Deflux ® The Family Friendly Option

1. Deflux®The Family Friendly Option

2. Presentation Overview • What is Vesicoureteral Reflux (VUR)? • The Clinical Consequences of VUR • Overview of Treatment Options • Antibiotics • Endoscopic injection • Surgery • Treatment Preferences

3. What is Vesicoureteral Reflux (VUR)? • VUR is a bladder valve defect that allows urine to reflux from the bladder through one or both ureters and up to the kidneys1 • Affects about 1% of children, usually diagnosed in the first few years of life, after a UTI 1Hensle 2007a

4. What is Vesicoureteral Reflux (VUR)? • The severity of VUR is based upon a grading system, reflecting the extent of reflux and ureter abnormality1 • More severe VUR is associated with more severe renal scarring and increased complications2,3 1Jacobson 1999; 2Gonzalez 2005; 3Caione 2004

5. The Clinical Consequences of VUR • Urine traveling back up to the kidneys increases the likelihood of having a urinary tract infection1 • There is a 70% overall incidence of upper UTI (acute pyelonephritis) in children with first febrile UTI2 • more than half (57%) of these children developed renal scars • Urinary tract infections resulting in renal scarring and damage can potentially lead to early hypertension and end-stage renal disease (ESRD)3 1Panaretto 1999; 2Lin 2003; 3American Academy of Pediatrics 1999

6. The risk of renal scarring increases with each febrile UTI episode1 Renal damage usually occurs within the first 3-5 years of life2 The Clinical Consequences of VUR • 1American Academy of Pediatrics 1999; 2Sherbotie 1991

7. The Clinical Consequences of VUR Consequences of Renal Scarring and Damage • These data are a graphical representation of the data within these studies. • 1Smellie 1998; 2McNiece 2007; 3Kiberd 2002; 42007 USRDS Annual Data Report; 5 US Census Bureau.

8. Definition of Success Aim of Treatment Definition of Success • In the United States success is defined as reduction of VUR to Grade 0 • Prevent Renal Scarring

9. Prophylactic Antibiotics Open Surgery Endoscopic Injection Not Curative 5 – 13% Annual Resolution1 Curative 95% Success Rate2 Curative 69% Success Rate3 Success rates higher than 69% have been reported4,5 Treatment of Vesicoureteral Reflux 1Schwab 2002; 2Capozza 2004; 3Deflux Package Insert (link); 4Kirsch 2004;5Yu 2006

10. Spontaneous Resolution Calculator2,3 Treatment of Vesicoureteral Reflux Spontaneous Resolution 13% annual resolution rate during first 5 years (Grades I-III)1 5% annual resolution rate during first 5 years (Grades IV-V)1 Deflux is approved for treatment of Grades II-IV 1Schwab 2002; 2www.deflux.com; 3AUA 1997 Guidelines

11. Prophylactic Antibiotics Open Surgery Endoscopic Injection Not Curative 5 – 13% Annual Resolution Curative 69% Success Rate** Curative 95% Success Rate Duration of Treatment 1 day (outpatient)1 Duration of Treatment 1 – 5 years* Duration of Treatment up to 3 days (inpatient)1 Cost of Treatment $6,5301 Cost of Treatment $2,2001(3-year) Cost of Treatment $15,4101 * Optimal duration of antibiotic prophylaxis is undetermined but clinical studies have used 1-5 years ** Majority of patients are cured after a single treatment Treatment Options 1Kobelt 2003

12. Prophylactic Antibiotics Not Curative 5 – 13% Annual Resolution Duration of Treatment 1 – 5 years Cost of Treatment $2,200(3-year) Treatment Options Antibiotic Effectiveness The 5-year rate of UTI recurrence in VUR patients treated with ABX is 29%-42%, with febrile UTI rates averaging 22%2 1Garin 2006; 2Wheeler 2003

13. Prophylactic Antibiotics Probability of Antibiotic Resistance Not Curative 5 – 13% Annual Resolution Duration of Treatment 1 – 5 years Cost of Treatment $2,200(3-year) • Pathogens: Escherichia coli (78%), other gram-negative rods, Enterococcus, and other organisms • Prophylactic antimicrobials prescribed: cotrimoxazole (61%), amoxicillin, nitrofurantoin, and other antimicrobials including first- through third-generation cephalosporins Treatment Options • These data are a graphical representation of the data within this study. 1Conway 2007

14. Antibiotic Resistance Prophylactic Antibiotics Not Curative 5 – 13% Annual Resolution Duration of Treatment 1 – 5 years Cost of Treatment $2,200(3-year) ABX includes: TMP-SMX, amoxicillin-clavulanate, ampicillin, cefazolin, ciprofloxacin, and nitrofurantoin Treatment Options • These data are a graphical representation of the data within this study. 1Gaspari 2006

15. Prophylactic Antibiotics Not Curative 5 – 13% Annual Resolution Duration of Treatment 1 – 5 years Cost of Treatment $2,200(3-year) Treatment Options Antibiotic Resistance Antibiotic Non-Compliance1 N=10,975 Antibiotic Resistance2 1Hensle 2007b; 2Who Antibiotic Fact Sheet

16. Treatment Options Re-implant Ureter inside the Bladder1 Open Surgery Ureter Curative 95% Success Rate Duration of Treatment 3 days (inpatient) Cost of Treatment $15,410 Bladder Wall Trigone 1Handbook of Pediatric Urology

17. Endoscopic Injection Curative 69% Success Rate Duration of Treatment 1 day (outpatient) Cost of Treatment $6,530 Treatment Options Impact on UTIs 1Elder 2007

18. Endoscopic Injection Curative 69% Success Rate Duration of Treatment 1 day (outpatient) Cost of Treatment $6,530 Treatment Options Impact on UTIs 1Wadie 2007 • These data are a graphical representation of the data within this study.

19. Endoscopic Injection Curative 69% Success Rate Duration of Treatment 1 day (outpatient) Cost of Treatment $6,530 Treatment Options Impact on Febrile UTIs1 Objective: To investigate outcomes and experiences with Deflux Methods: -Long term observational study -Eligible patients were sent a 21-item questionnaire Results: Of 179 patients initially treated successfully* with Deflux, 3.4% experienced a febrile UTI 7-12 years after treatment 1Stenberg 2006 • *In Europe Grades I-II are considered positive outcomes.

20. STING Subureteric transurethral injection1 Deflux injection Ureter Bladder Wall Treatment Options Some physicians report that using the HIT technique has improved success rates over the STING technique2 Endoscopic Injection Curative 69% Success Rate Duration of Treatment 1 day (outpatient) Cost of Treatment $6,530 1Handbook of Pediatric Urology; 2Kirsch 2004

21. The Deflux advantage Deflux for Grades II – IV VUR • Deflux has shown a greater response rate in the treatment of grades II – IV VUR1 • Deflux is FDA approved for treatment of grades II – IV VUR * A response was defined as reflux grade 0 or 1 1Capozza 2002

22. Risks and Limitations of Treatments Prophylactic Antibiotics1,2,3 Open Surgery4 Endoscopic Injection3 1. Allergic Reaction 2. Diarrhea 3. Resistance 4. Not Curative 5. Requires ongoing invasive diagnostics 6. Non-compliance • 1. Rare cases of obstruction have been reported • 2. Postoperative infection • Anesthesia risks • Postoperative discomfort (bladder spasm) • 1. Infection and bleeding • risk associated with • cytoscopic procedures • 2. Anesthesia risks • Rare cases of obstruction have been reported • 4. Rare cases of dilatation 1Hensle 2007a; 2Gupta 1999; 3Deflux Package Insert 2007 (link); 4Fanos 2004

23. Treatment Preference Parent preferences1 1Capozza 2003

24. Deflux is the Family Friendly Option • Minimally Invasive • Curative in Majority of Patients after Single Injection • Reduction of UTIs • Reduces Risk of Antibiotic Resistance

25. Additional Questions?

26. Product Information Intended Use/Indications Deflux® is indicated for treatment of children with vesicoureteral reflux (VUR) grades II-IV. Contraindications Deflux is contraindicated in patients with any of the following conditions: • Non-functional kidney(s) • Hutch diverticuli • Ureterocele • Active voiding dysfunction • Ongoing urinary tract infection Warnings • Do not inject Deflux intravascularly. Injection of Deflux into blood vessels may cause vascular occlusion. Precautions • Deflux should only be administered by qualified physicians experienced in the use of a cystoscope and trained in subureteral injection procedures. • Treatment of duplex systems has not been prospectively studied. • Ureters with grossly dilated orifices may render the patient unsuitable for treatment. • The risks of infection and bleeding are associated with the cystoscopic procedure used to inject Deflux. The usual precautions associated with cystoscopy (e.g. sterile technique, proper dilation, etc.) should be followed. • The safety and effectiveness of the use of more than 6 ml of Deflux (3 ml at each ureteral orifice) at the same treatment session have not been established. • The safety and effectiveness of Deflux in the treatment of children under 1 year of age have not been established.

27. Product Information Adverse Events List of treatment-related adverse events for 39 patients from a randomized study and 170 patients from nonrandomized studies. (Follow-up for studies was 12 months). Adverse EventRandomized (n=39 Deflux)Nonrandomized (n=170) Urinary tract infection (UTI) (i) 6 (15.4%) (ii, iii) 13 (7.6%) (ii, iii) Ureteral dilatation (iv) 1 (2.6%) 6 (3.5%) Nausea/Vomiting/Abdominal pain (v) 0 (0%) 2 (1.2%) (i) Cases of UTI typically occurred in patients with persistent reflux. (ii) Patients in the nonrandomized studies received antibiotic prophylaxis until the 3-month VCUG. After that only those patients whose treatment had failed received further antibiotic prophylaxis. The patients in the randomized study received antibiotic prophylaxis 1 month post-treatment. (iii) All UTI cases were successfully treated with antibiotics. (iv) No case of ureteral dilation required intervention and most cases resolved spontaneously. (v) Both cases of nausea/vomiting/abdominal pain were resolved.

28. Product Information Adverse Events Continued Although vascular occlusion, ureteral obstruction, dysuria, hematuria/bleeding, urgency and urinary frequency have not been observed in any of the clinical studies, they are potential adverse events associated with subureteral injection procedures. Following approval, rare cases of postoperative dilation of the upper urinary tract with or without hydronephrosis leading to temporary placement of a ureteric stent have been reported.

29. References • American Academy of Pediatrics. Practice parameter: the diagnosis, treatment, and evaluation of the initial urinary tract infection in febrile infants and young children. American Academy of Pediatrics Committee on Quality Improvement, Subcommittee on Urinary Tract Infection. Pediatrics. 1999 Apr;103(4 Pt 1):843-52. 1999 May;103(5 Pt 1):1052, 1999 Jul;104(1 Pt 1):118. Erratum in: Pediatrics. 2000 Jan;105(1 Pt 1):141. • American Urological Association 1997 Guidelines. • Caione P, Villa M, Capozza N, De Gennaro M, Rizzoni G. Predictive risk factors for chronic renal failure in primary high-grade vesico-ureteric reflux. BJU Int. 2004 Jun;93(9):1309-1312. • Capozza N, Caione P. Dextranomer/hyaluronic acid copolymer implantation for vesico-ureteral reflux: a randomized comparison with antibiotic prophylaxis. J Pediatr. 2002 Feb;140(2):230-234. • Capozza N, Lais A, Matarazzo E, Nappo S, Patricolo M, Caione P. Treatment of vesico-ureteric reflux: a new algorithm based on parental preference. BJU Int. 2003 Aug;92(3):285-288. • Capozza N, Lais A, Nappo S, Caione P. The role of endoscopic treatment of vesicoureteral reflux: a 17-year experience. J Urol. 2004 Oct;172(4 Pt 2):1626-1628; discussion 1629. • Conway PH, Cnaan A, Zaoutis T, Henry BV, Grundmeier RW, Keren R. Recurrent urinary tract infections in children: risk factors and association with prophylactic antimicrobials. JAMA. 2007 Jul; 11;298(2):179-186. • Deflux [Product Information] Uppsala, Sweden: Q-Med AG; 2007 May. Available at: http://deflux.qmed.episerverhotell.net/263dc0b5-c1f8-4cda-b0ba-4e10578d5cf9.fodoc • Elder JS, Shah MB, Batiste LR, Eaddy M. Endoscopic injection versus antibiotic prophylaxis in the reduction of urinary tract infection in patients with vesicoureteral reflux. Curr Res Med Opin. 2007 Sep;23(Suppl 4):S15-S20. • Fanos V, Cataldi L. Antibiotics or surgery for vesicoureteric reflux in children. Lancet. 2004 Nov 6-2;364(9446):1720-1722.

30. References • Garin EH, Olavarria F, Garcia Nieto V, Valenciano B, Campos A, Young L. Clinical significance of primary vesicoureteral reflux and urinary antibiotic prophylaxis after acute pyelonephritis: a multicenter, randomized, controlled study. Pediatrics. 2006 Mar;117(3):626-632. • Gaspari RJ, Dickson E, Karlowsky J, Doern G. Multidrug resistance in pediatric urinary tract infections. Microb Drug Resist. 2006 Summer;12(2):126-129. • Gonzalez E, Papazyan JP, Girardin E. Impact of vesicoureteral reflux on the size of renal lesions after an episode of acute pyelonephritis. J Urol. 2005 Feb; 173:571–575. • Gupta K, Scholes D, Stamm WE. Increasing prevalence of antimicrobial resistance among uropathogens causing acute uncomplicated cystitis in women. JAMA. 1999 Feb 24;281(8):736-738. • Handbook of Pediatric Urology, Second Edition, Laurence S. Basken, Barry A. Kogan. • Hensle TW, Grogg AL. Vesicoureteral reflux treatment: the past, present and future. Curr Res Med Opin. 2007 Sep;23(Suppl 4):S1-S6. (Hensle 2007a) • Hensle TW, Hyun G, Grogg AL, Eaddy M. Examining pediatric vesicoureteral reflux: a real-world evaluation of treatment patterns and outcomes. Curr Res Med Opin. 2007 Sep;23(Suppl 4):S1-S6. (Hensle 2007b) • Jacobson SH, Hansson S, Jakobsson B. Vesico-ureteric reflux: occurrence and long-term risks. Acta Paediatrica. 1999;431:22-30. • Kiberd BA, Clase CM. Cumulative risk for developing end-stage renal disease in the US population. J Am Soc Nephrol. 2002 Jun;13(6):1635-1644. Erratum in: J Am Soc Nephrol. 2002 Oct;13(10):2617. • Kirsch AJ, Perez-Brayfield M, Smith EA, Scherz HC. The modified sting procedure to correct vesicoureteral reflux: improved results with submucosal implantation within the intramural ureter. J Urol. 2004 Jun;171(6 Pt 1):2413-2416. • Kobelt G, Canning DA, Hensle TW, Lackgren G. The cost-effectiveness of endoscopic injection of dextranomer/hyaluronic acid copolymer for vesicoureteral reflux. J Urol. 2003 Apr;169(4):1480-1480; discussion 1484-1485.

31. References • Lin KY, Chiu NT, Chen MJ, et al. Acute pyelonephritis and sequelae of renal scar in pediatric first febrile urinary tract infection. Pediatr Nephrol. 2003 Apr;18(4):362-365. • McNiece KL, Poffenbarger TS, Turner JL, Franco KD, Sorof JM, Portman RJ. Prevalence of hypertension and pre-hypertension among adolescents. J Pediatr. 2007 Jun;150(6):640-644. • Panaretto K, Craig J, Knight J, Howman-Giles R, Sureshkumar P, Roy L. Risk factors for recurrent urinary tract infection in preschool children. J Paediatr Child Health. 1999 Oct;35(5):454-459. • Q-Med Scandinavia Inc. [homepage on the Internet]. Princeton, NJ. Spontaneous Resolution Calculator; [1 screen]. Accessed: 2007 Sep 20. Available at: http://deflux.qmed.episerverhotell.net/Templates/Page.aspx?id=1046 • Q-Med Scandinavia Inc. [homepage on the Internet]. Princeton, NJ. Injection Techniques; [4 screens]. Accessed: 2007 Sep 20. Available at: http://deflux.qmed.episerverhotell.net/Templates/Page.aspx?id=361 • Schwab CW, Wu HY, Selman H, Smith GH, Snyder HM, Canning DA. Spontaneous resolution of vesicoureteral reflux: a 15-year perspective. J Urol. 2002 Dec;168(6):2594-2599. • Sherbotie JR, Cornfeld D. Management of urinary tract infections in children. Med Clin North Am. 1991 Mar;75(2):327-338. • Smellie JM, Prescod NP, Shaw PJ, Risdon RA, Bryant TN. Childhood reflux and urinary infection: a follow-up of 10-41 years in 226 adults. Pediatr Nephrol. 1998 Nov;12(9):727-736. • Stenberg A, Läckgren G. Treatment of vesicoureteral reflux in children using stabilized non-animal hyaluronic acid/dextranomer gel: A long-term observational study. J Ped Urol. 2006 Nov;3:80-85. • United States Renal Data System Annual Data Report 2007. http://www.usrds.org • U.S.Census Bureau, Population Division, Interim State Population Projections, 2005. • Wadie GM, Tirabassi MV, Courtney RA, Moriarty KP. The deflux procedure reduces the incidence of urinary tract infections in patients with vesicoureteral reflux. J Laparoendosc Adv Surg Tech A. 2007 Jun;17(3):353-359.

32. References • Wheeler D, Vimalachandra D, Hodson EM, Roy LP, Smith G, Craig JC. Antibiotics and surgery for vesicoureteral reflux: a meta-analysis of randomised controlled trials. Arch Dis. Child. 2003;88:688-694. • World Health Organization Antibiotic Fact Sheet. http://www.who.int/mediacentre/factsheets/fs194/en/ • Yu R, Roth D. Treatment of VUR using endoscopic injection of nonanimal stabilized hyaluronic acid/dextranomer gel: Initial experience in pediatric patients by a single surgeon. Pediatrics 2006; 118; 698-703.