'fh,, NEW ENGLAND JOURNAL o_f IVIEDICIN E
`
`l~l __________ <_)_R_.r_c_¥1_N_,_~_1.._A_._R_T_1_c_L_r_, _________ ~II
`Effects of Semaglutide on Chronic I(idney
`Disease in Patients with Type 2 Diabetes
`V!ado Perkovic, M.f.L, B.S., Ph .D .. Katherine R. Tuttle, M.D.,
`Peter Rossing, fvl.D., D.M.Sc., \{enneth VV. V1ahaffoy, M.D.,
`Johannes F.E. Mann, fv1.D. , George IJakris, l'vl.D., Horian !'vUvt IJaeres, M.D.,
`Thomas ldorn , M.D ., Ph .D., Hcidwn Bosch-Traberg, M.D.,
`N,:nna Leonorn Lausvig, fv1.Sc., and Richard Pratley, fv1.D .,
`for the FLOW Trial Cormnittces and Investigators·,·,
`
`ABSTRACT
`
`BACl<<.ROUNO
`Patients with type 2 diabetes and chronic kidney disease are at high risk for kidney
`failure, cardiovascular events, and death. Whether treatment with semaglutide would
`mitigate these risks is unknown.
`
`MF.THO OS
`We randomly assigned patients with type 2 diabetes and chronic kidney disease
`(defined by an estimated glomerular filtration rate [eGFR) of 50 to 75 ml per minute
`per 1.73 m 2 of body-surface area and a urinary albumin-to-creatinine ratio [with
`albumin measured in milligrams and creatinine measured in grams] of >300 and
`<5000 or an eGFR of 25 to <50 ml per minute per 1.73 m 2 and a urinary albumin(cid:173)
`to-creatinine ratio of >100 and <5000) to receive subcutaneous semaglutide at a
`dose ofl.0 mg weekly or placebo. The primary outcome was major kidney disease
`events, a composite of the onset of kidney failure (dialysis, transplantation, or an
`eGFR of <15 ml per minute per 1.73 111 2), at least a 50% reduction in the eGFR
`from baseline, or death from kidney-related or cardiovascular callses. Prespecified
`confirmatory secondary outcomes were tested hierarchically.
`
`RESULTS
`Among the 3533 participants who underwent randomization (1767 in the semag!u(cid:173)
`tide group and 1766 in the placebo group), median follow-up was 3.4 years, after
`early trial cessation was recommended at a prespecified interim analysis. The risk
`of a primary-outcome event was 24% lower in the semaglutide group than in the
`placebo group {331 vs. 410 first events; hazard ratio, 0.76; 950/o confidence interval
`(CI], 0.66 to 0.88; P=0.0003). Results were similar for a composite of the kidney(cid:173)
`specific components of the primary outcome (hazard ratio, 0.79; 95% CI, 0.66 to 0.94)
`and for death from cardiovascular causes (hazard ratio, 0.71; 95% CI, 0.56 to 0.89).
`The results for all confirmatory secondary outcomes favored semaglutide: the
`mean annual eGFR slope was less steep (indicating a slower decrease) by 1.16 ml
`per minute per 1.73 1112 in the semaglt1tide group (P<0.001), the risk of major car(cid:173)
`diovascular events 18% lower (hazard ratio, 0.82; 95% CI, 0.68 to 0.98; P=0.029),
`and the risk of death from any cause 20% lower (hazard ratio, 0.80; 95% Cl, 0.67
`to 0.95, P=0.01). Serious adverse events were reported in a lower percentage of
`participants in the semaglutide group than in the placebo group (49.6% vs. 53.8%).
`
`CONCLUS IONS
`Semaglutide reduced the risk of clinically important kidney outcomes and death
`from cardiovascular causes in patients with type 2 diabetes and chronic kidney
`disease. (Funded by Novo Nordisk; FLOW Clinica!Trials.gov number, NCT03819153.)
`
`From the University of New South Wales,
`Sydney (V.P.); the Division of Nephrolo(cid:173)
`gy, University of Washington School of
`Medicine, Seattle, and Providence Medi(cid:173)
`cal Research Center, Providence Inland
`Northwest H ealth, Spokane -
`both in
`Washington
`(K.R.T.) ; Steno Diabetes
`Cen te r Copenhagen, Herlev (P.R.), the
`Department of Clinical Medicine, Univer(cid:173)
`sity of Copenhagen, Copenhagen (P.R.),
`and Novo No rdisk, S0borg (F.M .M .B.,
`T.I., H.8.-T. , N.L.L.) -
`all in Denmark;
`Stanford Center for Clinical Research, De(cid:173)
`partment of Medicine, Stanford School of
`Medicine, Palo Alto , CA (ICW.M.); KfH
`Kidney Center, Mu nich, and Uni versity
`Hospital, Friedrich-Alexande r University,
`Er!angen -
`both in Germany LJ.F.E.M.);
`the Department of Medicine, American
`Heart Association Comprehen sive Hyper(cid:173)
`tension Center, University of Chicago Medi(cid:173)
`cine, Chicago (G.B.); and Adven tH ea lth
`Translational Resea rch Institute, Orlando,
`FL (R .P.). Dr. Perkovic can be contacted
`at vlado.perkovic@unsw.edu.au or at the
`Chancellery, University of New Sou th
`Wales , Sydney, NSW 2052, Australia .
`
`''The FLOW Trial Cormnittees and lnve, ..
`tigators are listed in the Supp lementary
`Appendix , av;iiiable at NEJM.org.
`
`This artic:lewas p;,blished on May 2.4, 2024,
`at NEJM .org.
`
`DOI, lO.l0%iNEJMo~14(ff)47
`Copyright © 2024 Massachusetts Medical Society.
`
`N [NCL _j MED NEJM ,O R<i
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`I
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`T h.: NEW ENGLAND JOURNAL ,,JMEDICINE
`
`ORE THAN HALF A BILLION PEOPLE
`globally are affected by chronic kidney
`disease and are at high risk for kidney
`failure, cardiovascular events, and death.' Type 2
`diabetes is the most frequent cause of chronic
`kidney disease in many countries. Renin-angio(cid:173)
`tensin system (RAS) inhibitors,23 sodium-glucose
`cotransporter 2 (SGLI2) inhibitors, and finere(cid:173)
`none have been shown to protect the kidneys and
`reduce the risk of adverse cardiovascular out(cid:173)
`comes 4•8 and therefore are guideline-directed med(cid:173)
`ical therapies for chronic kidney clisease in patients
`with type 2 diabetes.9•10 Nevertheless, many pa(cid:173)
`tients continue to lose kidney function and go
`on to have kidney failure or to die, most com(cid:173)
`monly from cardiovascular events. Thus, the ef..
`fects of therapies such as glucagon-like peptide 1
`(GLP-1) receptor agonists are of great interest.11
`The FLOW (Evaluate Renal Function with
`Semaglutide Once Weekly) trial assessed the ef(cid:173)
`ficacy and safety of subcutaneous semaglutide at
`a dose of 1.0 mg once weekly for the prevention
`of kidney failure, substantial loss of kidney fonc(cid:173)
`tion, and death from kidney-related or cardiovas(cid:173)
`cular causes in patients with type 2 diabetes and
`chronic kidney disease.
`
`METHODS
`
`TRIAL DESIGN ANO OVERSIGHT
`We published the design of this international,
`double-blind, randomized, placebo-controlled trial
`previously.12 The trial was overseen by an academ(cid:173)
`ic-led steering committee (see the Supplementa(cid:173)
`ry Appendix, available with the full text of this
`article at NEJM.org) in partnership with the trial
`sponsor, Novo Nordisk, which also managed trial
`operations. The trial steering committee provided
`overall leadership; oversaw trial design, conduct,
`and analysis; and was responsible for reporting
`the results. Analyses were conducted by the spon(cid:173)
`sor and were independently verified with the use
`of the original data by Statogen Consulting. The
`first author wrote the first draft of the manu(cid:173)
`script, and all the authors contributed to subse(cid:173)
`quent revisions. Technical editorial assistance
`was provided by OpenHealth and fonded by the
`sponsor. The authors had access to the full data
`set, made the decision to submit the manuscript
`for publication, and vouch for the accuracy and
`completeness of the data and for the fidelity of
`the trial to the protocol (available at NEJM.org).
`
`Relevant approval from regulatory authorities
`and institutional review boards was obtained. Each
`participant provided written informed consent
`before undergoing any trial-related procedures.
`
`PARTICIPANTS
`Adults with type 2 diabetes (glycated hemoglo(cid:173)
`bin level, ~10%) were eligible for inclusion in the
`trial if they had high-risk chronic kidney disease
`and were receiving a stable maximal labeled dose
`(or the maximal dose without unacceptable side
`effects) of RAS inhibitors (angiotensin-convert(cid:173)
`ing-enzyme inhibitor or angiotensin-receptor
`blocker). Kidney disease was defined by an esti(cid:173)
`mated glomerular filtration rate (eGFR) of 25 to
`75 ml per minute per 1.73 m2 of body-surface
`area (calculated with the serum creatinine level
`and the Chronic Kidney Disease Epidemiology
`Collaboration [CKD-EPI] 2009 formula, 13 which
`were used to calculate all reported eGFR values
`llnless otherwise indicated), with a urinary albu(cid:173)
`min-to-creatinine ratio (with albumin measured
`in milligrams and creatinine measured in grams)
`of greater than 300 and less than 5000 if the
`eGFR was 50 ml per minute per 1.73 m 2 or
`higher or a urinary a!bumin-to-creatinine ratio
`of greater than 100 and less than 5000 if the
`eGFR was 25 to less than 50 ml per minute per
`1.73 m2• Patients who were unable to receive RAS
`inhibition because of side effects were eligible
`for inclusion. A full list of inclusion and exclusion
`criteria, including a range of specific kidney dis(cid:173)
`ease diagnoses, is provided in the Supplementary
`Appendix.
`
`TRIAL PROCEDURES
`Eligible participants were randomly assigned in
`a 1:1 ratio to receive semaglutide or matching
`placebo with the use of a central interactive Web(cid:173)
`based response system. The use of SGLT2 inhibi(cid:173)
`tors and mineralocorticoid-receptor antagonists
`(MRAs) was permitted, and randomization was
`stratified according to SGLT2 inhibitor use at
`baseline. An 8-week dose-escalation regimen
`was used, with dose escalation (as long as unac(cid:173)
`ceptable side effects did not occur) from 0.25 mg
`per week for 4 weeks and 0.5 mg per week for
`another 4 weeks, followed by a maintenance
`dose of 1.0 mg per week throughout the remain(cid:173)
`der of the treatment period. If unacceptable ad(cid:173)
`verse effects occurred, dose-escalation intervals
`could be extended, treatment could be paused,
`
`2
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`EFFECTS OF SE/1,IAG.LUTlDE ON CHRONIC KIDNEY DISEASE
`
`or lower maintenance doses could be used. Labo(cid:173)
`ratory-based inclusion criteria were based on local
`laboratory values recorded within 90 days before
`the screening visit or central laboratory values
`recorded at screening or at optional prescreen(cid:173)
`ing visits.
`
`TRIAL OUTCOMES
`The primary outcome was major kidney disease
`events, a composite of onset of kidney failure (ini(cid:173)
`tiation of long-term dialysis, kidney transplanta(cid:173)
`tion, or a reduction in the eGFR to <15 ml per
`minute per 1.73 m1 sustained for ~28 days), a
`sustained (for ?..28 days) 50% or greater reduc(cid:173)
`tion in eGFR from baseline, or death from kid(cid:173)
`ney-related or cardiovascular causes. Three key
`confirmatory secondary outcomes were defined
`and assessed with the use of a formal hierarchi(cid:173)
`cal testing strategy: total eGFR slope (i.e., the
`annual rate of change in eGFR from randomiza(cid:173)
`tion to the end of the trial); major cardiovascular
`events (a composite of nonfatal myocardial in(cid:173)
`farction, nonfatal stroke, or death from cardio(cid:173)
`vascular causes), assessed in a time-to-first-event
`analysis; and death from any cause. A range of
`additional supportive secondary, exploratory, and
`other outcomes were also prespecified and are
`listed in the Supplementary Appendix.
`Safety was assessed by collecting data on all
`serious adverse events, adverse events leading to
`discontinuation of semaglutide or placebo, and
`adverse events of special interest. Primary and sec(cid:173)
`ondary outcomes other than eGFR assessments
`derived from the central laboratory were adjudi(cid:173)
`cated in a blinded fashion by an event adjudication
`committee (see the Supplementary Appendix).
`
`STATISTICAL ANALYSIS
`This trial was event driven. We calculated that a
`minimum of854 primary-outcome events would
`provide 90% power to detect a 20% lower relative
`risk in the semaglutide group than in the placebo
`group at an overall one-sided significance level of
`2.5%. An interim analysis of efficacy was planned
`for after two thirds of the total planned number
`of primary-outcome events had occurred.
`Efficacy analyses were based on the intention(cid:173)
`to-treat principle and included aII unique partici(cid:173)
`pants who underwent randomization, irrespective
`of adherence to semaglutide or placebo or chang(cid:173)
`es to background medications. Time-to-first-event
`outcomes were analyzed with a stratified Cox
`
`proportional-hazards model with randomization
`assignment (semaglutide or placebo) as a fixed
`factor and stratified according to SGLT2 inhibi(cid:173)
`tor use at baseline. P values were obtained from
`a score test. For the primary outcome, the hazard
`ratio, 95% confidence interval, and P value were
`adjusted for the group sequential design with
`the use of likelihood-ratio ordering. The eGFR
`slope was analyzed with a linear mixed-effects
`model with randomization assignment, SGLT2
`inhibitor use at baseline, time, and the interac(cid:173)
`tion between randomization assignment and time
`as fixed effects, participant as a random intercept,
`and time as a random slope. Missing data were not
`imputed.
`If superiority was confirmed for the primary
`outcome, testing of the confirmatory secondary
`omcomes was performed in a prespecified hier(cid:173)
`archical order to ensure type I error control. To
`account for the prespecified interim analysis, the
`nominal significance level for the primary and
`confirmatory secondary outcomes was calculated
`with the Lan-DeMets alpha-spending fi.mction
`and the actual observed number of primary-out(cid:173)
`come events available for the primary analysis. On
`the basis of the available number of events, the
`one-sided nominal significance level for the pri(cid:173)
`mary and confirmatory secondary outcomes was
`updated to 0.0161 (equivalent to a two-sided level
`of 0.0322, which is used in this report). Details
`are provided in the Supplementary Appendix.
`Continuous supportive secondary outcomes
`were assessed by analysis of covariance with the
`use of multiple imputation for missing values
`under a missing-at-random assumption. Analyses
`of supportive and exploratory outcomes were not
`adjusted for multiplicity, and confidence intervals
`for these outcomes should not be used in place
`of hypothesis testing. All statistical analyses were
`performed with SAS software, version 9.4 TS1M5
`(SAS Institute).
`
`RESULTS
`
`TRIAL PARTICIPANTS
`The trial was conducted at 387 sites in 28 coun(cid:173)
`tries (see the Supplementary Appendix), with re(cid:173)
`cruitment occurring from June 2019 through May
`2021. Among the 5581 screened candidates (Fig. S1
`in the Supplementary Appendix), 3533 met the
`entry criteria and were randomly assigned to the
`semaglutide group (1767 participants) or the pla-
`
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`Th.: NEW ENGLAND JOURNAL ,,JMED IC I NE
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`····························································································································································· · · · · · - - - - - - - - - - - - - - - - - - ,
`Table 1. Characteristics of the Participants at Baseline.'"
`
`Characteristic
`
`Age-yr
`
`Fema;e sex -
`
`no. (%)
`
`Geographic region -
`
`no. (%)
`
`Asia
`
`Europe
`
`North America
`
`Other
`
`Race or ethnic group -
`
`no. (%)i"
`
`White
`
`Asian
`
`Black
`
`Other
`
`Hispanic or l.atinx ethnic group- no. (%)t
`
`Yes
`
`No
`
`Not reported
`
`G;ycated hemoglobin level - %
`
`Body-mass index:,,:
`
`Body weight······ kg
`
`Systolic blood pressure······ mm Hg
`
`Semaglutide
`(N=1767)
`
`66.6±9.0
`
`519 (29.4)
`
`478 (27.1)
`
`472 (26. 7)
`
`423 (23.9)
`
`394 (22.3)
`
`1155 (65.4)
`
`439 (24.8)
`
`78 (4.4)
`
`95 (5.4)
`
`273 (15.4)
`
`1421 (80.4)
`
`73 (4.1)
`
`7.8±1.3
`
`31.9±6.l
`
`89.5±19.8
`
`138.9±16.1
`
`Placebo
`(N=l766)
`
`66.7±9.0
`
`550 (31.l)
`
`434 (24.6)
`
`491 (27.8)
`
`442 (25.0)
`
`399 (22.6)
`
`1168 (66.1)
`
`407 (23.0)
`
`82 (4.6)
`
`109 (6.2)
`
`283 (16.0)
`
`1411 (79.9)
`
`72 (4.1)
`
`7.8±1.3
`
`32.0±6.5
`
`89.8±21.2
`
`138.4±15.4
`
`Total
`(N =3533)
`
`66.6±9.0
`
`1069 (30.3)
`
`912 (25.8)
`
`963 (27.3)
`
`865 (24.5)
`
`793 (22.4)
`
`2323 (65.8)
`
`846 (23.9)
`
`160 (4.5)
`
`204 (5.8)
`
`556 (15 . 7)
`
`2832 (80.2)
`
`145 (4.1)
`
`7.8±1.3
`
`32.0±6.3
`
`89.6±20.5
`
`138.6±15.8
`
`Diastolic blood pressure - mm Hg
`
`76.8±10.0
`
`76.1±10.0
`
`76.4±10.0
`
`Diabetes duration -
`
`no. {%)
`
`<15 yr
`
`.s:15 yr
`
`Previous myocardial infarction or stroke -
`
`no. (%)
`
`Chronic heart failure -
`
`no. (%)
`
`Smoking status -
`
`no. (%)§
`
`Current smoker
`
`Previous smoker
`
`Never smoked
`
`eGFR- mlimin/1.73 m' ,
`
`eGFR distribution -
`
`no. (%),
`
`2:60 mi/min/1.73 m 2
`
`.s:45 to <60 ml/min/1.73 m"
`
`2:30to <45 m:/min/1.73 m'
`
`<30 ml/min/1.73 m'
`
`Median ,;rinary a;bumin-to-creatinine rat io :!
`
`Category of albuminuria •••••· no. (%)''"''
`
`Al, normoalbuminuria
`
`A2, microalbuminuria
`
`A3, macroa;buminuria
`
`774 (43.8)
`
`992 (56.1)
`
`405 (22.9)
`
`342 (19.4)
`
`223 (12.6)
`
`661 (3 7.4)
`
`883 (50.0)
`
`46.9±15.6
`
`366 (20.7)
`
`515 (29.1)
`
`667 (37.7)
`
`218 (12.3)
`
`582.3
`
`52 (2.9)
`
`509 (28.8)
`
`1205 (68.2)
`
`753 (42.6)
`
`1013 (57.4)
`
`403 (22.8)
`
`336 (19.0)
`
`206 (11.7)
`
`696 (39.4)
`
`864 (48.9)
`
`47.1±14.7
`
`353 (20.0)
`
`540 (30.6)
`
`691 (39. 1)
`
`182 (10.3)
`
`557.8
`
`57 (3 .2)
`
`495 (28.0)
`
`1214 (68. 7)
`
`1527 (43.2)
`
`2005 (56.8)
`
`808 (22.9)
`
`678 (19.2)
`
`429 (12.1)
`
`1357 (38.4)
`
`1747 (49.4)
`
`47.0±15.2
`
`719 (20.4)
`
`1055 (29.9)
`
`1358 (38.4)
`
`400 (11.3)
`
`567.6
`
`109 (3.1)
`
`1004 (28.4)
`
`2419 (68.5)
`
`4
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`EFFECTS OF SE/1,IAG.LUTlDE ON CHRONIC KIDNEY DISEASE
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`······················································································································································································· · · · · · - - - - - - - - - - - - - - ,
`Table L (Continued.)
`
`Characteristic
`
`Medication 1;se -
`
`no. (%)
`
`SGLT2 inhibitor
`
`t,CE inhibitor
`
`ARB
`
`Lipid-lowering drug
`
`Diuretic agent
`
`Insulin
`
`Semaglutide
`(N=l767)
`
`Placebo
`(N=l766)
`
`Total
`(N=3533)
`
`277 (15.7)
`
`625 (35.4)
`
`1066 (60.3)
`
`1418 (80.2)
`
`870 (49.2)
`
`1083 (61.3)
`
`273 (15.5)
`
`615 (34.8)
`
`1061 (60.1)
`
`1416 (80.2)
`
`910 (51.5)
`
`1085 (61.4)
`
`550 (15.6)
`
`1240 (35.1)
`
`2127 (60.2)
`
`2834 (80.2)
`
`1780 (50.4)
`
`2168 (61.4)
`
`''" Plus-min,;s values are means .±SD. For ail characteristics except the urinary albt,min-to-creatinine ratio and estim ated
`glomerular filtration rate (eGFR). baseline was defined as the eligible assessment associated with the randomization
`visit if it was performed before or at the date of first dose. If the assessment was missing or performed after the date
`of first dose, the assessment from the screening visit was used. Percentages may not total 100 because of rounding.
`ACE denotes angiotensin-converting enzyme, ARB angiotensin-receptor blocker, and SGl.T2 sodium-glucose cotran s(cid:173)
`porter 2.
`)' Race and ethnic grnup were reported by t he participants. "Other" includes American Indian or Alaska Native, Native
`Hawaiian or other Pacific Islander, and "not reported ."
`~c The body-rnas.s Index is the weight ir. kilograms divided by the square of the height in meters.
`§ Smoking was defined as smoking at least one cigarette or the eqcJivalent daily.
`For eGFR, the baseline assessment is defined as t he mean of the two assessments from the randomization visit and
`,
`the screening visit. If only one of the assessments was available, it was used as the baseline assessment. The mean
`eGFR and the eGFR categories are based on the serum creatinine level and t he Chronic l(idney Disease Epidemiology
`Collaboration 2009 equat ion.
`The urinary albumin-to-creatinine ratio was calculated with albumin measured in milligrams and creatinine measured
`in grams.
`·k * Albuminuria categories are based on the urinary albtm1in-to-creati nine ratio, and the baseline assessment is defined
`as the mean of the two assessments from the randomizatio n visit. if only one of the assessments was available, it
`was 1;sed as the baseline assessment. Normoalbuminuria is defined by a lJt"inary albumin-to-creatinine ratio of less
`than 30, microalburninuria by a ratio ofat least 30 and less than 300, and rnacroalbuminuria by a ratio of300 or
`greater.
`
`cebo group (1766 participants) and included in
`the analyses. Four participants underwent ran(cid:173)
`domization more than once, and only the first
`randomization was included in analyses; one par(cid:173)
`ticipant was e..xduded from the analysis because of
`a lack of adherence to Good Clinical Practice
`guidelines at the relevant site.
`The baseline characteristics of the participants
`were well balanced between the groups (Table 1
`and Table Sl). The mean age was 66.6 years, and
`1069 participants (30.3%) were women. The mean
`eGFR was 47.0 ml per minute per 1.73 ml, and
`the median urinary albumin-to-creatinine ratio
`(with albumin measured in milligrams and cre(cid:173)
`atinine measured in grams) was 567.6. According
`to the Kidney Disease: Improving Global Out(cid:173)
`comes risk calculators,14 68% of the participants
`were at very high risk for kidney disease pro(cid:173)
`gression, kidney failure, cardiovascu !ar events,
`or death. The participants in the trial were
`broadly representative of the relevant population
`
`and consistent with those in previous tria!s,4•5•8
`as described in Table S2.
`A prespecified single interim analysis was
`triggered in October 2023 after approximately
`570 primary-outcome events had accrued. An in(cid:173)
`dependent data and safety monitoring committee
`reviewed the data and recommended early com(cid:173)
`pletion of the trial for efficacy. This recommen(cid:173)
`dation was accepted, participants were recalled
`for final visits, and the trial was completed with
`the final participant visit occurring on January 9,
`2024. At the time of completion of the trial, the
`median participant follow-up was 3.4 years
`(range, 0 to 4.5). The trial was closed early at
`two sites in Russia that had been sanctioned by
`the sponsor, and 14 participants at the affected
`sites ended participation early. In total, 34 par(cid:173)
`ticipants withdrew consent, and vital status was
`able to be confirmed at the end of trial for 3482
`participants (98.6%). Semag!utide or placebo was
`permanently discontinued by 26% of participants
`
`N [NCL_j MED NEJM,OR<i
`
`5
`
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`
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`Page 00005
`
`

`

`Th.: NEW ENGLAND JOURNAL ,,JMEDICINE
`
`A First Major Kidney Disease Event
`100
`35
`30 Hazard ratio , 0.76 (95% Cl, 0.56-0.88)
`P- 0.0003
`,,.,,,
`90
`80
`70
`60
`50-
`40
`30
`20
`10
`0
`
`Pia~~:::.:~/
`
`~;
`
`10
`
`£5,,,"··· Semaglutide
`~~ ~~~·;"-=;::;-::/""
`
`0
`
`6
`
`12
`
`18
`
`24
`
`30
`
`36
`
`42
`
`48
`
`0
`
`6
`
`}2
`
`24
`18
`30
`36
`Months since Randomization
`
`42
`
`4S
`
`ZJ
`r.:
`"' 0..
`·o
`.. 0.
`·1::
`
`....
`0 .,
`ti
`"°
`.,
`C
`I:!
`CJ
`0.
`
`B First Kidney-Specific Component Event
`25
`100··
`90·-
`80
`70
`60
`50·
`40
`30
`20
`10··
`0
`
`ZJ
`
`0..
`
`C: ..
`·o
`·-e
`"' C.
`
`4-
`0
`QJ
`bl)
`~
`"
`QJ I:!
`QJ
`C.
`
`Hazard ratio, 0.79 (959-'o Cl, 0.66-0.9•1}
`
`20--
`
`15-
`
`10--
`
`5 ·-
`
`0-- ·········r····
`0
`6
`
`12
`
`18 24
`
`30 36 42
`
`48
`
`()
`
`12
`
`'
`'
`2.4
`42
`18
`30
`36
`Months since Randomization
`
`48
`
`No. at Risk
`1766 1736 1682 1605 1516 1408 1048 660
`Placebo
`Semaglutide 1767 1738 1693 1640 1572 1489 1131
`742
`
`354
`392
`
`No. at Risk
`1766 1736 1682 1605 1516 1408 1048 660
`Placebo
`Semaglutide 1767 1738 1693 1640 1572 1489 1131 742
`
`354
`392
`
`C Death from Cardiovascular Causes
`100
`1.5
`90
`80-
`70
`
`lQ ..
`
`Hazard ratio, 0.71 (95% Cl , 0.56--0.89)
`
`,;l"
`Placebo /._,..,,.. _;--' ..
`..,..,./..,,,.r..,.,.,.✓l-.,,.,'' '''
`
`D Total eGFR Slope
`
`,., , .~ • ...-'-Semaglutide
`~,~{.:; ...... ~..#
`O-<~=--=··•-•'_'~_-··~·-·v"-_ _ _ _ _ _ _ _ _ _ ~
`0
`6
`12
`lS
`24
`30
`36
`42
`48
`
`60
`50
`40 ··
`30 ··
`20
`
`38
`
`il " t1l
`0..
`I~
`t:
`"' 0..
`'o .,
`C: .,
`ti
`"°
`t 0.
`
`l~ ·- ···--· 1'""" ..,,..~,,··-=··=·=~
`--:-::-.,;;::::-..::::::;:::::::::;::~;-;:::.:.
`0
`6
`12
`18
`24
`30
`36
`42
`48
`Months since Randomization
`
`Difference in annua l slope, 1.16 111 1/min/l. 73 111 2
`(95% Cl, 0.86·-·j .4 7)
`36
`of._P,&001
`'
`
`0 12
`
`52
`
`104
`156
`Months since Randomization
`
`208
`
`No. at Risk
`1766 1737 1697 1641 1601 1544 1185
`Placebo
`Semaglutide 1767 1739 1703 1665 1627 1583 123,1
`
`772
`838
`
`437
`460
`
`No. at Risk
`Placebo
`176616631573 1609 1490 1441 1284
`Sermglutide 1766166515901606 1521 1468 1345
`
`876
`952
`
`609
`651
`
`199
`218
`
`E First Major Cardiovascular Event
`
`201 Haza,d rat,o, 0.S2 (95% Cl. 0 68--0 98) ,,-J
`
`15
`
`10·
`.
`,
`
`P=0 029
`
`.~«.--, ,,.-
`.---•·
`
`Placebo /
`.,/" . : : : .~
`/--:::~ ..,.. •
`Serna~lut1de
`/ -... ---«··
`
`J #
`
`•
`
`lOO
`90
`i;
`80··
`~ 70
`~
`~ 60
`'o
`50
`~ 40·
`.13
`30-
`c:
`~ .,
`
`0..
`
`F Death from Any Cause
`100
`25 Hazard ratio, 0.80 (95% Cl, 0,67--•0.95)
`,,,;··
`90
`20
`P=0.01
`~ 80-
`"' 0.
`·o
`70
`·-e
`60
`"' c..
`so
`40··
`30··
`20
`•.... ·«•·«=···---,,e"'"·' ·· .................. ~--:::.-::.::::::.......
`l 0
`•··············
`0 ....... .-,,.•;c--•~·--- · - - - · · •~ -~ -~ - -~ -~ - - - - - -
`0
`6
`12
`18
`24
`30
`36
`42
`48
`Months since Randomization
`
`:: _//22,::
`-~
`
`I
`
`12
`
`18 24
`
`'
`30 36 42
`
`,18
`
`0
`
`0
`
`07· ·-""~ •
`0
`6
`
`12
`
`18
`
`'
`24
`
`30
`
`36
`
`'
`,12
`
`48
`
`Months since Randomization
`
`<+-
`0
`QJ
`bl)
`.13
`C:
`QJ
`.,
`~
`C>.
`
`No. at Risk
`Placebo
`1766 1721 1663
`Semaglutide 1767 1725 1672
`
`1583 1535 1478 1133
`1622 1575 1515 1176
`
`731
`793
`
`418
`430
`
`No. at Risk
`1766 1737 1697 1641 1601 1544 1185 772
`Placebo
`Sernaglutide 1767 1739 1703 1665 1627 1583 1234 838
`
`,137
`460
`
`6
`
`N Er.,JGLJ MED NEJM,ORG
`
`SEMA(JDG)_0008733
`
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`IPR2023-00724
`Page 00006
`
`

`

`EFFECT S OF SE/1,IAG.LUTlDE ON CHRONIC KIDNEY DISEASE
`
`Figure 1 (fadng page). Primary and Confirmatory
`Secondary Outcomes.
`Shown are cumulative incidence plots of the primary
`outcome, major kidney disease events {a composite of
`the onset of kidney failure [dialysis, transplantation, or
`an estimated glornerular fiitration rate {eGFR) of
`<15 ml per mirn;te per 1.73 m 2 of body-s,;rface area] ,
`;,,50% reduct ion in eGFR from baseline, or death from
`kidney-related or cardiovascu!ar ca1;ses) and severa!
`confirmatory secondary outcomes: kidney-specific
`components of the primary outcome (persistent
`;,,50% reduct ion in eGFR, persistent eGFR of <15 ml
`per minute per 1.73 rn'. initiation of long-term rena!-(cid:173)
`replacernent therapy, or death from kidney-related
`causes), death from cardiovascular causes. total eGFR
`s1ope, major cardiovasw1ar events (a composit e of
`nonfata! myocardial infarction, nonfat ai st roke, or
`death from cardiovascular cau5es), and deat h from
`any cause. Cumu!ative incidence estimates are based
`on the time from randomization to t he first event,
`wit h death not induded in the outcome mode!ed as a
`competing risk with the use of the Aalen--:Johansen es(cid:173)
`timator. Data from part icipan ts without events of in(cid:173)
`terest were censored at the end of each participant's
`in-triai observation period. E5timates are based on a
`Cox proportional-hazards mode! with t reatment as a
`categorical fixed factor and 5tratified according to so(cid:173)
`dium-glucose cotransporter 2 (SGLT2) inhibitor use
`at baseline. The eGFR data are least-squares means
`from a mixed model for repeated measures with treat(cid:173)
`ment as a fixed factor; ! bars indicate t he standard er-·
`ror. The annual rate of change in eGFR was ana!yzed
`with a linear random--effects mode! with randomiza(cid:173)
`tion assignment, SGLT2. inhibitor use at baseline, t ime
`(as a contirn;ous variable), and t he interaction of ran(cid:173)
`domization with time as fixed effects and including
`the participant effect as a random intercept and time
`as a random slope. On the basis of the avai!ab!e num(cid:173)
`ber of primary-outcome events, the nominal signifi(cid:173)
`cance ievel was updated t o 0.0322 with the use of the
`Lan ----DeMets alpha-spending function . Event s th at are
`not re!ated to eGFR were confirmed by t he event adju(cid:173)
`dication committee. The eGFR was cakuiated with the
`serum creatinine ievel and the Chronic l<idney Disease
`Epidemiology Collaboration (Cl<D-EPI) 2009 formu(cid:173)
`ia_ll The P value cutoff for significance was 0.032 in
`Pane!s A, D, E, and F. insets show the same data on
`an expanded y axis.
`
`during the trial, with adherence to the trial regi(cid:173)
`men averaging 89% of the planned time during
`the trial period.
`
`PRIMARY OUTCOME
`Primary-outcome events occurred less frequently
`in the semag!utide group than in the placebo
`
`group (331 first events [5.8 per 100 patient-years
`of follow-up] vs. 410 first events [7.5 per 100 pa(cid:173)
`tient-years]), which resulted in a 24% lower rela(cid:173)
`tive risk of the primary outcome in the semaglu(cid:173)
`tide group (hazard ratio, 0.76; 95% confidence
`interval [CI], 0.66 to 0.88; P = 0.0003) (Fig. 1 and
`Table 2). The number of persons who would
`need to be treated over 3 years to prevent one
`primary-outcome event was 20 (95% CI, 14 to 40).
`Lower risk with semaglutide was also observed
`for a composite of the kidney-specific compo(cid:173)
`nents of the primary outcome (hazard ratio, 0.79;
`95% CI, 0.66 to 0.94), as well as for death from
`cardiovascular causes (hazard ratio, 0.71; 95% Cl,
`0.56 to 0.89) (Table 2). Results were consistent
`across the range of prespecified sensitivity analy(cid:173)
`ses (Table S3) and were broadly consistent across
`prespecified participant su bgroups (Fig. 2).
`
`CONF I RMATORY SECONDARY OUTCOMES
`Benefits were observed for the three confinna(cid:173)
`tory secondary outcomes tested in a hierarchical
`fashion, all of which had two-sided P values be(cid:173)
`low the prespecified interim analysis threshold of
`0.0322 (Table 2). The mean annual slope of the
`eGFR was significantly less steep (indicating a
`slower decrease) in the semaglutide group than
`in the placebo group (-2.19 vs. - 3.36 ml per
`minute per 1.73 111 2 per year; between-group dif:
`ference, 1.16; 95% CI, 0.86 to 1.47; P<0.001.)
`(Fig. lD).
`The risk of major cardiovascular events was
`1.8% lower in the semaglutide group than in the
`placebo group (212 vs. 254 events; hazard ratio,
`0.82; 9.5% CI, 0.68 to 0.98; P::.:0.029) (Fig. lE).
`Effects on the individual components of this com(cid:173)
`posite outcome are shown in Table 2; findings for
`myocardial infarction and death from cardiovascu(cid:173)
`lar causes were consistent with those in the pri(cid:173)
`mary analysis, but the findings for stroke showed
`a numerical imbalance in favor of placebo.
`The risk of death from any cause was 20%
`lower in the semaglutide group than in the pla(cid:173)
`cebo group (227 vs. 279 events; hazard ratio,
`0.80; 95% CI, 0.67 to 0.95, P=0.01.) (Fig. lF).
`Over 3 years, 45 persons (95% CI, 23 to 623)
`wou ld need to be treated to prevent one major
`cardiovascular event, and 39 (9.5% CI, 21. to 238)
`would need to be treated to prevent one death
`from any cause.
`
`N [NCL_j MED NEJM,OR<i
`
`7
`
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`

`

`co
`
`Table 2. Efficacy and Safety Outcomes.''
`
`Outcome
`
`Semaglutide
`(N:1767)
`
`Placebo
`(N=l766)
`
`Hazard Ratio
`(95%CI)
`
`Estimated Difference
`(95%CI)
`
`Primary outcome: major kidney disease events - no.{%)!"
`
`331 (18.7)
`
`410 (23.2)
`
`0.76 (0.66 to 0.88)
`
`Components of primary 01Jtcome- r.o. (%)
`
`Persistent2:50% reduction from baseline in eGFR
`
`165 (9.3)
`
`213 (12.l)
`
`0.73 (0.59 to 0.89)
`
`P Value
`
`0.0003
`
`Persistent eGFR <15 ml/minil.73 m'
`
`Initiation of kidney-replacement therapy
`
`Death from kidney-related causes
`
`Death from cardiovascular causes
`
`Composite of k!dney-specifk components of the primary outcome
`
`Confirmatory secondary outcomes
`
`Mean annual rate of change in eGFR- m!/min/1.73 m 2
`
`Major cardiovascuiar events - no.{%)
`
`Death from cardiovascular causes
`
`92 (5.2)
`
`87 (4.9)
`
`5 (0.3)
`
`123 (7.0)
`
`218 (12.3)
`
`-2.19
`
`212 (12.0)
`
`123 (7.0)
`
`110 (6.2)
`
`100 (5.7)
`
`5 (0.3)
`
`169 (9.6)
`
`0.80 (0.61 to 1.06)
`
`0.84 (0.63 to 1.12)
`
`0.97 (0.27 to 3.49)
`
`0.71 (0.56 to 0.89)
`
`260 (14.7)
`
`0.79 (0.66 to 0.94)
`
`-3.36
`
`254 (14.4)
`
`169 (9.6)
`
`0.82 (0.68 to 0.98)
`
`1.16 (0.86 to l.47)
`
`<0.001
`
`0.029
`
`Nonfatal myocardial infarction
`
`Nonfatal stroke
`
`Death from any cause -
`
`no.