l1
`
`85
`
`Technology evaluation: Adalimumab, Abbott Laboratories
`Hanns M Lorenz
`
`
`
`
`
`-—Materialmaybeprotectedbycopyrightlaw(Title1.7.,US.Code)
`
`Address
`
`Rheumatologyllnstitute for Clinical Immunology
`Department of Medicine “I
`University of Erlangen-Nuremberg
`Krankenhausstrasse 12
`91054 Erlangen
`Germany
`Email: Hannes.Lorenz@med3.imed.uni-ertangen.de
`
`Current Opinion in Molecular Therapeutics (2002) 4(2):185-190
`© PharrnaPress Ltd ISSN 1464-8431
`
`Adalimumab (D2E7), a human monoclonal antibody that binds to
`and neutralizes TNFa,
`is being developed by Abbott
`(formerly
`Knoll), under license from Cambridge Antibody Technology (CAT),
`for
`the potential
`treatment of inflammatory disorders such as
`rheumatoid arthritis (RA) and Crohn's disease [398274]. It is also
`being investigated for the potential
`treatment of coronary heart
`disease [394921]. Phase II studies for Crohn ’5 disease and phase III
`for RA were ongoing throughout 2001 [398274], [429705]. Limited
`data are only available for RA. In january 2002, it was reported that
`phase III trials of adalimumab for RA had been completed. but
`details have not been published in the primary literature so far. At
`this time CAT and Abbott expected to tile for US approval in the
`second quarter of 2002 with a launch date anticipated for 2003
`[407424]. [409724]. [412323], [435220], [436224]. Phase III data
`are expected to be presented at
`the European League Against
`Rheumatism meeting in June 2002 [436224].
`
`In November 2000. Lehman Brothers predicted a US launch in
`june 2002 with peak US sales of $600 million in 2007 and a
`launch in non—US markets in 2003 with peak sales in these
`markets of $300 million in 2008.
`In December 2000, Merrill
`Lynch predicted regulatory clearance in the second half of 2003
`[396280]. The probability of adalimumab reaching the market is
`estimated to be 70% [394921]. In December 2000, Merrill Lynch
`predicted a 2003 launch, with estimated sales of £3. 65 million in
`that year rising to £30.14 million in 2010 [394844]. In March
`2001, ABN AMRO predicted sales of $ 73 million in 2003 rising to
`$392 million in 2007 [422953].
`
`introduction
`the most common chronic
`is
`Rheumatoid arthritis (RA)
`autoimmunopathy (prevalence of ~ 1%), and clinically leads
`to
`joint
`destruction
`as
`a
`consequence
`of
`chronic
`inflammatory processes. The pathogenesis of this disabling
`disease is not well understood, but the molecular events
`
`leading to tissue inflammation with cartilage and bone
`destruction are now better defined. Established therapy with
`slow acting
`disease-modifying
`antirheumatic
`drugs
`(DMARDs), such as low-dose methotrexate (MTX), which is
`the
`accepted gold standard,
`leads
`to
`a
`significant
`improvement of disease symptoms, but does not stop joint
`destruction. Due to these disappointing treatment options
`and the identification of some inflammatory mediators as
`potential therapeutic targets, novel therapeutic agents such
`as monoclonal antibodies (mAbs), cytokine receptor-human
`immunoglobulin constructs or recombinant human proteins.
`have been tested in RA with some success. In particular.
`clinical
`trials testing anti—TNFor agents. either alone or in
`combination with MTX. have convincingly demonstrated
`the feasibility and efficacy of these novel approaches to the
`
`Originator Knoll GmbH
`
`Licensees Cambridge Antibody Technology Group plc,
`Eisai Co Ltd, Genzyme Transgenics Corp
`
`Status Pre-registration
`
`Action TNF binding agent, TNF ligand
`
`Knoll/CAT
`
`Indications Inflammation, Crohn's disease, Rheumatoid
`arthritis, Heart disease
`
`Biotechnology Monoclonal antibody (human)
`
`Synonyms LU-200134, D2E7, mAb (anti-TNFcc), humanized,
`
`testing a
`trial
`a clinical
`Imponantly.
`therapy of RA.
`combination therapy of the chimeric (mouse-human) anti-
`TNFD’. mAb infliximab (Remicade; Centocor Inc) and MTX
`demonstrated - for the first time in any RA trial - that the
`average radiological progression in the infliximab/MTX
`groups could be completely prevented over a 24-month
`observation period.
`
`The central role of TNFot in chronic inflammatory diseases
`like RA and Crohn's disease (CD) has been suggested by
`experimental in vitro and in situ data. More importantly. these
`studies have been verified by the overwhelming success of
`TNth-targeted therapies employing the chimeric antibody
`infliximab. and also the fusion product of the soluble TNF-
`receptor
`type I] and human IgGl
`etanercept
`(Enbrel:
`Immunex Corp). Both of
`these
`immunobiologicals
`are
`approved by the FDA and the EMEA. Thus, there is much
`enthusiasm behind the development of further strategies
`aiming at blocking TNFot with new and innovative drugs.
`Adalimumab (D2E7) is a genetically engineered. completely
`human antibody directed against TNFot, leading to its
`neutralization. In phase I and II trials in RA. adalimumab has
`proven to be an efficient and well-tolerated third—generation
`TNFa—targeting immunobiological.
`
`Synthesis and SAR
`D2E7 was generated by phage-display technology [347260].
`The high-affinity murine antibody MAK—IQS, displaying the
`desired specificity characteristics, was used as a template for
`guided selection. which involved complete replacement of
`the murine heavy and light chains with human counterparts
`and subsequent optimization of the antigen-binding affinity
`[227721]. The selected human VH and VI. domains were
`recombined, and the phage display and selection procedures
`repeated in order to generate a fully human IgGlK anti—TNF
`molecule [347253]. A comparison of the conventional CIEX-
`HPLC and cTEF methods has been made for the analysis of
`antibodies. Different Crtermina] lysine variants have been
`separated and collected from the CIEX column and
`subsequently analyzed by cIEF and
`[347253]. [355903]. The final selected V r AMGEN INC
`construct a whole IgGl molecule.
`EXhibit 1041
`
`
`
`
`
`Ex. 1041 - Page 1 of7
`
`
`Ex. 1041 - Page 1 of 7
`
`AMGEN INC.
`Exhibit 1041
`
`

`

`Technology evaluation: Adalimumab, Abbott Laboratories
`Hanns M Lorenz
`
`
`
`185
`
`
`
`-—Materialmaybeprotectedbycopyrightlaw(Title1.7.,US.Code)
`
`Address
`Rheumatologyllnstitute for Clinical Immunology
`Department of Medicine “I
`University of Erlangen-Nuremberg
`Krankenhausstrasse 12
`91054 Erlangen
`Germany
`Email: Hannes.Lorenz@med3.imed.uni-ertangen.de
`
`Current Opinion in Molecular Therapeutics (2002) 4(2):185-190
`© PharrnaPress Ltd ISSN 1464-8431
`
`Adalimumab (D2E7), a human monoclonal antibody that binds to
`and neutralizes TNFa,
`is being developed by Abbott
`(formerly
`Knoll), under license from Cambridge Antibody Technology (CAT),
`for
`the potential
`treatment of inflammatory disorders such as
`rheumatoid arthritis (RA) and Crohn's disease [398274]. It is also
`being investigated for the potential
`treatment of coronary heart
`disease [394921]. Phase II studies for Crohn ’5 disease and phase III
`for RA were ongoing throughout 2001 [398274], [429705]. Limited
`data are only available for RA. In january 2002, it was reported that
`phase III trials of adalimumab for RA had been completed. but
`details have not been published in the primary literature so far. At
`this time CAT and Abbott expected to file for US approval in the
`second quarter of 2002 with a launch date anticipated for 2003
`[407424]. [409724]. [412323], [435220]. [436224]. Phase III data
`are expected to be presented at
`the European League Against
`Rheumatism meeting in June 2002 [436224].
`
`In November 2000. Lehman Brothers predicted a US launch in
`june 2002 with peak US sales of $600 million in 2007 and a
`launch in non—US markets in 2003 with peak sales in these
`markets of $300 million in 2008.
`In December 2000, Merrill
`Lynch predicted regulatory clearance in the second half of 2003
`[396280]. The probability of adalimumab reaching the market is
`estimated to be 70% [394921]. In December 2000, Merrill Lynch
`predicted a 2003 launch. with estimated sales of £3. 65 million in
`that year rising to £30.14 million in 2010 [394844]. In March
`2001, ABN AMRO predicted sales of $ 73 million in 2003 rising to
`$392 million in 2007 [422963].
`
`introduction
`the most common chronic
`is
`Rheumatoid arthritis (RA)
`autoimmunopathy (prevalence of ~ 1%), and clinically leads
`to
`joint
`destruction
`as
`a
`consequence
`of
`chronic
`inflammatory processes. The pathogenesis of this disabling
`disease is not well understood, but the molecular events
`
`leading to tissue inflammation with cartilage and bone
`destruction are now better defined. Established therapy with
`slow acting
`disease-modifying
`antitheumatic
`drugs
`(DMARDs). such as low-dose methotrexate (MTX), which is
`the
`accepted gold standard.
`leads
`to
`a
`significant
`improvement of disease symptoms. but does not stop joint
`destruction. Due to these disappointing treatment options
`and the identification of some inflammatory mediators as
`potential therapeutic targets. novel therapeutic agents such
`as monoclonal antibodies (mAbs), cytokine receptor-human
`immunoglobulin constructs or recombinant human proteins.
`have been tested in RA with some success. In particular.
`clinical
`trials testing anti—TNFa agents. either alone or in
`combination with MTX. have convincingly demonstrated
`the feasibility and efficacy of these novel approaches to the
`
`Originator Knoll GmbH
`
`Licencees Cambridge Antibody Technology Group plc,
`Eisal Co Ltd, Genzyme Transgenics Corp
`
`Status Pre-registration
`
`Action TNF binding agent, TNF ligand
`
`Knoll/CAT
`
`Indications Inflammation, Crohn's disease, Rheumatoid
`arthritis, Heart disease
`
`Biotechnology Monoclonal antibody (human)
`
`Synonyms LU-200134, D2E7, mAb (anti-TNFcc), humanized,
`
`testing a
`trial
`a clinical
`Imponantly.
`therapy of RA.
`combination therapy of the chimeric (mouse-human) anti-
`TNFO’. mAb infliximab (Remicade; Centocor Inc) and MTX
`demonstrated - for the first time in any RA trial - that the
`average radiological progression in the infliximab/MTX
`groups could be completely prevented over a 24-month
`observation period.
`
`The central role of TNFot in chronic inflammatory diseases
`like RA and Crohn's disease (CD) has been suggested by
`experimental in vitro and in situ data. More importantly. these
`studies have been verified by the overwhelming success of
`TNth-targeted therapies employing the chimeric antibody
`infliximab. and also the fusion product of the soluble TNF-
`receptor
`type D and human IgGl
`etanercept
`(Enbrel:
`Immunex Corp). Both of
`these immunobiologicals
`are
`approved by the FDA and the EMEA. Thus. there is much
`enthusiasm behind the development of further strategies
`aiming at blocking TNFot with new and innovative drugs.
`Adalimumab (D2E7) is a genetically engineered. completely
`human antibody directed against TNFot, leading to its
`neutralization. In phase I and II trials in RA. adalimumab has
`proven to be an efficient and well-tolerated third—generation
`TNFa—targettng immunobiological.
`
`Synthesis and SAR
`D2E7 was generated by phage-display technology [347260].
`The high-affinity murine antibody MAK—IQS, displaying the
`desired specificity characteristics. was used as a template for
`guided selection. which involved complete replacement of
`the murine heavy and light chains with human counterparts
`and subsequent optimization of the antigen-binding affinity
`[227721]. The selected human VH and VI. domains were
`recombined, and the phage display and selection procedures
`repeated in order to generate a fully human IgGlK anti—TNF
`molecule [347253]. A comparison of the conventional CIEX-
`HPLC and cTEF methods has been made for the analysis of
`antibodies. Different Catermina] lysine variants have been
`separated and collected from the CIEX column and
`subsequently analyzed by cIEF and mass spectometry
`[347253]. [355903]. The final selected V regions were used to
`construct a whole IgGl molecule.
`
`
`
`
`Ex. 1041 - Page 2 of 7
`
`
`Ex. 1041 - Page 2 of 7
`
`

`

`186 Current Opinion in Molecular Therapeutics 2002 Vol 4 No 2
`
`Pharmacology
`In receptor binding studies, adalimumab demonstrated [Cm
`values between 7.8 x 10” [282183] and 15.6 x 10” M [347260].
`Functionally. D2E7 performed comparably to the original
`murine antibody in a set of in vitro assays. D2E7 binding is
`characterized by a fast on-rate (1.9 x 10” Mls') and a slow off»
`rate (8.8 x 105 s') [347253]. In another report, these data are
`reported as 4.7 x 10"M 's' and 4.8 x 1035'. respectively [355903].
`Thus. the dissociation constant for D2E7 and TNFot is 1 x 10 w M
`[355903]. D2E7 inhibits TNFot binding to both receptors
`[347260]. It blocks TNFot-induced cytotoxicity (LQ29 cells 1C50 =
`12.5 x 10” M) or ELAM-l expression on HUVEC endothelial
`cells with an to... value of 18.5 x 10“ M [347253]. [347260]. D2E7
`binds
`to proTNFoc on cell membranes
`and mediates
`complement-dependent cytotoxicity. and also binds to Fc
`receptors on human cells to mediate antibody-dependent
`cytotoxicity [347253]. In animals. D2E7 protected mice from the
`lethal effect of a human TNF/D—galactosamine combination
`with an ED50 value of 1 to 2.6 pg/mouse [347253]. In rabbits. the
`molar ratio of D2E7 to TNF at the lowest dose that completely
`inhibited pyrexia was 3:1
`[347253]. In the TNFot
`transgene
`arthritis model. D2137 injected intraperitoneally prevented the
`induction of arthritis in a dose~dependent manner as evidenced
`on both clinical and histological grounds [347254], with an EDE0
`value of approximately 0.3 to 0.5 mg/kg [347253]. Spontaneous
`secretion of reactive oxygen species was inhibited during
`treatment of RA patients with D2E7 [347261].
`
`Metabolism
`Pharmacokinetic parameters calculated for 89 patients from
`all dose groups of one of the phase I studies demonstrated a
`systemic drug exposure (area under
`the curve: AUC)
`increasing proportionally with increasing dosages [355898].
`The mean total serum clearance was 0.18 to 0.271 ml/min.
`and the steady state volume of distribution ranged from
`0.063 to 0.76 l/kg. indicating that distribution of D2E7 was
`mostly in the intravascular space. The estimated mean
`terminal half—life was 11.6 to 13.7 days in these studies
`[355898]. There were no differences
`in the plasma
`concentrations between patients receiving the drug as a
`subcutaneous injection versus those receiving intravenous
`__, administration [347256]. [355898].
`
`Toxicity
`Apart from local injection site reactions, no further toxicities
`have been reported in phase I and II trials. For example, in the
`ARMADA phase II trial, injection site reactions occurred more
`frequently in D2E7-treated patients versus placebo (15.2
`versus 3.2%), whereas other adverse events were generally
`similar
`in
`the
`treatment groups
`[429104]. Since
`the
`therapeutical principle is identical to the two other anti—TNFOt
`immunobiologicals, the specific side effects of etanercept and
`infliximab (ie, the reactivation of tuberculosis and listeriosis.
`autoimmune phenomena
`(eg.
`induction of antinuclear
`antibodies),
`neutropenia.
`aplastic
`anemia.
`neurological
`symptoms) can be expected. However, none of these toxicities
`have been commented on in the publications on D2E7.
`
`Clinical Development
`Phase!
`In a single«dose ascending phase I trial, 120 RA patients
`were treated with adalimumab in a placebo—controlled.
`double-blinded fashion [347258]. After a wash-out period of
`
`3 weeks. the patients received a single intravenous dose of
`D2E7 (or placebo) as an injection over 3 to 5 min. Patients
`were treated in dose groups of 24 patients (18 verum. six
`placebo) at dose levels of 0.5, 1. 3. 5 and 10 mg/kg. Patients
`were followed up for at least 4 weeks or longer in case of
`lasting response as evaluated by disease activity score
`(DAS), Treatment was well tolerated. The therapeutic effect
`became evident within 24 h of drug administration and
`peaked at weeks 1
`to 2. A clinical response (drop in DAS
`score of at least 1.2) was reported for 19. 41, 72, 67. 56 and
`78% of the patients treated with placebo or the various D2E7
`dosages in ascending order. Response rates at day 29 after
`dosing were 0. 6. 28, 33. 44 and 39%, respectively. with some
`responses lasting up to 12 weeks [347258]. In parallel to this
`study,
`the short-term effects on the local and systemic
`homeostasis of interleukin-10 and TNth was investigated
`[441361]. The single dose of D2E7 reduced acute phase
`reactants
`and
`increased
`lymphocyte
`counts.
`Serum
`concentrations of IL—l—receptor antagonist, TNFu receptor I
`(p55) and II
`(p75), and IL—6 rapidly decreased. Despite
`clinical
`improvement
`of
`arthritis,
`no
`consistent
`immunohistological
`changes were seen 2 weeks after
`adalimumab administration [441361].
`
`received
`trial
`this
`In a follow-up study. patients of
`intravenous D2137 (0.5 to 10 mg/kg for one year) mostly at
`bi—weekly intervals. 66 Patients with a complete set of
`radiographs of hands, wrists and feet taken at baseline, 6
`and 12 months were evaluated for radiographic signs of
`disease progression. X-rays were read setwise blinded to
`patient identity and sequence of the films. During treatment
`with D2137 no evidence
`for
`radiological progression,
`particularly in Sharp erosion and the Ratingen score. was
`observed [355899]. This has again been prospectively
`investigated in the phase III trials, the data from which.
`however, are not currently available.
`
`Another phase I study in 24 RA patients evaluated the
`efficacy
`and
`tolerability
`of weekly
`subcutaneous
`administrations of D2E7. After a wash-out period of 3
`weeks, patients received weekly doses of 0.5 mg/kg D2137 or
`placebo for 3 months in a double-blinded fashion [347256].
`A clinical response was again defined as a drop in DAS
`score of at least 1.2. After the 3—month period. all patients
`were offered a continuation with 0.5 mg/ kg for responders
`or 1 mg/kg for non-responders. For D2E7—treated patients, a
`mean drop in DAS score of > 50% was reported [347256].
`
`Phase II
`A dose—finding phase II trial with three dose levels was
`performed and reported at the Congress of the American
`College of Rheumatology in 1999 [355902]. 283 RA patients
`were included in this double-blinded. placebo-controlled
`study with patients in whom DMARDs had been stopped at
`least 4 weeks before inclusion. Patients were randomized
`into four arms receiving weekly doses of either placebo or
`D2E7 at 20, 40 or 80 mg by subcutaneous self-injection for 3
`months. For all efficacy parameters evaluated (ie, DAS.
`number of swollen joints.
`tender joints and serologicaJ
`parameters of inflammation) all doses were significantly
`superior compared with placebo. and the best results were
`seen in the two highvdose groups (55 to 67% improvement)
`[355902]. This study was extended for another 9 months in a
`blinded fashion. At 12 months,
`the American College of
`
`
`
`Materialmaybeprotectedbycopyright-law(Title17.US.Code)
`
`Ex. 1041 - Page 3 of 7
`
`
`Ex. 1041 - Page 3 of 7
`
`

`

`Adalimumab Lorenz 187
`
`20%
`for
`criteria
`response
`(ACR)
`Rheumatology
`improvement were fulfilled by 14. 46. 60 and 56% 0f the
`patients treated with placebo. 20, 40 and 80 mg D2E7,
`respectively. whereas ACR 50% criteria were fulfilled by 3.
`25. 43 and 31% of
`the patients.
`respectively.
`It was
`concluded that all D2E7 doses were significantly superior to
`placebo without statistically significant differences between
`the verum groups [444685].
`
`The ARMADA trial (anti-TNF Research Study Program of
`the Monoclonal Antibody D2E7 in Patients with RA)
`included 271 patients who did not respond well to MTX.
`This was a 24—week. double~blinded. placebo-controlled
`phase II study. All patients had failed between one and four
`DMARDS prior to MTX therapy. All patients continued on
`MTX and were randomized to receive either D2E7 (n = 209)
`at 20. 40 or 80 mg doses or placebo (n = 62) administered
`subcutaneosuly by self injection every other week. Results
`were measured using ACR criteria. ACR 20. ACR 50 and
`ACR 70 represent the percentage of improvement (20. 50
`and 70%)
`in tender and swollen joint count and other
`relevant clinical measures. such as pain scale and physician
`assessment of disease activity. At 24 weeks, amongst all
`DZET patients, 62.2% achieved ACR 20 versus 14.5% in the
`placebo group, 43.5% achieved ACR 50 versus 8.1% in the
`placebo group. and 19.1% achieved ACR 70 versus 4.8% in
`the placebo group (p S 0.02 for all D2E7 doses versus
`placebo). 18 Patients withdrew from the study (nine from
`D2E7 and nine from placebo) [444686].
`
`Additionally. researchers examined the effect of D2E7 on
`serum concentrations of two enzymes possibly associated
`with joint destruction. pro~metalloproteinase-l and pro—
`metalloproteinase-3 (MMP-1
`and MMP~3).
`in the
`271
`patients through week 24 of the ARMADA trial. At 24
`weeks. patients in the D2E7 treatment group had a 23.3%
`decrease in MMP-1 and a 26.6% decrease in WIMP-3. versus
`an increase of 10.4% in MMP-1 and an increase of 17.8% in
`MMP-3 in the placebo group (p < 0.01) [444686]. These data
`have been confirmed in similar investigations performed in
`parallel to the other phase II study with 283 RA patients
`[415029].
`
`'Phase III
`A phase III trial has been completed [436224]. but no data
`are currently available.
`
`Side Effects and Contraindications
`As mentioned above,
`the only side effect attributable to
`D2E7 published so far are local
`injection site reactions
`(ARMADA phase II
`trial
`injection site reactions to D2E7
`versus placebo: 15.2 versus 3.2%). Other adverse events
`were generally similar in the treatment groups [429104].
`
`It should be emphasized that the therapeutic principle is
`identical
`to the two other anti-TNFot immunobiologicals.
`etanercept and infliximab. Therefore.
`special attention
`should be paid to their specific side effects. which include
`reactivation of infections such as tuberculosis (especially
`seen with infliximab within the first 3 months of treatment)
`or listeriosis, induction of autoimmune phenomena. such as
`the appearance of antinuclear antibodies. development of
`hematological disturbances like neutropenia or aplastic
`
`anemia or neurological symptoms (the latter two especially
`seen with etanercept). Thus. these toxicities can be expected.
`and it would be very surprising if none of these side effects
`are seen with D2137 treatment. However.
`in none of the
`sparse publications have these effects been commented on.
`
`Current Opinion
`is the third immunobiological agent
`Adalimumab (DZE7)
`(besides etanercept and infliximab) directed against TNFot,
`and has been intensively investigated in the treatment of RA.
`with great success. Similarly to etanercept and infliximab.
`adalimumab has great therapeutic potential in the treatment
`of RA and probably many other related diseases. such as
`Crohn's disease. chronic non-rheumatoid arthritides. chronic
`recurrent uveitis, vasculitis. plasmocytoma. chronic graft—
`versus»host
`disease.
`amyloidosis
`and many
`others.
`Contraindications could include chronic heart failure, sepsis.
`tuberculosis
`(at
`least
`if not concomitantly treated). and
`possibly also drug—induced systemic lupus erythematosus.
`However.
`this statement
`is only extrapolated from the
`datasets of etanecept and infliximab and has not been
`demonstrated in a clinical setting with D2137.
`
`Adalimumab is unique in its production procedure and
`structure as it is the first fully human anti-TNFOL antibody.
`This structure promises
`lower antigenic properties as
`compared with the chimeric (murine/human) antibody
`infliximab. or etanercept (a fusion protein of two TNF~type
`11
`receptors and human IgGl). However. glycosylation
`differences might still render certain sites immunogenic.
`although this is speculative at
`this point. None of the
`available data indicate that
`the company tested for
`the
`development of antibodies against DZE'.’ inpatients during
`the clinical trials.
`
`The clinical efficacy data do not suggest any particular
`advantage of one antivTNF drug over the other two. as ACR
`and DAS responses appear to be approximately equal for all
`three therapeutics. Adalimumab's onset of improvement
`seems to be similar to that seen with infliximab. but faster
`
`than etanercept. One advantage of adalimurnab over
`infliximab and etanercept
`lies
`in
`the
`fact
`that both
`subcutaneous and intravenous routes of administrations have
`
`that
`imply
`also
`data
`efficacy
`evaluated. The
`been
`to
`approximately 30% of patients are non~responders
`adalimumab. In some cases it has been observed that after
`
`switching a non-responder from infliximab to etanercept. or
`vice versa. clinical signs of disease activity improved. It will
`be intersting to see whether this will be true for D2E7 as well.
`
`Disease progression has been shown radiographically to be
`halted by treatment with infliximab plus MTX over a period
`of at
`least 24 months
`[444688]. Similarly.
`retrospective
`radiological data were obtained for D2E7 in monotherapy
`and are very promising [355899]. However. the patients in
`this study have been treated with various doses (0.5 to 10
`mg/kg iv mostly bi—weekly). No dose-response data were
`evaluated or have been demonstrated for
`radiological
`damage scores. Thus. these results need to be confirmed in a
`prospective study (these data have been assembled in the
`course of the phase III study). Etanercept in monotherapy
`has been less successful as it slowed disease progression
`without halting it. as shown radiologically [444690]. Thus. if
`
`lose of
`atients
`1m. six
`atients
`:ase of
`score
`: effect
`in and
`n DAS
`56 and
`s D2E7
`9 after
`1 some
`to this
`*stemic
`
`tigated
`phase
`Serum
`
`eptor I
`)espite
`ts'gstent
`. O
`.Oafter
`CD:3
`
`:géived
`igtly at
`get of
`rlfile. 6
`(U
`s of
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`ients. a
`i6].
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`is was
`ierican
`atients
`trolled
`
`iped at
`imized
`:ebo or
`n for 3
`DAS,
`[logical
`icantly
`s were
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`ege of
`
`
`
`
`
`Ex. 1041 - Page 4 of 7
`
`
`Ex. 1041 - Page 4 of 7
`
`

`

`f M
`
`188 Current Opinion in Moiecular Therapeutics 2002 Vol 4 No 2
`
`D2E7 indeed turns out to be potent enough to stop joint
`destruction in monotherapy (based on data obtained in a
`prospective. double-blinded fashion).
`it would prove to be
`more efficient than either infliximab or etanercept.
`
`Dosing studies indicate that weekly injections of 40 mg
`DZET alone. or biuweekly injections of 40 mg against an MTX
`background. promise optimal results. This dosing regime
`totals 320 mg (160 mg plus MTX) over 8 weeks, which
`compares with 200 to 400 mg of infliximab (only approved
`in combination with MTX) and 400 mg of etanercept
`required for
`the same time interval. Thus,
`the smaller
`amount of adalimumab required might
`lower the costs
`associated with its use in comparison with infliximab and
`etanercept. Certainly, as the market becomes more saturated
`(ie, if and when D2E7 is approved), it is likely that the prices
`of all three agents will decline.
`
`study results have been published in an acceptable form as
`full. peer-reviewed papers, Thus.
`the current opinion is
`based solely on information from abstracts. press releases
`and review papers. and is therefore speculative and not
`supported by peer-reviewed published data. This
`is
`especially true for side effects; none of the abstracts report
`any side effects. with the exception of injection site reactions.
`However, given the fact that short— and long-term treatment
`with infliximab and etanercept is not free of adverse events.
`it is expected that DEE? will have its own problems. The fact
`that
`there are no accessible data that
`focus on these
`problems. despite the fact that some patients have received
`the drug for more than three years. is unacceptable.
`
`In conclusion. D2E7 promises to qualify as an additional
`central player in the treatment of rheumatoid arthritis.
`Publication of the clinical
`response data and adverse
`effects is urgently needed in order to find acceptance in the
`clinical
`field as a valuable competitor to infliximab or
`etanercept.
`
`The major drawback in the current evaluation of DZE7 is the
`unavailability of confirmed data, as none of the clinical
`_____________————————————-
`
`Licensing
`Cambridge Antibody Technology Group plc
`isolated and optimized a human
`In collaboration with Knoll
`(now Abbott). Cambridge Antibody Technology (CAT)
`monoclonal antibody against TNFOL. Given the code D2E7,
`it has potential in the treatment of rheumatoid arthritis and
`Crohn's disease. Knoll was to be responsible for conducting clinical trials and CAT was to receive milestones and royalties.
`During the first quarter of 2000. CAT received a milestone payment from BASF in relation to the commencement of phase III
`trials with D2137 [367617].
`
`Eisai Co Ltd
`in June 1999, Knoll and Eisai signed a codevelopment agreement for D2E7 for rheumatoid arthritis in Japan. The companies
`were to conduct clinical trials jointly and Eisai was to also have rights to sell the product in Japan, Taiwan and Korea
`[328664].
`
`Genzyme Transgenics Corp
`Genzyme Transgenics was collaborating with BASF in the development of the antibody [333458].
`
`aterialmaybeprotectedbycopyri‘ght’law-(Title17,US.Code)
`
`'
`
`.
`
`.
`
`'
`
`'
`
`' -'
`
`Development history
`' County '-
`Develoggr
`US
`Abbott Laboratories
`_ _Western Europe _
`Abbott Laboratories:
`'Germany'
`_
`-
`Abbott Laboratories
`" Japan -.3
`,:
`Abbotttaboratories
`Japan: '-
`7
`'
`EisaiCo'Ltd-
`Cambridge Antibody Technology-.1 _ _:;UK ,
`Grouppic
`-
`_-
`_
`'Cambridge Antibody Technology,
`. UK'
`
`I
`
`_
`
`.
`
`_
`3
`
`'
`
`_
`
`1
`
`"
`Status“ '
`Pro-registration
`Preeregistration
`Phase“
`'_ Phase g
`'Phaséi
`[Discovery
`- Z.'
`{Discovery .
`
`3
`
`- Data
`' " '-
`'
`-- Indication
`_ OQ-APR-{H
`Rheumatoid arthritis
`DQdAPR-Oi
`. Rheumatoidarthrltis
`- 19‘MAR'451
`-_Croh'n's disease.
`'
`its-MAH-et
`Rheumatoid arthritis 3'
`14-SEP-oo
`' :Bheomaioid arthritis
`Rheumatoid arthritis -.3: m-see-sr
`'
`,.
`.
`:Heart disease-
`7
`
`'-
`
`3
`
`i
`
`iQaJAN-{ii
`
`Reference
`446715
`446715
`398274
`398274
`382197
`258755
`
`394921 I
`
`_
`
`Genzyme nansgmscem :_
`
`i.
`
`3 :US- _;
`
`.
`
`[Discovery -.
`
`Rheumatoid arthritis
`
`' moot-99
`
`333458
`
`Literature classifications
`Key references relating to the technology are classified according to a set of standard headings to provide a quick guide to
`the bibliography. These are as follows:
`Chemistry: References which discuss synthesis and structure-activity relationships.
`Biology: References which disclose aspects of the drug's pharmacology in animals.
`Clinical: Reports of clinical phase studies in volunteers providing, where available. data on the following: whether the
`experiment is placebo-controlled or double- or single-blind; number of patients: dosage.
`
`EX. 1041 - Page 5 of 7
`
`
`Ex. 1041 - Page 5 of 7
`
`

`

`——i
`Adaiimumab Lorenz 189
`
`
`
`ybeprotectedbycopyrightlaw(Title17,US.Code)
`
`Materialma
`
`Chemistry
`Stud T
`Synthesis and SAR.
`j
`
`-
`
`-
`Result
`The construction and characterization of'D2E7 is described.
`.
`
`.
`
`Biology
`Stud T _
`In vitro
`
`In vitro
`
`.
`
`Clinical
`Effect Studied
`Efficacy and
`tolerabiiity.
`-
`
`Efficacy.
`
`Efficacy.
`i
`
`Efficacy.
`
`.
`
`'
`
`Effect Studied
`Cyctotoxicity.‘
`
`'
`
`'
`rimental Model
`Ex
`TNF-mediated lysis of L929 cells;
`
`Result
`' Inhibition of TNF.
`
`Expression of adhesion moiecules.
`'
`
`TNF-mediated upregulation of
`ELAM-1 on endotheiiat ceiis.
`
`I Inhibition. of TNF;
`'
`
`;
`Model Used
`Phase i trial in 24 RA patients. Weeidy 5: injections (0.5
`mg/kg D2E7 or- placebo) for 3 months; after .3 months,
`continuation with 0.5 mgIkg for responders 1 mglkg for.
`non—responders.
`
`_
`
`_
`
`1
`-
`-
`-
`- Result
`Significant drop indisease activity
`score observed with 0257-.
`-
`.
`-
`
`Single dose was Well tolerated, with
`Phase I trial in 120 RA patients receiving D2E7 (placebo
`evidence of reduced disease activity
`_ 05,1 3, 5 and 10 mglkg iv).
`.
`. :Wellioiérafedand efficacious;The study.
`Phaseii, randomized, double-blind, placebo-controlled
`was prolonged for over one year.
`_
`trialin 233RA patients Weekly so injection withplacebo__
`.
`.
`.
`.
`.
`.or. 02E?at 29, 40 or 80- mg for 3 months.
`' Phase .Ii, 24-week, double-blind, placebo-controlledin271' Wail tolératedandsiilicacious.'_ "
`RA patients without sufficient response of MTX thorapr
`Placebo in; 62), D2E7-20 40 or 80 mg (n: 209} so -
`biweekly.
`
`_
`
`I
`
`Reference
`347253
`347250
`355903
`
`Relerence
`347260
`
`347260
`
`Reference
`347256
`
`347258
`
`355902 _.
`444685
`
`-
`I 444686
`
`'
`
`Associated patent
`
`Title Human antibodies that bind human TNFu.
`
`Assignee BASF AG
`
`Publication WO-09279131 14—AUG—97
`
`Priority USS-00599226 09-FEB-96
`
`Inventors Salield JG. Allen DJ. Kaymakcalan Z, Labkovsky B. Mankovich JA,
`McGuiness BT. Roberts AJ et al.
`
`Associated references
`
`.
`
`of special interest
`
`IBC International Conference on
`227721 Seventh annual
`Antibody Engineering: New Technology, Application
`&
`Commercialization, Coronado, USA.
`IDDB MEETING REPORT
`1996 December 2-4
`
`258755 Approval to start clinical trials for human anti-TGFB2
`monoclonal
`antibody. Cambridge Antibody Technology Ltd
`PRESS RELEASE 1997 August 08
`
`IBC Conference New
`-
`282183 Antibody Engineering
`Technology, Application and Commercialization, London, UK.
`Wilton J, Braddock P, Smith S, Smith S 1008 MEETING REPORT
`1998 March 2-3
`
`328664 Eisai and BASF Pharma announce agreement to co-
`develop Knoll's new anti-rheumatic in Japan.
`Elsai Co Ltd
`PRESS RELEASE 1999 June 21
`
`347253 Development of a fully human anti-TNF monoclonal
`antibody. Kaymakcalan Z, Kollias G, Haralambous S. Roberts A,
`Baneriee