A New Drug to Treat Myopia

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A New Drug to Treat Myopia

• R. Michael Siatkowski, MD
• Professor of Ophthalmology
• Dean A. McGee Eye Institute
• University of Oklahoma
• Oklahoma City, OK

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Disclosure

• I served as a consultant to Valley Forge
  Pharmaceuticals from 2001-2005.

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A Global Disease80M Children Suffer from Myopia
Europe 9.6Mil
U.S. 7.1Mil
Asia 57.6Mil
Latin America 5.7Mil
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Prevalence of Adult Myopiaby Country
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Earlier Onset Leads to Higher Levels of Myopia
Source Mäntyjärvi et al (1985) J Ped Oph Strab
22(2)71-75.
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Why Treat (Prevent) Myopia?

• Medical issues
• retinal detachment
• myopic retinal degeneration
• glaucoma
• Quality of life issues
• school
• athletics
• convenience

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Myopic Retinopathy Increases with Higher Myopia

• Source Vongphanet et al. (2002) Ophthalmol
  109704-711

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Retinal Detachment Risk is Elevated with Low and
Moderate Myopia
Source Eye Disease Case-Control Study Group
(1993) Am J Epidem 137749-757.
Ogawa and Tanaka (1998) Jpn J Ophthalmol
32310-315.
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Prior Studies

• Optical treatments
• Contact lenses
• Bifocal lenses with lines
• Progressive addition bifocals (no lines)
• NOT EFFECTIVE
• Pharmacologic agents
• Only Atropine shown to be effective

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Complications of Atropine

• Cycloplegia (blurred vision)
• Pupillary dilation (photophobia)
• Retinal/lens phototoxicity
• Poor compliance

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Pirenzepine (PIR)

• Atropine-like drug
• Works on M1 and M3 receptors like atropine
• More selective for M1 receptors than atropine
• 15X less sensitive for M3 receptors than atropine
• Less mydriasis (pupil dilation)
• Less cycloplegia (blurred vision)

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Pirenzepine

• Used in Europe for peptic ulcer disease since
  1977
• 400 million patient-days experience
• Good safety profile, including in children
• Use declined after H2-antagonists
  introduced--never marketed in US
• Shown by Stone et al to decrease myopia in chicks

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Phase II US Trial

• 8-12 years of age
• -0.75 to -4.00 D myopia
• Randomized 21 PIRPLACEBO
• n174
• 2-year data for n84
• No bifocals allowed

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U.S. 2-Year Cohort Demographic and Baseline
Characteristics
PIR 205 - A
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Phase II Clinical ProgramU.S. Year 2 Results
Spherical Equivalent Change from
Baseline Siatkowski et al, Journal of AAPOS
12232, 2008

.
.26
Plt 0.001
.58
p.008
.53
.99
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Cycloplegic autorefraction Proportion of
patients with criterion progression at 12
months Siatkowski et al, Arch Ophthalmol
1221667, 2004
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Phase II Clinical ProgramU.S. Year 2
ResultsProportion of Patients with Progression
at 2 YearsSiatkowski et al, Journal of AAPOS
12232, 2008
68
43
37
22
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Adverse Events

• Ocular
• 4 dropout from dilation or decreased near vision
  in PIR group in year one
• 2 dropout in year two
• 0 in PLACEBO group
• Mean pupillary dilation at 60 min
• Atropine pupils fixed and dilated at 7 mm
• PIR 1.5 mm
• PLACEBO 0.2 mm
• p lt 0.001
• Pupils remain reactive

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Pirenzepine Ophthalmic Gel Effects Are Confined
to the Eye

• Plasma levels lt 1 ng/ml with pirenzepine solution
  applied topically
• No systemic side effects
• Phase II dosing continued up to four years with
  pirenzepine ophthalmic gel in children.

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Asian PIR study

• Tan et al, Ophthalmology 11284, 2005
• One year effects similar to US
• 2 year effect not yet published but continues as
  in US data

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Two Times (2X) Treatment Effect Seen in Sub-group

• Children lt 9 years old
• Greater than 2.2 D myopia

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Summary

• PIRENZEPINE 2 gel significantly retards
  pediatric myopic progression over 2 years
• acceptable safety profile
• contrary to accommodative pathogenesis of myopia
• retina, sclera possible sites

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Future questions

• Best age to initiate treatment?
• Best refractive error to initiate treatment?
• How long to treat?
• Is there a rebound effect when stopped?
• Other delivery systems
• Sustained release agents in contact lenses?