PLAINTIFFS'
`TRIAL EXHIBIT
`PTX0227 e
`
`xhibitsticker.com
`
`Rhinitis, sinusitis, and upper airway disease
`
`A novel intranasal therapy of azelastine with fluticasone for
`the treatment of allergic rhinitis
`
`Warner Carr, MD,a Jonathan Bernstein, MD,b Phil Lieberman, MD,c Eli Meltzer, MD,d Claus Bachert, MD, PhD,e
`David Price, MD,f Ullrich Munzel, PD Dr rer nat,g and Jean Bousquet, MD, PhDh Mission Viejo and San Diego, Calif, Cincinnati,
`Ohio, Memphis, Tenn, Ghent, Belgium, Aberdeen, United Kingdom, Bad Homburg, Germany, and Montpellier, France
`
`Background: Moderate-to-severe allergic rhinitis (AR) is a
`challenge to treat, with many patients using multiple therapies
`and achieving limited symptom control. More effective
`therapies must be developed and tested in well-controlled,
`
`From aAllergy and Asthma Associates of Southern California, Mission Viejo; bthe De-
`partment of Internal Medicine, University of Cincinnati College of Medicine, Cincin-
`nati; cthe Department of Internal Medicine & Pediatrics, University of Tennessee
`College of Medicine, Memphis; dthe Allergy and Asthma Medical Group and Re-
`search Center, San Diego; ethe Department of Oto-Rhino Laryngology, Ghent Univer-
`sity Hospital; fthe Department of General Practice & Primary Care, University of
`Aberdeen; gMEDA Pharma GmbH & Co. KG, Biostatistics & Information, Bad Hom-
`burg; and hthe Department of Respiratory Diseases, Hopital Arnaud de Villeneuve
`University Hospital, Montpellier, and INSERM CSP1018.
`These studies were funded by Meda Pharmaceuticals, Inc, and were designed to be con-
`sistent with recommendations provided in the US Food and Drug Administration guid-
`ance document for clinical development of drug products for allergic rhinitis
`(Guidance for Industry, US Department of Health and Human Services, US Food
`and Drug Administration Center for Drug Evaluation and Research; April 2000).
`Disclosure of potential conflict of interest: W. Carr has consulted for and received
`research support from MEDA, Alcon, and Ista. J. Bernstein has received research sup-
`port from Meda and Dynova; is on the Board of Directors and a Fellow of the American
`Association of Allergy, Asthma & Immunology (AAAAI); is a Fellow at the American
`College of Allergy, Asthma & Immunology (ACAAI); and is Chairman of the Aller-
`gists for Israel (AFI). P. Lieberman is an advisor for the Allergy Foundation of America
`and Baxter and has given lectures for MEDA, Genentech, Ista, and TEVA. E. Meltzer
`has received research support from Amgen, Apotex, HRA, MedImmune, Schering-
`Plough, Alcon, AstraZeneca, Boehringer Ingelheim, GlaxoSmithKline, Novartis,
`Proctor & Gamble, Sunovion (Sepracor), and Teva; is a consultant and/or is on the ad-
`visory board for Alcon, AstraZeneca, Bausch & Lomb, Dey, Forest, Ista, Johnson &
`Johnson, Meda, Merck, ONO Pharma, OptiNose, Proctor & Gamble, Rady Children’s
`Hospital, Rigel, Sanofi-Aventis, Sepracor, Stallergenes, Teva, Alexa, Boehringer In-
`gelheim, Kalypsys, and Sunovion; is a speaker for the AAAAI, Alcon, Allergists for
`Israel, Dey, Florida Allergy Asthma Immunology Society, Ista, Sepracor, Teva, Merck,
`and Sunovion; and has provided expert designation in legal matters for Aventis Phar-
`maceuticals and Sanofi Aventis v. Barr Laboratories, Fexofenadine. D. Price has re-
`ceived consultancy and speaker
`fees
`from Merck, Mundipharma, Novartis,
`Medapharma, Kyorin, and TEVA; has received consultancy fees from GlaxoSmith-
`Kline, Almirall, and Chiesi; has received consultancy fees and grants from Pfizer,
`and AstraZeneca; has received consultancy and speakers’ fees and grants from Boeh-
`ringer Ingelheim; has received speakers’ fees and grants from Aerocrine; has received
`grants from the UK National Health Service, Nycomed, and Medapharma; is director
`of Research in Real Life Ltd; is a guideline group member for Allergic Rhinitis and its
`Impact on Asthma and EPOS; is a research committee member for International Pri-
`mary Care Respiratory Group; and has shares in AKL Ltd. J. Bousquet has received
`honoraria from Stallergenes, Actelion, Almirall, AstraZeneca, Chiese, GlaxoSmith-
`Kline, Merck, Novartis, OM Pharma, Sanofi, TEVA, and Uriach. The rest of the au-
`thors declare that they have no relevant conflicts of interest.
`Received for publication August 23, 2011; revised December 15, 2011; accepted for pub-
`lication January 19, 2012.
`Available online March 13, 2012.
`Corresponding author: Warner Carr, MD, Allergy and Asthma Associates of Southern
`California, 27800 Medical Center Rd, Suite 244, Mission Viejo, CA 92691. E-mail:
`wcarr@allergee.com.
`0091-6749/$36.00
`Ó 2012 American Academy of Allergy, Asthma & Immunology
`doi:10.1016/j.jaci.2012.01.077
`
`1282
`
`randomized, prospective studies with a direct comparison to
`current standards.
`Objectives: The aim of these studies was to investigate the
`efficacy of MP29-02 (a novel formulation of azelastine and
`fluticasone propionate [FP]) in patients with moderate-to-severe
`seasonal allergic rhinitis (SAR) and to compare its efficacy with
`2 first-line therapies (ie, intranasal azelastine and intranasal FP)
`in this population.
`Methods: Three thousand three hundred ninety-eight patients
`(>_12 years old) with moderate-to-severe SAR were enrolled into
`3 multicenter, randomized, double-blind, placebo- and active-
`controlled, parallel-group trials (MP4002 [NCT00651118],
`MP4004 [NCT00740792], and MP4006 [NCT00883168]). Each
`trial was conducted for 14 days during different allergy seasons.
`The primary efficacy variable was the sum of the morning and
`evening change from baseline in reflective total nasal symptom
`score (range, 0-24) over the treatment period. Outcomes for the
`meta-analysis included efficacy according to disease severity
`and time to response in relevant responder criteria.
`Results: In the meta-analysis MP29-02 reduced the mean
`reflective total nasal symptom score from baseline (25.7 [SD,
`5.3]) more than FP (25.1 [SD, 4.9], P < .001), azelastine (24.4
`[SD, 4.8], P < .001), or placebo (23.0 [SD, 4.2], P < .001). This
`benefit was observed from the first day of assessment, with
`improvement in each individual nasal symptom, even in the
`patients with the most severe disease. MP29-02 achieved response
`consistently days earlier and showed greater efficacy in patients
`with moderate-to-severe rhinitis than FP and azelastine.
`Conclusions: MP29-02 represents a novel therapy that
`demonstrated superiority to 2 first-line therapies for AR.
`Patients with moderate-to-severe SAR achieved better control,
`and their symptoms were controlled earlier with MP29-02 than
`with recommended medications according to guidelines. (J
`Allergy Clin Immunol 2012;129:1282-9.)
`
`Key words: Allergic rhinitis, azelastine, fluticasone propionate,
`MP29-02, moderate-to-severe
`
`Allergic rhinitis (AR) occurs in more than 500 million persons
`around the world and is a global health problem that causes major
`illness and disability.1,2 The effects of AR are far reaching and
`easily underestimated, with its negative effects affecting patient’s
`quality of life (QoL)3 and school and work performance.4,5 It is
`also a costly disease, estimated at V4260 per patient per year in
`Europe,6 and $3.4 billion annually in the United States in direct
`medical costs alone.7
`AR is a challenge to treat because many patients do not respond
`sufficiently to treatment. Furthermore, the disease severity is
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`J ALLERGY CLIN IMMUNOL
`VOLUME 129, NUMBER 5
`
`CARR ET AL 1283
`
`Abbreviations used
`ANCOVA: Analysis of covariance
`AR: Allergic rhinitis
`FP: Fluticasone propionate
`iTNSS: Instantaneous total nasal symptom score
`QoL: Quality of life
`RQLQ: Rhinitis Quality of Life Questionnaire
`rTNSS: Reflective total nasal symptom score
`rTOSS: Reflective total ocular symptom score
`SAR: Seasonal allergic rhinitis
`
`underestimated and, consequently, inadequately treated.8 Most
`patients have moderate-to-severe disease,3,9 frequently experi-
`ence severe symptoms while receiving therapy, and are dissatis-
`fied and noncompliant with currently available therapy.10,11
`Patients use multiple therapies (as many as 74.4% of patients)
`in an attempt to achieve symptom control,3,9,12-14 despite the lim-
`ited evidence to support this practice.2
`Given this unmet medical need, more effective therapies for the
`management of AR are clearly required. Current guideline-based
`therapy for AR includes oral and intranasal antihistamines and
`intranasal corticosteroids. Although intranasal corticosteroids are
`considered the most effective therapy, especially for more severe
`cases,2,15 they need some time to become effective. In contrast,
`intranasal H1-antihistamines, such as azelastine, have a rapid on-
`set of action.
`The recently updated Allergic Rhinitis and its Impact on
`Asthma guidelines15 highlighted the need for high-quality, direct
`comparison studies to further substantiate the current treatment
`recommendations. Three randomized, placebo- and active-
`controlled, parallel-group trials were performed to directly com-
`pare the efficacy and safety of intranasal azelastine, intranasal
`fluticasone propionate (FP), and intranasal MP29-02 (a novel for-
`mulation of azelastine and FP), with all 3 medications using ex-
`actly the same formulation, in patients with moderate-to-severe
`seasonal allergic rhinitis (SAR). Each study aimed to demonstrate
`and replicate that MP29-02 demonstrated superiority to either
`monotherapy in a head-to-head fashion. Moreover, in the meta-
`analysis responder analyses were added to further address rele-
`vance in treatment efficacy.
`
`METHODS
`Protocol
`Individual results and a meta-analysis of 3 phase III, multicenter, random-
`ized, double-blind, parallel-group trials (MP4002 [NCT00651118], MP4004
`[NCT00740792], and MP4006 [NCT00883168]) were assessed in patients
`with moderate-to-severe SAR to determine the efficacy of MP29-02 compared
`with intranasal H1-antihistamine (azelastine), corticosteroid (FP), and placebo
`using the same formulation. Placebo spray comprised exactly the same vehicle/
`formulation as the active treatments without any active agent. The same treat-
`ments and treatment periods and essentially similar protocols were used in the
`3 studies. The studies were conducted in accordance with US Food and Drug
`Administration and European Medicines Agency recommendations,16,17 and
`good clinical practice18 during the 2008-2009 US Spring and Fall allergy sea-
`sons. After institutional review board approval, written informed consent was
`obtained from all patients or legal guardians (subjects aged <18 years).
`
`to relevant pollen were randomized. All subjects had moderate-to-severe SAR
`defined by a reflective total nasal symptom score (rTNSS) of at least 8 of 12, with
`a congestion score of 2 or 3 during screening. Inclusion criteria for the duration
`of symptoms for the 3 studies were slightly different. For more information on
`this and exclusion criteria, see the Methods section in this article’s Online Re-
`pository at www.jacionline.org. Excluded therapies and medications are sum-
`marized in Table E1 in this article’s Online Repository at www.jacionline.org.
`
`Planned interventions and timing
`Each study comprised a 7-day, single-blind, placebo lead-in period and a
`14-day treatment period with 3 study visits at days 1, 7, and 14. On visit 2 (day
`1), eligible patients were randomized to 14 days of treatment (1 spray per
`nostril twice daily) with the following: (1) MP29-02 nasal spray (novel
`formulation of 137 mg of azelastine/50 mg of FP); (2) azelastine nasal spray
`(137 mg); (3) FP (50 mg) nasal spray; or (4) vehicle placebo nasal spray. Doses
`were separated by approximately 12 hours. Patients recorded application
`times and symptom scores in a diary. Compliance with treatment was assessed
`(see the Methods section in this article’s Online Repository).
`
`Efficacy variables
`The primary efficacy variable was the sum of the morning and evening
`overall change from baseline in 12-hour rTNSSs over the entire 14-day
`treatment period (sum of the individual nasal symptoms of congestion, itching,
`rhinorrhea, and sneezing).16,17 All nasal and ocular symptoms were scored by
`patients twice daily on each treatment day according to a 4-point scale. For nasal
`symptoms, a score of 0 was defined as none (no symptoms present), a score of
`1 was defined as mild (mild symptoms that do not interfere with any activity), a
`score of 2 was defined as moderate (slightly bothersome symptoms that slightly
`interfere with activity/nighttime sleep), and a score of 3 was defined as severe
`(bothersome symptoms that interfere with activity/nighttime sleep). Therefore
`the maximum rTNSS or instantaneous total nasal symptom score (iTNSS) was
`24 (ie, 4 symptoms 3 score of 3 3 2 for morning 1 evening). See the Methods
`section in this article’s Online Repository for calculation of baseline scores.
`Secondary efficacy variables included overall change from baseline (treat-
`ment period, days 2-14) in the individual reflective nasal symptom score,
`iTNSS, and reflective total ocular symptom score (rTOSS). For the symptoms of
`itchy eyes and watery eyes, the same scale was used as for nasal symptoms. For
`the symptom of red eyes, the following scale was used: 0, none (no redness
`present); 1, mild (slightly dilated blood vessels and pinkish color compared with
`the subject’s normal color); 2, moderate (more dilation of blood vessels and red
`color compared with subject’s normal color); and 3, severe (large, numerous,
`dilated blood vessels and deep red color compared with the subject’s normal
`color). The maximum rTOSS was 18 (ie, 3 symptoms 3 score of 3 3 2 for
`morning 1 evening). Onset of action was also determined clinically by means
`of assessment of iTNSS in the first 4 hours after administration.
`
`QoL
`QoL was assessed before randomization and at the end of the study by using
`the 28-item Rhinitis Quality of Life Questionnaire (RQLQ) for subjects older
`than 18 years.19 Total baseline RQLQ scores were used to categorize patients
`according to severity.
`
`Safety variables
`Safety was assessed based on the incidence, type, and severity of adverse
`events coded with the Medical Dictionary for Regulatory Activities. At each
`visit, patients underwent a direct visual nasal examination to determine
`potential side effects to the nasal mucosa or otherwise clinically relevant
`intranasal conditions. Vital signs were also measured.
`
`Participants
`Subjects (>_12 years old) with a minimum 2-year history of SAR, significant
`current clinical rhinitis symptomatology, and a positive skin prick test response
`
`Sample size
`For studies MP4002 and MP4004, sample size was determined based on the
`results of a previously published proof-of-concept exploratory study,20 which
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`1284 CARR ET AL
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`J ALLERGY CLIN IMMUNOL
`MAY 2012
`
`suggested that MP29-02 and FP might reduce the rTNSS by 25.92 and 24.19,
`respectively, and that a meta-analysis SD of 5 might be a conservative esti-
`mate. On the basis of these values, a 2-sided a value of 5%, and a 10% dropout
`rate, 195 randomized subjects per treatment arm were sufficient to achieve
`90% power. Sample size in study MP4006 was determined by excluding a
`treatment difference of less than 0.6 units in overall reduction in the rTNSS
`over a 14-day treatment period. Allowing for dropouts, a minimum of 450 sub-
`jects per group had to be randomized.
`
`Dropout rates were negligible (see Table E3 in this article’s On-
`line Repository at www.jacionline.org). When data were pooled
`for meta-analysis, 848, 846, 847, and 857 patients received
`MP29-02, FP, azelastine, and placebo, respectively. The baseline
`characteristics of the 4 treatment groups were similar, both within
`and between studies (Table I). Patients’ baseline rTNSSs were
`well matched and confirmed that the vast majority of these pa-
`tients had moderate-to-severe AR.
`
`Randomization
`Patients were randomized and balanced by study site in blocks of 4.
`Eligible subjects received the study site’s next available randomization num-
`ber in sequence.
`
`Blinding
`Individual nasal spray bottles were identity masked such that both patients
`and study personnel were blind to treatment assignment. The active controls
`comprised the individual components of MP29-02 in the same vehicle (ie,
`contained the same excipients assessed qualitatively and quantitatively), pump
`volume (0.137 mL per spray), and device (see the Methods section in this ar-
`ticle’s Online Repository). A blind randomization code was maintained at a
`central site apart from the sponsor and study centers. Study blinding was pre-
`served at the study sites until all subjects completed the study and the database
`had been locked.
`
`Statistical analyses
`A hierarchical test procedure was implemented to maintain the overall
`2-sided type I error level of .05 among the pairwise comparisons. As a first
`step, changes in combined rTNSSs were compared between patients receiving
`MP29-02 and placebo. If this was significant, MP29-02 was then compared
`with azelastine, and if this was also significant, it was then compared with FP.
`As prespecified in trial protocols and statistical analysis plans before
`unblinding, efficacy analyses were performed on the intent-to-treat population
`of all randomized patients with at least 1 postbaseline observation. An analysis
`of covariance (ANCOVA) model was applied to the primary efficacy variable
`of absolute change in combined morning plus evening rTNSSs. The model
`included the treatment days from day 2 (first day with postdose morning score)
`to day 14. Fixed effects were treatment group, day, and center, with baseline as
`a continuous covariate. The covariance matrix of the error terms was left
`unspecified and allowed to differ among treatment groups, with degrees of
`freedom calculated by using the Satterthwaite approximation. Treatment
`differences are presented as differences in least squares means resulting from
`this applied ANCOVA (ie, estimates are corrected for influence of covariates,
`such as center or baseline severity [see Methods section in this article’s Online
`Repository]), to account for the applied inferential statistical methods. Change
`from baseline in iTNSSs, individual reflective nasal symptom scores, rTOSSs,
`and RQLQ scores were assessed in the same way.
`The meta-analysis on efficacy data was conducted post hoc and comprised
`all 3 studies. The statistical models used for the meta-analysis were similar to
`those used in the individual studies, with an additional fixed effect for study.
`In addition, the rTNSS (overall and by day) was assessed based on patient
`severity. Patients were categorized into 2 severity groups according to their
`median baseline rTNSSs (ie, <_18.9 or >18.9) or median baseline RQLQ scores
`(ie, <_3.9 or >3.9). Moreover, time to response was analyzed by using Kaplan-
`Meier estimates. A change from baseline in (1) combined rTNSS of at least
`50%17 or (2) a score of 1 point or less for each nasal symptom (ie, complete or
`near-complete resolution of each symptom) were used to define response.
`
`RESULTS
`Patients
`Study completion rates were high (approximately 95%) and
`similar across studies and across treatment groups (see Table E2
`in this article’s Online Repository at www.jacionline.org).
`
`Outcomes
`Efficacy in individual studies (primary end point
`rTNSS). In each study MP29-02 significantly reduced the
`mean rTNSS from baseline by a greater margin than FP,
`azelastine, or placebo (Table II and Fig 1). All individual nasal
`symptoms contributed to the effect (see Tables E4 and E5 in
`this article’s Online Repository at www.jacionline.org). In each
`study all active treatments were statistically significantly superior
`to placebo, whereas MP29-02 demonstrated superiority to all
`other treatment arms.
`Safety. For each study, the proportion of subjects with a
`treatment-emergent adverse event was similar for the active
`groups (see Table E6 in this article’s Online Repository at www.
`jacionline.org). The higher proportion of treatment-related ad-
`verse events observed in the MP29-02 and azelastine treatment
`groups was due primarily to the taste of azelastine coded as dys-
`geusia in these patients (2.1% to 4.7% of MP29-02–treated pa-
`tients and 3.4% to 7.2% of azelastine-treated patients, see Table
`E7 in this article’s Online Repository at www.jacionline.org),
`but no patient discontinued therapy because of this event. For
`all studies, changes in vital signs and nasal examination were sim-
`ilar in all groups.
`Meta-analysis. rTNSSs, iTNSSs, individual symptom
`scores, and rTOSSs: Change from baseline. Patients
`treated with MP29-02 experienced significantly greater nasal
`symptom relief than those treated with either monotherapy. Over
`the entire 14-day treatment period, MP29-02 reduced the mean
`rTNSS from baseline (25.7 [SD, 5.3]) to a significantly greater
`degree than FP (25.1 [SD, 4.9], P < .001), azelastine (24.4 [SD,
`4.8], P < .001), or placebo (23.0 [SD, 4.2], P < .001; Table II and
`Fig 1). MP29-02 had an onset of action of 30 minutes, and the
`clinical benefit was observed during the first day of assessment
`and sustained over the entire course of treatment (see Fig E1 in
`this article’s Online Repository at www.jacionline.org).
`MP29-02 reduced the overall
`iTNSS from baseline to a
`than FP (P 5 .022), azelastine
`significantly greater extent
`(P < .001), or placebo (P < .001). MP29-02 targeted all of the
`symptoms of AR (see Tables E4 and E5). Compared with FP or
`azelastine monotherapy, patients who received MP29-02 had
`greater
`relief
`from their
`symptoms of nasal congestion
`(P 5 .005 vs FP and P < .001 vs azelastine), nasal itch (P 5
`.005 vs FP and P 5 .001 vs azelastine), rhinorrhea (P 5 .013 vs
`FP and P < .001 vs azelastine), and sneezing (P 5 .001 vs FP
`and P < .001 vs azelastine; see Tables E4 and E5). Patients treated
`with MP29-02 also experienced superior relief from their ocular
`symptoms than those treated with FP alone. Over the entire
`14-day treatment period, MP29-02 reduced the mean rTOSS
`from baseline (23.2 [SD, 4.0]) compared with FP (22.8 [SD,
`3.6]), azelastine (22.9 [SD, 3.8]), or placebo (21.8 [SD, 3.4]),
`achieving statistical significance versus FP (P 5 .003) and pla-
`cebo (P < .001; see Tables E4 and E5).
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`J ALLERGY CLIN IMMUNOL
`VOLUME 129, NUMBER 5
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`CARR ET AL 1285
`
`TABLE I. Baseline characteristics of study participants included in 3 randomized trials (ITT population)
`
`Age (y)
`Male sex, no. (%)
`White race, no. (%)
`History of SAR (y)
`
`Age (y)
`Male sex, no. (%)
`White race, no. (%)
`History of SAR (y)
`
`Age (y)
`Male sex, no. (%)
`White race, no. (%)
`History of SAR (y)
`
`MP29-02 (n 5 207)
`
`37.3 (14.1)
`65 (31.4)
`162 (78.3)
`21.7 (13.2)
`
`MP29-02 (n 5 193)
`
`38.8 (14.1)
`67 (34.7)
`154 (79.8)
`21.5 (13.5)
`
`MP29-02 (n 5 448)
`
`35.6 (14.5)
`171 (38.2)
`364 (81.3)
`20.4 (13.0)
`
`Study MP4002
`FP (n 5 207)
`
`38.6 (14.1)
`80 (38.6)
`161 (77.8)
`21.3 (13.5)
`
`Study MP4004
`FP (n 5 189)
`
`37.0 (13.6)
`68 (36.0)
`140 (74.1)
`21.1 (13.7)
`
`Study MP4006
`FP (n 5 450)
`
`34.2 (14.5)
`170 (37.8)
`356 (79.1)
`19.6 (12.5)
`
`Azelastine (n 5 208)
`
`Placebo (n 5 209)
`
`36.2 (14.6)
`78 (37.5)
`162 (77.9)
`21.6 (13.6)
`
`37.3 (16.0)
`77 (36.8)
`169 (80.9)
`21.2 (14.0)
`
`Azelastine (n 5 194)
`
`Placebo (n 5 200)
`
`38.2 (13.5)
`66 (34.0)
`153 (78.9)
`19.7 (13.1)
`
`37.2 (13.0)
`81 (40.5)
`164 (82.0)
`21.0 (12.8)
`
`Azelastine (n 5 445)
`
`Placebo (n 5 448)
`
`36.4 (14.8)
`174 (39.1)
`357 (80.2)
`19.5 (12.9)
`
`34.7 (14.1)
`179 (40.0)
`348 (77.7)
`19.6 (12.4)
`
`Data are presented as means (SDs) unless otherwise stated.
`ITT, Intent to treat.
`
`TABLE II. Total nasal symptom scores (baseline and change from baseline) for 3 randomized trials and the meta-analysis results (ITT
`population)
`
`Treatment
`
`No.
`
`Baseline
`
`Change from baseline
`
`Difference
`
`LS mean
`
`95% CI
`
`P value
`
`Study MP4002
`MP29-02
`FP
`AZE
`Placebo
`
`Study MP4004
`MP29-02
`FP
`AZE
`Placebo
`
`Study MP4006
`MP29-02
`FP
`AZE
`Placebo
`
`207
`207
`208
`209
`
`193
`189
`194
`200
`
`448
`450
`445
`448
`
`18.3 (3.0)
`18.2 (3.2)
`18.2 (3.5)
`18.6 (3.2)
`
`18.2 (3.3)
`18.6 (2.9)
`18.5 (3.1)
`18.2 (3.1)
`
`19.4 (2.4)
`19.4 (2.4)
`19.5 (2.5)
`19.5 (2.4)
`
`25.5 (5.2)
`25.0 (4.7)
`24.1 (4.6)
`22.6 (3.9)
`
`25.6 (5.2)
`25.0 (5.2)
`24.4 (4.6)
`22.8 (3.9)
`
`25.6 (5.2)
`25.1 (4.7)
`24.5 (4.8)
`23.2 (4.3)
`
`Meta-analysis (studies MP4002, MP4004, and MP4006)
`MP29-02
`848
`18.8 (2.9)
`FP
`846
`18.9 (2.8)
`AZE
`847
`18.9 (3.0)
`Placebo
`857
`19.0 (2.8)
`
`25.7 (5.3)
`25.1 (4.9)
`24.4 (4.8)
`23.0 (4.2)
`
`—
`MP29-02, FP
`MP29-02, AZE
`MP29-02, PLA
`FP, PLA
`AZE, PLA
`
`—
`MP29-02, FP
`MP29-02, AZE
`MP29-02, PLA
`FP, PLA
`AZE, PLA
`
`—
`MP29-02, FP
`MP29-02, AZE
`MP29-02, PLA
`FP, PLA
`AZE, PLA
`
`—
`MP29-02, FP
`MP29-02, AZE
`MP29-02, PLA
`FP, PLA
`AZE, PLA
`
`—
`20.9
`21.4
`22.7
`21.8
`21.3
`
`—
`21.0
`21.0
`22.5
`21.5
`21.5
`
`—
`20.6
`20.7
`22.1
`21.5
`21.4
`
`—
`20.8
`20.9
`22.3
`21.6
`21.4
`
`—
`21.74 to 20.07
`22.22 to 20.54
`23.48 to 21.91
`22.50 to 21.09
`22.04 to 20.60
`
`—
`21.91 to 20.05
`21.90 to 20.09
`23.33 to 21.67
`22.34 to 20.69
`22.31 to 20.71
`
`—
`21.22 to 20.07
`21.30 to 20.13
`22.70 to 21.57
`22.03 to 20.95
`21.96 to 20.87
`
`—
`21.18 to 20.34
`21.37 to 20.52
`22.75 to 21.95
`21.97 to 21.21
`21.78 to 21.02
`
`—
`.034
`.002
`<.001
`<.001
`.001
`
`—
`.038
`.032
`<.001
`.001
`.001
`
`—
`.029
`.016
`<.001
`<.001
`<.001
`
`—
`.001
`<.001
`<.001
`<.001
`<.001
`
`Data are expressed as means (SDs). Difference from active treatment is given as LS mean treatment difference with associated 95% CIs and P values.
`AZE, Azelastine (137 mg per nostril twice daily); FP, fluticasone propionate (50 mg per nostril twice daily); LS, least squares; MP29-02, azelastine/FP (137/50 mg/nostril twice
`daily); PLA, placebo.
`
`PTX0227-00004
`
`CIPLA LTD. EXHIBIT 2023 PAGE 4
`
`

`

`1286 CARR ET AL
`
`J ALLERGY CLIN IMMUNOL
`MAY 2012
`
`FIG 1. Effect of MP29-02, FP (FLU), and azelastine (AZE) on overall rTNSSs
`(morning plus evening) in patients with moderate-to-severe SAR. Data are
`presented as least squares (LS) mean change from baseline derived by
`means of ANCOVA minus placebo. The precision of these estimates are in-
`dicated by the upper bounds of the respective 95% CIs. Study MP4002: n 5
`831, *P 5 .034 versus FP;  P 5 .001 versus AZE; Study MP4004: n 5 776,
`*P 5 .038 versus FP;  P 5 .032 versus AZE; Study MP4006: n5 1791,
`*P 5 .029 versus FP;  P 5 .016 versus AZE; Meta-analysis: n5 3398, *P <
`.001 versus FP;  P < .001 versus AZE.
`
`rTNSS responder analyses. Fig 2, A, shows the proportion
`of patients in each treatment group who experienced a 50% or
`greater reduction in rTNSS over time. The results highlighted a
`time advantage of MP29-02 over FP (up to 3 days earlier) and aze-
`lastine (up to 5 days earlier) monotherapy in producing a clini-
`cally meaningful reduction in rTNSS, as well as an increased
`responder rate with MP29-02 (see Table E8 in this article’s Online
`Repository at www.jacionline.org). More patients treated with
`MP29-02 (12.4%) also exhibited complete or near-complete
`elimination of their symptoms (ie, reduction in all nasal symp-
`toms scores to <_1) than those treated with FP (9.3%), azelastine
`(7.1%), or placebo (4.2%; Fig 2, B). Moreover, this effect was
`also observed days earlier than either monotherapy: up to 5
`days faster than FP (P 5 .033) and up to 7 days faster than azelas-
`tine (P < .001).
`rTNSS change from baseline by baseline patient
`severity. MP29-02 provided benefits for all patients, providing
`significantly greater symptom relief
`than FP or azelastine
`monotherapy regardless of disease severity (Fig 3). When severity
`was split by median baseline rTNSS, MP29-02 was significantly
`superior to FP (difference, 20.6; P 5 .033 [95% CI, 21.16
`to 20.05]) and azelastine (difference: 20.8; P 5 .004 [95%
`CI, 21.41 to 20.27]) in patients with less severe disease (ie, base-
`line rTNSS of <_18.9), with a greater benefit observed in patients
`with more severe disease (ie, baseline TNSS of >18.9) compared
`with both FP (difference: 20.8; P 5 .008 [95% CI, 21.46
`to 20.23]) or azelastine (difference: 21.1; P 5 .001 [95%
`CI, 21.71 to 20.48]). When severity was alternatively split by
`median baseline RQLQ score, MP29-02 was again superior to
`FP and azelastine monotherapy (in terms of rTNSS improvement)
`in patients with moderate rhinitis (ie, RQLQ: <_3.9; difference
`of 20.4 [P 5 .159; 95% CI, 21.01 to 0.17] vs FP and difference
`
`FIG 2. Time-response curves showing the percentage of patients exhibiting
`50% improvement in rTNSSs (A) or a score of 1 point or less (ie, complete or
`near-complete resolution) for each nasal symptom (B) by treatment day af-
`ter treatment with MP29-02 (n 5 834), FP (FLU; n5 846), azelastine (AZE;
`n 5 847), or placebo (PLA; n 5 857). Data are presented as mean proportion
`of patients for the meta-analysis dataset (studies MP4002, MP4004, and
`MP4006). Fig 2, A, MP29-02 versus FLU: P 5 .071; MP29-02 versus AZE:
`P < .001; MP29-02 versus PLA: P < .001. Fig 2, B, MP29-02 versus FLU: P 5
`.033; MP29-02 versus AZE: P < .001; MP29-02 versus PLA: P < .001.
`
`of 20.9 [P 5 .006; 95% CI, 21.46 to 20.24] vs azelastine) and
`significantly superior in patients with severe rhinitis (ie, RQLQ:
`>3.9; difference of 21.0 [P 5 .004; 95% CI, 21.68 to 20.33]
`vs FP and difference of 21.1 [P 5 .001; 95% CI, 21.75
`to 20.44] vs azelastine).
`QoL. Patients were well matched for QoL impairment, with
`overall baseline RQLQ scores of 3.9 (SD, 1.0) in the MP29-02,
`azelastine, and placebo groups and 3.8 (SD, 1.0) in the FP group.
`By day 14, all active treatments
`significantly improved
`patient QoL (MP29-02: 21.6 [SD, 1.3]; FP: 21.5 [SD, 1.3];
`azelastine: 21.4 [SD, 1.3]) compared with placebo (21.0 [SD,
`1.2], P < .001).
`
`DISCUSSION
`Before MP29-02, no clinical development program had dem-
`onstrated additional benefit over 2 currently recommended first-
`line AR therapies in patients with moderate-to-severe disease. In
`the present program MP29-02 demonstrated superior efficacy
`over intranasal FP and intranasal azelastine monotherapy in
`patients with AR in a set of 3 randomized, double-blind, placebo-
`controlled clinical studies with active controls by using the same
`device and formulation. This provides sound clinical evidence,
`for the first time, that intranasal antihistamines and corticoste-
`roids have complementary pharmacologic effects on the patho-
`genesis of AR and satisfy the demands of the Allergic Rhinitis and
`its Impact on Asthma guidelines requesting high-quality direct
`comparison studies. The consistency of the results among the
`clinical trials and symptoms contributes to the robustness of the
`data. Adverse events were similar for all active groups, and only a
`few patients experienced mild dysgeusia.
`The advancement
`in the treatment of SAR derives from
`MP29-02 providing consistent and uniform relief from each of
`the individual nasal symptoms of congestion, itching, rhinorrhea,
`and sneezing. Whether intranasal corticosteroids are also effec-
`tive in treating ocular symptoms is an ongoing debate.21 In this re-
`gard MP29-02 has been shown to be more effective than FP, as
`well as placebo, in alleviating ocular symptoms.
`
`PTX0227-00005
`
`CIPLA LTD. EXHIBIT 2023 PAGE 5
`
`

`

`J ALLERGY CLIN IMMUNOL
`VOLUME 129, NUMBER 5
`
`CARR ET AL 1287
`
`FIG 3. Effect of MP29-02, FP (FLU), azelastine (AZE), and placebo (PLA) on rTNSSs (morning plus evening)
`by severity in patients with SAR. Patients were classified as having more or less severe disease based on
`median baseline rTNSSs or baseline RQLQ scores (ie, baseline rTNSS score <_18.9 [MP29-02: n 5 425; FP:
`n 5 407; AZE: n 5 417; PLA: n 5 407] or >18.9 [MP29-02: n 5 423; FP: n 5 438; AZE: n 5 427; PLA: n 5
`449] or baseline RQLQ score <_3.9 [MP29-02: n 5 374; FP: n 5 382; AZE: n 5 382; PLA: n 5 364] or >3.9
`[MP29-02: n 5 363; FP: n 5 356; AZE: n 5 365; PLA: n 5 373]). Data are presented as least squares (LS)
`mean change from baseline for the meta-analysis dataset (studies MP4002, MP4004, and MP4006). The pre-
`cision of these estimates are indicated by the lower bounds of the respective 95% CIs. *P <_ .001 versus all
`active treatments.  P < .040 versus MP29-02. àP < .010 versus MP29-02.
`
`MP29-02 has a fast onset of action, demonstrating superiority
`immediately from the first day of treatment. Additionally,
`MP29-02 provided a clinically relevant 50% rTNSS reduction
`significantly earlier (and in a larger number of patients), with a
`time advantage over 2 standard therapies measured in days and
`not hours (up to 3 days earlier than FP and up to 5 days earlier
`than azelastine). This is important because the time to achieve
`significant symptom reduction is crucial for patients with AR
`and is a trigger for maintaining patient compliance.22 Indirect
`evidence suggests that patients with SAR take their medication
`for 7 or fewer consecutive days.22,23 Therefore a 3-day advan-
`tage to a 50% rTNSS reduction of MP29-02 over FP represents
`a substantial improvement within the personalized treatment
`cycle.
`One of every 8 patients treated with MP29-02 exhibited
`complete or near-complete symptom resolution, which is sur-
`prising consideri