PNeumatic Trabeculoplasty(PNT)

An Alternative Approach for the Long An Alternative Approach for the Long Term Management of POAG and OH Term Management of POAG and OH

Patients Patients John W. Sharkey, Ph.D.

President – Ophthalmic International

Management Team G. Richard Smith – CEO Over 25 years in development and

manufacturing of ophthalmic devices and co-inventor of PNT

John W. Sharkey, Ph.D. – President. 20 years experience in global health care industry

Francesco Aspes, M.D. – Head of Europe. 25 yeas experience in global health care industry

Glaucoma World Health Organization found glaucoma to be second leading

cause of blindness worldwide, second only to cataracts

Glaucoma is leading cause of visual field loss in people over age 55, followed by stroke

Approximately 62% of patients discontinue and 18% change their initial glaucoma medication within 18 months of diagnosis

Surgical intervention does not eliminate need for pharmaceutical treatments

Glaucoma is a progressive disease and patients progress to multiple medications and surgery over time

What is Glaucoma? Glaucoma is a group of neurodegenerative eye diseases

The Optic Nerve is damaged

Several forms of glaucoma have associated with them Elevated Intraocular Pressure (IOP)

It is an asymptomatic disease that is significantly under diagnosed

The disease is typically associated with aging and there is no cure

Glaucoma Market Treatments for glaucoma account for almost half of the

present market for ophthalmic pharmaceuticals

Global ophthalmic marketplace is approximately USD $ 4 billion and is expected to grow to USD$ 7 billion by 2009

In excess of 1% of the U.S. population is estimated to have glaucoma

It is estimated that only 50% of U.S. glaucoma patients are diagnosed and therefore eligible for treatment

Market Drivers

Aging population – Incidence of glaucoma increases with age

More aggressive diagnosis – with growing recognition of the long term consequences of untreated glaucoma, several initiatives underway world-wide to improve diagnosis and initiate treatment

Improved Compliance – recognition that poor patient compliance is a major component of poor medical outcomes

What is Ocular Hypertension?

Ocular Hypertension (OH)

Intraocular Pressure (IOP) is elevated but Optic Nerve is normal therefore no visual deterioration

4-10% of the U.S. population over 40 years of age have elevated IOP.

The Ocular Hypertension Treatment Study (OHTS) estimated patients risk at 10% to develop glaucoma within a 5 year period.

Risk can be reduced to 5% with active IOP control

Why OH Is Not Aggressively TreatedMany physicians hesitate medically treating OH since

Most OH patients will not develop glaucoma

Side effect profile for ocular anti-glaucoma medications are not benign and treatment is life-long

Therefore a large number of physicians will monitor and if glaucoma develops will then try to manage

The OH market represents an equally large market for a safe, effective treatment with minimal side effects

Origins of PNT Relationship between corneal thickness and measured IOP has

been known for over 50 years

Several studies have shown that following PRK and LASIK procedures there is a drop on measured IOP which correlates to the amount of material removed

Goldmann H, Schmidt T. Goldmann H, Schmidt T. ÜÜber Applanationstonometrie.ber Applanationstonometrie.Ophthalmologica 1957;134:221–42.Ophthalmologica 1957;134:221–42.

Emara B, Probst LE, Tingey DP, et al. Correlation of intraocular pressure and central corneal thickness in normal myopic eyes and after laser in situ keratomileusis. J

Cataract Refract Surg 1998;24:1320–5.

Relationship Between Pachymetry and IOP

A significant number of patients exhibit a reduction of the IOP after refractive surgery

The explanation most frequently used was that the reduction was a secondary artifact to the change of rigidity of the cornea due to interrupting Bowman membrane

A number of studies proposed that that the reduction of the IOP post-LASIK was a real event and not fully attributable to changes in the thickness of the cornea

What happens to corneal thickness following Lasik and PRK

The study was designed to determine changes in the corneal thickness and IOP following LASIK (25 patients) or PRK (20 patients)

Near-sighted patients between -6.00 and -8.00 diopters. Examinations carried out at 1, 3, 6, 12, 36 months

Exams included– Topography– Corneal pachymetry– Tonometry Hjortdal JO, Moller-Pedersen T, Ivarsen A, Ehlers N.Hjortdal JO, Moller-Pedersen T, Ivarsen A, Ehlers N. Corneal power, Corneal power,

thickness, and stiffness: results of a prospective randomized controlled thickness, and stiffness: results of a prospective randomized controlled trial of PRK and LASIK for myopia. J Cataract Refract Surg. 2005 trial of PRK and LASIK for myopia. J Cataract Refract Surg. 2005

Jan;31(1):21-9Jan;31(1):21-9

Results Near term IOP is lowered more following LASIK versus

PRK even though corneal thickness decreased significantly less in LASIK eyes than in PRK eyes

Long term (3 years) the corneal thickness is the same in two groups but the IOP is significantly lower in LASIK patients

This would support that the difference in IOP following corneal surgery is not a result of changes in corneal thickness

Correlation LASIK-IOP

A study on 8113 consecutive eyes following LASIK Regression analysis demonstrated a reduction of 0.12 mm Hg per

diopter of refractive change which theoretically would be related to changes in corneal thickness

Extrapolation to “zero” diopters shows a reduction of 1.36 mmHg which cannot be related to the change in corneal thickness

Data supports an additional mechanism, independent of corneal thinning, which leads to an IOP reduction

DH Chang, R. Doyle Stulting. Change in Intraocular Pressure Measurements after LASIK. OphthalmologyOphthalmology 112,6,June 2005

Additional Change in IOP

Exact Relationship of Corneal Thickness to IOP is Unknown

It is accepted measurements underestimate IOP with thinner corneas and overestimate IOP with thicker corneas

It is unknown whether the relationship between corneal thickness and IOP in the general population is linear or non-linear across the range of naturally occurring thicknesses

It is unknown whether a cornea thinned by LASIK has the same implications in terms of tonometric artifacts as does a naturally thinned cornea

Samuelson TWSamuelson TW. Refractive surgery in glaucoma. Refractive surgery in glaucoma. Curr Opin Curr Opin Ophthalmol. 2004 Apr;15(2):112-8Ophthalmol. 2004 Apr;15(2):112-8

PNT Procedure

Indications

Patients 18 years of age or older Patients with:

– Primary open angle glaucoma (POAG)– Pigmentary glaucoma (PG)– Glaucoma secondary to pseudoexfoliation of the lens capsule (PXG)– Eyes with moderate ocular hypertension (OHT), defined as any non-

glaucomatous eye with an IOP in the range of 22-25 mm Hg– With or without concomitant medication

Contraindications Chronic iritis/uveitis in either or both eyes History of secondary glaucoma in one or both eyes History of penetrating keratoplasty (corneal transplants), diabetes with

rubeosis iridis, severe cupping (90% to complete; excavation), narrow angles and/or moderate to extensive visual field changes (i.e., only a central island of vision (advanced visual field loss within 10 degrees of central fixation as determined by automated perimetry) in either or both eyes.

Moderate visual field defect Macular degeneration (wet or dry) in either or both eyes Patients who have undergone a surgical trabeculectomy. Prior ATL and SLT

procedures are not considered to be contraindications Patients with keratitis Patients whose angles are not fully open (i.e. narrow angle, atypical angle,

closed angle). Patients with severe dry eye syndrome associated with Fuch's Corneal

Dystrophy Patients with corneal abnormalities or corneal disorders High Myopia defined as myopsis in excess of 6 diopters

The Equipment

A patented 3-port design allows for equal vacuum to be applied throughout the perimeter, essential for achieving consistent IOP reduction

The ring is single use, prepackaged as sterile and ready for use

The ring is connected to a microprocessor controlled vacuum pump which is activated using a unique barcode

PNT ProcedurePNT Procedure topical anesthesiatopical anesthesia

60 sec application60 sec application

5 minutes off5 minutes off

repeat 60 sec applicationrepeat 60 sec application

re-treat at 1 weekre-treat at 1 week

start reduction of meds atstart reduction of meds at3-4 weeks3-4 weeks

re-treat in 3-4 monthsre-treat in 3-4 months

Summary of Clinical Experience

Clinical Trials

Bucci Avalos and LiVecchi Bores Ceruti-Marchini-Marraffa Brogioni-Borgia Dorigo-Bandello-Roman Prigione-Rolando-Calabria Offermann-Augustin

Monotherapy TrialPilot Study to Evaluate Efficacy and Safety of Pneumatic Trabeculoplasty (PNT) in Glaucoma and Ocular Hypertensive

Principle Authors:

Prof. Massimo G. Bucci, M.D.Marco Centofanti, M.D.Francesco Oddone, M.D.Mariacristina Parravano,

M.D.

Prof. Corrado Balacco Gabrieli, M.D.

José Pecori-Giraldi, Ph.D.Aloisa Librando, M.D.Emanuele Paone, M.D.

Leo D. Bores, M.D.

Eur. J. Ophthal., 15(3), 2005 pp 347-352.

Bucci Trial Design Purpose: To independently determine the IOP lowering

effect of PNT Prospective, open-label fellow eye trial in POAG and OH

patients performed in 2 glaucoma centers in Italy Patients on glaucoma medication willing to stop

treatment and undergo adequate washout IOP between 22-28 mm Hg on Day 0 Extensive ocular examinations and safety monitoring Duration of trial 120 days

Mean Change in IOP For In-Study Subjects Italian Monotherapy Trial

% IOP Reduction

Result From Monotherapy Trial 73% (27/37) showed a PNT (pressure lowering) response and

completed studyFour of the 10 dropouts were due to issues not associated with PNT

procedureNo patients withdrew due to intolerability of procedure

A 15% reduction in IOP was achieved by approximately 50% of patients during the study period

No significant adverse events observed. All events resolved without medical intervention

PNT – Combination Therapy and Ability to Reduce Medication

Requirements “Pneumatic Trabeculoplasty

(PNT) – A new method to treat primary open-angle glaucoma (POAG) and reduce the number of concomitant medications”

G. Avalos Urza, M.D.John T. LiVecchi, M.D. Leo Bores, M.D., Ann. Ophthalmol. 2005; 37(1),pp. 37-46.

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Compilation of data from two separate trials involving PNT

Drs. Avalos and LiVecchi – First studies were performed at Dr. Avalos’s clinic to evaluate the potential of PNT to lower IOP in patients on existing medication

Dr. Bores – Study was performed at the Arizona Glaucoma Institute, to evaluate the potential of PNT to reduce medication requirements while maintaining IOP control

Study By Avalos and LiVecchi

Purpose: To test hypothesis that PNT can provide a clinically significant decrease in IOP

177 patients; 320 eyes treatedDuration of trial 6 months

Outcomes in PNT patients were compared to a historical cohort of patients, during the same time period, who were on meds alone

Summary of IOP Results Avalos and LiVecchi

Mean Age 65.3

Mean follow-up (months) 23.5

Pre-Treatment IOP range (mm Hg) 19-36

Post-Treatment IOP range (mmHg) 13-32

Mean Pre-Treatment IOP (mm Hg) 23.4

Mean Post-Treatment IOP (mm Hg) 17.1

Mean IOP Drop (mm Hg) 6.3

Observed Reduction in Medication Avalos and LiVecchi

Medications Study Initiation

Post-PNT(at mean follow-up)

No Medications 8 65

1 Med: [Beta blockers (BB)] 33 34

2 Meds: [BB + pilocarpine (pilo)] 68 33

3 Meds: [BB + pilo + andrenergic (adr)]

24 14

4 Meds: [BB + pilo + adr + diamox]

44 31

# of patients

19 eyes went on to require filtering procedures, 5 of these being those with capsular exfoliation and 1 with recessed angle due to trauma

Comparison of Medication Requirements Avalos/LiVecchi

8

33

68

24

34

0

10

20

30

40

50

60

70

# o

f P

ati

en

ts

No meds b-blocker b-blocker + pilo b-blocker + pilo+ adr

b-blocker + pilo+ adr + diamox

Medications

Medication requirements Prior to PNT

65

34 33

14

31

0

10

20

30

40

50

60

70

# o

f P

ati

en

ts

No meds b-blocker b-blocker + pilo b-blocker + pilo+ adr

b-blocker + pilo+ adr + diamox

Medications

Medication requirements Following PNT

Pre-PNT Post-PNT

Observed Side Effect Avalos and LiVecchi

Side Effects from PNT procedure were generally considered minor, resolved without medical intervention and included

Mild conjunctival edema and injectionSubconjunctival hemorrhageMild discomfort

No serious sight threatening complications and no visual field deterioration or retinal nerve damage were observed (VF analysis)

Arizona Glaucoma Institute

Study was undertaken by Leo D. Bores, M.D., beginning in the fall of 1997

320 eyes (165 patients)Mean follow-up was 14 months (Longest was 24

months)Outcomes compared to a historical cohort of

patients treated during the same period at the same institution

Summary of IOP Results Bores

Patients (N) 144

Mean follow-up (months) 9

Pre-Treatment IOP range (mm Hg) 16-48

Post-Treatment IOP range (mmHg) 15-20

Mean Pre-Treatment IOP (mm Hg) 19.2

Mean Post-Treatment IOP (mm Hg) 15.8

Mean IOP Drop (mm Hg) 3.4

Initial IOP 16 – 48 mm HG

Reduction in Study MedicationBores @ 3 months

Again, a shift towards fewer number of concomitant meds was observed post-PNT

Majority of patients required 0 or 1 medication following PNT to maintain safe IOP

Observations From Results Observed In Avalos/LiVecchi and Bores Studies

PNT can achieve good IOP control with a significant reduction or elimination of concomitant medications

The PNT effect is ‘reproducible’. When IOP drifts upwards in a patient who has responded to PNT a repeat application will again reduce the IOP

No safety issues were observed which would prevent using PNT in the glaucoma or ocular hypertension patient

Efficacy of Pneumatic Trabeculoplasty in Primary Open Angle Glaucoma

Dr. P. Ceruti, et.al., Department of Neurological and Visual Sciences, University of Verona, Verona, Italy

Presented – 2006 Annual Meeting of the Association for Research in Vision and Ophthalmology (ARVO)

The Study – Prospective 14 patient study, 120 days in duration, to determine the IOP lowering effect of PNT in patients not adequately controlled on anti-glaucoma medication. All patients received comprehensive ophthalmic monitoring, including Ultrasound Biomicroscopy examinations. Starting IOP was 22 ± 1.8 mm Hg

Results: A statistically significant reduction of greater than -15%, with a maximum -21% on day 8, was observed for the entire study. UBM analysis supports the apparent mechanism of action being the restoration of trabecular outflow.

UBM

Examinations performed pre and post PNT

– ACD (Anterior Chamber Depth)

– SCPA (Scleral Ciliary Process Angle)

– CBT (Ciliary Body Thickness)

UBM Parameters

SCPASCPA

1000

UBM Results

ACD and SCPA: No significant variation pre and post PNT

ACD

SCPA

Results of UBM

Reduction in Ciliary Body Thickness (CBT) following PNT (p<0.05) a 1000 µm from the scleral spur

2500 2000 1500 1000 2500 2000 1500 1000

sperone sclerale

sperone sclerale

Results

Increase in uveoscleral reflectivity following PNT

Efficacy of Pneumatic Trabeculoplasty in Primary Open Angle Glaucoma

Brogioni, C. et. al., Dip.di Medicina e Scienze dell’Invecchiamento Università di Chieti

Published – Boll. Ocul, 85 (3), 2006, pg 253-256

The Study – Prospective 20 patient study, 120 days in duration, to determine the IOP lowering effect of PNT in patients not adequately controlled on prostaglandins (10) or beta-blockers (10). All patients received comprehensive ophthalmic monitoring, including Ultrasound Biomicroscopy examinations. Starting IOP was 22 ± 1.8 mm Hg

Results: 17% drop in IOP observed for both groups. 33% reduction in “oscillations” from 3.6 +/- 0.62 to 2.4 +/- 0.5 mm Hg. UBM results consistent with those of Ceruti et. al.

Change in Angle following PNT

Change in Mean IOP

Dorigo-Bandello-Roman (part of multicenter trial )

Università di Padova

Primary objective: To verify the reduction in IOP Secondary objective: to determine impact on Central

Vision, RNFL and C/D ratio PNT Treatments on days 0 and 7. Additional visits on 1,

8, 14, 30, 60, 90 and 120 10 patients with POAG Follow up 12 months for final pathology

Results Mean IOP reduction: 4.0 mmHg Mean % Reduction: 20%

05

10152025

0 1 7 8 14 30 60 90 120

Mean post-treatment IOP

V ISUAL FIELDpre-PNT and post-PNT

-6.78 -6.41

6.38 6.08

-8

-6

-4

-2

0

2

4

6

8

dB

mean MD mean PSD

PRE-PNT POST-PNT4 months

OCT Results Mean Cup / Disk

0.45

0.44

0.434

0.436

0.438

0.44

0.442

0.444

0.446

0.448

0.45

0.452

pre-PNT post-PNT

Mean RNFL (Retinal Nerve Fiber Layer)

67.72

67.96

67.6

67.65

67.7

67.75

67.8

67.85

67.9

67.95

68

pre-PNT post-PNT

micronp=ns

Evaluation of Pneumatic Trabeculoplasty (PNT) on Intraocular Pressure with Different Treatment Sequences in Primary Open Angle Glaucoma

A. Librando, E. Pacella, A. Gabrielli, S. D’Angelo, S. De Gaetano, J. Percori Giraldi

Published: Boll Ocul 85(4) 2006 pgs 279 – 288

The Study: Thirty eyes suffering from Primary open-angle Glaucoma and Ocular Hypertension (IOP between 20-25 mm Hg) were treated by means of a sequence of three treatments of PNT. All patients IOP’s were under control with on Day 7 with monotherapy (either beta-blockers, carbonic anhydrase inhibitors or prostaglandins)

Results: A further reduction in IOP (maximum of 18%) was obtained following PNT (days 0, 7,30). No significant undesirable side-effects were observed, except for a moderate conjunctival hyperemia, which disappeared within 2-3 days. A prolong duration of the effect was demonstrated (16.5% @ Day 150, 9.3% @ Day 180)

Safety and Efficacy of Pneumatic Trabeculoplasty in African population

Dr. Guido Prigione, et. al.; Clinica Oculistica, Department of Neurological Sciences, Ophthalmology, Genetic, University of Genoa, Italy

Presented – 2006 Annual Meeting of the Association for Research in Vision and Ophthalmology (ARVO)

The Study – A study, carried out in Ghana, involving 82 glaucomatous eyes were consecutively included in this study. All the eyes were diagnosed primary open angle glaucoma. The mean pre-PNT IOP was 25.71 + 5.02 mmHg.

Results - Following 2-PNT treatments, a week apart, the IOP was reduced by 3.89 mm Hg (-15.13%). 87.7% response rate. No significant side-effects were found, except for 16 cases (19.51%) of subconjunctival haemorrhages which resolved without medical intervention

Results

Effect of PNT on IOP in Patients Suffering From Primary Open Angle Glaucoma.

Drs. Indre Offermann and Albert Augustin; Department of Ophthalmology, Klinikum Karlsruhe, Karlsruhe, Germany

Presented at the 2006 German Ophthalmic Surgeons (DOC) Meeting, Nuremburg, Germany

The Study: 20 patients with POAG who were poorly controlled with Latanoprost. Baseline intraocular pressure (IOP) ranged between 18 to 24 mmHg. 20 eyes were treated with PNT at day 0, 7 and 90, 180 (treatment group). Comprehensive visual assessments were performed 1 day, 1 month and 3 month after treatment

Results: Treatment group mean IOP at baseline was 20.15 mmHg and was reduced to 16.5 mm Hg at Day 120 (-3.65 mm Hg; -18.1%). They concluded that PNT seems to be a safe and effective treatment to decrease IOP in patients suffering from POAG.

Results

Mean reduction in IOP of Mean reduction in IOP of 3.653.65 mmHg (-18.1%, mmHg (-18.1%, p<0.01)p<0.01)

Mechanism of Action

The Problem is the Trabecular Meshwork

Most of the resistance to the flow occurs in the juxtacanalicular trabecular meshwork and the

inner wall of Schlemm's canal

Outflow ResistanceExcessive accumulation of extracellular

matrix material in the woven juxtacanalicular trabecular meshwork is the suspected cause for increased resistance to outflow in the eyes with

POAG

Dorigo 2006

Gentle “Stretching" of the Trabecular Meshwork Helps Eliminate Excessive Matrix Extracellular Material, Improve

Outflow and Reduce IOP

Why PNT? Broad Efficacy– Approximately 80% of POAG patients will

exhibit a lowering of their IOP following the PNT procedure Duration – The reduction in IOP usually last, on average, 3-

4 months Reproducibility – Responders typically respond in a similar

fashion with follow up PNT treatments Improved Compliance – For the non-compliant patients,

has the potential to offer some long term IOP reduction Medication Reduction – PNT reduces, and often

eliminates, the number of medications necessary for IOP control

Delay Initiation of Medication – PNT has the potential to postpone the introduction of IOP lowering medication

MOA appears to be physiological restoration of trabecular outflow

Intellectual Property Patents have been granted,

covering both the equipment and procedure– US #5,601,548

Issued Feb.11, 1997– EP #0 790 803 B1 Issued

Feb.19, 2003coverage in Japan, China, etc has

also been obtained Additional patents are being

pursued

Current Status Device is registered as a 2a medical device within the

European Economic Community (EEC) Sales, Marketing and Distribution agreements covering

Italy, Spain, Portugal, France and Poland are in place Advanced discussions covering distribution in

additional territories within the EEC Exclusive Sales, Marketing and Distribution agreement

in place covering the Peoples Republic of China

Strategy Going Forward

– Leverage additional device registrations using our CE mark as the basis for accelerated approvals

– Continue forward with U.S. registration activities– Where feasible, utilize government reimbursement

mechanism to gain access to government hospitals/clinics– Continued KOL development via our and our distributors

sponsoring several smaller trials in multiple countries– Initiate a 1-year, prospective, multi-center trial of PNT

versus additional medical intervention in a well defined group of early POAG patients

Thank you for your attention