I71)
`
`Ann Rheum The 1999;58: (Suppl 1)170-172
`
`Preliminary results of early clinical trials with the
`fully human anti-TNFa monoclonal antibody
`D2E7
`
`Joachim Kempeni
`
`Current pharmacological treatments for rheu-
`matoid arthritis (RA), including non-steroidal
`anti-inflammatory drugs (NSAIDs), disease
`modifying anti-rheumatic drugs (DMARDs),
`and corticosteroids, have been moderately suc-
`cessful in alleviating the discomforts associated
`with swollen, painful joints. However, conven-
`tional medical approaches to treatment have
`had little or no impact on the disease course of
`RA.' Innovative strategies, particularly those
`based on new concepts in the immunobiology
`of RA, are being developed to target cellular
`inflammatory mechanisms and potentially pre-
`vent disease progression. The more promising
`of these treatments seem to be those that block
`the effects of tumour necrosis factor (TNF) a,
`because this proinflammatory cytokine seems
`to play a central part in the immunopathogen-
`esis of RA.2
`
`
`Anti-TNF treatments
`Biological agents such as antibodies and
`soluble TNF receptors that bind TNF a with
`high specificity neutralise its activity and have
`been developed for use as therapeutic agents.
`Several are currently being evaluated in pa-
`tients with RA (table 1). Infliximab, cA2, is a
`chimeric monoclonal antibody (mAb) that
`consists of the variable region of a murine anti-
`TNF mAb coupled to the constant region of
`human IgGlx." The resulting construct is
`approximately two thirds human. CDP571 is a
`humanised mAb consisting of the comple-
`mentarity determining regions of a murine
`anti-TNF mAb grafted into a human immu-
`noglobulin (IgG4x).' This mAb is approxi-
`mately 95% human. Etanercept is a fusion
`protein consisting of two recombinant p75
`TNF receptors attached to the Fc portion of a
`human IgG1.7 Although this construct consists
`of two independent elements, which them-
`selves contain 100% human peptide se-
`quences, they are arranged in an unnatural
`configuration.
`The duration of the therapeutic efficacy of
`these TNF antagonists may be limited by an
`immune response to their non-human ele-
`ments or artificially fused human sequences.
`Table 1 Anti-TNF a treatments
`
`Department of Clinical
`OncologyRmmunology,
`Knoll AG-BASF
`Pharma, Knollstrasse,
`D-67008 Ludwigshafen,
`Germany
`
`Correspondence to:
`Dr J Kempeni.
`
`Name
`
`D2E7
`CDP571
`Etanercept
`
`Infliximab (cA2)
`
`Description
`
`Fully human anti-TNF a mAb
`Humanised anti-TNF a mAb (murine CDR)
`Fusion protein consisting of two recombinant p75 TNF a
`receptors and the Fc portion of human IgG1
`Chimeric murine/human anti-TNF-a mAb
`
`TNF=tumour necrosis factor; mAb=monoclonal antibody; IgG=inununoglobulin G;
`CDR=complementarity determining region.
`
`The development of antibodies to these
`biological agents could reduce their half life,
`thereby decreasing efficacy.' In addition, an
`immune response could result in adverse
`events from the formation of immune com-
`plexes or the development of hypersensitivity.
`For these reasons, an antibody that is fully
`human may have greater therapeutic potential.
`
`Development of a fully human anti-TNF
`antibody
`BASF Pharma set out to develop a fully
`human, anti-TNF mAb structurally identical
`to naturally occurring human antibodies and
`therefore less likely to engender an immune
`response in the recipient. The generation of a
`fully human anti-TNF mAb required bioengi-
`neering techniques' that mimic immune selec-
`tion in humans and contrast with existing
`means of "humanising" murine monoclonal
`antibodies in that the antibodies derived are
`completely human. The result of this effort is
`D2E7, a new class of anti-TNF mAb, which
`may have advantages in minimising antigenic-
`ity in humans.
`
`Preclinical pharmacology
`The efficacy and safety of D2E7 were evaluated
`in a number of experimental systems. The abil-
`ity of D2E7 to neutralise TNF bioactivity was
`demonstrated in three different in vitro cell
`systems. Additionally, the effectiveness of
`D2E7 in preventing polyarthritis was shown in
`a transgenic mouse model that mimics the
`clinical and histopathological progression of
`RA in humans.' D2E7 treated mice showed no
`clinical signs of arthritis during the 11 week
`study period. Microscopical examinations of
`the ankle joints of the animals showed no
`histopathological changes. In contrast, control
`mice developed severe arthritis with cartilage
`destruction and bone erosion.
`
`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-
`tions of acute phase reactants, and prolonged
`early morning stiffness. In addition, all trials
`involved RA patients with long disease dura-
`tion and a history of failure of several
`DMARDs. During the trials, patients were
`allowed to continue stable doses of NSAIDs
`and corticosteroids. Efficacy was assessed
`
`Ex. 1004 - Page 1
`
`

`

`I
`
`I
`
`4
`
`Ghia vials mirk the fully human anti-TNFu monoclonal antibody D2E7
`
`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 patient's 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 D2E7 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 D2E7, 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
`
`171
`
`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 after D2E7 administration and reached the
`maximum effect after 1-2 weeks, with dose
`response reaching a plateau at 1 mg/kg D2E7. 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 reaching 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 rill/min, and the steady state volume of
`distribution ranged from 0.063 to 0.076 1/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.
`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 D2E7 doses according
`to their dose group). D2E7 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 effects 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 intrave-
`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 D2E7 was
`
`evaluated in 24 patients with active RA in a
`phase I placebo controlled trial.' After a wash
`
`4
`
`43
`
`4
`
`4
`
`4
`
`4
`
`4
`
`a
`
`4
`
`4
`
`4
`
`4
`
`4
`
`I
`
`•
`
`Table 2 Early trials of D2E7 in rheumatoid arthritis
`
`Trial design (cid:9)
`
`Randomised, double blind, placebo controlled
`
`Randomised, double blind, placebo controlled
`
`Randomised, double blind, placebo controlled
`
`Patients
`n=120; 83% RV; mean disease
`duration=12 years; mean DMARDs
`failed=3.6
`n=24; mean disease duration=10 years;
`mean DMARDs
`n=54; 87% RF'; mean disease
`duration=11 years; mean DMARDs
`failed (including MTX)=3.6
`RF'=rheumatoid factor positive; DMARD=disease modifying anti-rheumatic drug; Nurx= methotrexate; iv=intravenous; sc=subcutaneous. *With subcutaneou-
`administration.
`
`D2E7 dosing schedule
`Single and multiple iv injections, (cid:9)
`ascending doses ranging from
`0.5 to 10 mg/kg
`Weekly 0.5 mg/kg sc injections (cid:9)
`Single iv or sc injection of 1 mg/kg (cid:9)
`
`Maximum
`Concurrent ACR 20
`response
`DMA RD (cid:9)
`
`No (cid:9)
`
`No (cid:9)
`
`MTX (cid:9)
`
`78%
`
`70%
`
`67%*
`
`Ex. 1004 - Page 2
`
`(cid:9)
`(cid:9)
`

`

`172
`
`Kempeni
`
`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
`
`injections. Additional studies are underway to
`further define optimal use of this novel
`treatment.
`
`1 Brooks P. Clinical management of rheumatoid arthritis.
`Lancet 1993;341:286-90.
`2 Maini R, Brennan F, Williams R, et al. TNF-a in rheumatoid
`arthritis and prospects of anti-TNF therapy. Clin Exp
`Rheumatol 1993;1 I (suppl 8):S173-5.
`3 Feldmann M, Brennan F, Chu C, a al. Does TNF-a have a
`pivotal role in the cytokine network in rheumatoid arthritis?
`In: Friers W, ed. Tumor necrosis factor: molecular and cellular
`biology and clinical relevance. Basel: Karger, 1993:144-52.
`4 Elliott MJ, Maini RN, Feldmann M, et al. Treatment of
`rheumatoid arthritis with chimeric monoclonal antibodies
`to tumor necrosis factor alpha. Arthritis Rheum 1993;36:
`1681-90.
`5 Scallon B, Moore M, Truth H, Knight D, Ghrayeb J.
`Chimeric anti-TNF-alpha monoclonal antibody cA2 binds
`recombinant transmembrane TNF-alpha and activates
`immune effector functions. Cytokine 1995; 7:251-9.
`6 Rankin EC, Choy EH, Kassimos D, et al. The therapeutic
`effects of an engineered human anti-tumour necrosis factor
`alpha antibody (CDP571) in rheumatoid arthritis. Br J
`Rheumatol 1995; 34:334-42.
`7 Moreland LW, Baumgartner SW, Schiff MH, ct al.
`Treatment of rheumatoid arthritis with a recombinant
`human tumor necrosis factor receptor (p75)-Fc fusion
`protein. N Engl J Med 1997;337:141-7.
`8 Kavanaugh AF. Anti-tumor necrosis factor-alpha mono-
`clonal antibody therapy for rheumatoid arthritis. Rheum
`Dis Clin North Am 1998;24:593-614.
`9 Jespers L, Roberts A, Mahler S, Winter G, Hoogenboom H.
`Guiding the selection of human antibodies from phage dis-
`play repertoires to a single epitope of an antigen. Biotech-
`nology (NY) 1994;12:899-903.
`10 Keifer J, Probert L, Cazlaris H, er al. Transgenic mice
`expressing human tumour necrosis factor: a predictive
`genetic model of arthritis. EMBO J 1991;10:4025-31.
`11 Felson D, Anderson J, Boers M, er 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 Geste! A, Prevoo M, Van'T Hoff M, et al. Development
`and validation of the European League Against Rheuma-
`tism response criteria for rheumatoid arthritis. Arthritis
`Rheum 1996;39:34-40.
`13 van de Putte L, van Riel P, den Broeder A, a al. A single
`dose placebo-controlled phase 1 study of the fully human
`anti-TNF antibody D2E7 in patients with rheumatoid
`arthritis. Arthritis Rheum 1998;41 (suppl):57.
`14 Rau R, Sander 0, den Broeder A, et al. Long term efficacy
`and tolerability of multiple iv doses of the fully human anti-
`TNF antibody D2E7 in patients with rheumatoid arthritis.
`Arthritis Rheum 1998;41 (suppl):55.
`15 Schattenkirchner M, Kruger K, Sander 0, et al. Efficacy and
`tolerability of weekly subcutaneous injections of the fully
`human anti-TNF antibody D2E7 in patients with rheuma-
`toid arthritis. Arthritis Rheum 1998;41 (suppl):57.
`
`Ex. 1004 - Page 3
`
`

`

`ADDITIONAL COMMENTS
`1 Rare cases of lupus-like disease have occurred in patients
`receiving TNF blocking agents and treatment should be
`stopped if there is clinical evidence of a lupus-like
`syndrome. There is thus far no evidence that RA patients
`who have positive ANA and/or ACL are susceptible to
`develop symptoms of drug induced lupus and treatment
`in this group of patients can probably be continued.
`2 As TNF blocking agents are proved efficacious and their
`toxicity profile is demonstrated in patients with polyar-
`ticular juvenile chronic arthritis, these treatments should
`be used in that population.
`3 The safety of primary vaccinations and live-attenuated
`vaccines during TNF blockade treatment is not known.
`4 The safety of sequential use of different TNF blocking
`agents is unknown, but cross reactivity is at least
`theoretically possible.
`
`Summary
`TNF inhibitors seem to be promising therapeutic agents
`for RA. The use of these new agents will require physicians
`experienced in the diagnosis, treatment and assessment of
`RA. These physicians will need to make long term
`observations for efficacy and safety. Further considerations
`when using TNF blocking agents in this disease must
`include cost issues and recognition that data in subpopula-
`tions are still being acquired. It is hoped that this
`statement, which is based upon the best evidence available
`at the time of its creation and modified by expert opinion,
`will facilitate the optimal use of these agents for our
`patients with RA.
`
`D E FURST, F C BREEDVELD
`G-R BURMESTER, L CROFFORD
`P EMERY, M FELDMAN
`J R KALDEN, A KAVANAUGH
`E KEYSTONE, P E LIPSKY
`R N MAINI, L MORELAND
`J S SMOLEN, L VAN DE PUTTE
`T VISCHER, M WEINBLATT
`M WEISSMAN
`representing the approximately 80 rheumatologists at the Advances in
`Targeted Therapies TNF Blockade in Clinical Practice.
`
`Professor Michael Doherty acted as guest editor for this article.
`
`Consensus sumo
`
`Supported by unrestricted educational grants from: Amgen, Centocor,
`Immunex Corp, Knoll AG, Schering Plough, Wyeth Ayerst.
`None of the 17 primary authors are under retainer as consultants to mon.
`interested in TNFu blocking treatment, although they may have received gr7
`for research (basic and/or clinical) from the sponsor.
`
`Selected list of references
`Elliott MJ, Maini RN, Feldmann M, er at. Treatment of rheumatoid sr&
`with chimeric monoclonal antibodies to tumor necrosis factor a. Arth
`Rheum 1993;36:1681-90.
`Elliott MJ, Maini RN, Feldmann M, et al. Randomised double-blind comp
`son of chimeric monoclonal antibody to tumor necrosis factor a antib
`(cA2) versus placebo in rheumatoid arthritis. Lancet 1994;344:1105-1,
`Maini RN, Elliott MJ, Charles PJ, a al. Immunological intervention TeR
`reciprocal roles for TNFa and IL-10 in rheumatoid arthritis and
`Springer Semin Immunopathol 1994;16:327-36.
`Maini RN, Elliott MJ, Brennan FM, et al. Monoclonal anti-TNFa antibody;
`probe of pathogenesis and therapy of rheumatoid disease. Immtmol I
`1995;144:195-223.
`Feldmann M, Elliott MJ, Woody JN, et al. Anti-tumor necrosis factor-th
`therapy of rheumatoid arthritis. Adv linmunol 1997;64:283-350.
`Moreland LW, Baumgartner SW, Schiff MH, a al. Treatment of rheum'
`arthritis with a recombinant human tumor necrosis factor real
`(p75)-Fc fusion protein. N Engl J Med 1997;337:141-7.
`Kalden-Nemeth D, Grebmeier J, Antoni C, a al. NMR monitoring of an
`toid arthritis patients receiving anti-TNFa monoclonal antibody their
`Rheumatol Int 1997;16:249-55.
`Maini RN, Breedveld FC, Kaldcn JR, a al. Therapeutic efficacy of mul
`intravenous infusions of anti-tumor necrosis factor a monoclonal and
`combined with low-dose weekly methotrexate in rheumatoid artb
`Arthritis Rheum 1998;41:1552-63.
`Paleolog EM, Young S, Stark AC, et al. Modulation of angiogenic cos
`endothelial growth factor by tumor necrosis factor a and interleukie
`rheumatoid arthritis. Arthritis Rheum 1998;41:1258-65.
`Moreland L. Soluble tumor necrosis factor receptor (p75) fusion pri
`(ENBREL) as a therapy for rheumatoid arthritis. Rheum Dis Clin
`Am 1998;24:579-91.
`Fenner H. Immunopharmacologic profile and therapeutic prosper
`anti-TNF-alpha therapy. Z Rheumatol 1998;57:294-7.
`Felson D, Lafyatis R, Korn J. Rheumatology. Biologic agents—is the pn
`realised? Lancet 1998;352 (suppl 4):s25.
`Kavanaugh AF. Anti-tumor necrosis factor-alpha monoclonal antibody rh
`for rheumatoid arthritis. Rheum Dis Clin North Am 1998;24:593-6
`Anonymous. New drugs for rheumatoid arthritis. Med Lett Drugs Iher
`40:110-12.
`Goldenberg MM. Entanercept, a novel drug for the treatment of patient
`severe, active rheumatoid arthritis. Clin Ther 1999;21:75-87.
`Weinblatt E, Kremer JM, Bankhurst AD, et al. A trial of etanerc,.
`recombinant tumor necrosis factor receptor:Fc fusion protein, in Patient'
`with rheumatoid arthritis receiving methorrexate. N Engl J Med 1999;110
`253-9.
`
`NEW YORK LOADEVIY OF MEDICINE
`
`DEC
`
`1999
`
`LIBRARY
`
`Ex. 1004 - Page 4
`
`(cid:9)
`

`

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