treating the infection

8/3/2019 Treating the Infection

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Treating the InfectedPeriodontal Foundation

OraPharma, Inc. 2008


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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


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Periodontal disease is a common, chronic,

and persistent infection1-6

References: 1. Socransky SS, Haffajee AD. Dental biofilms: difficult therapeutic targets. Periodontol 20002002;28:12-55. 2. Page RC. Periodontal diseases: a new paradigm. J Dent Educ1998;62:812-821.3. Loesche WJ, Grossman NS. Periodontal disease as a specific, albeit chronic, infection: diagnosis andtreatment. Clin Microbiol Rev2001;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 Periodontol1999;70:13-29. 5. Williams RC. Periodontal disease. N Engl J Med1990;322:373-382. 6. American DentalAssociation. For the dental patient. Women and periodontal disease. J Am Dent Assoc2002;133:671.

Periodontal disease is:

A persistent infection that can spread rapidlythroughout the periodontium1,2

The most common chronic bacterial infectionin adults1,3

A problem that affects more than 35.7million Americans4

The #1 cause of adult tooth loss in the US5

Three out of 4 American adults develop aperiodontal infection6


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Red complex bacteria are found at the

infection site

References: 1. Socransky SS, Haffajee AD, Cugini MA, Smith C, Kent RL Jr. Microbial complexes insubgingival plaque. J Clin Periodontol1998;25:134-144. 2. Socransky SS, Haffajee AD. Dental biofilms:difficult therapeutic targets. Periodontol 20002002;28:12-55.

Specific bacteria are implicated in periodontal disease and are

commonly found at the site of infection1,2

There is a direct association between red complex bacteria and 2 ofthe most meaningful parameters in periodontal disease diagnosis1:

Pocket depth

Bleeding on probing


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Periodontal bacteria form dense biofilms

References: 1. Socransky SS, Haffajee AD. Dental biofilms: difficult therapeutic targets. Periodontol20002002;28:12-55. 2. Scannapieco FA. Periodontal inflammation: from gingivitis to systemic disease?Compend Contin Educ Dent2004;25(suppl 1):16-25. 3. Page RC. Periodontal diseases: a newparadigm. J Dent Educ1998;62:812-821.

The bacteria associated withperiodontal disease residewithin biofilms above andbelow the gingival margin1-3

Biofilms are dense mixturesof organisms resistant tonatural antibodies and proteinsthat the body uses to fightinfection1

Slide content adapted with permission from Dr. Richard H. Nagelberg.


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Collectively, the structure and properties ofbiofilms make it difficult to remove them with

SRP alone1,2

References: 1. Socransky SS, Haffajee AD. Dental biofilms: difficult therapeutic targets. Periodontol 20002002;28:12-55. 2. Page RC. Periodontal diseases: a new paradigm. J Dent Educ1998;62:812-821.

Biofilms possess a self-protective matrix shield1

Each contains a microenvironment of bacteria1,2

Bacteria exist in large numbers

Bacteria rapidly multiply, spread, and recolonize

Biofilms cross-feed and cross-communicate1,2

Loosely attached and unattached bacteria found at the biofilmsurface have direct contact with the epithelium of the gingival tissue2



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Approximately 10 million to 1 billion bacteria have been observed in

the biofilm-infected periodontal pocket1

The depth of biofilm-infected pockets ranges from 4 mm to 12 mm1

Biofilms shelter millions of bacteria1

Reference: 1. Loesche WJ, Grossman NS. Periodontal disease as a specific, albeit chronic, infection:diagnosis and treatment. Clin Microbiol Rev2001;14:727-752.



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Biofilms can induce bacteremia1

Biofilms release a variety of biologicallyactive inflammatory products, including: Bacterial endotoxins

Protein toxins

Peptides

Organic fatty acids

These destructive molecules causegingival inflammation and can enterthe bloodstream, resulting in bacteremia

Reference: 1. Scannapieco FA. Periodontal inflammation: from gingivitis to systemic disease? CompendContin Educ Dent2004;25(suppl 1):16-25.



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Bacteremia generates an inflammatory

response1,2

The body responds to bacteremia with

inflammation and tissue destruction1

The body releases cytokines, smallproteins responsible for gingivalinflammation1

Cytokines induce and enhance theproduction of a destructive family ofenzymes, also known as MMPs1,2

MMPs break down gingival tissue,leading to the formation of periodontaldisease2

References: 1. Scannapieco FA. Periodontal inflammation: from gingivitis to systemic disease? CompendContin Educ Dent2004;25(suppl 1):16-25. 2. Page RC. Periodontal diseases: a new paradigm. J Dent Educ1998;62:812-821.



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Statistically significant increases in CRP

have been observed in patients withperiodontal infection vs healthy patients1

CRP has been linked to a number of

important systemic events2,3

References: 1. Noack B, Genco RJ et al. Periodontal infections contribute to elevated systemic C-reactiveprotein level. J Periodontol2001;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 firstcardiovascular events. N Engl J Med2002:347:1557-1565. 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.

C-reactive protein (CRP) levels are elevated

in patients with periodontal infection

Slide content adapted with permissionfrom Dr. Richard H. Nagelberg.


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Routine, effective treatment for

periodontal infection is needed

References: 1. Levin RL. Periodontal profitability. Available at: http://www.dentaleconomics.com. AccessedDecember 26, 2005. 2. American Dental Association. For the dental patient. Women and periodontaldisease. J Am Dent Assoc2002;133:671. 3. Blair C. The economic impact of the underdiagnosis of

periodontal disease in general practice. Triage2005;1:21-25. 4. American Dental Association, SurveyCenter. 1999 Survey of Dental Services Rendered. Chicago, IL: American Dental Association; 1999. 5. Dataon file. OraPharma, Inc., Warminster, PA; 2004.

*According to a utilization tracking survey evaluating 14,945 patient records from 647 offices.The average number of pockets per patient was 9.

Despite the prevalence of periodontal infection and the persistentnature of bacteria and biofilms, more than 70% of dental practicesdo not perform regular full-mouth probing and charting1

Although 3 out of 4 American adults are affected by

periodontal disease2

: Prophylaxis procedures outnumber SRP procedures by a

ratio of 20:13,4

Less than 1/2 of periodontal pockets are treated withadjunctive therapy5*


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Left untreated, serious consequences

can occur

Without proper diagnosis and treatment, periodontal disease can lead to

The spread of infection1

Loss of teeth2

Surgery2

References: 1. Page RC. Periodontal diseases: a new paradigm. J Dent Educ1998;62:812-821.2. Williams RC. Periodontal disease. N Engl J Med1990;322:373-382.


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References: 1. Socransky SS, Haffajee AD. Dental biofilms: difficult therapeutic targets. Periodontol 20002002;28:12-55. 2. Cobb CM. Non-surgical pocket therapy: mechanical. Ann Periodontol1996;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 ofresidual calculus. J Peridontol1990;61:3-8.

Scaling and root planing (SRP) has

mechanical limitations

Instrumentation

does not always

reach thefurcation region.

Deep pockets can

restrict access and

create a reservoir

for bacteria.

Even after SRP, the bacteria in biofilmscan remain, multiply, and return to baselinelevels within days1

SRP instrumentation is limited in areas ofrestricted access2,3

In a clinical study, 58% of sites hadresidual calculus after SRP4


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References: 1. Williams RC, Paquette DW, Offenbacher S, et al. Treatment of periodontitis by localadministration of minocycline microspheres: a controlled trial. J Periodontol2001;72:1535-1544. 2.American Academy of Periodontology Research, Science, and Therapy Committee. Guidelines for

periodontal therapy. J Periodontol2001;72:1624-1628. 3. ARESTIN (minocycline hydrochloride) 1 mgMicrospheres [Prescribing Information]. Warminster, PA: OraPharma, Inc., 2005. 4. Data on file.OraPharma, Inc., Warminster, PA; 2004.

Adding an LAA to SRP can benefit patients

Adding a locally administered antibiotic (LAA) to SRP is proven tosignificantly improve periodontal treatment1

The American Academy of Periodontology (AAP) supports the useof LAAs as an adjunct to SRP2

The LAA ARESTIN (minocycline hydrochloride) Microspheres,1 mg can help eliminate the bacteria that SRP can leave behindincluding3,4:

P gingivalis

T denticola

T forsynthensis


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ARESTINMicrospheres technology provides asustained release of minocycline in the

periodontal pocket1

References: 1. Data on file. OraPharma, Inc., Warminster, PA; 2004. 2. ARESTIN (minocyclinehydrochloride) 1 mg Microspheres [Prescribing Information]. Warminster, PA: OraPharma, Inc., 2005.

Baseline

2 Days

10 Days

ARESTINMicrospheresdeliver minocycline directly tothe periodontal pocket and helpmaintain therapeutic drugconcentrations for up to 21days, managing the infection

long after treatment with SRP1

ARESTINMicrospheres arebioadhesive and completelybioresorbed2

ARESTINMicrospheres killthe bacteria SRP leavesbehind, including P gingivalis,T denticola, andT forsynthensis


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Minocycline effectively treats the common

periodontal pathogens1

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. OConnor BC, Newman HN, Wilson M. Susceptibility and resistance of plaque bacteria to minocycline.J Periodontol1990;61:228-233.


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ARESTIN treats the bacterial cause ofperiodontal infection more effectively than

SRP alone1*

Significantly reduced the

quantity of red complexbacteria vs SRP alone(P=0.002)

Reference: 1. Goodson, JM. Antimicrobial Efficacy of Arestin in Periodontitis Therapy. Presented at the35th Annual Meeting of the American Association for Dental Research; March 8-11, 2006; Orlando, FL.

In a recent microbiological study

of patients with moderate-to-severe periodontitis,ARESTIN+ SRP:

*Phase IV, single-blind, randomized, parallel-group study of 127 patients withmoderate-to-severe periodontitis and at least 5 teeth with 5 mm pocket depths.


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ARESTIN treats the bacterial cause ofperiodontal infection more effectively than

SRP alone1*

Significantly reduced

proportions of red complexbacteria vs SRP alone(P=0.0005)

Significantly reduced pocket

depths and bleeding on probing,and increased clinicalattachment levels2

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 ARESTINin patients with periodontitis. Presented at the35th Annual Meeting of the American Association for Dental Research; March 8-11, 2006; Orlando, FL.

In a recent microbiological study

of patients with moderate-to-severe periodontitis,ARESTIN+ SRP:

*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.


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ARESTIN+ SRP is significantly more effectivethan SRP alone in reducing pocket depth1

ARESTIN + SRP demonstrated a greater therapeutic effect than SRP

alone throughout 9 months (P


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ARESTIN+ SRP is significantly more effective

than SRP alone in reducing pocket depth1

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 Periodontol2001;72:1535-1544.

More than 60% of pockets that responded to ARESTIN + SRP had a

reduction of >2 mm1*

*In clinical studies, 37% of pockets treated with SRP alone did not respond to therapy vs29% of pockets treated with ARESTIN+ SRP.1

In 65% of patients, ARESTIN

+ SRP reduced pocket depthfrom >6 mm to 6

mm to


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Smoking may be responsible for more than 1/2 of adult periodontalcases in the US3

Clinical studies show that smokers exhibit increased1,2:

Pocket depth

Alveolar bone loss

Gingival recession

Tooth loss

Clinical attachment loss Number of furcations

References: 1. Kerdvongbundit V, Wikesj UME. Prevalence and severity of periodontal disease atmandibular molar teeth in smokers with regular oral hygiene habits. J Periodontol2002;73:735-740.

2. American Academy of Periodontology Research, Science and Therapy Committee. Tobacco use and theperiodontal patient. J Periodontol1999;70:1419-1427. 3. Tomar SL, Asma S. Smoking-attributableperiodontitis in the United States: findings from NHANES III. J Periodontol 2000;71:743-751.

Smoking is a major risk factor for

periodontal infection1,2

Radiograph showing bone loss insmoker with periodontal disease.


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ARESTIN+ SRP is more effective than SRP alonein reducing pocket depth in smokers with

periodontal disease1

*Subgroup analysis (n=271)1 of the single-blind, Phase III trial comparing ARESTIN+ SRP to SRP alone andSRP + placebo (n=748).2 SRP was performed for all groups at baseline. ARESTINor vehicle wasadministered 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 Periodontol2003;30:787-794. 2. Williams RC, Paquette DW,Offenbacher S, et al. Treatment of periodontitis by local administration of minocycline microspheres: acontrolled trial. J Periodontol2001;72:1535-1544.

Statistically significant pocket depth reduction vs SRP alone1*


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References: 1. Data on file. OraPharma, Inc., Warminster, PA; 2004. 2. American Academy ofPeriodontology Research, Science and Therapy Committee. Tobacco use and the periodontal patient.J Periodontol1999;70:1419-1427.

*Multivariate analysis of the univariate, multicenter Phase III trials of ARESTIN that comparedthe efficacy and safety of ARESTIN+ SRP to SRP + placebo and SRP alone. Odds ratios wereadjusted to allow for the simultaneous effect of influential variables, such as treatment center,smoking status, age, and baseline pocket depths.

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 toexhibit periodontal destruction vs nonsmokers2

Compared to SRP alone, ARESTIN+ SRP is nearly 4x more likelyto reduce periodontal pockets to


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ARESTIN+ SRP has a greater therapeutic effectthan SRP alone* in other difficult-to-treat

patient groups1-3

Based on pocket depth reduction scores at 9 months

*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. Clinicalassessments were conducted at baseline and 1, 3, 6, and 9 months. ARESTINor vehicle was administered to all sites withpocket 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 Med1990;322:373-382. 2. Cobb CM. Non-surgicalpocket therapy: mechanical. Ann Periodontol1996;1:443-490. 3. Fleischer HC, Mellonig JT, Brayer WK, Gray

JL, Barnett JD. Scaling and root planing efficacy in multirooted teeth. J Periodontol1989;60(7):402-409.4. Williams RC, Paquette DW, Offenbacher S, et al. Treatment of periodontitis by local administration ofminocycline microspheres: a controlled trial. J Periodontol2001;72:1535-1544.

Greater therapeuticeffect*


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ARESTIN is easy to administer

The administration of ARESTINdoes not require local anesthesia.Sterilize the handle tip between patients. ARESTINdoes not have tobe removed, as it is bioresorbable. ARESTINdoes not require anadhesive or dressing.

Insert the ARESTIN

cartridge into the handlewhile exerting slight

pressure.

Twist until you feel and

hear the cartridgelock into place.

Should you need to manipulate thecartridge tip to reach difficult-to-access

areas, gently bend the tip, leaving the

blue cap on. Bending the tip afterremoval of the blue cap may cause

the internal plunger to rupture the

cartridge wall.


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ARESTIN is easy to administer

Place the cartridge tip

into the periodontalpocket, 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 fromthe base of the pocket. If

you feel any resistance

during delivery, withdraw thedevice further.

Once delivery is complete,

retract the thumb ring andremove the ARESTIN

cartridge with your free hand.Appropriately discard the

cartridge and sterilize the

handle prior to reuse.


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ARESTINis safe and well tolerated in

clinical trials1

Reference: 1. ARESTIN (minocycline hydrochloride) 1 mg Microspheres [Prescribing Information].Warminster, PA: OraPharma, Inc., 2005.


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Summary

References: 1. American Dental Association. For the dental patient. Women and periodontal disease.J Am Dent Assoc2002;133:671. 2. Blair C. The economic impact of the underdiagnosis of periodontaldisease in general practice. Triage2005;1:21-25. 3. American Dental Association, Survey Center. 1999Survey 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 Academyof Periodontology Research, Science, and Therapy Committee. Diabetes and periodontal diseases.

J Periodontol1999;70: 935-949. 7. Cobb CM. Non-surgical pocket therapy: mechanical. Ann Periodontol1996;1:443-490. 8. Cobb CM. Implementing New Strategies for Treating Periodontal Disease: A SystematicApproach. Symposium. October 2, 2002. Chicago, IL.

Three out of 4 American adults develop periodontal disease,1 yet

this persistent infection often goes untreated2-4

The AAP reports that periodontal bacteria can enter the bloodstream, travel to major organs, begin new infections, and potentially

lead to additional health problems5,6*

SRP instrumentation has mechanical limitations and can leavebacteria behind in the periodontium7,8

*A causal relationship has not been fully established.


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ARESTIN

is a locally administered antibiotic that can help eliminate thebacteria that SRP leaves behind1

ARESTINmaintains therapeutic drug concentrations in the periodontalpocketfor up to 21 days,2 managing the infection long after treatment withSRP

ARESTIN+ SRP has been shown to significantly reduce quantity andproportions of red complex bacteria vs SRP alone3

ARESTIN is significantly more effective than SRP alone in reducing

periodontal pocket depth, even in smokers and difficult-to-treat patients4

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: acontrolled trial. J Periodontol2001;72:1535-1544.

Summary, continued


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ARESTINSafety Information

ARESTIN is indicated as an adjunct to scaling and root planing (SRP)

procedures for reduction of pocket depth in patients with adult periodontitis.ARESTINmay be used as part of a periodontal maintenance program whichincludes good oral hygiene, and scaling and root planing.

ARESTINcontains minocycline, a tetracycline derivative, and therefore

should not be used in children and in pregnant or nursing women. The useof drugs of the tetracycline class during tooth development may causepermanent 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%). Theseoccurred at a similar rate to SRP and SRP + placebo.

Please see accompanying full Prescribing Information.

2006 OraPharma, Inc. A-456-06 12/06ARESTIN is a registered trademark of OraPharma, Inc.

treating the infection

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