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`
`Ex. 1017 - Page 2
`
`

`

`MASTHEAD
`
`Editorship
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`
`Ex. 1017 - Page 3
`
`

`

`ORIGINAL WORK
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`Experience with D2E7
`
`R. Rau1, M. Schattenkirchner2, L. van der Putte3
`
`
`
`
`
`1Rheumatology Clinic at the Evangelischen Fachkrankenhaus Ratingen [Ratingen Evangelical Hospital]
`2 Rheumatology Unit, Ludwig-Maximilians-Universität [Ludwig Maximilian University], Munich
`3 Department of Rheumatology, Nijmegen University Hospital
`
`
`
`83
`
`
`
`
`
`Abstract: [see source for abstract in German]
`
`© Georg Thieme Verlag Stuttgart • New York
`ISSN 0341-015X
`
`___________________________________
`Akt Rheumatol [Rheumatology Today] 2000; 25: 83-88
`
`
`
`Ex. 1017 - Page 4
`
`

`

`84 Akt Rheumatol 2000: 25
`
`Rau Ret al.
`
`D2E7 is a fi.llly human antibody against TNFo: [ttm1or necrosis Age (median, years)
`factor a], the sequence of which is entirely derived from the Median disease duration of chronic polyarthritis
`genome of human lymphocytes, and therefore contains no non- Patients positive for rhetm1atic factor (%)
`htllllan or attificial sequences. It should
`therefore be
`less Median Disease Activity Score
`inlmm10genic than cmTently used chimeric and pattially hmnanized Nmnber of swollen joints
`antibodies and soluble receptor constructs, and is therefore
`(median of 44 joints)
`particularly well adapted for long-term therapy. Phase 1 studies on Nmnber of painful joints
`the clinical development of the substance have been can-ied out
`(median of 53 joints)
`since 1997 in Nimwegen, Mtmich, and Ratingen. These sites have ,.C"'RP""-"'(m..,e,.d,.ia,.n .... .<;n.,.lgii</L-=<.~)-------------~5""'1'--­
`also participated in a multi-centt-ic phase 2 study. The data
`collected have been published only in abstract form up to now [1 - Tab. 2 Previous Treatment with Basic Therapeutics
`11 ]; they were slllllll13rized in a presentation made by Joachim Mean mm1ber of basic therapeutics per patient 3.6
`Kempeni in May 1999 [12].
`
`57
`10.9
`83
`5.3
`
`19
`
`23
`
`Methott·exate
`Gold
`Sulfasalazine
`Chlot'Oquinelhydroxychloroquine
`Azathioprine
`D-penicillanune
`Cyclosporin
`
`105 (88%)
`93 (78%)
`93 (71%)
`53 (43%)
`48 (40%)
`35 (29%)
`12 (10%)
`
`received D2E7 intt·avenously in an injection over 3-5 nlinutes, and
`six patients received a placebo. T11e first cohott of 24 patients was
`treated with 0.5 mg per kg of body weight; the second cohort with
`1 mg; the third w'ith 3 mg; the fourth with 5 mg; and the fifth cohott
`with 10 mg D2E7 per kg of body weight. Tiuee weeks prior to the
`start of the tt·eatment, the previous basic therapy was discontinued,
`the patients were randomized and treated. It was required that at
`least four weeks pass between the first and second injections in
`order to be able to collect phannacokinetic data. After the second
`injection, the next one in each case was applied when the activity
`again increased, but the tninimum interval had to be two weeks.
`After the second injection the placebo patients were converted to
`the venun.
`
`T11e tt·eattnent plan for Study DE001/003 is found in Figure 1.
`
`T11e first phase 1 stltdy (DE001) represented the first expet-ience
`with htmlall beings, and above all served to collect phannacokinetic
`and phannacodynatnics data, as well as data on tolerability and
`clinical efficacy. The studies were carried out in two centers in
`Gem1any - Munich and Ratingen -
`and one center in the
`Netherlands - Nimwegen. They have been continued as an open
`observational study DE003 over the intervening two and one-half
`years.
`
`One lumdred twenty patients were enrolled in the study with a
`years-long "treatment-resistant" high activity chronic polyartht-itis
`(median duration of the disease 10.9 years, 83% positive for
`rhetllllatic factor, median Disease Activity Score 5.3), who had
`been previously treated, on average, with 3.6 basic therapeutics
`(Tab. 1 and 2).
`
`Since this involved a phase 1 dosage escalation study, the
`respective higher dosages were applied only after the conclusion of
`testing of the lower doses. Five cohorts were fonned of24 patients
`each, and for each of these cohotts 18 patients
`
`Tab. 1 Patient Data at the Statt ofTreattnent
`Nmnber of patients
`
`120
`
`I
`Trial Arrangement for DE 001/003
`lt==oEOOl
`
`Double blind, placebo-controlled
`
`Figure 1 Treatment Plan for
`Study DE001/003
`
`()+.:··~-=-=-=OE;=oo:::, :~:=-3=-=-=-;=-=-=-~~--::--_--::----.-_--:_-~---:-_--:-_-; __ -_-.~(""")
`
`J
`~------------' L Open treatment study
`rl~~~=~==~====D~2~E7~1~.~=======~==============~( )
`.gN_ ~6 pt:S .-=----~
`D t
`
`Six cohorts of 24
`O;ttiPnt c:;
`
`DMARD(cid:173)
`Washout
`phase
`
`1
`
`Examination at
`<t~rt of <tllnV
`
`·•
`.E
`.g
`c:
`"' a::
`1-J
`
`_
`
`Placebo intravenously
`
`1f
`
`'
`ITJ
`
`-rr
`
`-rr
`
`.,.
`
`Minimum
`4weeks
`
`Minimum
`')weeks
`
`Minimum
`')weeks
`L....L.J ~~
`
`Up to
`') VP.;lrs
`
`L..b_J
`
`Dose increase is by cohort from 0.5-1-3-5-10 mg/kg body weight
`
`
`
`
`
`Ex. 1017 - Page 5
`
`

`

`Experience with D2E7
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
` Akt Rheumatol 2000; 25 85
`
`Results of Study 001
`
`Within three weeks after the discontinuation of the presumably
`insufficiently effective basic therapeutic, there appeared an increase
`in the number of swollen joints in many cases. The data of this at
`the start of treatment was taken as 100%; thereafter there was,
`starting already after 24 hours, a distinct improvement, which
`amounted to about 40% after one week. This improvement persisted
`at the higher dose for four weeks; after the lower doses (0.5 or 1 mg
`per kg of body weight), the number of swollen joints gradually
`increased again. In the placebo group there was no improvement;
`rather, on the contrary, a slight worsening was observed (Fig. 2).
`
`In terms of ESR (erythrocyte sedimentation rate), after the
`discontinuation of the previous basic therapeutic there was likewise
`a distinct increase in the sedimentation reaction, which was
`sustained in the placebo group, while in the verum group an
`improvement of roughly 40% appeared after one to two weeks and
`was sustained over four weeks. In the 0.5 mg group there was a
`worsening again already after one week (Fig. 3).
`
`An ACR-20 response has been achieved if five of the following
`seven criteria have each
`improved by 20%
`(in addition,
`improvement of the first two criteria is obligatory): number of joints
`painful to pressure; number of swollen joints; ESR; global
`estimation of disease activity by the physician and by the patient;
`pain by the Visual Analog Scale (VAS); and functional impairment.
`
`The Disease Activity Score (DAS) is a so-called composite index,
`calculated from the number of joints painful to pressure, the number
`of swollen joints, the ESR, and the general condition of health.
`
`In this process a good response is defined by an improvement by >
`1.2 with the current DAS simultaneously remaining < 2.4. A
`moderate improvement is given with an improvement of the DAS
`by 0.6-1.2 and the achievement of a current DAS between 2.4 and
`3.7. Under the EULAR response criteria, it is thus not only the
`relative change which is considered, but also the current disease
`activity.
`
`Results of Continuation Study DE003
`
`Observation of an ACR-20 [American College of Rheumatology]
`response was determined, at any point in time, with about 42% of
`patients under 0.5 mg per kg of BW, with about 65% under 1 mg,
`and with roughly 80% of the patients under 3-10 mg. The
`percentage of patients with a “moderate response” in the DAS
`[Disease Activity Score] (EULAR [European League Against
`Rheumatism] Response Criteria) was marginally lower in each case.
`X-ray data from Study 001/003
`
`During the open continuation of the study there was a further drop
`of the DAS and of the ESR to values between 50% and 60% of the
`baseline data (Figs. 4 and 5 show the semiannual data). In the
`meanwhile all the patients have completed two years of treatment.
`
`Fig. 2 Mean value of the number of swollen joints. The level at the
`start
`of
`treatment
`was
`taken
`as
`100%.
`
`The X-ray evaluation was certainly not a goal of this study, but X-
`ray images of the hands and the front of the foot were prepared,
`when possible, at the time therapy began and after six and 12
`months. These X-ray images were evaluated as a set for each
`patient, blinded regarding the patient’s identity and acceptance date,
`and thus regarding the sequence of the images. The evaluation was
`performed by the Ratingen Score, the Sharp Erosion Score, and the
`Sharp Joint Space Narrowing Score.
`
`[proximal
`(PIP
`joints
`The Ratingen Score evaluates 38
`interphalangeal], MCP [metacarpophalangeal], each of four regions
`of the wrist, the big toe end joint, and MTP [metatarsophalangeal]
`joint II-V), each evaluated according to the degree of destruction of
`the joint surface: The evaluation is graded with 0 = normal,
`
`
`Fig. 3 Mean value of the ESR during the study. Baseline level =
`100%.
`
`
`
`Fig. 4 Mean value of ESR during the study. Baseline value =
`100%.
`
`Ex. 1017 - Page 6
`
`

`

`86 Akt Rheumatol 2000; 25
`
`
`
`
`
`
`
`
`
`
`
`
`
` Rau R et al.
`
`Tab. 3 X-ray Data of 66 Patients (Complete Data Set)_____
`
`
`
` Start Month 6 Month 12
`Mean disease activity of
` 12.1 12.6 13.1
` the chronic polyarthritis (years)
`Ratingen Score*
`
` 47.0 46.5 46.7
`Sharp Erosion Score*
` 59.2 58.5 59.0
`Sharp Joint Space Narrowing Score* 53.9 54.2 55.0__
`* Mean value
`
`During the treatment with D2E7 the median value of the scores fell
`from 39.5 to 38.0. It should be noted that in the pre-observation
`phase under basic therapy (the great majority of the patients were
`treated with > 15 mg MTX [methotrexate] per week), an increase in
`the scores could be seen in nearly all patients, but in almost none of
`the patients during the treatment. It should further be noted in this
`respect that the prior images were read blinded, together with the
`other images, with no knowledge of the time sequence.
`
`In the Sharp Erosion Score, one sees in the pre-treatment phase a
`strongly significant increase from 42.0 to 52.5; almost no change
`during the treatment with D2E7; the same is true for the Joint Space
`Narrowing Score (Figs. 6,7,8).
`
`Calculated on a yearly basis, before the start of treatment there is a
`progression in the Ratingen Score of 4.5% of the maximum possible
`score per year, which fell under the treatment to -0.75% per year. In
`the Sharp Erosion Score the increase shrank from 6.5% of the
`maximum possible score per year, to 0.9%.
`
`In a further phase 1 study (DE004), 24 patients with long-term (10.1
`years) “therapy-resistant” (3.4 DMARDs [disease modifying anti-
`rheumatic drugs]) chronic polyarthritis were given 0.5-1 mg per kg
`of D2E7, subcutaneously, weekly over 12 weeks; this led in 78% of
`patients to a “moderate response” in the DAS, which was not
`reached in any placebo patient. D2E7 is therefore also effective
`subcutaneously.
`
`Multi-centric phase 2 study
`
`The results of the phase 1 study were confirmed by a randomized,
`four-arm phase 2 study with 283 patients receiving 20, 40, 80 mg
`D2E7 weekly, subcutaneously, or a placebo; after 12 weeks an
`improvement by > 60% in the CRP (C-reactive protein) and in the
`number of swollen joints was attained in the patient groups treated
`with 40 or 80 mg, while no change appeared in the placebo group.
`The difference in the verum group compared to the placebo was
`significant (P<0.001). Here again we had patients with a high
`activity disease (swollen joint count 19, CRP 59 mg/L, ESR 52
`mm/h) with a duration of the disease of 10 years, who had already
`been
`
`
`
`Fig. 5 Mean value of ESR during Study DE001/003. Baseline value
`= 100%.
`
`1 = <20% destruction of the joint surface, 2 = up to 40%, 3 = up to
`60%, 4 = up to 80%, and 5 = >80% destruction of the joint surface.
`
`In the Sharp Erosion Score, 44 joints are counted, and in
`comparison to the Ratingen Score, two areas on the wrist and the
`base joint of the big toe. The erosions per joint are counted; thus 1 =
`1 erosion, 2 = 2 erosions, 3 = 3 erosions, 4 = 4 erosions, and 5 is
`reached if 50% or more of the joint surface has been destroyed. In
`the Joint Space Narrowing Score, 42 joints are counted and graded,
`with 1 = questionable joint space narrowing, 2 = narrowing by <
`50%, 3 = > 50% of the original joint space, and 4 = ankyloses.
`
`The total number of patients in the study was 120. One treatment
`year was completed by 93 patients; of these, X-ray images were
`available for 90. Sixty-six patients had a complete set of X-ray
`images at time points 0, 6, and 12 months. In order to be able to
`compare the progression during the treatment with that before the
`start of treatment, we have proposed to assess X-ray images which
`had been taken 1-2 years before the start of treatment against X-ray
`images during treatment. Prior images of the hands and feet could
`be found for 22 patients from Ratingen, on average taken 19.2
`months before the start of treatment.
`
`Tab. 3 shows the X-ray data of the 66 patients with a complete data
`set. The mean duration of the disease in these patients was 12.1
`years at the start, and 13.1 years after 12 months. The mean values
`of the Ratingen Scores did not change; there was also no change in
`the Sharp Erosion Score, and only a minimal, insignificant and
`clinically meaningless increase in the Sharp Joint Space Narrowing
`Score, from 53.9 to 55.0.
`
`If one now looks at the Ratingen Score of the 22 Ratingen patients
`for whom prior images existed, these patients showed an increase in
`the Ratingen Score before the start of treatment from 32.5 to 39.5.
`This increase is significant; had it continued at the same intensity, in
`ten years a score of > 50% of the maximum possible total score
`would have been reached, which would have meant complete
`invalid status for most of the patients.
`
`
`
`Ex. 1017 - Page 7
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`

`

`Experience with D2E7
`
`
`
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`
`
` Akt Rheumatol 2000; 25 87
`
`The effect of combination with an inadequately effective MTX
`treatment was proven in Study DE010. Fifty-four patients were
`enrolled in this study with a similar disease duration and disease
`activity to those in the previously named studies. All the patients
`were adjusted to a stable dose of methotrexate, which was
`maintained unchanged. Each group of 18 patients was regulated,
`on a randomized basis, on 1 mg D2E7 intravenously, 1 mg
`subcutaneously, or on a placebo. After the second injection the
`patients were then treated openly with 1 mg per kg subcutaneously.
`After the first injection there is a drop in the number of swollen
`joints by 40%, of joints painful to pressure by 50%, of the
`sedimentation reaction by 40%, and of the C-reactive protein by
`80%. Intravenous administration gives advantages in terms of
`joints painful to pressure, ESR, and C-reactive protein. The
`somewhat better efficacy of the intravenous injection is also
`reflected in the DAS and ACR-20 response criteria: after
`intravenous administration, 72% achieve a response in both
`categories; after subcutaneous administration only 45% attain a
`DAS response and 67% an ACR-20 response. Long-term data from
`this study are not yet available to us.
`
`Adverse effects
`
`Since D2E7 consists only of human sequences, allergic reactions
`are less probable than with non-human monoclonal antibodies.
`Nevertheless, idiotypical epitopes can represent a theoretical
`potential for allergic reactions. Thus, reactions which were
`described as allergic were observed in a total of five patients,
`which, however, did not recur in the same patients with
`continuation of the treatment, and which with one exception did
`not require any therapeutic intervention. In two patients there were
`muscle cramps, dizziness, blood pressure rises, chest pain,
`tachycardia and skin eruptions for the space of a few minutes,
`possibly as the result of too rapid an injection. These symptoms
`were not repeated with later, slower injections. Maculopapulous
`eruptions appeared
`in a few cases, which responded
`to
`antihistamines and did not necessitate any interruption of the
`treatment. Hospitalizations were required due to various infections
`in a total of 10 patients. It cannot currently be determined whether
`these infections have appeared statistically more frequently than is
`to be expected with this patient population with long-term severe
`polyarthritis.
`
`In summary, it can be established that the completely human TNFα
`antibody D2E7 is quickly (within the space of days) effective in
`the majority of patients, and has not lost its efficacy in the course
`of long-term treatment over, up to now, two and one-half years.
`D2E7, with a half-life of 12 days, can be administered every two
`weeks as an
`intravenous
`injection over 3-5 minutes or
`subcutaneously. D2E7 is well tolerated and must be called a
`therapeutic step forward.
`
`Fig. 6. Median values of the Ratingen Scores 19 months before
`start of treatment and at 0, 6, and 12 months.
`
`Fig. 7. Median values of the Sharp Erosion Scores 19 months
`before start of treatment and at 0, 6, and 12 months.
`
`Fig. 8. Median values of the Sharp Joint Space Narrowing Scores
`19 months before start of treatment and at 0, 6, and 12 months.
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`treated on average with 3.8 basic therapeutics. In this study it was
`also possible to document a functional improvement, measured in
`the Health Assessment Questionnaire (HAQ).
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`Combination with MTX
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`Ex. 1017 - Page 8
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`88 Akt Rheumatol 2000; 25
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` Rau R et al.
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`Prof. R. Rau, M.D.
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`Rheumaklinik am Evangelisches Fachkrankenhaus Ratingen
`Rosenstraße 2
`40882 Ratingen
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`E-mail: rrau@uni-duesseldorf.de
`
`References
`
`1 Rau R, Sander O, den Broeder A, et al. Long-term efficacy and
`tolerability of multiple i.v. doses of the fully human anti-TNF
`antibody D2E7 in patients with rheumatoid arthritis. Arthritis
`Rheum 1998; 41: pg. 55
`2 Schattenkirchner M, Krüger K, Sander O, Rau R, et al. Efficacy
`and tolerability of weekly subcutaneous injections of the fully
`human anti-TNF antibody D2E7 in patients with rheumatoid
`arthritis – results of a phase 1 study. Arthritis Rheum 1998; 41:
`pg. 57
`3 van der Putte LBA, van Riel PLCM, den Broeder A, Sander O,
`Rau R, et 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: pg. 57
`4 Rau R, Simianer S, Weier R, Kroot EJ, et al. Effective
`combination of the fully human anti-TNF antibody D2E7 and
`methotrexate in active rheumatoid arthritis. Ann Rheum Dis
`(Suppl) 1999; 58: 207 (abstract)
`5 Rau R. Experience with D2E7. MedNet symposium “Progress in
`the treatment of rheumatoid arthritis with biologicals vs. TNF-
`alpha”. Z. Rheumatol 1999; 58: pg. 51
`6 van der Putte LBA, Sander O, Rau R, et al. A placebo-controlled
`study of the human anti-TNF antibody D2E7 in patients with
`active chronic polyarthritis. Z Rheumatol (Suppl) 1999; 58: I/34
`7 Rau R, Simianer S, Weier R, et al. Combination therapy with the
`human anti-TNF antibody D2E7 and methotrexate with active
`rheumatoid arthritis. Z Rheumatol (suppl) 1999; 58: I/35
`8 Rau R, Sander O, Weier R, et al. Effect and tolerability of repeated
`intravenous administration of the human anti-TNF antibody
`D2E7 in patients with chronic polyarthritis. Z Rheumatol (Suppl)
`1999; 58: I/41
`9 Schattenkirchner M, Krüger K, Sander O, Rau R, et al. Phase 1
`study of the efficacy and tolerability of weekly subcutaneous
`injections of the human anti-TNF antibody D2E7 in patients with
`chronic polyarthritis. Z Rheumatol (Suppl) 1999; 58: I/42
`10van der Putte LBA, Rau R, Breedveld FC, et al. Efficacy of the
`fully human anti-TNF antibody D2E7 in rheumatoid arthritis.
`Arthritis Rheum 1999; 42: pg. 400
`11Rau R, Herborn G, Sander O, van der Putte LBA, et al. Long-term
`treatment with the fully human anti-TNF antibody D2E7 slows
`radiographic disease progression in rheumatoid arthritis. Arthritis
`Rheum 1999; 42: pg. 400
`12Kempeni J. Preliminary results of early clinical trials with the fully
`human anti-TNFα monoclonal antibody D2E7. Ann rheum Dis
`1999; 58: 70-72.
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`Ex. 1017 - Page 9
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`DECLARATION UNDER 28 U.S.C. § 1746
`
`I, Isa Carter, am fluent in both the German and English languages. I hereby certify that the attached
`translation for “R. Rau et al., Erfahrungen mit D2E7, 25 Akt Rheumatol 83 (2000)” is accurate and
`complete. I understand that willful false statements and the like are punishable by fine or
`imprisonment, or both, pursuant to 18 U.S.C. § 1001.
`
`I certify under penalty of perjury under the laws of the United States that the foregoing is true and
`correct.
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`
`
`___________________
`__________________
`
`Isa Carter
`
`
`
`Executed on this 22 day of December, in 2015.
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`Ex. 1017 - Page 11
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