what's on the horizon for atrophic amd? a (very) brief review · 2014. 10. 15. · what's...
TRANSCRIPT
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…