`
` The Bese=ah
`
`)\
`
`“4
`
`k \
`
`iNew Englanw-a
`Journal of Medicine
`
`
`
`Established in 18]2 as THE NEW ENGLAND JOURNAL OF MEDICINE AND SURGERY
`
`VOLUME 341
`
`NOVEMBER 18, 1999
`
`NUMBER 21
`
`ORIGINAL ARTICLES
`
`Light-To-Moderate Alcoho] Consumption
`and the Risk of Stroke among
`U.S. Male Physicians..............
`K. BERGER AND OTHERS
`AntitumorActivity of Thalidomide
`in Refractory Multiple Myeloma....................(5)
`
`ween
`
`+ 1557 .
`
`S. SINGHAL ANDOTHERS
`
`a
`Reduction of False Negative Results in
`Screening of Newborns for Homocystinuria 1572
`M.J. PETERSCHMITT, J.R. SIMMONS,
`AND H.L. Levy
`
`Brief Report: Leuprolide Acetate Therapy
`in Luteinizing Hormone—Dependent
`Cushing’s Syndrome ...........6s.ccsesssseessseeseecereseies 1577
`A. Lacroix, P. HAMET, AND J.-M. BouriIN
`
`IMAGES IN CLINICAL MEDICINE
`
`Gangrene and Type I Cryoglobulinemia
`in Multiple Mycloma .............c.scessecessecseseeeenes 1582
`L, CIRASINO AND P.R, BARBANO
`
`SPECIAL ARTICLE
`
`Mortality among Recent Purchasers
`Of Handguns oo.e.ccseccesssseecssscsssnecesssensnecsavescserseeniesnees
`G.J. WINTEMUTE, C.A. PARHAM,
`J.J. BEAUMONT, M. WRIGHT, AND C. DRAKE
`
`REVIEW ARTICLE
`Benign Paroxysmal Positional Vertigo.................
`J.M. FURMAN AND S.P. Cass
`
`1590
`
`CASE RECORDS OF THE
`MASSACHUSETTS GENERAL HOSPITAL
`A Five-Month-Old Girl
`with Coffee-Grounds Vomitus ..........:0c00008 1
`S. Harpy AND S.B, KEEL
`
`‘
`. EDITORIALS
`Alcohol for Stroke Prevention? ..........c.ccceneee 1605
`Thalidomide — A Revival Story .............:0000
`N. RayE AND K. ANDERSON
`
`M. HOMMEL AND A. JAILLARD
`
`Firearms and Suicide@ 000.0...cusses ceeeceeneeeteeneees 1609
`M.L. ROSENBERG, J.A. MERCY,
`AND L.B. POTTER
`
`SOUNDING BOARD
`
`Medical Professionalism in Society «0... 1612
`M.K, Wynta, S.R. LATHAM, A.C. Kao,
`J.W. BERG, AND L.L. EMANUEL
`
`INFORMATION FOR AUTHORS uence 1617
`
`CORRESPONDENCE
`
`Authors’ Conflicts of Interest: A Disclosure
`and Editors’ Reply ........ccsccscssscssssecssstseeetesserserenenssnes 1618
`Reimbursement for Evaluation
`and Management Services: ...........ss0essseesssnessneresees 16197
`Neostigmine for Acute Colonic Pseudo-Obstruction 1622
`DNA Vaccines .....cscssssscsssseesessseserssenessersseceneeseeseenenseerneees 1623
`The Effects of Vancomycin and 6-Lactam
`Antibiotics on Vancomycin-Resistant
`Steapleylococcus Murcus ...ecscsecesssncecesvereessnesecenerseneeeee 1624
`Priming with Human Chorionic Gonadotropin
`before Retrieval of Immature Oocytes
`in Women with Infertility Due to the
`Polycystic Ovary Syndrome ooo...sssssetcesrereeeeee 1624
`
`BOOK REVIEWS ciecccssscssescssscsseesnecsntssnecesnecetecsneentee 1627
`NOTICES ececcsssssssssessscssescncestesneeseessessesssrsanesseesencneensenes 1629
`CORRECTIONS
`Treatment of Asthma with Drugs Modifying
`the Leukotriene Pathway ......cccscssessucsessenseesseertens 1632
`Zolpidem in Progressive Supranuclear Palsy.............. 1632
`
`Owned, published, and © copyrighted, 1999, by THE MASSACHUSETTS MEDICAL SOCIETYeR
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`0024
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`Univ. of
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`BioMode
`Seanailest
`11 19 99
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`5
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`THe New ENGLAND JOURNAL OF MeEDICINE (ISSN 0028-4793) is published weekly
`from editorial offices at 10 Shattuck Street, Boston, MA 02115-6094. Subscription price:
`$129.00 per year. Periodicals postage paid at Boston and at additional mailing offices.
`POSTMASTER:Send address changes to P.O. Box 540803, Waltham, MA 02454-0803.
`
`DOES NOT
`LEAVE LIBRARY
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`Dr. Reddy’s Laboratories,Inc. v. Celgene Corp.
`IPR2018-01509
`Exhibit 2023, Page 1.
`
`
`
`

`

`
`
`ANTITUMOR ACTIVITY OF THALIDOMIDE IN REFRACTORY MULTIPLE MYELOMA
`-— sheen wee -
`‘
`87 Sei efay.
` tie 8
`
`tet gy Gravis
`
`'
`«
`soap ne Sa}
`
`ANTITUMOR ACTIVITY OF THALIDOMIDE IN REFRACTORY
`MULTIPLE MYELOMA
`
`Seema SINGHAL, M.D., JAveSH MEHTA, M.D., RAMAN DesikAN, M.D., DAN Ayers, M.S., PauLa Roserson, P#.D.,
`~
` Paut Epptemon, B.S., NikHit MunsHi, M.D., Euias Anatssiێ, M.D., CARLA Witson, M.D., PH.D.,
`Mapxav DHopapkar, M.D., Jerome ZeLpis, M.D., AND BART BARLoGiE, M.D., PH.D.
`
`ABSTRACT
`Background Patients with myeloma whorelapse
`after high-dose chemotherapy have few therapeutic
`options. Since increased bone marrow vascularity
`imparts a poor prognosis in myeloma, we evaluated
`the efficacy of thalidomide, which has antiangiogenic
`properties, in patients with refractory disease.
`Methods Eighty-four previously treated patients
`with refractory myeloma (76 with a relapse after high-
`dose chemotherapy) received oral thalidomide as a
`single agent for a median of 80 days (range, 2 to 465).
`The starting dose was 200 mgdaily, and the dose was
`increased by 200 mg every two weeksuntil it reached
`800 mg per day. Response was assessed on the ba-
`sis of a reduction of the myeloma protein in serum
`or Bence Jonesprotein in urine that lasted for at least
`six weeks,
`Results The serum orurine levels of paraprotein
`were reduced byat least 90 percentin eight patients
`(two had a complete remission), at least 75 percent
`in six patients, at least 50 percent in seven patients,
`and at least 25 percentin six patients, for a total rate
`of response of 32 percent. Reductions in the parapro-
`tein jevels were apparent within two monthsin 78
`percentof the patients with a response and were as-
`sociated with decreased numbers of plasmacells in
`bone marrow andincreased hemoglobin levels. The
`microvascular density of bone marrow did not change
`significantly in patients with a response.At jeast one
`third of the patients had mild or moderate constipa-
`tion, weakness or fatigue, or somnolence. More se-
`vere adverse effects were infrequent (occurring in less
`than 10 percent of patients), and hematologic effects
`were rare. As of the most recent follow-up, 36 pa-
`tients had died (30 with no response and 6 with a re-
`sponse). After 12 months of follow-up, Kaplan-Meier
`estimates of the mean (+SE) rates of event-free sur-
`vival and overall survival for all patients were 22+5
`percent and 58+5 percent, respectively.
`Conclusions Thalidomide is active against ad-
`vanced myeloma. It can induce marked and durable
`responses in some patients with multiple myeloma,
`including those whorelapse after high-dose chemo-
`therapy. (N Engl J Med 1999;341;1565-71.)
`©1999, Massachusetts Medical Society.
`
`ULTIPLE myeloma accounts for ap-
`proximately 1 percentofal) cancers and
`10 percent of hematologic cancers. It
`is incurable with conventional chemo-
`therapy.! Melphalan-based high-dose chemotherapy
`with hematopoietic stem-cell support increases the
`rate of complete remission and extends event-free and
`overall survival.?4 However, manypatients still relapse,
`and options for salvage therapy are limited.5¢
`Angiogenesis is important in embryogenesis, wound
`healing, diabetic retinopathy, and tumorprogression.”8
`The immunomodulatory drug thalidomide can inhib-
`it angiogenesis and induce apoptosis of established
`neovasculature in experimental models.%}° For these
`reasons, angiogenesis-inhibiting drugs such as tha-
`lidomide may be useful for treating cancers that de-
`pend on neovascularization.
`Prominent bone marrow vascularization occurs in
`multiple myeloma. It correlates positively with a high
`plasma-cell—labeling index (a poor prognostic sign)
`and disease activity and independently confers a poor
`prognosis.!16 Plasmalevels of various angiogenic cy-
`tokines, such as basic fibroblast growth factor and
`vascular endothelial growth factor, are elevated in pa-
`tients with active myeloma.}?4416 In 1965, Olsonet al.
`reported slowing of disease progression in one pa-
`tient who was treated with thalidomide.!” These con-
`siderations led us to administer thalidomide to five
`patients with end-stage myeloma through a compas-
`sionate-use protocol. One patient with a large tumor
`burden(as indicated by an IgA level of 8.4 g per dec-
`iliter, the presence of more than 95 percent plasma
`cells in bone marrow, and the need for transfusion),
`whohad had no response to two cycles of high-dose
`chemotherapy followed by multiple salvage therapies,
`had a nearly complete remission within three months
`after the initiation of thalidomide therapy. This ob-
`servation prompted a phase 2 investigation of tha-
`
`
`
`From the Myeloma and Lymphoma Program, South Carolina Cancer
`Center, University of South Carolina, Columbia (S.S., J.M.); the Myeloma
`and Transplantation Rescarch Center, University of Arkansas for Medical
`Sciences, Little Rock (R.D., D.A., P.R., PE., N.M., E.A., CW.,J.Z., B.B.);
`and the
`of Cellular Physiology and Immunology, Rockefeller
`University, New York (M.D.). Address reprint requests ro Dr. Barlogie at
`the Myeloma and Transplantation Research Center, University of Arkansas
`for Medical Sciences, 4301 W. Markham,Slot 623, Litthe Rock, AR 72205.
`Other authors were David Siegel, M.D., Ph.D., University of Arkansas
`for Medical Sciences, Little Rock, and John Crowley, Ph.D., Fred Hutch-
`inson Cancer Research Center, Searde.
`
`Dr. Redty'SAaborAtbrie’ He ¥teigene cps
`IPR2018-01509
`Exhibit 2023, Page 2
`
`

`

`The New England Journal of Medicine
`
`lidomide in patients with advanced and refractory
`myeloma.
`
`TaBLe 1. CHARACTERISTICS OF THE PATIENTS.
`
`METHODS
`
`Patients and Treatments
`
`CHARACTERISTIC
`
`No,or
`PATIENTS {%)
`
`cen
`of 1
`pro
`ing
`
`He:
`
`BOFQHASESESRE.B
`ARABRASaAGE
`evpuSsrmEnaeAS
`nniinee|
`
`.
`
`19 (23)
`
`54 (64)
`9 (11)
`1 (1)
`1 (1)
`
`QOf2ks
`
`Between December 1997 and June 1998, 84 consecutive,eligi-
`ble patients with previously treated and progressive myeloma began
`treatment with oral thalidomide as a single agent after providing
`written informed consent. No patients were excluded on the basis
`of renal or cardiopulmonary function, whereaspatients could be
`excludedif the results ofliver-function tests were more than twice
`the upperlimit of normal levels. All patients were treated at a single
`center according to a phase 2 protocol approved by the institution-
`al review board and the Food and Drug Administration (FDA).
`Thalidomide was supplied in 50-mg capsules by Celgene (War-
`ren, N.J.) and was administered nightly at a dose of 200 mg. The
`' dose was increased by 200 mg every two weeks for six weeks, so
`that the final dose was 800 mg per day. Data were analyzed as of
`June 17, 1999, when the duration oftreatment ranged from 2 to
`465 days (median, 80) and the median follow-up of surviving
`patients was 13 months.
`Table 1 summarizes the characteristics of the patients and de-
`tails ofprior therapy, Seventy-six patients (90 percent) had received
`at least one cycle of high-dose chemotherapy with autologous hem-
`atopoietic stem-cell support, and 58 (69 percent) had received two
`or more cycles of intensive chemotherapy. The median time from
`the last course of high-dose chemotherapy to the beginning of
`treatment with thalidomide was 14 months. A high-risk cyto-
`genetic abnormality (deletion of chromosome 13) was presentin
`35 patients (42 percent).2° One patient had received an allograft
`as a second intervention, with evidence of full donor-type chi-
`merism in normal lymphohematopoietic cells. Ar the time of en-
`rollment, all patients had progressive disease, with an increase in
`paraprotein levels of at least 25 percent orat least 50 percentplas-
`macells in bone marrow. Approximately half the patients had been
`retreated with dexamethasone or other regimens, but the disease
`had progressed before thalidomide treatment was begun.
`
`Evaluation
`
`The pretreatment evaluation included complete blood counts,
`tests of renal andliver function, serum and urine protein electro-
`phoresis, and measurements of serum levels of immunoglobulins,
`beta,-microglobulin, and C-reactive protein. Bone marrow aspi-
`rates were obtained and biopsies were performed to determine
`the percentage ofplasmacells in bone marrow, to identify kary-
`otypic abnormalities (Giemsa-banded cells in metaphase), and to
`assess the proliferative activity in plasma cells according to the
`bromodeoxyuridine method to derive the plasma-cell~labeling
`index.® Follow-up studies included a weekly estimation ofpara-
`protein levels — the myelomaprotein in serum and Bence Jones
`protein in urine — for the first two months, followed thereafter
`by monthly measurements. Wheneverpossible, bone marrow was
`examined at the time of the maximal response or when patients
`with no responseleft the study.
`The microvascularity of bone marrow was studied in a semi-
`quantitative fashion in biopsy samples that were obtained with
`a wephineand stained with an anti-CD34 monoclonal antibody
`(prediluted Clone QBEnd/10, Cell Marque, Austin, Tex.). The
`results were expressed as the number of vessels per high-power
`field (400%).
`
`Assessment of Response
`The primary end point of the study was the finding of a decline
`in the level ofparaprotein in serum orurine ofat least 25 percent,
`50 percent, 75 percent, or 90 percent on rwo occasions at least
`six weeks apart. Among patients with detectable levels of both
`urine and s¢rum paraprotein, the response was judged on the ba-
`sis of the component showing the smaller decline, Patients with
`
`1566 + November 18, 1999
`
`61 (73)
`51 (61)
`51 (61}
`18 (21)
`76 (90)
`58 (69)
`43 (57)
`
`32 (38)
`19 (23)
`17 (20)
`22 (26)
`22 (26)
`24 (29)
`20 (24)
`5] (61)
`44 (52)
`18 (21)
`13 (15)
`19 (23)
`35 (42)
`
`“
`Male sex
`Durie—Salmon stage II] multiple myeloma
`IgG paraprotein
`Duration ofprior therapy >60 mo
`Prior high-dose chemotherapy
`Receipt of >1 cycle of high-dose chemotherapy
`Interval betweenlast cycle of high-dose chemotherapy
`andinitiation of thalidomide >12 mo
`Age >60 yr
`Hemoglobin <9 g/dl
`Platelet count <50 x 10*/mm?
`Serum albumin <3.5 g/d!
`Serum creatinine >1.5 mg/dl (133 pmol/liter)
`Serum beta,-microglobulin >6 mg/liter
`Serum C-reactive protein >3 mg/liter
`Serum monoclonal immunoglobulin >1 g/dl
`Urine Bence Jones protein >1 g/day
`>50% Plasmacells in bone marrow on biopsy
`Plasma-cell-labeling index >1%*
`Bart) grade It
`Deletion of chromosome 13
`Outcome
`Completion of study
`Withdrawal from study
`Progression
`Intolerance of thalidomide
`Death of patient with a responsct
`Personal reasons
`Final dose of thalidomide
`72 (86)
`400 mg/day
`57 (68)
`600 mg/day
`
`800 mg/day 46 (55)
`
`*The plasma-cell—labeling index represents the percentage of light-chain-
`restricted plasmacells incorporating bromodeoxyuridine.!8
`{The Bart! grading system distinguishes myeloma cells according to their
`morphologic maturation.!® Grade II refers to immature plasma cells of
`cleaved, asynchronous, or polymorphous appearance.
`$This patient had a response to treatment butdied on day 37 oftreatment.
`
`a reduction of Jess than 25 percent and those who discontinued
`ueatment before a response could be assessed were considered to
`have had no response to thalidomide, Thus, the results were eval-
`uated on an intention-to-treat basis. In patients with a response,
`an increase in serum or urine paraprotein levels by more than 25
`percent above the nadir value was considered evidence ofrelapse.
`In patients who had a complete remission, evidence of reemer-
`gence of the monoclonal protein (determined by immunofixation)
`on at least two occasions was considered to indicate a relapse. In
`patients who had a complete remission or a nearly complete re-
`mission (#90 percent reduction in serum or urine paraprotein lev-
`els), a bone marrow response was defined as the finding ofless
`than 5 percentplasmacells in the biopsy specimen oraspirate. For
`the remaining patients with a paraprotein response, the percent-
`age ofplasma cells had to decrease by at least 50 percent to qual-
`ify as a bone marrow response.
`
`Assessment of Adverse Effects
`
`All patients, irrespective of the duration of therapy, were in-
`cluded in the evaluation of adverse effects, All patients received
`diaries after providing informed consent, and 83patients (99 per-
`
`Dr. Reddy’s Laboratories, Inc. v. Celgene Corp.
`IPR2018-01509
`Exhibit 2023, Page 3
`
`

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`
`Dr. Reddy’s Laboratories, Inc. v. Celgene Corp.
`IPR2018-01509
`Exhibit 2023, Page 4
`
`

`

`The New England Journal ofMedicine
`
`np—-
`
`TABLE 2. PARAPROTEIN RESPONSE AND BONE MARROW RESPONSE.«elllLA,
`cal
`
`ASSESSMENT OF BONE
`Current STATUS
`Marrow ResPonse
`NO. WITH
`NO. WHO
`TOTAL
`NO. WITH
`RELAPSE (%) DIED (%)
`NO."—RESPONSE (%)}
`
`PaRAPROTEIN RESPONSE
`
`No,OF
`PATIENTS
`(% OF ToTAL)
`
`lev
`res
`cel
`
`0
`2 (100)
`2
`2 (2)
`Complete remission
`2
`5 (83)
`6
`6 (7)
`3»90% decrease in paraprotein
`3
`3 (60)
`5
`6 (7)
`75% decrease in paraprotein
`3,
`4 (100)
`4
`7 (8)
`50% decrease in paraprotein
`4
`3 (75)
`4
`6 (7)
`25% decrease in paraprotein
`6 (22)
`12 (44)
`~—s-17 (81)
`21
`27 (32)
`Total
`
`
`
`4 (15) —27 30 (53)
`57 (68)
`No response
`
`0
`2
`1
`0
`
`*The response could not be evaluated in 6 of the patients with a paraprotein response and in 30
`of the patients with no paraprotcin response,
`tA bone marrow response was defined as the presenceofless than 5 percent plasmacells in bone
`marrow in patients who had a complete paraprotein response or at least a 90 percent reduction in
`paraprotein levels and‘ as a reduction in plasma cells of at least 50 percent in patients with all other
`types of paraprotcin responses.
`
`0.5
`eo 04
`
`© F
`
`
`
`25% reduction in paraprotein
`.
`jeotesseners3poresssernscosovore 50% reduction in paraprotein
`@
`
`se
`_prveceneeenetsretnnnadrece »75% reduction in paraprotein
`% °
`=
`:
`5
`
`4 eee awe PT ae 90% reduction in paraprotein
`—
`0.1
`.
`3
`aww errr Complete response
`=8 ;
`44:2
`v 0.0
`10 14~«1612
`
`
`2
`6
`8
`0
`4
`
`03
`
`32
`
`ssnervoroondce
`
`eeee
`
`Monthsafter the Start of Thalidomide
`
`Figure 1. Times to Various Paraprotein Responses.
`Amongpatients with a response, the median times to a reduction in the serum or urine paraprotein
`level of at least 25 percent, 50 percent, 75 percent, and 90 percent were one, two, four, and four
`months, respectively, Seventy-eight percent of the responses at the lowest level (=25 percent reduc-
`tion) were apparent within two monthsafter the initiation of treatment.
`
`Microvascular Density of Bone Marrow
`The microvascular density of bone marrow was
`scheduled to be assessed every 50 days for a total of
`seven measurements, including the pretreatmentval-
`ue. At least one measurement of the microvascular
`density of bone marrow was madein 74 patients (88
`percent); two or more measurements were made in
`37 patients (44 percent). In all, measurements were
`made in 69 patients before treatment and (in 50-
`day increments) in 17 at time 2, in 22 at time 3, in
`1] at time 4, in 12 at time 5, in 4 at time 6, and in
`3 at time 7. The microvascular density of bone mar-
`row andthe percentage of plasmacells in bone mar-
`row correlated significantly at all times except the last
`(r>0.5, P=0.01). Although the microvascular den-
`sity of bone marrow decreased markedly in somepa-
`
`tients with a complete or nearly complete remission,
`estimates of the slope were notsignificantly different
`from zero among those with a response (P=0.39)
`and those without a response (P=0.22).
`
`Other Changes
`The percent changes from base line to the time of
`the maximal response amongpatients with a response
`and the time of the last follow-up visit among those
`without a response were assessed for beta,-micro-
`globulin, C-reactive protein, lactic dehydrogenase,
`creatinine, albumin, and hemoglobin levels and the
`platelet count. Hemoglobin levels increased only in
`patients with a response (median increase, 11 percent;
`P<0.001 for the comparison with base-line values).
`Serum levels of beta,-microglobulin rose (median in-
`
`1568 + November 18, 1999
`
`Dr. Reddy’s Laboratories, Inc. v. Celgene Corp.
`IPR2018-01509
`Exhibit 2023, Page 5
`
`

`

`ANTITUMOR ACTIVITY OF THALIDOMIDE IN REFRACTORY MULTIPLE MYELOMA
`
`TABLE 3. INCIDENCE OF GRADE 1 OR 2 ADVERSE EFFECTS.”
`
`crease, 43 percent; P<0.001) and serum albumin lev-
`els fell (median decrease, 4 percent, P<0.001) signifi-
`cantly in patients with no response. Serum creatinine
`levels did not change significantly in patients with a|apvense Errect Dost oF THALIDOMMDE
`
`response, and they increased by a median of 13 per-
`_ 200mg/par
`400 mg/pay 600mg/pay 800mg/DAY
`cent in those without a response (P<0.001).
`(N=83)
`(N=72)
`(N57)
`(N=46)
`percentage of patientst
`59
`44
`35
`Constipation
`Adverse Effects
`44
`
`Side effects reported by at least 10 percent of pa-|Weakness or 29 31 39 48
`
`
`
`tients at most dose.levels are listed in Table 3. Most
`fatigue
`
`
`
`adverse effects were mild or moderate (grade 1 or|Somnolence 34 43 40 43
`
`2 according to the system ofclassification of the
`Tinglingor
`12
`«
`1¢
`19
`%
`
`World Health Organization). Constipation, weakness|pines. 7 35 23 38
`
`
`
`
`or fatigue, and somnolence occurred in one third or|gas, 16 18 21 "6
`
`
`
`
`moreof the patients. Reports of grade 3 or 4 adverse|Mood changes 16 4 23 2
`
`
`
`effects were infrequent (less than 10 percentin all
`or depression
`
`
`
`cases). One quarterofthe paticnts had no appreciable|Iscoordination 16 v7 4 22
`
`
`side effects at the 200-mg dose, whereas virtually all|Tremors 10 13 9 22
`
`
`
`
`patients had adverse effects of grade 1 or 2 at higher|dem 6 10 12 22
`
`
`
`
`doses, Fewer than 5 percentofpatients had grade 1 or|“m*** a 6 23 M
`
`
`
`Headache
`2
`10
`4
`il
`2 leukopenia at any dose, and grade 3 or 4 thrombo-
`cytopenia or anemia occurred in only three patients.
`In most of the patients who had no response, pre-
`treatment anemia or thrombocytopenia did not wor-
`sen, whereas significant increases in the hemoglobin
`levels occurred in patients with a response. Nine pa-
`tients could not tolerate thalidomide (four with a re-
`sponse and five with no response) and discontinued
`treatment after a median of 36 days (range, 10 to
`241). In eight patients, an increase in serum creati-
`nine levels of more than 50 percent was related to
`progressive disease, with increasing Bence Jones pro-
`teinuria. One of the patients with a response died
`suddenly on day 37 of treatment. The death was
`thoughtto be related to sepsis, although a possible
`contribution of thalidomide could not be ruled out.
`
`
`
`Time to Progression, Event-free Survival,
`and Overall Survival
`
`Ofthe 27 patients with a decrease in paraprotein
`levels of at least 25 percent, 12 had a recurrence of
`the disease. After a median follow-up of 14.5 months
`(range, 12 to 16), the median time to progression
`had not been reached. The disease in a mean (+SE)
`of 44+10 percent ofpatients was judged to have pro-
`gressed at 12 months. The median event-free survival
`for all 84 patients was three months (Fig. 2). After 12
`months of follow-up, 22+5 percent ofthe 84 patients
`remained event-free and 58+5 percent were alive.
`Nineteen patients were still receiving thalidomide 4 to
`15 monthsafter starting the treatment (median, 13),
`including 15 patients with a response and 4 with no
`response who had had some improvementin various
`disease indicators but who had not had a decrease in
`paraprotein levels of at least 25 percent. Multivariate
`analysis indicated that increasesin lactic dehydrogen-
`ase levels (P=0.001), the plasma-cell—labeling index
`(P=0.006), and C-reactive protein levels (P=0.007)
`
`Exhibit 2023, Page 6
`
`*The classification system of the World Health Organization was used.
`Grade1 effects are mild, and grade 2 are moderate.
`{Values are the percentages of patients at cach dose level.
`
`were all predictive of a brief period of event-free sur-
`vival, whereas low albumin levels (P<0.001),the de-
`letion of chromosome13 (P=0.004), and high num-
`bers of plasmacells in bone marrow (P=0.05) were
`associated with a relatively short overall survival.
`Thalidomide was discontinued after a median of
`52 days (range, 2 to 286) because ofa lack of response
`in 53 patients (4 patients continued to receive the
`drug without a response) and because of relapse in
`12 patients who had had a response. One patient who
`had a decrease in the paraprotein level of at least 25
`percent and who had notpreviously received high-
`dose therapy subsequently underwent autologous
`stem-cell transplantation at his own request. As of
`June 17, 1999, 36 patients had died, including 30 pa-
`tients without a response who died of progressive
`disease or complications of subsequentsalvage ther-
`apy, as well as 6 patients with a response who subse-
`quently relapsed anddied of progressive disease (3) or
`toxicity from salvage therapy (3).
`
`DISCUSSION
`
`Wefound thatthalidomide had substantial antitu-
`moractivity in patients with advanced myeloma. Ten
`percent of patients had complete or nearly complete
`remission, and 32 percent had a reduction in serum
`or urine paraprotein levels of at least 25 percent. In
`most patients, the decline in paraprotein levels was
`accompanied by a reduction in the percentage ofplas-
`ma cells in bone marrow and an increase in hemo-
`globin levels, both of which are consistent with the
`
`1569
`Volume 34) Number 21
`Dr. Reddy’s Laboratories, Inc. v. Celgene Corp.
`IPR2018-01509
`
`

`

`The New England Journal of Medicine
`
`ProportionofPatients
`
`1.0
`
`0.8
`
`0.6
`
`0.4
`
`0.2
`
`0.0
`
`
`
`
`Overall survival
`
`8
`
`10
`
`#12
`
`Wm 6 18
`
`Monthsafter the Start of Thalidomide
`
`No, aT Risk
`84
`Overall! survival
`Event-free survival 84
`
`78
`65
`
`69
`39
`
`58
`24
`
`56
`19
`
`54
`18
`
`4
`11
`
`Figure 2, Kaplan-Meier Estimates of Overall Survival and Event-free Survival,
`Event-free survival was caleulated from the start of thalidomide therapy to progression, removal from
`. the study for any reason, death from any cause,or the last follow-up visit, whichever occurred first. I bars
`indicate standard errors at 12 months.
`
`presence ofatrue antitumoreffect. Although notex-
`amined quantitatively, bone pain decreased markedly
`in patients with a response. Wedid not evaluate lytic
`bonelesions, which seldom heal,even in patients with
`a sustained complete remission.
`Thalidomide has a numberof properties that could
`explain its activity in myeloma;it can alter the expres-
`sion of adhesion molecules,?5 suppress the production
`oftumornecrosis factor a,?¢ increase the production
`of interleukin-10,27 and enhance cell-mediated im-
`munity by directly stimulating cytotoxic T cells,?8 Its
`interactions with type 1 and type 2 helper T cells pro-
`duce complex effects on the levels of cytokines such as
`interleukin-4, interleukin-5, and interferon-y.?? Tha-
`lidomide also increases the total number of lympho-
`cytes as well as CD8+ and CD4+- T-cell counts, along
`with substantially increasing mean plasma levels of
`soluble interleukin-2 receptor.”
`Thalidomide has been shownto inhibit angiogen-
`esis induced by fibroblast growth factor and vascular
`endothelial growth factor in a rabbit-cornea micro-
`pocket assay? and a murine model of corneal vascu-
`larization.!° It has also been shown to cause apoptosis
`of established tumor-associated angiogenesis in exper-
`imental models.!° The bone marrow ofpatients with
`hematologic cancers shows extensive vascularity,!25
`which has prognostic implications in myeloma.'* The
`apparentlack of a consistent decrease in the microvas-
`cular density of bone marrow in patients in whom
`thalidomide had a marked antitumoreffect requires
`further study. The persistence of extensive vascular-
`ization in somepatients with a response is consistent
`with the finding of persistent neovascularity in pa-
`tients with multiple myeloma who had a response to
`high-dose chemotherapy.!® The production of an-
`
`1570 - November 18, 1999
`
`giogenic cytokines such as fibroblast growth factor
`and vascular endothelial growth factor by undetect-
`able residual myelomacells may sustain the increased
`microvascular density of bone marrow in patients con-
`sidered to be in remission on the basis of bone mar-
`row findings. The persistence of extensive vasculariza-
`tion in patients with a response makes it seem likely
`that the antimyelomaaction ofthalidomide depends
`on more than one ofthe actions of the drug out-
`lined above, The mouse model of severe combined
`immunodeficiency, which can be used for the in vivo
`growth of primary human myelomacells, is ideally
`suited to study the mechanisms by which thalidomide
`induces responses in myeloma.3?
`The antitumorproperties of thalidomide are being
`evaluated in various malignantdiseases,3!5 although
`only limited efficacy data are available so far. Pro-
`longed responses to thalidomide in somepatients with
`advanced refractory disease suggest that the mecna-
`nism of action of thalidomide is distinctly different
`from that of the other agents active against myeloma.
`The absence of myelosuppressive and other impor-
`tant adverse effects suggests that thalidomide could
`be an idea] agent for use in combination with che-
`motherapy. Indeed, a complete remission has been
`achieved with such an approach. in several patients
`with myeloma whohad noresponse to treatment with
`cither regimen alone.*6 This approach has also been
`shown to have greater antitumoractivity than chemo-
`therapy alone in a murine model of breast cancer.3”
`In our study, most patients had adverse effects,
`but the majority of these reactions were mild or mod-
`erate. Reducing the dose of thalidomidealleviated the
`effects in most cases, and only nine patients discon-
`tinued therapy altogether. The gradual reduction in
`
`Dr. Reddy’s Laboratories, Inc. v. Celgene Corp.
`IPR2018-01509
`Exhibit 2023, Page 7
`
`fhe
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`ANTITUMOR ACTIVITY OF THALIDOMIDE IN REFRACTORY MULTIPLE MYELOMA
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`drowsiness and fatigue in-some patients with contin-
`ued treatmentat the same dose (data not shown) sug-
`gests the occurrence of tachyphylaxis.
`We conclude that thalidomide is active against mul-
`tiple myeloma, even in patients whorelapsed after
`repeated cycles of high-dose chemotherapy. Larger
`studies of thalidomide, its analogues, and other in-
`hibitors of angiogenesis are therefore warranted in
`patients with myeloma and other cancers. We are
`currently evaluating thalidomide in c