OcularisOcularis PharmaPharma –– Kalbe Vision Kalbe Vision DiscussionDiscussion

August 21, 2008August 21, 2008

AgendaAgenda

● Introduction● Kalbe Group and Kalbe Vision company profile●Ocularis Pharmaceuticals company profile

● Discussion on Nyxol eye drops● Clinical study results● Licensing arrangements

● Action plan

Introduction on Refractive ErrorsIntroduction on Refractive Errors

● ‘Lower’ order aberration● Myopia, hyperopia, astigmatism

● Can be corrected with spectacles / contact lenses / standard refractive surgery

● ‘Higher’ order aberration● Subtle aberration in refraction caused by minute

optical abnormalities in the peripheral cornea.

● Causes annoying effects: glare, halo, light sensitivity, image distortion.

Epidemiology of HOAEpidemiology of HOA● HOA is in origin caused by:

● Genetic● Contact lens use related● LASIK related

● In their website, Ocularis Pharma stated that the prevalence rate of HOA in the US population is 50%.

● Ocularis survey in March ’08● 35 optometrists in Milwaukee, USA● >25% of patients have night vision complaints

● “Shedding Light on Driving in the Dark” – Sept ‘07● 515-subject study● 20% of vision-corrected Americans have difficulty driving in the

dark

HOA ExaminationHOA Examination

Higher order aberration is examined by wavefront technology; analyzing waves of light as they are reflected from inside of the eye to the outside.●LEFT: Eye with no aberration since the CCD image is made up of aregular lattice of image points and the wave front is planar or regular. ●RIGHT: Eye with aberrations since the CCD image is made up of anirregular lattice of image points and the wave front is irregular. Note that the irregular lattice of image points is round. This is due to the round pupil.

Source: www.grendahl.com

HOA Classification: HOA Classification: ZernickeZernicke PolynomialsPolynomials

1st & 2nd

order aberration

3rd order aberration

4th order aberration and so on

L to R : Myopia, Hyperopia, Astigmatism

Note: Cold colors (blue) represent photons that lag or are slowed up from a longer path length or more tissue to travel through. Hot colors (red) represent photons that are advanced or are sped up from a shorter path length or less tissue to travel through.

Source: Source: www.grendahl.comwww.grendahl.com

HigherHigher--Order AberrationOrder AberrationRadial

Order, n

0

1

2

3

4

5

6

Common Names7

Piston

Tilt

Astigmatism (m=-2,2), Defocus(m=0)

Coma (m=-1,1), Trefoil(m=-3,3)

Spherical Aberration (m=0)

Secondary Coma(m=-1,1)

Secondary Spherical Aberration (m=0)

Source: www.scien.stanford.edu

HOA ClassificationHOA Classification

● HOA types that are clinically relevant are 3rd and 4th order aberrations: coma, trefoil, and spherical aberration.

● The higher the order of aberration, the less it contributes to image degradation in a normal eye. ● Above the 4th order, aberrations have more

mathematical than clinical meaning.

Current Therapy for HOACurrent Therapy for HOA● Spectacles

● Essilor Varilux 360°™ Spectacle Lenses (Essilor)● Essilor adapted wavefront technology to correct vision by detecting and

eliminating surface distortions to perfect progressive lenses. ● Claims to provide a 30% improvement in contrast sensitivity.

● iZon™ Spectacle Lenses (Ophthonix)● Customized spectacle lenses to the wearer’s eyes by using wavefront

aberrometry● Contact lenses

● Acuvue Contact Lenses (Vistakon/Johnson & Johnson)● Sponsored the Shedding Light in Driving in The Dark study

● PureVision™ Contact Lenses (Bausch & Lomb)● Conducted an on-line survey of 74,086 subjects that were given PureVision,

an aspheric CL to reduce spherical aberration● Improvements in night vision: >90% of recipients

● WaveTouch™ Contact Lenses (WaveTouch Technologies)● Individualized CL suited to patient’s wavefront aberrometry readings● Designed to correct HOA and improve night vision

● Wavefront-guided LASIK

New Concept:New Concept:Pupil Size in Dim Lighting Pupil Size in Dim Lighting

● Because the optical imperfection lies in the peripheral area of the cornea, when the pupil enlarges (as in dim light) the HOA becomes more prominent as more light enters the eye through the edges ofthe cornea.

● Pupil size varies in its diameter in darkness between individuals from 3 mm to 9 mm. ● 3mm pupils are large enough to allow sufficient light to enter the eye in

scotopic situations.● Those with wide pupils (>6mm) suffer more from light scatter, glare,

halo, and related aberrant focus on light rays.● By reducing the size of the pupil enlargement in dim light, the

incidence of HOA symptoms can be decreased

InnervationInnervation of Iris Musclesof Iris Muscles● The muscles responsible for pupil size are:

● Mm. sphincter pupillae – constrict the pupil (miosis)● Mm. dilator pupillae – dilates the pupil (mydriasis)

● To achieve reducing pupil size in dim light, the muscle to retard is pupil dilator muscles. The pupil dilator muscle is controlled by sympathetic autonomic nervous system via adrenergic receptors.

● There are 2 types adrenergic receptor on the iris:● Alpha 1 activation: 1a – controls pupillary dilation; 1b – constriction of

conjunctival / scleral vessels● Alpha 2 activation: suppressing sympathetic output, increasing vagal

tone, facilitating platelet aggregation, inhibiting the release of norepinephrine and regulating metabolic effects

Alpha Adrenergic BlockersAlpha Adrenergic Blockers● Because dilator pupil muscles are controlled by the

activation of alpha-1 adrenergic receptors, instillation of an alpha-1 adrenergic antagonist (α-1 blocker) could inhibit excessive dilation of the pupil.

● Adverse reaction of α-1 blocker is dilation of blood vessels, appearing as redness in the eye.

● Instillation of an α-2 blocker does not have any effect on the pupil size.

AlkylatingAlkylating Agents & Agents & αα--Blocker Blocker PropertiesProperties

● Chemical classes of α-blocker are occupied by 3 types of alkylating agents:● Indoles – is an α-2 blocker, have no clinical benefit in optimizing

pupil size.● Piperazinyl quinazolines – α-1 blockers; have significant effect

on pupil diameter, but not clinically effective because of its short duration.● Exp: prazosine, dapiprazole

● Imidazolines – non-selective α-blockers; have lower potency to inhibit pupil dilation, but in clinical practice the effect is enhanced by other properties, such as blocking receptors for serotonin, histamine, and K+ channel.● Exp: phentolamine, phenoxybenzamine

NyxolNyxol™™ from from OcularisOcularis PharmaPharma

● Nyxol contains a mixture of:● Phentolamine (imidazoline derivative)● Phenoxybenzamine● Tetrahydrozoline HCl

● Because phentolamine is a non-seletive α-blocker, it causes conjunctival & scleralvasodilation.

● Tetrahydrozoline is used to counteract such side effect, as it is commonly used to treat redness in the eye.

Autonomic Nervous System: Autonomic Nervous System: αα--BBlockerslockers

Source: Titcomb, Lucy C. Revision of pharmacology. Optometry Times, Jan 2002

Patents on Patents on αα--AntagonistAntagonist● Patent no.: 6,291,498 (published Sept 15, 2000)

● Title: Method for optimizing pupil size using alpha antagonist● Claim: reducing the diameter of the pupil using an imidazoline compound

(phentolamine)● Patent no.: 6,420,407 (published Nov 8, 2000)

● Title: Ophthalmic formulation which modulates dilation● Claim: controlling perceived light scattering with an imidazoline compound

(phentolamine) by reducing the pupil diameter in dim light● Patent no.: 6,515,006 (published Jun 7, 2002)

● Title: Ophthalmic formulation which modulates dilation● Claim: improving scotopic vision by administering an amount of α-antagonist

(phentolamine) to inhibit pupil dilation and reduce scattered light perceived by the eye, and tetrahydrozoline to reduce eye redness

● Patent no.: 6,730,065 (published May 4, 2004)● Title: Night vision composition● Claim: subjecting the eye of a patient to refractive surgery and administering a

formulation comprising an imidazoline (phentolamine) and an alkylatingagent (phenoxybenzamine) that is capable of contracting then pupil so it is twice the size or less in dim light as compared to its size in bright light.

Source: http://patft.uspto.gov

Clinical Trials CompletedClinical Trials Completed● Night Optic and Vision Assessment (NOVA) Study

● N = 100● Conclusion: reducing pupil size improves dim light visual acuity in

four patient groups (night myopia, post-refractive surgery, high myopia, CL wearer)

● Phase 1● N = 77● Conclusion: Nyxol Eye Drops are well tolerated by the eye, inhibit

pupil dilation, improve low contrast visual acuity.● Phase 2

● N = 24● Demonstrated efficacy of Nyxol Eye Drops in treating subjects

with moderate to severe NVCParameter used to measure severity of NVC?

Antihistamine Effect of Antihistamine Effect of ImidazolinesImidazolines

Inhibit mast cell degranulation

Inhibit prostaglandin formation

Hinders pupillary constriction ??

Source: Titcomb, Lucy C. Revision of pharmacology. Optometry Times, Jan 2002

DiscussionDiscussion● Pharmacological background

● The previous patent used phentolamine only as α-1 blocker. In what factor is the combination of phentolamine and phenoxybenzamine more superior?

● Phentolamine: blocking receptors for serotonin, histamine, K+

channel → Mechanism of action to inhibiting pupil dilation?● Clinical background

● Grading of NVC severity → literature?● Clinical trial result (especially phase III)?● Nyxol only targets spherical aberration, is it highest prevalence

among other HOA?● Manufacturing site in relation to dosage form● Business model● Licensing arrangements

Thank youThank you……