The world is advancing and so are we ! Then why not learn about recent advances in drug therapy of degenerative eye diseases Remember our eyes can too be subjected to these degenerative diseases once we get old, hence let's learn about the new treatment modalities right here, right now ! Hope this helps !

1. By Dr. Nishtha Khatri
Guide: Dr. Raakhi Tripathi
Recent advances in drug therapy of
degenerative diseases of the eye

2. Outline of the seminar

3. Degenerative diseases of the eye: Classification
Conjunctiva1: Pinguecula
Pterygium
Cornea1: Keratoconus
Lens1: Cataract
Retina2: Age-related Macular Degeneration
Diabetic Retinopathy
Retinitis pigmentosa
Optic Nerve2: Glaucoma
1. Eye disorders. 2019 [Last accessed on 2nd June 2019]. Available from : https://www.britannica.com/science/eye-disease
2. Schmidt KG, Bergert H, Funk RH. Neurodegenerative diseases of the retina and potential for protection and recovery. Curr
Neuropharmacol. 2008 Jun;6(2):164-78.

4. Glaucoma

5. Definition and prevalence
Glaucoma is characterized by progressive loss of retinal
nerve fiber layer tissue and visual field loss. The optic nerve
acquires a characteristic loss of the neuroretinal rim,
frequently referred to as “cupping.”1
The global prevalence of glaucoma for population aged 40–80
years is 3.54%2
In India, the estimated number of cases of glaucoma is 12
million, around one fifth of the global burden of glaucoma3
1. Brunton L, Hilal-Dandan R, Knollmann B. Goodman and Gilman's The pharmacological basics of therapeutics. 13th ed. New York: Mcgraw-Hill; 2018.
2. Tham YC, Li X, Wong TY, Quigley HA, Aung T, Cheng CY. Global prevalence of glaucoma and projections of glaucoma burden through 2040: a systematic
review and meta-analysis. Ophthalmology. 2014 Nov;121(11):2081-90
3. Saxena R, Singh D, Vashist P. Glaucoma: An emerging peril. Indian journal of community medicine: official publication of Indian Association of
Preventive & Social Medicine. 2013 Jul;38(3):135.

6. Pathophysiology
Although the pathogenesis of glaucoma is not fully understood, the level of
intraocular pressure is related to retinal ganglion cell death
Weinreb RN, Aung T, Medeiros FA. The pathophysiology and treatment of glaucoma: a review. JAMA. 2014 May 14;311(18):1901-11.

7. Primary open-angle glaucoma
Weinreb RN, Aung T, Medeiros FA. The pathophysiology and treatment of glaucoma: a review. JAMA. 2014 May 14;311(18):1901-11.
Increased resistance to aqueous outflow through the trabecular meshwork

8. Primary closed-angle glaucoma
The access to the drainage pathways is typically obstructed
Weinreb RN, Aung T, Medeiros FA. The pathophysiology and treatment of glaucoma: a review. JAMA. 2014 May 14;311(18):1901-11.

9. Optic disc changes
Weinreb RN, Aung T, Medeiros FA. The pathophysiology and treatment of glaucoma: a review. JAMA. 2014 May 14;311(18):1901-11.

10. Optic disc cupping
Glaucoma results in "cupping" as the neural rim is destroyed and the central
cup becomes enlarged and excavated
Harrison T, Isselbacher K, Wilson J. Harrison's principles of internal medicine. 19th ed. New York: McGraw-Hill; 2015.

11. Current treatment & its
limitations

12. Moroi SE, Raoof DA, Reed DM, Zöllner S, Qin Z, Richards JE. Progress toward personalized medicine for glaucoma. Expert Rev Ophthalmol. 2009
Apr;4(2):145-161.
Current therapy targets

13. Medication Dosage regimen Mechanism of
action
1. Prostaglandins
analogues
Latanoprost
Bimatoprost
Travoprost
0.005% ophthalmic solution once daily
0.03% ophthalmic solution once daily
0.004% ophthalmic solution once daily
↑ Uveoscleral
outflow
2. Beta blockers
Betaxolol
Timolol
0.25 and 0.5% eye drops twice daily
0.25 and 0.5% eye drops twice daily
↓ Aqueous
production
3. Cholinergic
agonists
Pilocarpine
0.5 to 8% eye drops 2-4 times daily ↑ Aqueous
outflow
Gupta SK, Niranjan D G, Agrawal SS, Srivastava S, Saxena R. Recent advances in pharmacotherapy of glaucoma. Indian J Pharmacol.
2008 Oct;40(5):197-208

14. Medication Dosage regimen Mechanism of action
4. Non-selective
adrenergic
agonists
Epinephrine
Dipivefrine
0.25-2% eye drops twice daily
0.1% eye drops 2-3 times daily
↑ Aqueous outflow &
↑ Uveoscleral outflow
5. α-2-Agonists
Apraclonidine
Brimonidine
0.5% and 1% drops twice daily
0.2 and 0.5% drops applied
twice daily
↓ Aqueous
production &↑ minor
in aqueous outflow
6. CA inhibitors
Dorzolamide
Brinzolamide
Acetazolamide
2% solution three times daily
1% solution three times daily
125/250 mg tablets four times
daily
↓ Aqueous
production
Gupta SK, Niranjan D G, Agrawal SS, Srivastava S, Saxena R. Recent advances in pharmacotherapy of glaucoma. Indian J Pharmacol.
2008 Oct;40(5):197-208

15. Target IOP not achieved à systemic therapy with a CAI is a final
medication option before resorting to laser or incisional surgical
treatment
If not tolerated carbonic anhydrase inhibitors,
sympathomimetics, miotics or a combination of treatments
If not tolerated or effective à beta-blocker
PG analogues (first line)
IOP of 24 mmHg or more (OHT) or if risk of visual impairment
Glaucoma: diagnosis and management. NICE guidelines. 2017 [Accessed on 3rd June 2019]. Available from:
https://www.nice.org.uk/guidance/ng81/resources/glaucoma-diagnosis-and-management-pdf-1837689655237
Treatment Algorithm

16. Limitations of the current treatment
Non-responders to available therapy
Presence of preservatives (e.g., benzalkonium
chloride): ocular surface disease
Lack of adherence to topical therapy
New theories in Glaucoma pathophysiology
Single mechanism of action
Kalouda P, Keskini C, Anastasopoulos E, Topouzis F. Achievements and Limits of Current Medical Therapy of Glaucoma. Dev
Ophthalmol. 2017;59:1-14.

17. Molecular mechanisms of retinal ganglion cell apoptosis
secondary to elevated IOP
Agarwal R, Gupta SK, Agarwal P, Saxena R, Agrawal SS. Current concepts in the pathophysiology of glaucoma. Indian J Ophthalmol.
2009 Jul-Aug;57(4):257-66.

18. Role of Rho Kinase
Ashwinbalaji S, Senthilkumari S, Gowripriya C, Krishnadas S, Gabelt BAT, Kaufman PL, Muthukkaruppan V.
SB772077B, A New Rho Kinase Inhibitor Enhances Aqueous Humour Outflow Facility in Human Eyes. Sci Rep. 2018
Oct 19;8(1):15472

19. Role of Nitric oxide (NO)
Siegfried C. Nitric oxide: A therapeutic target for glaucoma. 2017 [Accessed on 5th June 2019] Available from:
http://glaucomatoday.com/2017/10/nitric-oxide-a-therapeutic-target-for-glaucoma

20. Novel compounds with action
on old targets

21. Tafluprost
US FDA approval: February 2012
Mechanism of action (MOA):
Fluorinated analog of PG F2a
Selective FP prostanoid receptor agonist à reduces IOP by
increasing uveoscleral outflow
Pharmacokinetics (PK): Absorbed through the cornea and
hydrolyzed to tafluprost acid (Biologically active metabolite)
Dosage regimen : Ophthalmic solution of tafluprost 0.015 mg/mL
One drop in the affected eye(s) once daily in the evening
Tafluprost prescribing information. US FDA. 2012 [Accessed on 5th June, 2019]. Available
from:https://www.accessdata.fda.gov/drugsatfda_docs/label/2012/202514s000lbl.pdf

22. Advantage:
• Topical drugs à concomitant ocular surface disease and dry eyes
• The preservative – mostly benzalkonium chloride (BAC) – is the
causative agent leading to the symptoms of dry eye
• Tafluprost à only preservative-free prostaglandin analog
available; Tafluprost significantly ↓ the symptoms and signs of
ocular surface disease compared to latanoprost
Adverse drug reactions: Conjuctival hyperemia, ocular stinging,
allergic conjunctivitis, ocular pain, eyelash changes, blurred vision
Uusitalo H, Egorov E, Kaarniranta K, Astakhov Y, Ropo A. Benefits of switching from latanoprost to preservative-free
tafluprost eye drops: a meta-analysis of two Phase IIIb clinical trials. Clin Ophthalmol. 2016 Mar 15;10:445-54.
Tafluprost

23. Latanoprostene bunod
US FDA approval: November 2017
Based on APOLLO, LUNAR and JUPITER phase III trials
MOA: PGF2𝜶 analog with a NO donating action
↑ outflow through the uveoscleral pathway (mediated by
latanoprost acid)
↑ outflow through the TM pathway (mediated by NO)
Dosage regimen: Latanoprostene bunod (0.024%)
One drop in the affected eye(s) once daily in the evening
PK: Action starts in 1-3 hours and peak effect at 11-13 hours
Hoy SM. Latanoprostene Bunod Ophthalmic Solution 0.024%: A Review in Open-Angle Glaucoma and Ocular Hypertension. Drugs.
2018;78(7):773-780.

24. Advantages: Lowers IOP via a dual mechanism of action
Significantly more effective than timolol 0.5% in lowering IOP
Adverse drug reactions:
• Pigmentation
• Eyelash changes
• Conjunctival hyperemia
• Eye irritation
• Eye pain
• Instillation site pain
Latanoprostene bunod
Hoy SM. Latanoprostene Bunod Ophthalmic Solution 0.024%: A Review in Open-Angle Glaucoma and Ocular
Hypertension. Drugs. 2018;78(7):773-780.

25. New drugs new targets

26. Netarsudil
US FDA approval: December 2017
MOA: Rho Kinase inhibitor
↑ outflow of aqueous humor through TM by cellular relaxation à
↓ IOP
Regulates cell shape and apoptosis
↑ optic nerve head perfusion
Dosage regimen: 0.02% ophthalmic solution
One drop in the affected eye(s) once daily in the evening
Netarsudil prescribing information. US FDA. 2017 [Accessed on 5th June, 2019]. Available from:
https://www.accessdata.fda.gov/drugsatfda_docs/label/2017/208254lbl.pdf

27. Netarsudil
Adverse reactions:
Hyperemia (most common) Instillation site erythema
Corneal verticillata Corneal staining
Instillation site pain Increased lacrimation
Reduced visual acuity Erythema
Khouri AS, Serle JB, Bacharach J, Usner DW, Lewis RA, Braswell P, Kopczynski CC, Heah T; Rocket-4 Study Group. Once-Daily Netarsudil vs
Twice-Daily Timolol in Patients with Elevated Intraocular Pressure, the Randomized Phase 3 ROCKET-4 Study. Am J Ophthalmol. 2019 Mar 9.
pii: S0002-9394(19)30098-4

28. Netarsudil and latanoprost
Fixed-dose combination
Approved by USFDA in March 2019 based on MERCURY trials
The average IOP lowering effect of this FDC was 1 to 3 mmHg greater
than monotherapy with either netarsudil 0.02% or latanoprost 0.005%
throughout 3 months
Dosage regimen: Ophthalmic solution containing netarsudil 0.2 mg/mL
and latanoprost 0.05 mg/mL.
Adverse drug reactions: Conjunctival hyperemia, corneal verticillata,
eye pruritus, ↓ visual acuity, ↑ lacrimation, instillation site discomfort,
and blurred vision
Rocklatan prescribing information. US FDA. 2019 [Accessed on 5th June 2019]. Available from:
https://www.accessdata.fda.gov/drugsatfda_docs/label/2019/208259s000lbl.pdf

29. Drugs in pipeline

30. Drug Mechanism of action Dose Phase of clinical trial
Adenosine receptor
agonist:
Trabodenoson1
Upregulates protease
Proteases remove
hydrolyzed collagen type
IV à component of
resistive ECM in the TM
4.5% BID Phase III completed
Results not published
EP4 receptor agonist:
Omidenepag
isopropyl2
EP2 and EP4 agonists
dose-dependently
decrease TM cell
stiffness
0.002%
ophthalmic
solution
1 Phase III trial
Completed; 4 phase III trials
ongoing
Drug approved in Japan in
September 2018
Cytoskeleton
modulating drugs:
Latrunculin-B3
Actin cytoskeleton
modulator
0.005%,
0.01%, 0.02%,
or 0.05%
solution
Phase I trial completed
Si RNA:
Bamosiran4
Gene silencer àbeta-2
adrenergic receptor
blockade
0.2 % solution Phase II trial completed
1. Study of Trabodenoson in Adults With Ocular Hypertension or Primary Open-angle Glaucoma. 2016 [Accessed on 4th June 2019]
2. Duggan S. Omidenepag Isopropyl Ophthalmic Solution 0.002%: First Global Approval. Drugs. 2018 Dec;78(18):1925-1929
3. Rasmussen CA, Kaufman PL, Ritch R, Haque R, Brazzell RK, Vittitow JL. Latrunculin B Reduces Intraocular Pressure in Human Ocular Hypertension and Primary Open-Angle
Glaucoma. Transl Vis Sci Technol. 2014 Sep 3;3(5):1.
4. YL040012, Treatment for Open Angle Glaucoma (SYLTAG). 2016 [Accessed on 3rd June 2019]. Available from:
https://clinicaltrials.gov/ct2/show/NCT02250612?term=bamosiran&cond=Glaucoma&rank=1

31. Advances in drug delivery
systems in Glaucoma

32. Punctal plugs
Rod-shaped, dried polyethylene glycol-based hydrogel punctum plug
The microspheres à slowly degrade via hydrolysis and gradually release the
drug in a controlled fashion over a period of upto 90 days
Advantages: Non-invasive, patient acceptance, 90% retention rate at 60 days
Eg: The travoprost punctum plug (OTX-TP) and latanoprost punctum plug
(Evolute); Phase II trials completed
Perera SA, Ting DS, Nongpiur ME, Chew PT, Aquino MC, Sng CC, Ho SW, Aung T. Feasibility study of sustained-release travoprost punctum plug for
intraocular pressure reduction in an Asian population. Clin Ophthalmol. 2016 Apr 26;10:757-64

33. Periocular ring
Fornix based ring that releases the drug for almost 6 months
Eg: Bimatoprost ring
Phase II trial completed
Kresch S. Reinventing glaucoma therapy. 2017 [Accessed on 5th June 2019]. Available from:
https://www.reviewofoptometry.com/article/reinventing-glaucoma-therapy

34. Durasert
• A bioerodible, subconjunctival implant roughly the size of a
grain of rice (3mm to 4mm in length, 0.4mm in diameter)
containing drug in a tiny translucent cylindrical polymer tube
• The device would not need to be surgically removed and may
work for 3-6 months
• Phase I trial
• Eg: Latanoprost durasert
Kresch S. Reinventing glaucoma therapy. 2017 [Accessed on 5th June 2019]. Available from:
https://www.reviewofoptometry.com/article/reinventing-glaucoma-therapy

35. Age-related Macular
Degeneration

36. Leading cause of vision loss among the elderly
Atrophic AMD, accounts for ~90% of all cases
Multifactorial degeneration: chronic inflammation, oxidative
stress and aging components
The number of AMD patients is predicted to increase to ~30
million worldwide by 2020
Age Related Macular Degeneration
Li H, Chintalapudi SR, Jablonski MM. Current drug and molecular therapies for the treatment of atrophic age-related
macular degeneration: phase I to phase III clinical development. Expert opinion on investigational drugs. 2017 Oct
3;26(10):1103-14.

37. Pathophysiology
• Deposition of modified proteins (amyloid β) in drusen within the macula
• Drusen à hallmark of the early stage of the disease
• Association between mitochondrial dysfunction and atrophic AMD
• Mast cells, IL, resident choroidal inflammatory cells, and pericapillary
macrophages à GA
• Neovascularization in AMD is driven by vascular endothelial growth factor
A (VEGF-A)
• Complement pathway associated with AMD pathogenesis
Li H, Chintalapudi SR, Jablonski MM. Current drug and molecular therapies for the treatment of atrophic age-related macular
degeneration: phase I to phase III clinical development. Expert opinion on investigational drugs. 2017 Oct 3;26(10):1103-14.

38. Stages of AMD
No AMD
0-5 small drusen
Early AMD
Multiple small drusen
Macular pigmentary changes
Intermediate AMD
Extensive intermediate drusen or atleast
1 large drusen (≥ 125 𝜇𝑚) not involving
the fovel centre
Advanced AMD
GA involving the foveal centre or any
evidence of neovascularisation
l-Zamil WM, Yassin SA. Recent developments in age-related macular degeneration: a review. Clin Interv Aging. 2017 Aug 22;12:1313-1330.

39. Current treatment & its
limitations

40. Current treatment guidelines
• Antioxidant vitamins and minerals for slowing the progression to
later stages of AMD1,2
• Anti-VEGF therapies have become first-line therapy for treating
and stabilizing most cases of neovascular AMD1
• If needed, offer photodynamic therapy offered only as an adjunct
to anti-VEGF as second-line treatment3
• Three compounds (pegaptanib, ranibizumab and aflibercept) have
been approved for the treatment of neovascular AMD3
1. Age-related Macular Degeneration preferred practice pattern. American Academy of Ophthalmology. 2015 [Last accessed on
3rd June, 2019]. Available from: https://www.aao.org/preferred-practice-pattern/age-related-macular-degeneration-ppp-
2015
2. Evans JR, Lawrenson JG. Antioxidant vitamin and mineral supplements for slowing the progression of age-related macular
degeneration. Cochrane Database of Systematic Reviews. 2017(7).
3. Age-related Macular Degeneration. NICE guidance. 2018 [Last accessed on 3rd June 2019]. Available from:
https://www.nice.org.uk/guidance/ng82/chapter/Recommendations#pharmacological-management-of-amd

41. Ranibizumab
Pegaptanib
FDA approval in 2006
Dose: 0.3- 0.5 mg to be administered by intravitreal injection
once a month
FDA approval in 2004
Dose: 0.3 mg to be administered once every 6 weeks
Ip MS, Scott IU, Brown GC, Brown MM, Ho AC, Huang SS, Recchia FM. Anti–vascular endothelial growth factor pharmacotherapy for
age-related macular degeneration: a report by the American Academy of Ophthalmology. Ophthalmology. 2008 Oct
1;115(10):1837-46.

42. Limitations of the current treatment
• Few approved drugs
• Burden of the disease increasing
• No specific FDA-approved drug yet exists to retard
drusen formation in early/ intermediate AMD or to
inhibit lesion enlargement in GA
• Anti VEGF ADRs: the main cardiovascular effects
(thrombosis, hemorrhage, hypertension, proteinuria),
CVA, MI , transient ischemic attacks, DVT
Li H, Chintalapudi SR, Jablonski MM. Current drug and molecular therapies for the treatment of atrophic age-related
macular degeneration: phase I to phase III clinical development. Expert opinion on investigational drugs. 2017 Oct
3;26(10):1103-14.

43. New drugs old targets

44. Aflibercept
US FDA approval: November 2011
VEGF trap eye (VTE)à Acts as a decoy receptor for VEGF
Binds both ends of activated dimerized VEGF very tightly between its
arms and prevents it from interacting and activating native VEGFR1
and VEGFR2 receptors and cross linkingà blockage of VEGF activity
and inhibits abnormal growth of blood vessels
Dose: Intravitreal injections 2 mg
Stewart MW. Aflibercept (VEGF Trap-eye): the newest anti-VEGF drug. Br J Ophthalmol. 2012 Sep;96(9):1157-8.

45. VIEW trial1: All aflibercept groups were noninferior and clinically
equivalent to monthly ranibizumab for the primary end point (best
corrected visual acuity)
Advantage2: Binds more strongly to VEGF
Longer duration of action à bimonthly injections unlike
ranibizumab (monthly) given for 3 months
Common ADRs2 à Conjunctival hemorrhage, eye pain, cataract,
vitreous detachment, vitreous floaters, and ↑ IOP
1. Heier JS, Brown DM, Chong V, Korobelnik JF, Kaiser PK, Nguyen QD, Kirchhof B, Ho A, Ogura Y, Yancopoulos GD, Stahl N, Vitti R, Berliner AJ,
Soo Y, Anderesi M, Groetzbach G, Sommerauer B, Sandbrink R, Simader C, Schmidt-Erfurth U; VIEW 1 and VIEW 2 Study Groups. Intravitreal
aflibercept (VEGF trap-eye) in wet age-related macular degeneration. Ophthalmology. 2012 Dec;119(12):2537-48.
2. Stewart MW. Aflibercept (VEGF Trap-eye): the newest anti-VEGF drug. Br J Ophthalmol. 2012 Sep;96(9):1157-8.
Aflibercept

46. Drugs in pipeline and new drug
delivery systems

47. Bevacizumab
Both drugs equally efficacious however GI bleeding more with Bevacizumab
but mentioned that furthur was investigation needed2
Open label, multicenteric, Phase III trial completed in 2018
Results awaited3
1. Avastin and Lucentis are equivalent in treating age-related macular degeneration. NIH. 2012 [Accessed on 2nd June, 2019]. Available from:
https://www.nih.gov/news-events/news-releases/avastin-lucentis-are-equivalent-treating-age-related-macular-degeneration
2. ATT Research Group, Martin DF, Maguire MG, Ying GS, Grunwald JE, Fine SL, Jaffe GJ. Ranibizumab and bevacizumab for neovascular age-
related macular degeneration. N Engl J Med. 2011 May 19;364(20):1897-908.
3. Safety and Clinical Effectiveness of Intravitreal Bevacizumab (Lumiere®) in Patients With Wet Age-related Macular Degeneration (Wet AMD).
[Last accessed on 4th June, 2019]. Available from: https://clinicaltrials.gov/ct2/show/NCT03668054
Bevacizumab is not approved by the FDA for macular degeneration
Has been widely used off-label on account of the low cost. Off label à good
clinical results. 1

48. 1. Brolucizumab: New anti-VEGF drug in phase III clinical trials, can
act as long as 12 weeks. FDA approval is expected in late 2019
2. Dorzolamide-timolol : ↓ retinal fluid accumulation in wet AMD in
combination with injected anti-VEGF drugs. Phase III trial ongoing
3. Sunitinib: VEGF in phase II clinical trial
4. Port delivery system: Device implanted into the wall of the eye in
the operating room that can store, and slowly release,
ranibizumab. Phase II clinical trial (LADDER) completed in March
2019
Dunaief J. Update on the AMD Drug Pipeline. 2018 [Accessed on 3rd June 2019]. Available from
https://www.brightfocus.org/macular/article/update-on-the-age-related-macular-degeneration-drug-pipeline
Other pipeline drugs

49. Li H, Chintalapudi SR, Jablonski MM. Current drug and molecular therapies for the treatment of atrophic age-related
macular degeneration: phase I to phase III clinical development. Expert opinion on investigational drugs. 2017 Oct
3;26(10):1103-14.
Recent advances in dry AMD

50. Drug Mechanism of
action
Phase of
clinical trial
Dose Safety and efficacy
Zimura 1 Inhibits
complement
factor C5
Phase II a à
wet AMD
Phase II 2b
(ongoing) à
dry AMD
2 mg
IVI
Phase II a à
Improvement in visual
acuity
Phase II b à
completion date is
November 2019
Lampalizumab2 Humanized
IgG Fab
fragment
directed
against
complement
factor D
Phase II
Phase III
(Chroma &
Spectri trials)
10 mg
IVI
Phase II à 20 %
reduction in GA
reduction
Phase III à No benefit
Endophthalmitis
1. Nebbioso M, Lambiase A, Cerini A, Limoli PG, La Cava M, Greco A. Therapeutic Approaches with Intravitreal Injections in
Geographic Atrophy Secondary to Age-Related Macular Degeneration: Current Drugs and Potential Molecules. Int J Mol Sci. 2019
Apr 4;20(7):1693.
2. Holz FG, Sadda SR, Busbee B, et al. Efficacy and Safety of Lampalizumab for Geographic Atrophy Due to Age-Related Macular
Degeneration: Chroma and Spectri Phase 3 Randomized Clinical Trials. JAMA Ophthalmol. 2018;136(6):666–677
Anti-inflammatory agents and complement system inhibitors

51. Drug Mechanism of
action
Phase of
clinical trial
Dose Safety and efficacy
Eculizumab
(Soliris)1
Humanized
monoclonal
IgG antibody
Inhibitor of
terminal
complement
activation
Phase II
(COMPLETE
study)
Induction:
600-900
mg
Maintenan
ce: 900-
1200 mg IV
infusion
No improvement in
GA area and visual
acuity
Tesidolumab
(LFG316)2
Fully human
IgG1 targeting
complement
factor C5
Phase II Part A à 5
mg/50 µL
Part B à 10
mg/100 µL
IVI route
Acceptable safety
profile but not
effective in reducing
GA growth rate or
improving visual
acuity
1. Yehoshua Z, de Amorim Garcia Filho CA, Nunes RP, Gregori G, Penha FM, Moshfeghi AA, Zhang K, Sadda S, Feuer W, Rosenfeld
PJ. Systemic complement inhibition with eculizumab for geographic atrophy in age-related macular degeneration: the
COMPLETE study. Ophthalmology. 2014 Mar;121(3):693-701.
2. Nebbioso M, Lambiase A, Cerini A, Limoli PG, La Cava M, Greco A. Therapeutic Approaches with Intravitreal Injections in
Geographic Atrophy Secondary to Age-Related Macular Degeneration: Current Drugs and Potential Molecules. Int J Mol Sci.
Anti-inflammatory agents and complement system inhibitors

52. Drug Mechanism of
action
Phase of
clinical
trial
Dose Safety and efficacy
Fenretinide Synthetic retinoid
preventing the
uptake of retinol by
RPE
Phase II 100 mg
and 300
mg softgel
capsules
No improvement in
GA growth rate
though well
tolerated
Emixustat Non-retinoid visual
cycle modulator
Prevents conversion
of all-trans-retinol
to 11-cis-retinal in
the RPE
Phase II a
Phase II/III
2, 5, 7, 10
mg tablets
2.5, 5 and
10 mg
tablets
Showed a biological
effect in GA eyes
Completed but
results awaited
Bandello F, Sacconi R, Querques L, Corbelli E, Cicinelli MV, Querques G. Recent advances in the management of dry age-related
macular degeneration: A review. F1000Res. 2017 Mar 9;6:245
Visual cycle modulators

53. Drug Mechanism of
action
Phase of
clinical trial
Dose Safety and
efficacy
Brimonidine Release BDNF
from retinal
ganglion cells
Modulation of Aβ
Phase II
multicentric
trial1
Phase II
multicentric
trial
(BEACON)2
200 and 400
𝜇𝑔 implant
400
𝜇𝑔 implant
No reliable data
Significant
change in GA
lesion area
Ciliary
neurotrophi
c factor1
Member of the IL-
6 cytokine family
Protection of
photoreceptors
Phase II Encapsulated
cell technology
NT-501 implant
High dose and
low dose
Increase in
retinal thickness
and stabilization
of visual acuity
1. Bandello F, Sacconi R, Querques L, Corbelli E, Cicinelli MV, Querques G. Recent advances in the management of dry age-related macular
degeneration: A review. F1000Res. 2017 Mar 9;6:245
2. A Safety and Efficacy Study of Brimonidine Intravitreal Implant in Geographic Atrophy Secondary to Age-related Macular Degeneration
(BEACON). [Last accessed on 3rd June 2019]. Available form https://clinicaltrials.gov/ct2/show/results/NCT02087085
Neuroprotective agents

54. PGE1 Alprostadil
A phase III trial proved that a (Dose: 60 µg alprostadil/d i.v.) was
superior to placebo treatment in improving visual acuity in patients
affected by d-AMD
MC-1101
Additional anti-inflammatory and an antioxidant profile
phase II/III trial MC-1101 (1 % ophthalmic solution)
Bandello F, Sacconi R, Querques L, Corbelli E, Cicinelli MV, Querques G. Recent advances in the management of
dry age-related macular degeneration: A review. F1000Res. 2017 Mar 9;6:245
Vascular enhancers

55. Poly(lactide-co-glycolide) (PLGA) microspehres
In vitro studies with anti-VEGF Bevacizumab
Joseph RR, Venkatraman SS. Drug delivery to the eye: what benefits do nanocarriers offer?. Nanomedicine. 2017
Mar;12(6):683-702.
New drug delivery systems

56. Verteporfin à self-aggregation in
aqueous media, which can severely limit
drug bioavailability to biological systems
Selectively closes the CNV vessels by
thrombosis
It has been the only ocular liposomal
drug approved by FDA
Liposomal drug delivery
Joseph RR, Venkatraman SS. Drug delivery to the eye: what benefits do nanocarriers offer?. Nanomedicine. 2017
Mar;12(6):683-702.

57. Diabetic Retinopathy

58. • Diabetic retinopathy (DR) is a chronic progressive, potentially
sight-threatening disease of the retinal microvasculature
associated with the prolonged hyperglycemia and other
conditions linked to diabetes mellitus such as hypertension
Diabetic Retinopathy Guidelines. The Royal College of Ophthalmologists. 2012 [Accessed on 6th June, 2019].
Available from: https://www.rcophth.ac.uk/wp-content/uploads/2014/12/2013-SCI-301-FINAL-DR-GUIDELINES-
DEC-2012-updated-July-2013.pdf
• About one third of the patients with Diabetes Mellitus have
signs of DR
Definition

59. Proposed Disease
Severity Level
Ophthalmoscopy findings
No apparent retinopathy No abnormalities
Mild NPDR Microaneurysms only
Moderate NPDR More than just microaneurysms but less severe NPDR
Severe NPDR Any of the following (4-2-1 rule) and no signs of
proliferative retinopathy:
•Severe intraretinal hemorrhages and microaneurysms
in each of four quadrants
•Definite venous beading in 2 or more quadrants
•Prominent IRMA in 1 or more quadrants
PDR One or both of the following:
•Neovascularization
•Vitreous/preretinal hemorrhage
Diabetic Retinopathy. American Academy of Ophthalmology. 2016 [Accessed on 6th June 2019]. Available from: https://www.aao.org/topic-
detail/diabetic-retinopathy-europe
Classification

60. Pathophysiology
Mechanism of Diabetic Retinpathy. [Accessed on 6th June 2019]. Available from:
http://www.diabeticretinopathy.org.uk/diabetic_retinopathy_mech.html

61. Current treatment & its
limitations

62. Improve glycemic control if HbA1c >7.5%, manage HTN or dyslipidemia
No DR, Mild or Moderate NPDR: dilated eye examinations and retinal
imaging at recommended intervals. Treat DME
Severe NPDR: Follow closely for development of PDR. Consider early
panretinal photocoagulation for patients at high risk of progression to
PDR or poor compliance with follow-up
PDR: Anti- VEGF injections (ranibizumab, aflibercept) as a safe and
effective treatment of PDR through at least 2 years
Panretinal photocoagulation (PRP)
Treatment Guidelines
International Council for Ophthalmology Guidelines for Diabetic Eye Care. 2017 [Accessed on 6th June 2019]. Available from:
http://www.icoph.org/downloads/ICOGuidelinesforDiabeticEyeCare.pdf

63. • PRP complications à pain during treatment, loss of peripheral
vision, uveal effusions, worsening of macular oedema, vitreous
haemorrhage and advanced cataract
• These complications brought the need for new modalities in
treating PDR, such as anti-VEGF
Advantages of Anti-VEGF
Osaadon P, Fagan XJ, Lifshitz T, Levy J. A review of anti-VEGF agents for proliferative diabetic retinopathy. Eye (Lond). 2014 May;28(5):510-20.

64. Anti-VEGF
drugs
Aflibercept: Approved in 2019
Ranibizumab: Approved in 2015
Pegatanib: Approved in 2011
Bevacizumab: Used off label
Osaadon P, Fagan XJ, Lifshitz T, Levy J. A review of anti-VEGF agents for proliferative diabetic retinopathy. Eye (Lond). 2014 May;28(5):510-20.

65. Corticosteroids
• Reduces DME and stabilizes vision
• S/E: Elevated IOP and cataract formation
• Preferable in pseudophakic eyes with persistent or recurrent
disease
• Mode of administration: Peribulbar injection, intravitreal injection,
or intravitreal implant
• Triamcinolone acetonide, fluocinolone acetonide, and
dexamethasone
Nurözler Tabakcı B, Ünlü N. Corticosteroid Treatment in Diabetic Macular Edema. Turk J Ophthalmol. 2017 Jun;47(3):156-
160.

66. Drugs in pipeline

67. Integrin inhibitors1
• The early step of inflammation and adherence of leukocytes to the
endothelium is dependent on specific endothelium integrins
• Phase II trial using an integrin antagonist, Luminate, ongoing in DME
patients for comparison with BVZ and focal laser therapy
Chemokine inhibitors2
• Chemokines play an important role in vascular inflammation by
inducing leukocyte recruitment and activation
• An oral inhibitor targeting the receptors for chemokine, CCR2/CCR5
recently completed phase II clinical trial in DME
1. Allegro Ophthalmics Begins Phase 2 Clinical Trial of LuminateR (ALG-1001) for the Treatment of Diabetic Macular Edema. [Last accessed on 2015 Nov
18]. Available from: http://www.allegroeye.com/press/
2. Gale JD, Berger B, Gilbert S, Popa S, Sultan MB, Schachar RA, Girgenti D, Perros-Huguet C. A CCR2/5 Inhibitor, PF-04634817, Is Inferior to Monthly
Ranibizumab in the Treatment of Diabetic Macular Edema. Invest Ophthalmol Vis Sci. 2018 May 1;59(6):2659-2669.

68. Summary
Glaucoma: First line PGs, new drugs à Rho kinase
inhibitors, PGs NO donating action
Age-related Macular Degeneration: First line anti-
VEGFs for wet AMD, pipeline drugs for dry AMD
Diabetic Retinopathy: Anti-VEGF

69. Thank You
Now my vision is clear !