From Idea to Medicine

Sandy Lai, Ph.D.

Allgenesis Biotherapeutics
April 8th 2021
 Eye See You
 Introduction of Human Eye’s Structure and Function

 Considerations for Ocular Drug Development

 Ocular vs. Systemic drugs

 Beyond the Disease… Beyond the Imagination

 Summary

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 Tear Film

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 Normal Tear Film Disrupted Tear Film

Oil
Water
Mucin

Dry Eye Signs and Symptoms

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 Age-related
Macular
Degeneration

Glaucoma

Diabetic
Eye

Nerve
damage

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https://www.sunshineoptometry.com/news/2019/7/17/17-eye-diseases-through-anothers-perspective
 UNMET MEDICAL
NEED

Anterior Segment Posterior Segment

(front of eye) (back of eye)
1. Dry Eye Disease (DED) 1. Diabetic Macular Edema
2. Pterygium (DME)
3. Glaucoma 2. Wet Age-related Macular
4. Neovascular Glaucoma Degeneration (wetAMD)
5. Uveitis 3. Non-proliferative &
6. Ocular Surface proliferative diabetic
Angiogenesis retinopathy
7. Allergic conjunctivitis, 4. Retinal Vein Occlusion
8. Blepharitis, etc. 5. Angioid Streaks
6. Dry Age-related Macular
Degeneration (dry AMD), etc.

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Who we are: Allgenesis Biotherapeutics
• Seasoned ophthalmology experts from global pharma
• Develop novel treatments for unmet medical needs in
ophthalmology
• Advance THREE ophthalmology assets for 5+ indications

1. Retinal Program: First-in-class bi-specific molecule with anti-angiogenic, anti-

inflammation, and anti-fibrotic activity, with potential to be used as first-line
treatment for retinal diseases.

2. Dry Eye: In-licensed from (now AbbVie), a novel, first-in-class FPR

agonist to reduce inflammation via resolution pathway that is non-steroidal and
non-immunosuppressive

3. Pterygium: First novel therapeutic for pterygium. Phase 2a completed which

identified an efficacious dose that was safe and tolerable to proceed to Phase 2b/3.
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 WIP = work in process

Confidential Nature Reviews Drug Discovery 9, 203-214 (March 2010) | doi:10.1038/nrd3078 11

How to improve R&D productivity: the pharmaceutical industry's grand challenge
 Pre- Clinical
Clinical Development Regulatory
Discovery Market
Research I II III Evaluation

Monetize assets by out-licensing/co-development

after Phase 2 or IPO

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 Where is the target site?
Administration route?
 Pharmacodynamics: Primary &
Secondary
 Pharmacokinetics: Adsorption,
Distribution, Metabolism,
Excretion
 Toxicology: Local & Systemic
 CMC: API & formulation
 Clinical: Patient population and
endpoint designs
Image from Bachu R. et al. (2018). Ocular Drug Delivery Barriers—Role of
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Nanocarriers in the Treatment of Anterior Segment Ocular Diseases. Pharmaceutics
10(1):28.
 Understand the pathology
 Is the disease model correlated to the MoA of test drug?
 Is the endpoint to be tested suitable for the disease model?
 Can the clinical endpoints be assessable in animal models?

 Select the species (anatomical and target similarity)

 Does the drug demonstrate the effect on the target in the test
species?
 How similar is the ocular structure

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 Rat Rabbit Dog Cynomolgus Human
Monkey
Aqueous 16 300 770 106 240
humor volume
(μL)
Lens thickness 3.9 7.9 7.8 3 4.5
(mm)
Vitreous humor 50 1200 1700 2000 4000
volume (μL)
Corneal 4.5 10 17 10 11.5
diameter (mm)
Corneal 0.25 360 640 460 600
thickness (μm)
Axial length 6 16 21 18 24
(mm)
IOP (mmHg) 12-22 20-30 14-24 12-30 10-20

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Confidential Information adapted from RxGen
 Retina
Topical Dosing Choroid
Ciliary body
(35 μL/drop)
Aqueous humor Iris

5%
into the
95% Lost eye
Nasolacrimal Drainage:
topical dosed solution is
drained from conjunctiva sac in Vitreous
Cornea
15-30 sec
(100x faster than absorption) Cornea

Tear turnover: restore normal Optic nerve

tear volume 2-3 min after Conjunctiva
Conjunctiva
topical dosing

Other factors (blinking) Sclera

Drug absorption after topical dosing
Drug cleared after absorption via anterior chamber, uvea, or posterior route, etc.
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* Reflex blinking, Metabolism, Protein binding, Tear film barrier, corneal barrier
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Ophthalmol J 2016; Vol. 1, No. 1, 29–35
 Over 70% of prescribed ocular drugs are conventional formulations

Liposome or
Solution Suspension Emulsion Ointment, Gel micelle etc,
Pros Provide high Longer retention Improved Longer retention Compatible with
peak time as the solubility time hydro-phobic or -
concentrations particles can philic drugs,
retain in cul-de- Increased
sac (~10-20 μL) penetration

Cons Rapid clear Slow dissolution Slow dissolution Slow dissolution High barrier of
rate; irritation rate; discomfort rate; discomfort manufacturing
and regulatory

Nanosuspension:
Has potential to maintain the
penetration1/retention-time2 balance
compared to solution and suspension 1. Dependent on amount of dissolved drug. Dissolution rate of nanoparticle > microparticle
2. Depot effect leading to sustained release. Large particles can lead to irritation
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1. Phase I metabolism: Cytochrome P-450-dependent metabolism in ocular tissues
Enzyme
7-Ethoxyresorufin-O-dealkylase
(EROD)
7-Pentoxyresorufin-O-dealkylase
(PROD)
7-Ethoxycoumarin O-deethylase
(ECOD)
Aryl hydrocarbon hydroxylase (AHH)
Substrate Ocular Tissue
7-Ethoxyresorufin Porcine ciliary body, and bovine ciliary body
7-Pentoxyresorufin Porcine ciliary body, and bovine ciliary body
7-Ethoxycoumarin Bovine corneal epithelium, retinal pigment epithelium, retina, ciliary body and
corneal epithelium
Benzo(a)pyrene Bovine retina, cornea, iris, choroid, ciliary body; Bovine retinal pigment epithelium,
corneal endothelium; Mouse eye; Chick embryo retinal pigmented epithelium

Benzphetamine demethylase
(BPDM)
Prostaglandin hydroxylase
Cyclooxygenase
Benzphetamine Bovine retinal pigment epithelium, and ciliary body
Prostaglandin Porcine iris, ciliary body
Arachidonic acid Bovine and rabbit corneal epithelium; Bovine corneal epithelium, ciliary body and
corneal endothelium

2. Phase II metabolism: Various eye tissues are capable of Phase II conjugation activity.
• Iris/ciliary body had the highest glutathione S-transferase activity
• Cornea exhibited the highest specific activities for N-acetyl-, sulfo-, and UDP-glucuronosyl-transferases.
Molecules. 2007 Mar; 12(3): 373–388.
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 Evaluate the toxicity after administration via the clinical
route
 Local tolerability and toxicity
 Systemic toxicity

 Evaluate the toxicity after administration via the systemic

route
 Systemic toxicity
 Developmental and Reproductive Toxicology

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 API Solubility: Formulation design
 Sterility: Hurdle of manufacturing sterile product
 Terminal sterilization, aseptic process

 Low dose: Challenge of accuracy on the manufacturing and analytical

methods
 Stability: Compound’s physical and chemical stability in aqueous
formulation for long shelf-life at room temp
 Preservative: Consideration for long-term use
 Single-use packaging, multidose preservative-free bottle

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 Patient population: inclusion and exclusion criteria
 Tolerability of the compound and formulation
 Redness, tearing, stinging, irritation, undesired taste, etc.

 Follow-up on patient compliance

 Self-dose correctly?
 Compliance

 Endpoint assessments can be challenging

 PI’ experiences and techniques to conduct specific ocular exams
 Sufficient training is necessary and instruments are often needed.
 Require well-established scoring systems for the disease signs (hyperemia
images, gland function, staining, etc.).
 Require well-established questionnaires for patient-reported outcomes for
symptom relief.

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• Prostaglandin analougues, first-line
treatment for glaucoma
• Produce IOP to a greater extent
• Provide good control over IOP
fluctuations
• Produce few systemic adverse
events
• Side effect: hyperemia, iris
pigmentation changes, and eyelash
growth

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 New drug development is never easy, requiring a multi-disciplinary
project team of experienced experts.
 Ocular drug development is a unique field in terms of targets,
endpoints, administration routes, tissue barriers & pharmacokinetics,
formulation challenges and local toxicity issues.
 The global ophthalmic drugs market size is expected to reach
USD 60 billion by 2028, making the ocular drug development from a
niche area to a major field.
 With more experts entering this field, we are hoping to bring novel
treatments for unmet medical needs in ophthalmology very soon.

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