25% population has poor night vision. Nyxsol allows treatment.

1. Ocularis Pharma – Kalbe Vision
Discussion
August 21, 2008

2. Agenda
● Introduction
● Kalbe Group and Kalbe Vision company profile
● Ocularis Pharmaceuticals company profile
● Discussion on Nyxol eye drops
● Clinical study results
● Licensing arrangements
● Action plan

3. Introduction 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.

4. Epidemiology 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

5. HOA 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 a
regular lattice of image points and the wave front is planar or regular.
●RIGHT: Eye with aberrations since the CCD image is made up of an
irregular 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

6. HOA Classification: Zernicke Polynomials
1st & 2nd L to R :
order Myopia,
aberration Hyperopia,
Astigmatism
3rd order
aberration
4th order
aberration
and so on
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: www.grendahl.com

7. Higher-Order Aberration
Radial
Common Names7
Order, n
Piston
0
Tilt
1
Astigmatism (m=-2,2),
2
Defocus(m=0)
3 Coma (m=-1,1),
Trefoil(m=-3,3)
4 Spherical Aberration
(m=0)
Secondary Coma
5 (m=-1,1)
Secondary Spherical
6 Aberration (m=0)
Source: www.scien.stanford.edu

8. HOA 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.

9. Current 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

10. New Concept:
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 of
the 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

11. Innervation of 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

12. Alpha 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.

13. Alkylating Agents & α-Blocker
Properties
● 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

14. Nyxol™ from Ocularis Pharma
● Nyxol contains a mixture of:
● Phentolamine (imidazoline derivative)
● Phenoxybenzamine
● Tetrahydrozoline HCl
● Because phentolamine is a non-seletive α-
blocker, it causes conjunctival & scleral
vasodilation.
● Tetrahydrozoline is used to counteract such side
effect, as it is commonly used to treat redness in
the eye.

15. Autonomic Nervous System: α-Blockers
Source: Titcomb, Lucy C. Revision of pharmacology. Optometry Times, Jan 2002

16. Patents on α-Antagonist
● 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 alkylating
agent (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

17. Clinical 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 NVC
Parameter used to measure severity of NVC?

18. Antihistamine Effect of Imidazolines
Inhibit mast cell
degranulation
Inhibit prostaglandin
formation
Hinders pupillary constriction ??
Source: Titcomb, Lucy C. Revision of pharmacology. Optometry Times, Jan 2002

19. Discussion
● 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

20. Thank you…