy. The
`divided dosage method given
`once weekly was devise
`d specifically to provide drug
`effect correlating with th
`a very rapid rate of epidermal
`
`cell proliferation in psoriasis [20]
`'
`'
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`compared before and after one
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`.
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`Page 4 of 5
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`' D
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`FIAL GOLD 3YMF‘iZ'1SiLJM—HOFFMEiBTER
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`_
`.
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`-
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`°°"c"U5'°"5
`The increasing enthusiasm for methotraxate in .-he”-
`matoid arthritis would appearjustified. During the 15.
`year span or this study 73 patients have received a total
`of 337 patiaaayaara at marapa 1-ha amaaay at maaa
`low doses given weekly compares well with that re-
`pa,-tad for inn-amuaaaiar aaiav aaaiamam.-aa and hy_
`d,-mcyci-,im-aauiaa [21_ 2_r._i]_ 1-hia araaa ataafiama had
`_
`aa._.a,a_ raaiatam aiaaaaa_ pa
`aa an aaaalaataa araua
`_ Wauia hava an avan mara imaraaaiva raaaanaa ta
`methotrexate. in our experience it is seldom beneficial
`to continue therapy beyond four to six months if a satm
`fgfac-wry raaaaaaa ta not aahia.,aa_
`Lia to ma ti,-na_ aariauataxia,-a, haa amaaaa ,-aaa,-tad
`with simiiar trials in rheumatoid arthritis using low-dose
`pulse therapy. The possibility of producing serious liver
`damage appears unlikely with this protocol. but only
`further experience can answer this question. other
`potentially hepatctoxic agents should be avoided. We
`instruct patientsto avoidall alcoholic beverages for 48
`hours after the weeltiy dose and to ingest no more than
`two ounces of hard liquor. or the equivalent, per day.
`Unfortunately. there is no simple test for early detection
`
`-
`
`of significant hepatotoxlcity. Although some would
`disagree. we believe the risks involved in liver biopsies
`tile not justify their routine use in following these os-
`lieiits The ssnnrns slutsmrl trsnsoeotioeso appears to
`be too sensitive to be useful on a routinebasis. We have
`teoentlr ielllrlted lie the eerlil'l1 itlil-iti'=ll'l'li'¢-‘ PiI'Fl-Weie
`transaminase as a screening test. if it is persistently
`increased. andother potential sources of livertoxicity
`have been eliminated, the clinician must then choose
`between {1} monitoring liver enzymes while reducing
`"'9 d°5" °f ’“°”‘°t’e’‘'“°- (33 °b"’3i"‘"9 3 "Var bi°P5Y-
`°" (3) '-1"5°°““"”"”9‘“9 d'”9-
`iiilethctrexate should probably continue to be re-
`served for patients unresponsive to conventional
`lhersor until more orolonseo observations reasrdlns
`"V9" *°"l°”3’ “EVE 539” a¢°””‘“'at9d~
`'
`ACKNOWLEDGMENT
`Stacey. S. K.
`iiitcilvanie. and G. L. Saue.
`I am also
`i appreciate the assistance and support of Drs. Ft. Fl.
`grateful to Helen MacGregor, Ft. N. for her assistance
`in data retrieval and analysis, and Irene Qualtieri for
`secretarial assistance.
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`1
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`REFERENCES
`1. Curry HLF. Harris J. Mason RM. etai: Comparison otazathi-
`oprine, cyclcphosphamide and gold in treatmentof it-iau—
`rnatoid arthritis. Br MedJ 1974; 3: 763-?6B.
`2.
`Llrowitz Ma, an-iythu HA. Able T, Norman (35 and Travis G:
`Long-term affects ofazathioprine in rheumatoidarthritis.
`Ann Ftheurn ois iasa; 4-1{suppI]: is.
`3.
`l-ioffrneistarHT: Methctreiiate in rheumatoidarthritisiabstr).
`Arthritis Rheum 1972; 15; 114.
`1
`.
`4. Gowans JDC, Arnold G. l-Capian MM. Wiigram Ci. Chang LW:
`Longtermtherapyofpsioriaticandrheumatoidarthritis with
`orai rriethorlrexate monitored by serial liver biopsies iaosiri.
`Arthritis Fiheum 15179; 22: 515-515.
`5. Wilitens RF, Watson MA. PaitscnC5:Low-dosepulsetherapy
`in rheumatoidarthritis. J Ftheurriatoi 1930; 1': 501-505.
`6. Stoinsscn K, Wainsteln A: Lowdose mathotrexate therapy
`‘It rh urn t
`'d arth 't'
`. Arthritis Rheum 1931; 24 (Suppl):
`-
`E;-;_ E
`a 0'
`n .5
`WilkaW3,CaiabreseLH, ScherbelAi_-Mdilhfltrfixateélithe
`gl§lg33Li;ir3.amidafim S Mat 5 My G W n
`ti:i
`t
`.1
`iii]
`8. Black Ft. O'Brien W. van soon E. etal: Methotreitatetherapy
`in psoriatic arthritis. JAMA 1964; 139: 743-747.
`Fa'rrf?':;t‘i:1'l1;is'.-ritFi‘fi'-?f'l'|i1Eifsztitijiftreaacfiel"3.1tv.iiilA isBs":r2‘t'i§-yirricfle
`A
`'
`'
`se: Ft
`'
`'
`111. oiayssa AM. Cathay WJ. oaitiiiright GE. ot'ai; Pulmonary
`‘disease complicating intermitterit therapy with rnetho-
`trexate. _JAMA 1989; 209: 1361-1364.
`Ji
`'
`D‘
`G. Lift
`Ga oi E, M
`h
`t A. F'er'anes J:
`n:|'$g§t2fTiEl:tzUf i‘hE::'fE10il; a?thritisB:it11alrjiifirogen mustard.
`Proiiminsmrrgpgn, JAMA 1951; 147'; 1413-_-1419.
`L .1-’-- Gubner Ft. August S. Ginsberg V.'The1"apBLifiC suppression of
`-1
`
`tissue reactivity: ii. Effect of aminopterin In rheumatoid
`arthritis and psoriasis. Am J Med Sci 1951; 221: 176-
`139-
`_
`13. Wainsteln A. Ficenigk H, Maibech H: Psoriasis-livar—rnctho—
`trexate interactions. Arch Deririatoi 19?3: 103: 36-42.
`14. wsinstein c: Methotrexete. Ann int Mad as:
`isa—2c4,
`197?.
`_
`_
`15. Lefltcvits AM. Farrow. U: The liver in rheumatoid arthritis. Ann
`'
`I
`Rheum Elie 1955. 14: 162-169.
`16. EioncrnoL, Tursi A. Miners V: lrnrnunoiiucresoencestudy of
`rheumatoid factor in livertissue of patients Willi rheutrelelil
`E;I;lrt;t:§1£l.t'ld hepatic diseases. J Path Eiact 1966; 92:
`it
`—
`-
`_
`1?. Ohabner EA, Myers GE. ColemanChi. JohnsDG: The elinleel
`pharrnaiaoiogtqofantineopiasticagents. NEngl JMed 1975:
`292: 11 7-1 13.
`16. Baiiin PL,TlndallJP.Fioegniit HH.atat: isrnelhotrei-zatetherapy
`for psoriasis carc:nc§i:m:?1;-T5m;ggie§5;eggZPeCiiVe"
`19.
`Freremsaph-Narrold M.yGerstieyBJ. Ei'ig511‘Oi‘l1PF. Bometeifl R3!
`-ro ectieanass.
`:
`I
`-
`-
`Comparison of5El"l.ll'i'1 conoai-iti-atioits oi‘n-iatl-iotrexataafter
`t1.~:r1li-aiuasgcitnes of administration. Cancer 1975. 35.
`20. Wainsteln GD. Frost P: Methotrexate for peerleeie A new
`—
`—
`i‘.|'ierapei.rtii: soheduia. ArchDermatcil‘1Q7"l: 103: elgfiiia
`21.
`Ftoth SH: Comparisonet‘I:ll-ll_Se fl1eil_il?“"iJ’a‘”:'t‘r"3l‘t5:‘S9'I;'aI_l:’gu‘r";‘ 151‘
`;.:ltEthar.a'::iy7i:1rheurriaitoidarthritie.
`r i
`.
`S-Llifllil
`I
`-
`_
`_
`.
`PeulusHE;AnoverviewofbanafitrriskofdiseasemDFt:ltfl"lflQ
`22.
`treatment of rheumatoid arthritis as cl today. Ann heurn
`Dis 1932; 41 let-liePli5 93-39-
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`December 30. 1933 The American Journal of Medicine
`
`73
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`Page 5 of 5