Sandoz v. AbbVie
`Sandoz Ex. 1003
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`Ex. 1003 - Page 1
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`Ex. 1003 - Page 1
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`NOTES
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`Ex. 1003 - Page 2
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`Ex. 1003 - Page 2
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`1kB KINASE 2 (IKK2) IS A KEY REGULATOR OF SYNOVIAL INFLAMMATION. P P Tak. D M Gerlag.
`IA A van de Geest. K 11 Aupperie, H I. Bennett. A M Manning. 0 S Firestein La Jolla. CA
`
`'Introduction. NI'-k6 Is a key regulator of inflammatory gene transcription and plays an
`important role in the pathogenesis of riteuniatoid arthritis_ NFkli activation in synoviocytes is
`controlled by IKK2, which initiates IkH degradation. Subsequently. NE-RR is released from
`cytoplasmic 1kB and is translocated to the nucleus. In contrast, the other key member of the IKK
`complex. IKKI, is not involved in synoviocyte NE-kB acne-anon. In these studies. we examined the
`effects of IKK2 activation and suppression on adjuvant arthritis (AA).
`Methods and Results. Fibroblast-like synoviocytes (f1.5) were initally infected with an
`adenoviral vector expressing a dominant negative IKK2 gene (DN-IKK2) containing a K>M
`mutation. Transgene expression was driven by the CMV promoter. Immunofluorescence demon-
`strated production of the transgene in FISH Its DN function was confirmed since DN-IKK2
`prevented nuclear transliwation of NF4c6 in transduced HS stimulated for 1 hr with TNF-a (100
`ng/m1). AA was induced in Lewis rats with AL tuberculosis in mineral oil. DN-IKK2 (0=15) or
`control adenoviral construct expressing green fluorescent protein (GFP) (n=15) was injected
`intraarticularly in the right ankle on day 12. Paw swelling was measured by plethysmometry. After
`I week the mean increase in the volume of the right paw was 1.0610.12 ml in the 1)NIKK2 treated
`rats compared with I.39±0.072 nil in the control rats (P=0.02). Improvement was also noted in
`the uninjected paws of DN-IKK2-treated animals, suggesting a "contralateral effect'. An adenoviral
`construct encoding the wild type (wt) IKK2 gene. which is constitutively activated when
`overexpressed In cells, was then injected into normal rat joints. wt-IKK2 gene transfer resulted in
`ankle erythema and significant paw swelling compared with the contralareral joint and GFP-treated
`rats (P<0.03). Histologic evaluation revealed synovial mononuclear infiltration and intimal lining
`hyperplasia In animals injected with wild type IKK2 but not in the GFP-treated rats.
`Conclusion. Blocking NEkli by gene therapy with a dominant negative IKK2 mutant ameliorates
`rat AA, whereas activation of NP-kB by wild type IKK2 in vivo induces arthritis in normal rats. These
`data suggest that IKK2 plays a central role In the pathogenesis of arthritis.
`
`Disclosure: work reported in this abstract was supported by:
`Signal Pharmaceuticals
`
`1974
`
`1MMUNOMODUIATION OF EXPERIMENTAL CHIAMYDIA-ASSOCIATED REACTIVE ARTHRIIIS.
`Judith A Whitium-Hudson, Nerve Gerard, Erin Davis, Gary Vora, W Mark Saltzman, Elizabeth S
`Stuart, H Ralph Schumacher. Alan P 'Hudson Detroit, Ml. Amherst, MA, Ithaca, NY. Philadelphia, PA
`
`We previously remitted development of a murine model of Chlamythasissociated reactive
`arthritis. Following experimental ocular or genital infection with human biovars of Chlantydia
`trachootatis, the organism disseminates to synovial tissue and histopathologic signs of synovitis
`develop. We tested whether immunization with an antichlamydial vaccine candidate prior to
`infectious challenge modulated joint inflammation. C3H/HeJ mice (5-8/treatment group) were
`immunized with a monoclonal anti-idiotypic antibody 6nAb2) which is a molecular mimic of the
`chlarnydial exoglycolipid antigen (GLXA). We demonstrated previously in mice that this vaccine
`protects against ocular chlarnydial infection. In the present studies, we compared the oral,
`intranasal. and subcutaneous routes for delivery of mAb2 encapsulated in poly (lactic acid)
`microspheres. After two immunizations (4 reg mAb2/dose) and confirmation that positive controls
`were serum positive fur anti-GOLA Ah by ELISA, all mice and recipients of normal IgGI or nothing
`were topically challenged intravaginally with K serovar of C trachoma's (200(1 TC1050). Vaginal
`swabs were taken weekly for microbiologic assays. Eight-10 wks later, mice were sacrificed and
`tissues processed for histology or molecular analyses for chlarnydial genes. Infectious loads were
`at d.14, all Immunized mice showed
`significantly reduced by oral immunization even at 0_7 (cid:9)
`significant reductions which correlated with reduced genital tract inflammation at 8-10 wks. Knee
`pathology was assessed in a masked fashion. The mAh2 vaccine recipients all showed highly
`significant reduction (p<.001) in synovial histopothologic scores; the major difference from
`controls was a marked reduction in synovial money toinfiltration. Oral immunization was the most
`protective by all criteria tested. Screening PCR on harvested tissues did not distingush altered levels
`of organism in genital tract or synovium based on vaccination and competitive PCR will be used for
`this. Our results show that the mAb2 vaccine reduces acute chlamydial infection as well as the
`synovial inflammation associated with disseminated infection. Current studies arc testing whether
`the vaccine reduces dissemination directly and/or by reduction of damaging synovial inflammatory
`responses.
`
`1976
`
`SAFETY AND EFFICACY OF ALENDRONATE FOR THE TREATMENT OF OSTEOPOROSIS IN
`PEDIATRIC RHEUMATIC DISEASES. R CIM2Z, F Falcini, M Bardare, F (cid:9)
`L Lenore. A
`Buoncompagni, M L Bianchi Trieste, Genova Italy, Milano. Italy
`
`Treatment of secondary osteoporosis with bisphosphonates is well established in Adults. hut
`clinical studies in the pediatric age are limited
`An open multicenter prospective study was performed to assess safety and eflicay .if alendmnate
`in children with rheumatic diseases. To he included, patients had to he on chronic (cid:9)
`6 months)
`corticostemid treatment or to have a low hone mineral density Forty-three patients (t0 Irmalo,
`males) completed the study.. Diagnoses were juvenile arthritis (1-). SLE 112c demotomyostirs
`3 7 years: 11 patients had already reached
`other (7). Mean age at study entrance was 12.9 (cid:9)
`pubertal maturity. Alendronate was administered orally at the daily (image o(5 or 10 nig IlAwhns-
`Z-scorcs ranged from -1.3 to -5.3. Each patient underwent serial clinical and lahornori Mainatlern
`Standard biochemical test were performed at each participating center. while bone-sped&
`parameters were measured centrally. lumbar spine bone mineral density (1)511)) was measured
`every 6 months with DXA using a standardized protocol. crosscalibratkm of insinuncets. and
`quality control procedures.
`Results showed 3 substantial increase of bone mass in all children. with an average HMI) Int.-RAW
`of 14.2 ± 10% after 1 year. One third of patients obtained a normal HMI) value. In comparison ihr
`average HMI) in 16 of the patients of the study followed during the year immediately preceding the
`onset of alendronaie therapy had increased by only 1% !fright mere-aux' by an an crape of 4 A .4 3
`cm during the study period. Scrum alkaline plitophataw decreased by lb 3 I I 2%. and urinary
`r.8%. Knee radiographs performed in prepubenal children
`procollagen telopeptyde by 26.8 (cid:9)
`showed absence of rickets and presence of metaphyscal lines The drug was well tolerated. except
`for occasional abdominal pain and one episode of esophagitis
`We conclude that alenelronate can be safely administered even in the pediamc age. and ilut ti
`significantly improves bone MASS in children or adolescents with rheumatic diseases and wrondin
`osteoporosis.
`
`Disclosure: work reported in this abstract was supported by:
`
`ACR Abstract Concurrent Session
`RA: TNF-Blockade
`Wednesday, November 17, 1999, 10:30 Am-12:00 em
`
`1977 (cid:9)
`
`EFFICACY OF ME FULLY IILIMAN ANTI-TNE ANTIBODY 1121.- IN RHEUMATOID ARTHRITIS L
`BA van de Pune, R Rau, F C lireedveld, J R Kalden, MG :Malaise vt schattenkirchner. P F.mery G I
`Burmener, H 7.ddler, H H MOMSOpOtliO3, D (:ompagnone, J Kempen'. El Kupper The Netherlands,
`Germany, Belgium. United Kingdom, Greece
`
`Objective: Dose-finding phase 11 study comparing 3 dose levels of 1)2E7 and placebo over
`3 months in patients with long standing active rheumatoid arthritis.
`Methods: A total of 283 patients were included In this randomised double-blind. placeba-
`controlled study. DMARDs were discontinued at least 4 weeks before study treatment Patients
`were randomised equally into lour arms to receive weekly doses of either D2E7 at 20. 10.80 nig
`or placebo by subcutaneous (s.c.) self injection for 5 months.
`Results: overall patient characteristics at baseline (median): age 53 years. duration of RA Syrtis.
`SWIC 18. TIC 30, ESR 45 nun/h. CRP 51 mg/I, 4 previous DMARDs. Clinical responses after 3
`months arc summarised below based on EIT analysis
`
`% of pis achieving ACR 20 response
`Median 94) improvement in TJC
`Median % improve lent in SWJC
`Median N improvement in (:101,
`
`Placebo
`
`D2E7 (cid:9)
`
`(n=70)
`10
`
`16
`
`20 mg (cid:9)
`(n=7I) (cid:9)
`49 (cid:9)
`57 (cid:9)
`42 (cid:9)
`55 (cid:9)
`
`1)2E7
`
`40 mg (cid:9)
`(n=70) (cid:9)
`57 (cid:9)
`61 (cid:9)
`59 (cid:9)
`6- (cid:9)
`
`D2E7
`
`80 rag
`(n=72)
`56
`55
`61
`65
`
`Conclusion: For all efficacy parameters studied, all doses of D28 were Statistically Significaraly
`superior to placebo (p < 0.001). 20. 40 and 8.0 mg/week were nearly equally efficacious when
`given s.c. in patients with active RA.
`
`Dtsclosure: work reported in this abstract was supported by:
`Grants supporting this work: Arthritis Foundation (1W-H). The Hirsh Foundation (EIiS), NIH
`AI44493 (JW-F1), AR4254 I (AM). and 05141873 (W515).
`
`Disclosure: work reported in this abstract was supported by:
`Study sponsored by Knoll AG, Ludwigshafen. Germany
`
`1975
`
`1978
`
`GLICOSAMINE SULFATE SIGNIFICANTLY REDUCES PROGRESSION OF KNEE GCNEOARLEIRMS OVER 3 YEARS, A
`LARGE RANI/MP:ED, PIACE110-CONTROLLED, DOUBLEBLIND, PROSPECTIVE TRIAL J-Y Reginster, R Deroisy,
`Paul, R 1. lay, Y. lienunin. G Giactwclli. J Dacre, L C Ratt. C Grasso
`
`Background Results of clinical trials suppon a rule for phnosamine sulfate. a s!inplisrn Modifying Deng in imourthritis
`(047. "nue testy sely designed to test the lorneterrn Hints Male slag efi the prop:J.04On of knee CLAjoint structural
`and symptoms Methods 212 patients with limn L/A (211:11 mite.) were randomly assigned. in a dethic-Mind Fashion. to
`the contintiolei treatment with oral gluommine sulfate 1500 rep otaccasini or plasrbo for 3 years Wright.lwaring
`ants-nip en or radiographs of each knee were. Liken at enrolment and after I and 3 years standardising patient positioning
`anal radinimphir procedure. Total mean joint spare wick', (I(Wl of the medial cnmpartnwnt of the tibk dens:oral joint was
`image analyst hy a validated :anum-Med algorithin. win the nommen medial Mint space at ornament
`lining taken for the primary outwit:on (Small:Sim :wring.). were scored in sack .1.momit Usk hr the 00141 WONLM:
`index, VA3.0 version. lama were analysed seiranitel) :nosed:lig to a per-Firinneiti IPIn approach on ,Ayear oimploces. in on
`an intentiortutu-at (fret) basis including all randomised patients by the lastobramationnanioklimsanl. Results. Tlw two
`palms.: of 106 patients each were [Ornineahie for demographic and disease eloractenstka. Pitcchotreated patients had an
`avenue joint space namming (ESN) of approximately 0.0/14/1 truniyear. while ms JSN occurred In the glass:minims sulfate
`group. A slight worsening in symptoms as ecident At Ihe end of treatment with placebo compared to the unpnreennnt
`olviervist after glitcosainine
`
`PP (cid:9)
`
`PP
`
`Placebo
`(.9-71)
`5.46 (0.15)
`4t 31 (0.13)
`094 (591
`-1-9.11% (12.3)
`
`Glatorsamine sulfate
`(N4:68)
`5.39 (0.16)
`40.07 (0.12)b
`1024 (591
`3% (6.4)d
`
`ITT (cid:9)
`
`Placebo
`(N=1116)
`5.39 (0.12)
`.0.24 (0.10)
`910 (47)
`+5.55 01.61
`
`ter
`
`Glueosamine sulfate
`(N=105).
`5.23 (11.13)c
`40.1210.0'2)
`Wth (46)
`45.4% (5.4)
`
`.1.211 enrolment (mm)
`.tsts 3 years finM)
`WOMAC enrolment
`varittion 3 roan
`
`allel are prennted as mean (SE).
`enrolment radiograph missing.
`(Hr. dp=11.016, `p.--11.04 vs. placebo (ANOVA)
`hp.-01130, (cid:9)
`Conclusions. Combined structure and Symptom Modifying effects suggest that glairosainthe sulfate may he a
`possible Disease Modifying agent In OA.
`
`Disclosure: work reported in this abstract was supported by:
`Work reported In this abstract W. supported hr the Roust Research Group
`
`LONG-TERM TREATMENT WITH THE FULLY HUMAN ANTI-TNF-ANTIBODY 02E7 SLOWS RADIO.
`GRAPHIC DISEASE PROGRESSION IN RHEUMATOID ARTHRITIS. R RAU, 0 Herborn. 0 Sander'.
`BA van de Putte, PLC van Riel, A den Brooder, M Schattenkirchner. J Wastlhuber. M Rill. R Rnner.
`J Kempen), H Kopper Germany, The Netherlands, Switzerland
`Objective: Long-term study of the effect of D2E7 on radiographic disease progressi1n) m parents
`with long standing active rheumatoid arthritis (RA).
`Methods: Patients were treated with iv 02E7 doses from 0.5 to 10 mg/kg for one vear month' at
`biweekly Intervals (study DE001/003). 66 patients with a complete set of X-rays of hands wrist. and
`feet taken at baseline, 6 and 12 months were evaluated . Additional X-rays preceding study cony
`(pre-value. mean minus t9 months) were available for 22 patients from the Ratingen cellar
`compare
`progression raant,ei svprequeanncdedoufritnhge fitrelmastment with 02r. X-rays were read setwee
`
`blinded ; he patientpr
`irresnkt
`Results: Mean radiographic score values over time are summarised for the total study P)Pula'iun
`01 = 66) as well as for the subgroup with preceding X-rays (n = 22).
`
`Mean RA duration
`Ratingen Score (0-190)
`Sharp erosion score (0-220)
`Sharp JSN wore ((-168)
`
`All centres (cid:9)
`
`(n=66) (cid:9)
`
`Centre (cid:9)
`
`Ratingen (cid:9)
`
`Baseline
`(12.1 yrs)
`47.0
`59.2
`53.9
`
`12 months
`(13-1 yrs)
`46.7
`59.0
`55.0
`
`Pre-value
`(10.2 yrs)
`34.6
`43.9
`45.5
`
`Baseline
`(11.8 yrs)
`41.2
`52.3
`51.7
`
`(n=22)
`
`12 [Waft
`(12.8 311)
`41.4
`52.3
`53.5
`
`During the treatment with 02E7 no evidence for radiographic progression was deserted in
`contrast to the preceding time period with DMARD treatment where a deterioration war 0hvlous
`Conclusion: The data suggest D2E7. a fully human anti-TNF antibody, slows disease P".
`in RA. This result warrants further evaluation.
`
`Disclosure: work reported in this abstract was supported by:
`Manly was supported by Knoll AG, Ludwigshafen. Germany
`
`Ex. 1003 - Page 3
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