Treating the Infected Periodontal Foundation

Treating the Infected Periodontal Foundation OraPharma, Inc. 2008

Topics included in this discussion Prevalence and pathogenesis of periodontal disease Red complex bacteria Properties of biofilms Links to systemic complications Limitations of mechanical treatment Treatment with ARESTIN (minocycline hydrochloride) Microspheres, 1 mg Microsphere technology Eradication of red complex bacteria Proven clinical outcomes Smokers and difficult-to-treat patient groups Safety and ease of use

Periodontal disease is a common, chronic, and persistent infection 1-6 Periodontal disease is: A persistent infection that can spread rapidly throughout the periodontium 1,2 The most common chronic bacterial infection in adults 1,3 A problem that affects more than 35.7 million Americans 4 The #1 cause of adult tooth loss in the US 5 Three out of 4 American adults develop a periodontal infection 6 References: 1. Socransky SS, Haffajee AD. Dental biofilms: difficult therapeutic targets. Periodontol 2000 2002;28:12-55. 2. Page RC. Periodontal diseases: a new paradigm. J Dent Educ 1998;62:812-821. 3. Loesche WJ, Grossman NS. Periodontal disease as a specific, albeit chronic, infection: diagnosis and treatment. Clin Microbiol Rev 2001;14:727-752. 4. Albandar JM, Brunelle JA, Kingman A. Destructive periodontal disease in adults 30 years of age and older in the United States, 1988-1994. J Periodontol 1999;70:13-29. 5. Williams RC. Periodontal disease. N Engl J Med 1990;322:373-382. 6. American Dental Association. For the dental patient. Women and periodontal disease. J Am Dent Assoc 2002;133:671.

Red complex bacteria are found at the infection site Specific bacteria are implicated in periodontal disease and are commonly found at the site of infection 1,2 There is a direct association between red complex bacteria and 2 of the most meaningful parameters in periodontal disease diagnosis 1 : Pocket depth Bleeding on probing References: 1. Socransky SS, Haffajee AD, Cugini MA, Smith C, Kent RL Jr. Microbial complexes in subgingival plaque. J Clin Periodontol 1998;25:134-144. 2. Socransky SS, Haffajee AD. Dental biofilms: difficult therapeutic targets. Periodontol 2000 2002;28:12-55.

Periodontal bacteria form dense biofilms The bacteria associated with periodontal disease reside within biofilms above and below the gingival margin 1-3 Biofilms are dense mixtures of organisms resistant to natural antibodies and proteins that the body uses to fight infection 1 Slide content adapted with permission from Dr. Richard H. Nagelberg. References: 1. Socransky SS, Haffajee AD. Dental biofilms: difficult therapeutic targets. Periodontol 2000 2002;28:12-55. 2. Scannapieco FA. Periodontal inflammation: from gingivitis to systemic disease? Compend Contin Educ Dent 2004;25(suppl 1):16-25. 3. Page RC. Periodontal diseases: a new paradigm. J Dent Educ 1998;62:812-821.

Collectively, the structure and properties of biofilms make it difficult to remove them with SRP alone 1,2 Biofilms possess a self-protective matrix shield 1 Each contains a microenvironment of bacteria 1,2 Bacteria exist in large numbers Bacteria rapidly multiply, spread, and recolonize Biofilms cross-feed and cross-communicate 1,2 Loosely attached and unattached bacteria found at the biofilm surface have direct contact with the epithelium of the gingival tissue 2 Slide content adapted with permission from Dr. Richard H. Nagelberg. References: 1. Socransky SS, Haffajee AD. Dental biofilms: difficult therapeutic targets. Periodontol 2000 2002;28:12-55. 2. Page RC. Periodontal diseases: a new paradigm. J Dent Educ 1998;62:812-821.

Biofilms shelter millions of bacteria 1 Approximately 10 million to 1 billion bacteria have been observed in the biofilm-infected periodontal pocket 1 The depth of biofilm-infected pockets ranges from 4 mm to 12 mm 1 Slide content adapted with permission from Dr. Richard H. Nagelberg. Reference: 1. Loesche WJ, Grossman NS. Periodontal disease as a specific, albeit chronic, infection: diagnosis and treatment. Clin Microbiol Rev 2001;14:727-752.

Biofilms can induce bacteremia 1 Biofilms release a variety of biologically active inflammatory products, including: Bacterial endotoxins Protein toxins Peptides Organic fatty acids These destructive molecules cause gingival inflammation and can enter the bloodstream, resulting in bacteremia Slide content adapted with permission from Dr. Richard H. Nagelberg. Reference: 1. Scannapieco FA. Periodontal inflammation: from gingivitis to systemic disease? Compend Contin Educ Dent 2004;25(suppl 1):16-25.

Bacteremia generates an inflammatory response 1,2 The body responds to bacteremia with inflammation and tissue destruction 1 The body releases cytokines, small proteins responsible for gingival inflammation 1 Cytokines induce and enhance the production of a destructive family of enzymes, also known as MMPs 1,2 MMPs break down gingival tissue, leading to the formation of periodontal disease 2 Slide content adapted with permission from Dr. Richard H. Nagelberg. References: 1. Scannapieco FA. Periodontal inflammation: from gingivitis to systemic disease? Compend Contin Educ Dent 2004;25(suppl 1):16-25. 2. Page RC. Periodontal diseases: a new paradigm. J Dent Educ 1998;62:812-821.

C-reactive protein (CRP) levels are elevated in patients with periodontal infection Statistically significant increases in CRP have been observed in patients with periodontal infection vs healthy patients 1 CRP has been linked to a number of important systemic events 2,3 Slide content adapted with permission from Dr. Richard H. Nagelberg. References: 1. Noack B, Genco RJ et al. Periodontal infections contribute to elevated systemic C-reactive protein level. J Periodontol 2001;72:1221-1227. 2. Ridker PM, Rifai N, Rose L, Buring JE, Cook NR. Comparison of C-reactive protein and low-density lipoprotein cholesterol levels in the prediction of first cardiovascular events. N Engl J Med 2002:347:1557-1565. 3. American Heart Association. Inflammation, heart disease, and stroke: the role of C-reactive protein. Available at: http://www.americanheart.org/presenter.jhtml?identifier=4648. Accessed June 18, 2006.

The American Academy of Periodontology (AAP) links periodontal disease to other serious health risks* According to the AAP 1 : Periodontal bacteria can enter the blood stream, travel to major organs, and begin new infections Current research suggests that periodontal bacteremia may lead to: Heart disease, stroke, and/or diabetes Increased risk of delivering a preterm, low birth-weight baby Increased health risk for people with diabetes, respiratory disease, or osteoporosis *A causal relationship has not been fully established. Reference: 1. American Academy of Periodontology. Mouth body connection. Available at: http://www.perio.org/consumer/mbc.top2.htm. Accessed June 17, 2006.

Routine, effective treatment for periodontal infection is needed Despite the prevalence of periodontal infection and the persistent nature of bacteria and biofilms, more than 70% of dental practices do not perform regular full-mouth probing and charting 1 Although 3 out of 4 American adults are affected by periodontal disease 2 : Prophylaxis procedures outnumber SRP procedures by a ratio of 20:1 3,4 Less than 1/2 of periodontal pockets are treated with adjunctive therapy 5 * *According to a utilization tracking survey evaluating 14,945 patient records from 647 offices. The average number of pockets per patient was 9. References: 1. Levin RL. Periodontal profitability. Available at: http://www.dentaleconomics.com. Accessed December 26, 2005. 2. American Dental Association. For the dental patient. Women and periodontal disease. J Am Dent Assoc 2002;133:671. 3. Blair C. The economic impact of the underdiagnosis of periodontal disease in general practice. Triage 2005;1:21-25. 4. American Dental Association, Survey Center. 1999 Survey of Dental Services Rendered. Chicago, IL: American Dental Association; 1999. 5. Data on file. OraPharma, Inc., Warminster, PA; 2004.

Left untreated, serious consequences can occur Without proper diagnosis and treatment, periodontal disease can lead to The spread of infection 1 Loss of teeth 2 Surgery 2 References: 1. Page RC. Periodontal diseases: a new paradigm. J Dent Educ 1998;62:812-821. 2. Williams RC. Periodontal disease. N Engl J Med 1990;322:373-382.

Scaling and root planing (SRP) has mechanical limitations Even after SRP, the bacteria in biofilms can remain, multiply, and return to baseline levels within days 1 Instrumentation does not always reach the furcation region. SRP instrumentation is limited in areas of restricted access 2,3 In a clinical study, 58% of sites had residual calculus after SRP 4 Deep pockets can restrict access and create a reservoir for bacteria. References: 1. Socransky SS, Haffajee AD. Dental biofilms: difficult therapeutic targets. Periodontol 2000 2002;28:12-55. 2. Cobb CM. Non-surgical pocket therapy: mechanical. Ann Periodontol 1996;1:443-490. 3. Cobb CM. Implementing New Strategies for Treating Periodontal Disease: A Systematic Approach. Symposium. October 2, 2002. Chicago, IL. 4. Sherman PR, Hutchens LH Jr., Jeson LG, Moriarty JM, Greco GW, McFall WT Jr. The effectiveness of subgingival scaling and root planing. I. Clinical detection of residual calculus. J Peridontol 1990;61:3-8.

Adding an LAA to SRP can benefit patients Adding a locally administered antibiotic (LAA) to SRP is proven to significantly improve periodontal treatment 1 The American Academy of Periodontology (AAP) supports the use of LAAs as an adjunct to SRP 2 The LAA ARESTIN (minocycline hydrochloride) Microspheres, 1 mg can help eliminate the bacteria that SRP can leave behind including 3,4 : P gingivalis T denticola T forsynthensis References: 1. Williams RC, Paquette DW, Offenbacher S, et al. Treatment of periodontitis by local administration of minocycline microspheres: a controlled trial. J Periodontol 2001;72:1535-1544. 2. American Academy of Periodontology Research, Science, and Therapy Committee. Guidelines for periodontal therapy. J Periodontol 2001;72:1624-1628. 3. ARESTIN (minocycline hydrochloride) 1 mg Microspheres [Prescribing Information]. Warminster, PA: OraPharma, Inc., 2005. 4. Data on file. OraPharma, Inc., Warminster, PA; 2004.

ARESTIN Microspheres technology provides a sustained release of minocycline in the periodontal pocket 1 ARESTIN Microspheres deliver minocycline directly to the periodontal pocket and help maintain therapeutic drug concentrations for up to 21 days, managing the infection long after treatment with SRP 1 ARESTIN Microspheres are bioadhesive and completely bioresorbed 2 ARESTIN Microspheres kill the bacteria SRP leaves behind, including P gingivalis, T denticola, and T forsynthensis References: 1. Data on file. OraPharma, Inc., Warminster, PA; 2004. 2. ARESTIN (minocycline hydrochloride) 1 mg Microspheres [Prescribing Information]. Warminster, PA: OraPharma, Inc., 2005. Baseline 10 Days 2 Days

Minocycline effectively treats the common periodontal pathogens 1 References: 1. ARESTIN (minocycline hydrochloride) 1 mg Microspheres [Prescribing Information]. Warminster, PA: OraPharma, Inc., 2005. 2. Data on file. OraPharma, Inc., Warminster, PA; 2004. 3. O Connor BC, Newman HN, Wilson M. Susceptibility and resistance of plaque bacteria to minocycline. J Periodontol 1990;61:228-233.

ARESTIN treats the bacterial cause of periodontal infection more effectively than SRP alone 1* In a recent microbiological study of patients with moderate-tosevere periodontitis, ARESTIN + SRP: Significantly reduced the quantity of red complex bacteria vs SRP alone (P=0.002) *Phase IV, single-blind, randomized, parallel-group study of 127 patients with moderate-to-severe periodontitis and at least 5 teeth with 5 mm pocket depths. Reference: 1. Goodson, JM. Antimicrobial Efficacy of Arestin in Periodontitis Therapy. Presented at the 35th Annual Meeting of the American Association for Dental Research; March 8-11, 2006; Orlando, FL.

ARESTIN treats the bacterial cause of periodontal infection more effectively than SRP alone 1* In a recent microbiological study of patients with moderate-tosevere periodontitis, ARESTIN + SRP: Significantly reduced proportions of red complex bacteria vs SRP alone (P=0.0005) Significantly reduced pocket depths and bleeding on probing, and increased clinical attachment levels 2 *Phase IV, single-blind, randomized, parallel-group study of 127 patients with moderate-tosevere periodontitis and at least 5 teeth with 5 mm pocket depths. Reference: 1. Goodson, JM. Antimicrobial Efficacy of Arestin in Periodontitis Therapy. Presented at the 35th Annual Meeting of the American Association for Dental Research; March 8-11, 2006; Orlando, FL. 2. Bland PS. Clinical efficacy and safety with ARESTIN in patients with periodontitis. Presented at the 35 th Annual Meeting of the American Association for Dental Research; March 8-11, 2006; Orlando, FL.

ARESTIN + SRP is significantly more effective than SRP alone in reducing pocket depth 1 ARESTIN + SRP demonstrated a greater therapeutic effect than SRP alone throughout 9 months (P<0.001) 1 *P<0.01 ARESTIN vs SRP alone P<0.001 ARESTIN vs SRP alone P<0.001 ARESTIN vs SRP + placebo Reference: 1. Williams RC, Paquette DW, Offenbacher S, et al. Treatment of periodontitis by local administration of minocycline microspheres: a controlled trial. J Periodontol 2001;72:1535-1544.

ARESTIN + SRP is significantly more effective than SRP alone in reducing pocket depth 1 More than 60% of pockets that responded to ARESTIN + SRP had a reduction of >2 mm 1* In 65% of patients, ARESTIN + SRP reduced pocket depth from >6 mm to <5 mm 1 Compared to SRP alone, ARESTIN + SRP is nearly 3 times more likely to reduce mean probing depth from >6 mm to <5 mm 2 *In clinical studies, 37% of pockets treated with SRP alone did not respond to therapy vs 29% of pockets treated with ARESTIN + SRP. 1 References: 1. Data on file. OraPharma, Inc., Warminster, PA; 2004. 2. Williams RC, Paquette DW, Offenbacher S, et al. Treatment of periodontitis by local administration of minocycline microspheres: a controlled trial. J Periodontol 2001;72:1535-1544.

Smoking is a major risk factor for periodontal infection 1,2 Smoking may be responsible for more than 1/2 of adult periodontal cases in the US 3 Clinical studies show that smokers exhibit increased 1,2 : Pocket depth Alveolar bone loss Gingival recession Tooth loss Clinical attachment loss Number of furcations Radiograph showing bone loss in smoker with periodontal disease. References: 1. Kerdvongbundit V, Wikesjö UME. Prevalence and severity of periodontal disease at mandibular molar teeth in smokers with regular oral hygiene habits. J Periodontol 2002;73:735-740. 2. American Academy of Periodontology Research, Science and Therapy Committee. Tobacco use and the periodontal patient. J Periodontol 1999;70:1419-1427. 3. Tomar SL, Asma S. Smoking-attributable periodontitis in the United States: findings from NHANES III. J Periodontol 2000;71:743-751.

ARESTIN + SRP is more effective than SRP alone in reducing pocket depth in smokers with periodontal disease 1 Statistically significant pocket depth reduction vs SRP alone 1 * *Subgroup analysis (n=271) 1 of the single-blind, Phase III trial comparing ARESTIN + SRP to SRP alone and SRP + placebo (n=748). 2 SRP was performed for all groups at baseline. ARESTIN or vehicle was administered to periodontal pockets >5 mm in the adjunctive therapy groups at baseline, 3 months, and 6 months. Efficacy was evaluated over 9 months. References: 1. Paquette D, Oringer R, Lessem J, et al. Locally delivered minocycline microspheres for the treatment of periodontitis in smokers. J Clin Periodontol 2003;30:787-794. 2. Williams RC, Paquette DW, Offenbacher S, et al. Treatment of periodontitis by local administration of minocycline microspheres: a controlled trial. J Periodontol 2001;72:1535-1544.

ARESTIN + SRP is more likely than SRP alone to reduce pockets to maintenance levels in smokers 1 According to the AAP, smokers can be up to 6x more likely to exhibit periodontal destruction vs nonsmokers 2 Compared to SRP alone, ARESTIN + SRP is nearly 4x more likely to reduce periodontal pockets to <5 mm in smokers 1* *Multivariate analysis of the univariate, multicenter Phase III trials of ARESTIN that compared the efficacy and safety of ARESTIN + SRP to SRP + placebo and SRP alone. Odds ratios were adjusted to allow for the simultaneous effect of influential variables, such as treatment center, smoking status, age, and baseline pocket depths. References: 1. Data on file. OraPharma, Inc., Warminster, PA; 2004. 2. American Academy of Periodontology Research, Science and Therapy Committee. Tobacco use and the periodontal patient. J Periodontol 1999;70:1419-1427.

ARESTIN + SRP has a greater therapeutic effect than SRP alone * in other difficult-to-treat patient groups 1-3 Based on pocket depth reduction scores at 9 months Greater therapeutic effect* *Adapted from Williams RC, Paquette DW, Offenbacher S, et al. 4 748 patients with moderate or advanced periodontitis with bleeding on probing. SRP was performed at baseline. Clinical assessments were conducted at baseline and 1, 3, 6, and 9 months. ARESTIN or vehicle was administered to all sites with pocket depths >5 mm. Change in pocket depth from baseline to 9 months was recorded for ARESTIN + SRP and SRP alone. Therapeutic effect was derived by calculating the percent difference between the 9-month scores. References: 1. Williams RC. Periodontal disease. N Engl J Med 1990;322:373-382. 2. Cobb CM. Non-surgical pocket therapy: mechanical. Ann Periodontol 1996;1:443-490. 3. Fleischer HC, Mellonig JT, Brayer WK, Gray JL, Barnett JD. Scaling and root planing efficacy in multirooted teeth. J Periodontol 1989;60(7):402-409. 4. Williams RC, Paquette DW, Offenbacher S, et al. Treatment of periodontitis by local administration of minocycline microspheres: a controlled trial. J Periodontol 2001;72:1535-1544.

ARESTIN is easy to administer The administration of ARESTIN does not require local anesthesia. Sterilize the handle tip between patients. ARESTIN does not have to be removed, as it is bioresorbable. ARESTIN does not require an adhesive or dressing. Insert the ARESTIN cartridge into the handle while exerting slight pressure. Twist until you feel and hear the cartridge lock into place. Should you need to manipulate the cartridge tip to reach difficult-to-access areas, gently bend the tip, leaving the blue cap on. Bending the tip after removal of the blue cap may cause the internal plunger to rupture the cartridge wall.

ARESTIN is easy to administer Place the cartridge tip into the periodontal pocket, parallel to the long axis of the tooth. Be sure not to force the tip into the base of the pocket. Gently press the thumb ring to express the ARESTIN powder while withdrawing the cartridge tip away from the base of the pocket. If you feel any resistance during delivery, withdraw the device further. Once delivery is complete, retract the thumb ring and remove the ARESTIN cartridge with your free hand. Appropriately discard the cartridge and sterilize the handle prior to reuse.

ARESTIN is safe and well tolerated in clinical trials 1 Reference: 1. ARESTIN (minocycline hydrochloride) 1 mg Microspheres [Prescribing Information]. Warminster, PA: OraPharma, Inc., 2005.

Summary Three out of 4 American adults develop periodontal disease, 1 yet this persistent infection often goes untreated 2-4 The AAP reports that periodontal bacteria can enter the blood stream, travel to major organs, begin new infections, and potentially lead to additional health problems 5,6* SRP instrumentation has mechanical limitations and can leave bacteria behind in the periodontium 7,8 *A causal relationship has not been fully established. References: 1. American Dental Association. For the dental patient. Women and periodontal disease. J Am Dent Assoc 2002;133:671. 2. Blair C. The economic impact of the underdiagnosis of periodontal disease in general practice. Triage 2005;1:21-25. 3. American Dental Association, Survey Center. 1999 Survey of Dental Services Rendered. Chicago, IL: American Dental Association; 1999. 4. Data on file. OraPharma, Inc, Warminster, PA; 2004. 5. American Academy of Periodontology. Mouth body connection. Available at: http://www.perio.org/consumer/mbc.top2.htm. Accessed June 17, 2006. 6. American Academy of Periodontology Research, Science, and Therapy Committee. Diabetes and periodontal diseases. J Periodontol 1999;70: 935-949. 7. Cobb CM. Non-surgical pocket therapy: mechanical. Ann Periodontol 1996;1:443-490. 8. Cobb CM. Implementing New Strategies for Treating Periodontal Disease: A Systematic Approach. Symposium. October 2, 2002. Chicago, IL.

Summary, continued ARESTIN is a locally administered antibiotic that can help eliminate the bacteria that SRP leaves behind 1 ARESTIN maintains therapeutic drug concentrations in the periodontal pocket for up to 21 days, 2 managing the infection long after treatment with SRP ARESTIN + SRP has been shown to significantly reduce quantity and proportions of red complex bacteria vs SRP alone 3 ARESTIN is significantly more effective than SRP alone in reducing periodontal pocket depth, even in smokers and difficult-to-treat patients 4 References: 1. ARESTIN (minocycline hydrochloride) 1 mg Microspheres [Prescribing Information]. Warminster, PA: OraPharma, Inc., 2005. 2. Data on file. OraPharma, Inc., Warminster, PA; 2004. 3. Goodson, JM. Antimicrobial Efficacy of Arestin in Periodontitis Therapy. Presented at the 35th Annual Meeting of the American Association for Dental Research; March 8-11, 2006; Orlando, FL. 4. Williams RC, Paquette DW, Offenbacher S, et al. Treatment of periodontitis by local administration of minocycline microspheres: a controlled trial. J Periodontol 2001;72:1535-1544.

ARESTIN Safety Information ARESTIN is indicated as an adjunct to scaling and root planing (SRP) procedures for reduction of pocket depth in patients with adult periodontitis. ARESTIN may be used as part of a periodontal maintenance program which includes good oral hygiene, and scaling and root planing. ARESTIN contains minocycline, a tetracycline derivative, and therefore should not be used in children and in pregnant or nursing women. The use of drugs of the tetracycline class during tooth development may cause permanent discoloration of the teeth. The most common treatment-emergent adverse events were headache (9.0%), infection (7.6%), flu syndrome (5.0%), and pain (4.3%). These occurred at a similar rate to SRP and SRP + placebo. Please see accompanying full Prescribing Information. 2006 OraPharma, Inc. A-456-06 12/06 ARESTIN is a registered trademark of OraPharma, Inc.