I70
`
`Ann Rheum Dis 1999;58;(Suppl I) [70—173
`
`I)?
`
`Prehmlnary results of early clinical trials Wlth the
`fully human anti—TNFOL monoclonal antibody
`D2E7
`
`Joachim Kempeni
`
`to these
`Current pharmacological treatments for rheu- The development of antibodies
`matoid arthritis (RA), including non-steroidal
`biological agents could reduce their half life,
`anti~infiarnmatory drugs (NSAIDs), disease
`thereby decreasing efficacy.a In addition, an
`modifying anti-rheumatic drugs ('DMARDS),
`immune response could result
`in adverse
`and corticosteroids,have been moderately suc-
`events from the formation of immune com-
`cessful in alleviating the discomforts associated
`plexes or the development of hypersensitivity.
`with swollen, painful joints. However, conven— For these reasons, an antibody that is fully
`tional medical approaches to treatment have
`human may have greater therapeutic potential.
`had little or no impact on the disease course of
`RA.‘ Innovative strategies, particularly those Development of a fully human anti—INF
`based on new concepts in the immunobiology
`antibody
`to develop a fully
`of RA, are being developed to target cellular BASF Pharma set out
`inflammatory mechanisms and potentiallypre-
`human, anti-TNF mAb structurally identical
`vent disease progression. The more promismg
`to naturally occurring human antibodies and
`of these treatments seem to be those that block
`therefore less likely to engender an immune
`the effects of tumour necrosis factor.(TNF) a,
`response in the recipient. The generation of a
`because this proinflarnmatory cytolune seems
`fully human anti-TNF mAb required bioengi—
`to'play a central part “1 the immunopathogen— neering techniques” that mimic immune selec-
`eSis OfRA‘
`tion in humans and contrast with existing
`means of "humanising” murine monoclonal
`antibodies in that the antibodies derived are
`Aflfl'TNF treatments
`completely human. The result of this effort is
`Bidogica] agents sum as mfibOdies and
`soluble TNF receptors that bind TNF a with D2E7, a new c1355 of anti—TNF mAb, which
`high SPECifiCiW neutralise its activity and have may have advantages in minimising antigenic—
`been developed for use as therapeutic agents.
`ity in humans.
`Several are currently being evaluated in pa-
`
`tients with RA (table 1). Infliximab, CA2, is a Preclinical pharmacology
`chimeric figsnoclo{:11} antibodfy (Mb) that The eflicacy and safety ofD2E7 were evaluated
`TlCODIFs’sitfixb
`e veil: e 1:510“ 0 a mun“? mu} in a number of experimental systems. The abil-
`coupse
`to
`e constant region 9
`ity of D2137 to neutralise 'I'NF bioactivity was
`human. IgGlK'
`“Fe resulting consn'uct 15
`demonstrated in three different in vitro cell
`approximately two third? human. CDPS“ ls a
`systems. Additionally,
`the
`effectiveness of
`humanised mAb 'conSistmg of the comple- D2E7 in preventing polyarthritis was shown in
`mentanty deternumng regions Of a munne
`a transgenic mouse model
`that mimics the
`“mm mm) grafted Him a hm?“ “mm!"
`clinical and histopathological progression of
`noglobulino (IgG41c). Th's mAb .13 approxr- RA in humans." D2E7 treated mice showed no
`mately 95% .human. Etanercept 15. a fuston
`clinical signs of arthritis during the 11 week
`protein CODSISUDg of two recombinant p75
`study period Microscopical examinations of
`TNFreceptors attached to the Fc portion of a
`th ankl
`.
`I
`ts
`f th
`.
`al
`h w d
`humanlgGl.’ Although this construct consists
`.e
`'e ’01.“
`0
`e mm s s o e
`no
`.
`.
`histopathological changes. In contrast, control
`Of two independent elements, meh them- mice developed severe arthritis with cartilage
`selves
`contain 100% human peptide se-
`destruction and bone erosion
`quences, they are arranged in an unnatural
`'
`configuration.
`The duration of the therapeutic eflicacy of
`these TNF antagonists may be limited by an
`immune response to their non-human ele-
`Correspondence to:
`Dr I Kempeni.
`ments or artificially fused human sequences.
`771171: I Ami-INF a treatment:
`
`Devartment “Clinical
`Oncology/Immunology,
`KnonAG-BASF
`PhamaaKnollsl-fissea
`13-67008 Ludwigshafen,
`Germany
`
`Daunp'rim
`N
`I
`"M
`Fully human and-TNF a mAb
`D2137
`Humanised anti-Na mAb (mufine CDR)
`CDPS'II
`Fusion protein consisting of two recombinant p75 TNP :1
`Eraneroept
`receptors and the P: portion ofhumnn Ith
`Chum!“ mumdh‘mI-‘m “WW4 Mb
`hflmm'b (=52)
`factor,
`necrosis
`TNF=tumour
`rnAbL‘monaclonnl
`antibody;
`IgG=immunoglubulin G;
`CDR=complcmcntarity determining region.
`
`Preliminary clinical data
`There are important similarities in the designs
`of the early clinical trials assessing D2E7 in
`RA. All studies enrolled patients with an estab-
`lished diagnosis of RA who also had active dis—
`ease, as evidenced by having a combination of
`swollen and tender joints, increased concentra-
`.
`trons of acute phase reactants, and prolonged
`e
`'
`fiffn
`.
`'
`‘
`'
`. arl}; flea-3:3 s .
`ess .gladdlté9n’ all trials
`“ENG ve
`Fallen“ WI
`OPE lsease dura'
`tron and a history of failure of several
`DMARDs. During the trials, patients were
`allowed to continue stable doses of NSAIDs
`and corticosteroids. Efl'icacy was
`assessed
`
`AMGEN INC.
`
`Exhibit 1040
`
`EX. 1040 - Page '1 Of 4
`
`Ex. 1040 - Page 1 of 4
`
`AMGEN INC.
`Exhibit 1040
`
`

`

`Clinical trials with thefully human anti-TNFa monoclonal antibody DZE7
`
`[71
`
`using composite criteria, such as the American
`College of Rheumatology improvement criteria
`(ACR 20)” and the Disease Activity Score
`(DAS)? Such criteria, which require improve-
`ment in multiple variables, are more stringent
`than is improvement in one or only selected
`clinical variables. For example, to be classified
`as a responder according to ACR 20 criteria,
`patients must demonstrate: (1) greater than or
`equal
`to 20% improvement in swollen joint
`count;
`(2) greater
`than or equal
`to 20%
`improvement in tender joint count and; (3) at
`least 20% improvement in three of five other
`measures (patient global assessment of disease
`activity, physician global assessment of disease
`activity, patient assessment of pain, an acute
`phase reactant (for example, erythrocyte sedi-
`mentation rate (ESR) or C reactive protein),
`and a measure of disability (for example, the
`Health Assessment Questionnaire». The DAS
`is a composite score of tender joints, swollen
`joints, ESR and patients assessment of disease
`activity as measured on a visual analogue scale.
`Preliminary results of early trials of D2E7
`are available (table 2). At
`the time of this
`review, some of the studies referenced have
`only been published in abstract form. In a ran-
`domised, double blind, placebo controlled
`phase I study, 120 patients were treated with
`single doses of D2E7 given in an ascending
`fashion ranging from 0.5 to 10 mg/kg.”
`Patients were treated in cohorts of 24 (18
`patients were treated with D2137 and six
`received placebo). After a wash out period of
`three weeks, the patients received a single dose
`of D2E7 or placebo by intravenous injection
`over 3—5 minutes. Patients were followed up for
`at least four weeks to determine the pharma-
`cokinetics of DZE7, as well as to evaluate the
`safety and clinical efficacy of the compound in
`terms of onset, duration and magnitude of
`response. Positive response was defined as a
`decrease of at
`least 1.2 (compared with
`baseline) in the DAS. All parameters needed to
`calculate the response criteria as defined by the
`ACR 20 were also measured. Patients in whom
`the effect of D2E7 had declined below
`response status by week 4 entered an open label
`extension study. However, patients who main-
`tained a response at week 4 were continued
`without retreatment until their response status
`was lost. Thereafter, these patients could also
`continue in the extension study.
`The data from this first therapeutic trial in
`humans were very encouraging. In the three
`highest dose groups, 40—70% of patients
`Table 2 Early trials of D257 in rheumatoid arthritis
`
`achieved DAS and ACR 20 response status at 24
`hours to 29 days of treatment. The therapeutic
`effects became evident within 24 hours to one
`week alter D2137 administration and reached the
`maximum effect after 1-2 weeks, with dose
`response reaching a plateau at 1 mykg D2137. In
`contrast, only 19% of patients taking placebo
`achieved response status. Single doses of D2E7
`were well
`tolerated and the dose increment
`scheme was followed as planned resetting the
`maximum dose of 10 mg/kg without any
`evidence of clinically relevant or dose related
`adverse effects. Pharmacokinetic parameters
`were calculated for a total of 89 patients from all
`dose groups. The systemic drug exposure
`(AUC) increased proportionally with increased
`dose. The mean total serum clearance was 0.180
`to 0.271 ml/min, and the steady state volume of
`distribution ranged from 0.063 to 0.076 llkg
`indicating that distribution of D2137 was mostly
`in the intravascular space. The estimated mean
`terminal half life was 11.6 to 13.7 days.
`Patients who participated in the open label
`extension study received a second blinded dose
`identical to their first dose (medication was
`given after a minimum period of four weeks
`and only after loss of their initial response
`status)." From the third dose onwards, all
`patients were given active drug (that is, the pla-
`cebo patients received D2137 doses according
`to their dose group). D2137 was administered
`every two weeks until responses could be rated
`as “good", defined as an absolute DAS of <
`2.4. To measure the duration of the good
`response, these patients were retreated only
`upon disease flare up. To keep as many patients
`as possible in the study for the long term evalu-
`ation of safety, patients who did not respond
`well after 0.5 or 1 mg/kg received higher doses
`of up to a maximum of 3 mg/kg. Doses Were
`kept constant in the patients on 3, 5 or 10
`mg/kg. Treatment
`lasting several years
`is
`intended. The response in the DAS over time
`demonstrated sustained therapeutic eflects and
`some continuing improvement after multiple
`infusions of D2E7. Response rates of more
`than 80% have been achieved with a mean
`dosing interval of 2.5 weeks. After six months,
`86% of patients continued to receive treatment
`with D2E7 indicating that long term inn-ave-
`nous treatment with D2E7 in the dose range
`from 0.5 to 10 mg/kg was well tolerated.
`The safety and efficacy of weekly subcutane-
`ous administration of 0.5 mg/kg D2137 was
`evaluated in 24 patients with active RA in a
`phase I placebo controlled trial." After a wash
`
`Martin-m:
`ACR 20
`Cmrmnunr
`
` Trial dm‘gn Paulina D287dosing schedule DMARD tarpon“
`
`
`
`Randomised, double blind, placebo controlled
`n=120; 83% RF; mun disease
`Single and multiple iv iniections.
`No
`78%
`duration=l 2 years; mean DMARDs
`ascending class ranging from
`failed=3.6
`0.5 to 10 rug/kg
`n=24; mean disease duration=10 years;
`Weekly 0.5 rug/kg ac iniections
`Randomised, double blind. placebo controlled
`mean DMARDs failed=14
`n=54; 87% RF; mean disuse
`Single iv or sc injection of l mg/lcg
`Randomised,double blind, placebo controlled
`duralion=l l yurs; mean DMARD:
`failed (including MTX)=3.6
`RF‘=rheumatoid factor positive; DMARDflismse modifying anti-rheumalic drug; MTX= metholrumte; iv=intrnvcnous; ac=subcuuncous. *With subcutaneous
`administration.
`
`70%
`67%;"
`
`No
`MIX
`
`Ex. 1040 - Page 2 of 4
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`

`

`x»
`
`lo
`
`out period of three weeks, patients were treated
`with subcutaneous D2E7 or placebo for three
`months. The dose of D2E7 was increased to 1
`mg/kg
`subcutaneously weekly
`for
`non—
`responders or those losing their responder sta-
`tus. Blood samples were collected to determine
`D2E7 plasma concentrations. All responding
`patients continued in an open label extension
`of this study. Based on preliminary data,
`plasma concentrations of D2E7 after multiple
`subcutaneous doses were comparable to those
`achieved with intravenous administration. Up
`to 78% of patients achieved a DAS/ACR 20
`response after three months of treatment with
`subcutaneous D2E7. With the exception of
`mild and transient
`injection site reactions,
`adverse events occurred with the same fre-
`quency and distribution in the D2E7 and pla-
`cebo groups. The investigators concluded that
`D2E7 given subcutaneously was safe and as
`effective as when administered intravenously
`demonstrating that subcutaneous self adminis—
`tration is a promising approach for D2E7
`delivery.
`Monotherapy is often inadequate to control
`arthritic symptoms and rapid progression of
`RA. D2E7 (1 mg/kg as a single subcutaneous
`or intravenous injection) was evaluated in a
`randomised, double blind, placebo controlled
`trial in patients whose stable dose of meth-
`otrexate was insufficient to control symptoms.
`An ACR 20 response was seen in 67% and
`72% of patients receiving D2E7 by subcutane-
`ous and intravenous injection, respectively. The
`safety profile of single dose D2E7 administra-
`tion was comparable to that of placebo.
`Collectively, these early data suggest that the
`fully human anti-TNFa mAb D2E7 is safe and
`effective as monotherapy or in combination
`with methotrexate when administered by single
`and multiple intravenous and subcutaneous
`
`Kempem‘
`
`injections. Additional studies are underway to
`further define optimal use of
`this novel
`treatment.
`
`1 Brooks 1’. Clinical management of rheumatoid arthritis.
`Lariat l993;34l:..86—90.
`2 MoiniR, Brennan F, Williams R,“ ol. TNF-a in rheumatoid
`arthritis and prospects of anti-TNF therapy. Clin Exp
`Rheumatoi 1993;! l (su
`18):Sl73—5.
`3 Pddmnnn M, Brennan , Chu C, or nL Does TNF-n have a
`ivotal role in the
`okine network in rheumatoid arthritis?
`: Priors “9', ed. unmr mam} factor: nmleeulor and «Euler
`biology and dortal nirvana. Basel: Kruger, 1993: 1 44—52.
`4 Elliott MI, Maini RN, Fcldmann M, a al. Treatment of
`rheumatoid arthritis with chimeric monoclonal antibodies
`to tumor necrosis factor alpha. Arthritis Rheum 1993;36:
`1631-90.
`5 Smllon B, Moore M, Trinh H, Knight D, Ghmyeb I.
`Chimeric anti-TNF-olpha monoclonal antibody PA}. binds
`recombinant
`transmcmbmnc TNF-aiphn and activates
`immune effector functions. Cytokine 1995; 7:251—9.
`6 Rankin EC, Chew EH, Kassimos D, at al. The therapeutic
`effects efnn engineered human anti-tumour necrosis factor
`alpha antibody (CDP571) in rheumatoid arthritis. Br J
`Rheumatol 1995; 34:334-42.
`7 Morelrmd LW, Bnumgnrurer SW. Schifl MH,
`:1 al.
`Treatment of rheumatoid arthritis with a recombinant
`human tumor necrosis factor receptor (p75)-Fc fusion
`protein. N EngIJMed 1997;937:1414.
`B Knvnnnufli AP. Anti-tumor necrosis factor-alpha mono-
`clonal antibody therapy for rheumatoid arthnu's. Rheum
`Dis Clin North Am 1998;24:593—614.
`9 Ieipcrs L. Roberts A,Mnhlcr S,Winrer G, Hoogenboom H.
`Guiding the selection ofhuman antibodies from phage dis-
`play repertoire: to a single epitope of an antigen. Biotech—
`nology (NY) 1994;12:899—903.
`l0 Radar 1’, Probett L, Calm-is H, er a1. Transgenic mice
`expressing human tumour necrosis factor: a predictive
`enetic model ofarthritia EMBO I 1991;10:4025—3l.
`Alarm D, Anderson I. Boers M, at Al. The American College
`of Rheumatology preliminary core set of disease activity
`measures for rheumatoid arthritis clinical studies. Arthritis
`Rheum 1995;38:727—35.
`12 van Gestcl A, Prcvoo M, Von'T Hofi M, :1 :11. Development
`and volidation of the European League Against Rheuma-
`tism response criteria for rheumatoid arthritis. Arthritis
`Rheum 1996;39:34—40.
`13 van do Putte L,vnn Rid P, den Breeder A," al. A single
`anti-
`F antibody D2E7 in patients with rheumatoid
`doscpgceho-conu’oilm‘l phase I study of the fully human
`arthritis. Arthritis Rheum 1998,41 (suppl):57.
`141 Ran R, Sander 0, dm BmederA, at al. Long term efficacy
`and tolerability ofmultiple iv doses of the fully human anti-
`TNF antibody D237 in patiuus with rheumatoid arthritis.
`15 Scbattenkirchner M, [(n‘r
`r
`,Sander O, :1 ol. Eifieaey and
`Arthritis Rheum 1993;“ (ellippl):55.
`tolerabiliry of weekly su cutaneous injections of Ihc fully
`human anti-TNF antibody D257 in patients with rheuma-
`toid arthritis. Arthritis Rheum 1998;41 (suppl):57.
`
`l 1
`
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`

`

`
`
`Preliminary results of early clinical trials with
`the fully human anti-TNF or monoclonal
`antibody D2E7
`
`Joachim Kempeni
`
`Ann Rheum Dis 1999 58: I70—l72
`doi: 10.1136/ard.58.2008.i70
`
`
`Updated information and services can be found at:
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`Ex. 1040 - Page 4 of 4
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