AZ44531_hochberg:AZ44531_hochberg 2/6/08 10:31 Page 1
`
`A novel, single-tablet formulation that delivers immediate-release omeprazole followed by enteric-coated (EC) naproxen
`significantly reduces the incidence of gastric ulcers compared with EC naproxen alone: results of a prospective,
`randomised, double-blind, 6-month study including patients with OA and RA
`Marc Hochberg,1 Jay L. Goldstein,2 John G. Fort,3 Mark Sostek,4 John Plachetka3
`1Division of Rheumatology and Clinical Immunology, University of Maryland School of Medicine, Baltimore, Maryland, USA; 2Department of Medicine, University of Illinois at Chicago, Chicago, Illinois, USA;
`3POZEN Inc., Chapel Hill, North Carolina, USA; 4AstraZeneca, Wilmington, Delaware, USA
`
`THU0104
`
`䊳 There were significantly fewer upper GI adverse events in
`patients receiving PN200 BID compared with patients receiving
`EC naproxen 500 mg BID, and fewer premature discontinuations
`due to upper GI adverse events (Table 2).
`
`Table 2. Treatment-emergent adverse events; n (%)
`
`PN200
`BID
`n=206
`
`105 (51.0)
`86 (41.7)
`
`17 (8.3)
`145 (70.4)
`
`EC naproxen
`500 mg BID
`n=203
`
`144 (70.9)
`133 (65.5)
`
`18 (8.9)
`170 (83.7)
`
`9 (4.4)
`
`22 (10.8)
`
`p
`
`⬍0.001
`⬍0.001
`
`NS
`0.001
`
`0.012
`
`Any upper GI AE
`Any upper GI AE related to
`study drug
`Dyspeptic symptomsa
`Use of antacid
`rescue medication
`Upper GI AE leading
`to discontinuation
`
`GI, gastrointestinal; AE, adverse event; NS, not significant
`aupper abdominal pain, dyspepsia, eructation, gastric discomfort
`
`PN200 (n=206)
`EC naproxen (n=203)
`
`23.1%
`
`**
`72% RR
`
`29.4%
`
`10.3%
`
`3.4%
`
`5.1%
`
`8.3%
`
`1 month
`
`3 months
`
`6 months
`
`40
`
`30
`
`20
`
`10
`
`0
`
`Gastric ulcers, %
`
`PN200
`(n=207)
`
`ITT population
`(n=206)
`
`EC naproxen
`(n=206)
`
`ITT population
`(n=203)
`
`Premature
`discontinuations
`(n=51)
`● AE (n=24)
`● Withdrew consent (n=14)
`● Lost to follow-up (n=3)
`● Duodenal ulcer (n=1)
`● Other (n=9)
`
`Premature
`discontinuations
`(n=68)
`● AE (n=30)
`● Withdrew consent (n=9)
`● Lost to follow-up (n=3)
`● Duodenal ulcer (n=14)
`● Other (n=12)
`
`RR, relative risk
`**p⬍0.001 between groups at 6 months
`
`Figure 5. Cumulative incidence of gastric ulcers over 6 months: ASA
`vs no ASA
`
`No ASA
`69% RR
`
`p<0.001
`
`ASA
`69% RR
`
`p=0.012
`
`28.8
`
`Completed study
`(n=155)
`
`Completed study
`(n=135)
`
`Figure 2. Study design
`
`Figure 3. Study disposition
`
`Figure 4. Survival analysis of incidence of gastric ulcers over time
`
`Consent
`
`Endoscopy
`
`Endoscopy
`
`Endoscopy
`
`Screening
`
`Baseline/
`randomisation
`
`Safety
`evaluation
`
`Safety
`evaluation
`
`Washout
`for PPIs
`
`Begin study
`medication
`
`Endoscopy
`
`Safety
`evaluation
`
`End of study
`
`Screened (n=649)
`
`Randomised (n=413)
`
`Introduction
`
`䊳 Upper gastrointestinal (GI) complications associated with non-
`steroidal anti-inflammatory drug (NSAID) therapy are a significant
`cause of morbidity and mortality and are associated with
`decreased persistence.1
`䊳 The efficacy of proton-pump inhibitors (PPIs) for the prevention
`of mucosal injury, endoscopic ulcers and upper GI symptoms
`associated with NSAID therapy, is well documented.2,3
`䊳 Non-adherence to concomitant PPI therapy is associated with
`decreased relative effectiveness of preventing upper GI bleeding
`events.4 Persistence of concomitant PPI therapy is often low;5
`hence, novel therapeutic approaches would be beneficial to
`reduce the incidence of upper GI events in patients requiring
`chronic NSAID therapy.
`䊳 A single-tablet formulation of a non-enteric-coated PPI and an
`enteric-coated (EC) NSAID could address the issue of non-
`adherence. PN200 provides sequential delivery of omeprazole
`20 mg + EC naproxen 500 mg. The PN200 formulation delivers
`omeprazole before absorption of EC naproxen (Figure 1).
`
`Figure 1. Pharmacokinetic profile of PN200
`
`400
`
`60
`
`PN200 BID
`
`EC naproxen 500 mg BID
`
`Day -14 to -7
`
`Day 1
`
`Day 30
`
`Day 90
`
`Day 180
`
`䊳 Patients were seronegative for H.pylori and were at risk of
`NSAID-associated gastric ulcers (aged 18-49 years with a history
`of gastric ulcer or duodenal ulcer within the past 5 years, or
`aged ⭓50 years).
`
`䊳 Major exclusion criteria included use of antisecretory agents or
`misoprostol within 14 days prior to the baseline endoscopy
`(esophagogastroduodenoscopy [EGD]); and any gastric ulcer or
`duodenal ulcer (⭓3 mm diameter with depth) at baseline EGD.
`
`䊳 EGD was performed at baseline and 1, 3 and 6 months.
`
`䊳 Safety evaluations were performed at 1, 3 and 6 months.
`
`Conclusions
`䊳 Compared with EC naproxen, PN200 was
`associated with a significantly lower incidence of
`both gastric ulcers and duodenal ulcers.
`
`䊳 Concomitant low-dose aspirin therapy had no
`significant effect on the observed gastric ulcer
`risk reduction seen with PN200.
`
`䊳 The PN formulation may offer a potential treatment
`option for patients at risk of NSAID-associated
`gastric ulcers or duodenal ulcers and may help
`address issues of persistence of use and
`compliance with gastroprotective agents.
`
`References
`1. Lanas A et al. Am J Gastroenterol 2005; 100: 1685-1693.
`2. Hawkey CJ et al. N Engl J Med 1998; 338: 727-734.
`3. Scheiman JM. Curr Treat Options Gastroenterol 2008; 11: 125-134.
`4. Goldstein JL et al. Clin Gastroenterol Hepatol 2006; 4: 1337-1345.
`5. Sturkenboom MC et al. Aliment Pharmacol Ther 2003; 18: 1137-1147.
`
`Acknowledgements
`Study PN200-301 was funded by POZEN Inc.
`Editorial support was provided by Complete Medical Communications and was
`funded by AstraZeneca.
`
`EULAR 2008, Paris, France, 11-14 June 2008
`
`21.9
`
`8.9
`
`6.7
`
`PN200
`n=150
`
`Naproxen
`n=151
`
`PN200
`n=56
`
`Naproxen
`n=52
`
`45
`40
`35
`30
`25
`20
`15
`10
`
`05
`
`Gastric ulcers, %
`
`NS
`
`NS
`
`ASA, acetylsalicylic acid
`RR, relative risk
`NS, not significant
`
`Figure 6. Survival analysis of incidence of duodenal ulcers over
`6 months (ITT)
`
`20
`
`15
`
`10
`
`PN200 (n=206)
`EC naproxen (n=203)
`
`5.4%
`
`10.8%
`
`8.9%
`
`0.5%
`
`0.5%
`
`0.5%
`
`1 month
`ITT, intent-to-treat
`
`3 months
`
`6 months
`
`05
`
`Duodenal ulcers, %
`
`Endpoints
`
`䊳 The primary endpoint was the incidence of gastric ulcer
`(⭓3 mm diameter with depth) during the study estimated by
`survival analysis.
`
`䊳 Secondary endpoints included the incidence of duodenal ulcers.
`
`Results
`
`䊳 Study disposition is shown in Figure 3 and patient demographics
`are shown in Table 1.
`
`䊳 290 patients completed the 6-month study: PN200 BID (n=155
`[75.2%]) and EC naproxen 500 mg BID (n=135 [66.5%]).
`
`䊳 The incidence of gastric ulcers during the course of the study
`was significantly lower in the PN200 group compared with the EC
`naproxen group (8.3% vs 29.4% for PN200 and EC naproxen,
`respectively; relative risk [RR] of 72%, p⬍0.001) (Figure 4).
`
`䊳 The reduction in the incidence of gastric ulcers associated with
`PN200 in comparison with EC naproxen was similar in patients
`taking low-dose aspirin (⭓325 mg) compared with patients not
`taking low-dose aspirin (Figure 5).
`
`䊳 The incidence of duodenal ulcers was significantly lower in
`patients receiving PN200 BID compared with patients receiving
`EC naproxen 500 mg BID (Figure 6).
`
`ITT (intent-to-treat) population: all patients randomised who received at least one dose of
`study drug with no ulcer at baseline
`(At baseline: 4 subjects: 1 PN200, 3 EC naproxen)
`
`Table 1. Patient demographics (ITT population)
`
`Gender, n (%)
`Race, n (%)
`
`Age
`
`Aspirin use
`Ulcer Hx, n (%)
`
`Indication NSAID use, n (%)
`
`PN200
`BID
`n=206
`
`73 (35)
`175 (85)
`24 (12)
`7 (3)
`61
`106 (51)
`199 (97)
`56 (27)
`13 (6)
`2 (1)
`168 (82)
`8 (4)
`1 (0.5)
`36 (18)
`
`EC naproxen
`500 mg BID
`n=203
`
`60 (30)
`173 (85)
`20 (10)
`10 (5)
`61
`100 (49)
`201 (99)
`52 (26)
`4 (2)
`0
`169 (83)
`14 (7)
`0
`25 (12)
`
`Male
`White
`Black
`Other
`Mean
`⬍60 years, n (%)
`⭓50 years, n (%)
`
`Gastric
`Duodenal
`Osteoarthritis
`Rheumatoid arthritis
`Ankylosing spondylitis
`Othera
`
`aOther includes: back pain; back pain-herniated disc surgery; chronic back pain; chronic dental
`pain; chronic headache; chronic knee pain; chronic lower back pain; chronic plantar fasciitis;
`chronic spondylosis; degenerative arthritis; degenerative disc disease; Dequervain’s
`tenosynovitis; fibromyalgia; herniated discs; hip fracture; inflammatory arthritis; left Achilles
`calcific insertional peritendinitis; leg pain; low back pain; neck, shoulder, bilateral hand pain; pain
`in bilateral hips; psoriatic arthritis; shoulder pain; spinal stenosis
`
`Naproxen concentration (µg/mL)
`
`50
`
`40
`
`30
`
`20
`
`10
`
`0
`
`24
`
`Omeprazole
`EC naproxen
`
`350
`
`300
`
`250
`
`200
`
`150
`
`100
`
`50
`
`0
`
`Omeprazole concentration (ng/mL)
`
`0
`
`4
`
`8
`
`12
`
`16
`
`20
`
`Time (hours)
`First-dose kinetics from Study PN200-301; a single-dose crossover
`pharmacokinetic study, n=30 (POZEN: data on file)
`
`䊳 The objectives of this study were to compare the safety and
`tolerability of PN200 with EC naproxen 500 mg alone.
`
`Methods
`
`䊳 The protocols were reviewed and approved by an independent
`ethics committee and all subjects gave written, informed consent.
`䊳 Study PN200-301 was a 6-month, randomised, double-blind,
`parallel-group, multicentre study in patients with arthritis
`requiring chronic NSAID treatment. Patients were randomised to
`either PN200 BID or EC naproxen 500 mg BID (Figure 2).
`
`MYLAN PHARMS. INC. EXHIBIT 1012 PAGE 1
`
`