This document discusses new treatments for age-related macular degeneration (AMD), which is a leading cause of blindness. It outlines several anti-inflammatory therapies, anti-oxidative stress therapies, visual cycle modifying agents, and choroidal blood flow enhancing agents that are being studied in clinical trials to treat dry AMD. It also discusses emerging therapeutic options for wet AMD such as anti-platelet-derived growth factor agents, new anti-VEGF drugs, and sustained drug delivery devices. Finally, it reviews several new intraocular lens designs that aim to improve vision for patients with AMD through magnification or image displacement.

1. New Frontiers in AMD treatment
Dr Nikita Dash
Senior Resident

2. INTRODUCTION
• Leading cause of irreversible blindness.
• Advanced stages: Geographic Atrophy and Neovascular AMD
• Lead to severe central impairment or legal blindness
Newer treatments in dry AMD:
 Anti-inflammatory therapies
 Anti-oxidative stress therapies
 Visual cycle modifying agents
 Choroidal blood flow enhancing agents
 Regenerative stem cell therapies

3. ANTI-INFLAMMATORY THERAPIES
• Target complement pathways which has been associated with
AMD.
• Various agents in clinical trials include:
 Lampalizumab
 Sirolimus
 Eculizumab
 Zimura

4. • LAMPALIZUMAB:
• Fab of a humanized monoclonal antibody directed against
complement factor D (activates alternate complement
pathway).
• 1st to enter Phase III trials. MAHALO study was multi centre,
randomized, single-masked study. Injected intravitreally and
reduction rate of GA area was found to be 20.4%. No adverse
effects/death.
• SIROLIMUS:
• Immunosuppressive agent, inhibits mTOR pathway regulating
cell metabolism and survival.
• Phase II single centre study, subconjunctival injection of
440mcg. Rate of change in GA area noted at 3 months.
• Well tolerated, no positive anatomic or functional effects

5. • ECULIZUMAB:
• Humanized IgG antibody that acts by inhibition of terminal
complement activation (C5)
• COMPLETE (complement inhibition with eculizumab for the
treatment of non-exudative age-related macular
degeneration) trial- Phase II , measured change in GA area at
26 weeks. Oral administration.
• Well tolerated but no decrease in GA area.
• ZIMURA:
• Aptamer that inhibits complement factor C5. Phase IIa clinical
trial when administered in combination with ranibizumab for
wet AMD.
• PhaseII/III clinical trial investigating Zimura for treatment of
GA.

6. ANTI-OXIDATIVE STRESS THERAPIES
• Metabolic wastes containing oxidative products and amyloid-
ß have been shown to cause inflammatory response and lead
to degeneration of photoreceptors and RPE cells.
Age-Related Eye Disease Study
• AREDS- Vit C, Vit E, beta-carotene, zinc and copper.
• AREDS-2: Lutein and zeaxanthin safer alternative to beta-
carotene.

7. • OT-551: Anti-oxidant molecule. Topically administered as eye
drops, 3 times/day for 3 years.
• Well tolerated but no significant effect on lesion enlargement
on Phase II study.
• Amyloid-ß targets: Prevent accumulation and thereby
modulate levels. Investigative molecule GSK 933776 is under
Phase II trials. Other molecules include:MRZ-99030 and RN6G,
whose Phase I trials are completed.
• Administered intravenous.

8. VISUAL CYCLE MODIFYING AGENTS
• Advanced glycation end products and byproducts of visual
cycle such as A2E have been observed at the sites of RPE
atrophy in GA eyes and associated with the GA pathogenesis.
• Excess accumulation of oxysterols in Bruch’s membrane leads
to RPE and photoreceptor death.
• FENRETINIDE:
• Inhibits formation of A2E and other lipofuscin fluorophores in
vivo. However Phase II study did not show any benefit.

9. • EMIXUSTAT:
• Non-retinoid compound that directly affects biosynthesis of
visual chromophores through inhibition of RPE-specific
protein isomerase 65 (RPE 65). PhaseII/III clinical trial is
underway to determine efficacy of orally delivered emixustat
hydrochloride.
• ALK-001:
• ALK-001 modulates vitamin A metabolism leading to 7-fold
decrease in formation of toxic vit-A aggregates. Phase I trial
ongoing.

10. CHOROIDAL BLOOD FLOW ENHANCING
AGENTS
• MC-1101
• FDA-approved oral anti-hypertensive drug with hydralazine as
its active ingredient.
• Shown to increase choroidal blood flow, prevent the rupture
of Bruch’s membrane in animal studies.
• Phase Ib trial showed that topical instillation of 1% MC-1101
was safe with no systemic adverse effects.
• PhaseII/III trials are undergoing.

11. STEM CELL THERAPY
• Stem cell-derived RPE cells can be transplanted in the
subretinal space and can prevent photoreceptor death in GA.
• RPE cells are derived from human embryonic stem
cells(hESCs) or human induced pluripotent stem cells (iPSCs).
• Shown to remain viable and improve retinal function in
animal models.
• PhaseI/II trials show improvement in BCVA as compared to
non-injected fellow eyes.

12. EMERGING THERAPEUTIC OPTIONS IN
WET AMD
• Steroids
• Inhibitors of complement factors
• Anti-platelet-derived growth factor agents (anti-PDGF)
• New anti-VEGF drugs
• Designed ankyrin repeat proteins
• Sustained drug-delivery devices
• Encapsulated cell technology
• Adeno-associated virus vectors.

13. Anti-PDGF Agents
• Several studies like CATT study, ANCHOR, HORIZON and
MARINA trials demonstrated plateau effect with anti-VEGF
monotherapy.
• Anti-PDGF: Act on pericytes, serve as adjuvant.
• Fovista is currently under Phase III trial to establish its safety
and efficacy in combination with ranibizumab as compared to
ranibizumab alone.

14. • STEROIDS:
• Intravitreal triamcinolone has been used as adjunct to PDT.
• Combination of Ozurdex and ranibizumab has also been used
to treat wet AMD.
• Currently, Iluvien implant (Fluocinolone acetonide) is being
evaluated in combination with ranibizumab.
• INHIBITORS OF COMPLEMENT FACTORS:
• Zimura
• POT-4: Phase I has proved safety profile, now in Phase II trials

15. New Anti-VEGF agents
• Conbercept:
• VEGF binding domains of the human VEGFR-1 and VEGFR-2
combined with Fc portion of human IgG.
• Pazopanib:
• Multi-tyrosine kinase inhibitor with effect on VEGFR-1,2,3 and
PDGFR-alpha and beta.
• Phase I testing done.

16. • Designed Ankyrin Repeat Protein Family:small, single-domain
molecules that bind to a target protein with high affinity and
specificity. Abicipar pegol is now in Phase II randomised trials.
• Sustained Drug deivery devices: Alternate to anti-VEGF
therapy. RTH258 is currently over with Phase I trials regarding
safety and efficacy as compared to ranibizumab.
• Encapsulated cell technology: Involves biocompatible
implants that are able to produce continuously recombinant
therapeutics. NT-503 is being used for a Phase II trial.

17. • Adeno-associated Virus Vectors :
• sFLT-1 is a tyrosine kinase protein which encodes for he EGF
receptor 1 and has anti-angiogenic properties.
• AAV-sFLT01 is an adeno-associated virus vector that expresses
a modified soluble FLT receptor.
• Phase I trial is currently underway.

18. NEW LENSES FOR AMD
• Seven types of IOLs recommended for AMD: an implantable
miniature telescope,the IOL-VIP System, the Lipshitz macular
implant, the sulcus-implanted Lipshitz macular implant LMI-SI, the
Fresnel Prism Intraocular Lens, the iolAMD and the Scharioth
Macula Lens.
• The implantable miniature telescope (IMT) enlarges patient’s
central 20-24° field of view by up to three-fold. It is composed of a
4.4mm telescope with a PMMA base that sits in the capsular bag.
• The IOL-VIP System consists of two IOLs, a high minus-power
biconcave IOL in the capsular bag and a high plus-power biconvex
IOL in the anterior chamber. The two PMMA lenses together
provide a 1.3-fold magnification and shift the enlarged image
towards the preferred retinal locus.

19. • The iolAMD is another double-implant system, in which the
high plus-power lens is implanted in the sulcus. The high plus-
power IOL has a hyper-aspheric-optic that is slightly de-
centred. 1.2-fold magnification achieved.
• The Lipshitz macular implant (LMI), and sulcus-implanted
Lipshitz macular implant (LMI-SI) is based on a reflecting
telescope, and combines a primary concave mirror and a
secondary convex mirror within a normal IOL configuration. In
addition to providing a 2.5-fold magnification, the LSI implants
also provide normal unmagnified peripheral vision.

20. • The Fresnel Prism Intraocular Lens, which provides no magnification
but instead displaces the retinal image to a healthy part of the
retina.
• The add-on bifocal Scharioth Macula Lens (A45 SML, Medicontur),
designed to provide near vision to the pseudophakic AMD patients
while preserving normal peripheral vision.
• Eyemax IOL is an injectable, hydrophobic acrylic lens designed to
improve the quality of retinal image in all areas of the macula up to
10 degrees from fixation, therefore patients with central macular
scar but relatively healthy surrounding macula can benefit from this
implant. Designed for insertion into the capsular bag, the lens has
an optic diameter of 6.0mm, an overall length of 11mm and
modified C-loop haptics.

21. THANK YOU