What's On The Horizon For Atrophic AMD?

A (Very) Brief Review

Sam C. Spalding, M.D.

Disclaimers

Financial Interest: No

Investigational Treatments: Nothing But

Definitive Results: Stay Tuned…

Objectives

•  Review risk factors and disease mechanisms

•  Discuss several potential treatment strategies

•  Describe current status of clinical trials •  Propose future treatment paradigms

Heroes of AMD Treatment

Laser (OATH) Few patients were treatable

50% recurrence

Photodynamic Therapy (2000)

Lots more patients treatable Visual results fair- most gradually worse

VEGF Inhibition (2006) Very elegant and widely applicable

95% avoid severe vision loss

Atrophic AMD (2000 BC)

What does it take to get some respect around here?

Atrophic AMD

•  85-90% of AMD cases never develop CNV •  #1 cause of legal blindness if >55 years

old •  Geographic Atrophy accounts for 20% of

legal blindness in North America •  Demographics point to rising disease

burden

Atrophic AMD Disease Risks

•  Age •  Heredity •  Race •  Smoking •  Age •  Diet •  Age

Clinical Characteristics

OCT Findings: OD

OCT Findings: OS

Fundus Autofluorescence: OD

Fundus Autofluorescence: OS

Anatomic Correlation (Holz, et al Ophthalmol May, 2014)

Functional Correlation

Atrophic AMD Disease Mechanisms

(aka: Treatment Targets) •  Byproducts of Visual Cycle •  Inflammation/Complement •  Lipid/Lipoprotein Deposition •  Amyloid Deposition •  Oxidative Stress •  Choriocapillaris Atrophy •  Neurodegeneration/Cellular Loss

Byproducts of Visual Cycle

X Fenretinide (Sirion) retinoid derivative visual cycle inhibitor 2/3 Emixustat (Acucela) inhibits A2E production by interfering with RPE65 PC ALK-001 (Alkeus) modified Vit A prevents A2E and lipofuscin production

Inflammation/Complement

•  Complement cascade amplifies humoral and cellular immunity

•  Numerous mechanisms interact to promote or restrain complement activation

•  Numerous SNP’s associated with AMD •  Alternate pathway is primary actor in AMD •  Lipofuscin (A2E, etc) activate alternate

complement pathway

Complement

Complement Modulation

Inflammation/Complement 2  Fluocinolone (Iluvien- Alimera) steroid implant

(2015) 2/3 Glatiramer (Copaxone- Teva) immunomodulator X Sirolimus (Rapamycin- Wyeth) antifungal 2  LFG316 (Novartis) anti-C5 activation antibody PC POT-4 (Appellis) C3 activation inhibitor X Eculizumab (Soliris- Alexion) anti-C5 activation X ARC-1905 (Ophthotech) anti-C5 aptamer 2/3 Oracea (Galderma) MMP inhibitor (2017) 3 Lampalizumab (Genentech) Factor D inhibitor

Lipid/Lipoprotein Deposition

•  Hepatic Lipase (LIPC) associated with

AMD

•  Preclinical trials only thus far

•  Statins are ineffective

Amyloid Deposition

2 RN6G (Pfizer) inhibits amyloid accumulation 2 GSK933776 (GlaxoSmithKline) anti-amyloid antibody

Oxidative Stress

•  AREDS 1 & 2 (NEI) multiple anti-oxidants, zinc

X OT-551 (Othera) free radical inhibitor

•  Omega-3 Fatty Acids, Omega-3 to Omega-6 Ratios, Lutein, Zeaxanthin (AREDS, others)

Choriocapillaris Atrophy

X Trimetazidine (Servier) ischemia protection 2/3 MC-1101 (MacuCLEAR) increases blood flow now recruiting (topical)

Neurodegeneration/Cellular Loss

P UF-021 (Ocuseva) prostaglandin analog X CNTF-2 (Neurotech) IL-6 cytokine X Tandospirone (Alcon) serotonin 1A agonist 2  Brimonidine (Allergan) photoreceptor

rescue 3  MA09-hRPE (Advanced Cell Technology) 2 HuCNS-SC (StemCells) neural stem cells

Regenerative Medicine for AMD www.thelancet.com Published online October 15, 2014

http://dx.doi.org/10.1016/S0140-6736(14)61376-3

•  Schwartz, et al describe medium to long term success with implanted human embryonic stem cell derived RPE cells

•  18 patients (Stargardts and Atrophic AMD) •  No adverse events due to inappropriate

graft behavior •  Requires complex vitreoretinal surgery

and systemic immunosuppression

Retina Update 2014 Summary

•  GA is a leading cause of legal blindness •  Therapies for GA are currently lacking •  Many novel treatment ideas under study •  Strategies exploiting inflammatory,

complement and oxidative pathways seem to be most promising at this time

•  Regenerative medicine may come into its own in the treatment of our AMD patients

Retina Update 2024 Treatment Sequence

•  Early aging changes – AREDS vitamins, behavioral changes,

oxidative stress reduction •  Intermediate atrophic changes

–  Inflammation/Complement inhibition, visual cycle modulation, neuroprotection

•  Advanced GA with visual loss due to cell loss – Cell therapies, regenerative medicine,

adaptive therapies

The Take Away •  Tell patients why they should stop smoking •  Encourage use of AREDS vitamins •  Encourage a “heart healthy” diet •  Encourage exercise

•  Multifactorial diseases need multiple treatment strategies to succeed

Stay Tuned…