A new clinical trial for Disclosures geographic atrophy: None 10 - PowerPoint PPT Presentation

A new clinical trial for Disclosures geographic atrophy: • None 10 reasons it might work Jay M. Stewart, MD University of California, San Francisco Mechanisms A B C • Complement components found in drusen • Genetic studies implicate complement system (CFH) 1

AMD treatments directed toward complement system Rhoades et al, Clin Ophth 2015;9:1049-56 Complement Brimonidine • Lampalizumab – anti-factor D • Brimonidine: phase 2 data – 22g injection at baseline and 6 months • MAHALO (phase 2) – 12 months: 19% and 28% reduction in – 18 months: 20.4% reduction in mean progression rate in low- and high-dose groups change from baseline – Neuroprotection – Larger effect with biomarkers • Phase 2b (BEACON): q3 months • Phase 3 (CHROMA/SPECTRI): q4-6 week injections 2

Metformin • Biguanide, first described 1922 • Related to components in French lilac, used in medieval times for diabetes • FDA approved 1994 • Generic Aspect of geographic atrophy Aspect of geographic atrophy Reported action of metformin Reported action of metformin ✔ pathogenesis pathogenesis Oxidative stress Oxidative stress Reduces oxidative stress Kaarniranta et al, Autophagy 2013 3

Aspect of geographic atrophy Aspect of geographic atrophy Reported action of metformin ✔ Reported action of metformin ✔ pathogenesis pathogenesis ✔ Oxidative stress Reduces oxidative stress Oxidative stress Reduces oxidative stress mTOR signaling pathway in mTOR signaling pathway in lysosomal dysregulation and lysosomal dysregulation and Inhibits mTOR pathway autophagy autophagy RPE hypertrophy and dedifferentiation due to mTOR activation Aspect of geographic atrophy Reported action of metformin ✔ pathogenesis ✔ Oxidative stress Reduces oxidative stress mTOR signaling pathway in lysosomal dysregulation and Inhibits mTOR pathway autophagy Mitochondrial stress; production of ROS by complex I Ricci et al, Cell Death & Differentiation 2003 4

Aspect of geographic atrophy Aspect of geographic atrophy Reported action of metformin ✔ Reported action of metformin ✔ pathogenesis pathogenesis ✔ ✔ Oxidative stress Reduces oxidative stress Oxidative stress Reduces oxidative stress mTOR signaling pathway in mTOR signaling pathway in lysosomal dysregulation and Inhibits mTOR pathway ✔ lysosomal dysregulation and Inhibits mTOR pathway ✔ autophagy autophagy Mitochondrial stress; production Mitochondrial stress; production Inhibits mitochondrial complex I Inhibits mitochondrial complex I of ROS by complex I of ROS by complex I C-reactive protein elevated in choroid and drusen, and gene variant associated with AMD CFH Polymorphism High C-reactive protein levels • Higher levels of C-reactive protein seen • Odds ratio = 9 for advanced AMD in choroid and drusen CRP staining pink (left) and white (right) HH (homozygous for Y to H mutation) shows a lot of staining for CRP in both samples Seddon, Ophthalmology 2010 Johnson, PNAS 2006 5

Aspect of geographic atrophy Aspect of geographic atrophy Reported action of metformin ✔ Reported action of metformin ✔ pathogenesis pathogenesis ✔ ✔ Oxidative stress Reduces oxidative stress Oxidative stress Reduces oxidative stress mTOR signaling pathway in mTOR signaling pathway in lysosomal dysregulation and Inhibits mTOR pathway ✔ lysosomal dysregulation and Inhibits mTOR pathway ✔ autophagy autophagy Mitochondrial stress; production Mitochondrial stress; production Inhibits mitochondrial complex I ✔ Inhibits mitochondrial complex I ✔ of ROS by complex I of ROS by complex I C-reactive protein elevated in C-reactive protein elevated in choroid and drusen, and gene Reduces C-reactive protein choroid and drusen, and gene Reduces C-reactive protein variant associated with AMD variant associated with AMD Chronic inflammation Aspect of geographic atrophy Reported action of metformin ✔ pathogenesis ✔ Oxidative stress Reduces oxidative stress mTOR signaling pathway in lysosomal dysregulation and Inhibits mTOR pathway ✔ autophagy Mitochondrial stress; production Inhibits mitochondrial complex I ✔ of ROS by complex I C-reactive protein elevated in ✔ choroid and drusen, and gene Reduces C-reactive protein variant associated with AMD Chronic inflammation Suppresses inflammation via NFk-B Saisho Y, Endocr Metab Immune Disord Drug Targets 2015 6

Aspect of geographic atrophy Reported action of metformin ✔ pathogenesis Receptor for ✔ Oxidative stress Reduces oxidative stress Advanced Glycation mTOR signaling pathway in Endproducts lysosomal dysregulation and Inhibits mTOR pathway ✔ (RAGE) autophagy Mitochondrial stress; production Inhibits mitochondrial complex I ✔ of ROS by complex I C-reactive protein elevated in ✔ choroid and drusen, and gene Reduces C-reactive protein variant associated with AMD Chronic inflammation Suppresses inflammation via NFk-B Activation of RAGE (receptor for advanced glycation end-products) Rauvala, Biochim Biophys Acta 2010 Aspect of geographic atrophy Aspect of geographic atrophy Reported action of metformin ✔ Reported action of metformin pathogenesis pathogenesis ✔ Oxidative stress Reduces oxidative stress RPE cell senescence mTOR signaling pathway in lysosomal dysregulation and Inhibits mTOR pathway ✔ autophagy Mitochondrial stress; production Inhibits mitochondrial complex I ✔ of ROS by complex I C-reactive protein elevated in ✔ choroid and drusen, and gene Reduces C-reactive protein variant associated with AMD ✔ Chronic inflammation Suppresses inflammation via NFk-B Activation of RAGE (receptor for Reduces RAGE expression; reduces advanced glycation end-products) AGE-induced apoptosis Cao et al, IOVS 2013 7

Aspect of geographic atrophy Aspect of geographic atrophy Reported action of metformin Reported action of metformin pathogenesis pathogenesis ✔ ✔ Prevents senescence by various Prevents senescence by various RPE cell senescence mechanisms including AMPK RPE cell senescence mechanisms including AMPK activation activation DICER1 loss and inflammasome activation Aspect of geographic atrophy Reported action of metformin pathogenesis ✔ Prevents senescence by various RPE cell senescence mechanisms including AMPK ✔ activation DICER1 loss and inflammasome Increases DICER1; inhibits activation inflammasome activation Kim et al, PNAS 2014 8

Aspect of geographic atrophy Reported action of metformin pathogenesis Amyloid-containing vesicles ✔ Prevents senescence by various RPE cell senescence mechanisms including AMPK ✔ activation DICER1 loss and inflammasome Increases DICER1; inhibits activation inflammasome activation Amyloid-beta activation of complement and inflammation Green = Amyloid beta Red = iC3b, an activation-specific fragment of complement C3 Johnson et al, PNAS 2002 Aspect of geographic atrophy Aspect of geographic atrophy Reported action of metformin Reported action of metformin pathogenesis pathogenesis ✔ ✔ Prevents senescence by various Prevents senescence by various RPE cell senescence mechanisms including AMPK RPE cell senescence mechanisms including AMPK ✔ ✔ activation activation DICER1 loss and inflammasome Increases DICER1; inhibits DICER1 loss and inflammasome Increases DICER1; inhibits activation inflammasome activation activation inflammasome activation ✔ ✔ Increases beta-amyloid clearance; Increases beta-amyloid clearance; Amyloid-beta activation of dephosphorylates tau43 and reduces Amyloid-beta activation of dephosphorylates tau43 and reduces complement and inflammation the main amyloidogenic protein, complement and inflammation the main amyloidogenic protein, BACE14 BACE14 Mast cell degranulation 9

Aspect of geographic atrophy Flat mount of choroid from subject with geographic atrophy Reported action of metformin pathogenesis ✔ Prevents senescence by various RPE cell senescence mechanisms including AMPK ✔ activation DICER1 loss and inflammasome Increases DICER1; inhibits activation inflammasome activation ✔ Increases beta-amyloid clearance; Amyloid-beta activation of dephosphorylates tau43 and reduces complement and inflammation the main amyloidogenic protein, ✔ BACE14 Attenuates activation of mast cells via Mast cell degranulation AMPK Degranulated mast cells Bhutto et al, BJO 2016 Metformin in non-diabetics • Polycystic ovarian disease • Adjunctive therapy for cancer • Borderline/pre-diabetics (recommended by the American Diabetic Association for the prevention of diabetes) 10

Randomized trial Inclusion Criteria • Oral metformin vs. observation (1:1) • AMD with GA area between 0.5 and 7 disc areas • Target enrollment = 100 subjects total • VA 20/20 to 20/400 • Normal kidney function Exclusion Criteria Visit schedule Baseline 6 months 12 months 18 months ✔ ✔ ✔ ✔ • Diabetes Spectralis FAF ✔ ✔ ✔ ✔ • Active CNV or anti-VEGF injections in Spectralis OCT the past 12 months ✔ ✔ ✔ ✔ Fundus • Potentially confounding retinal photography ✔ ✔ ✔ ✔ ETDRS conditions such as pathologic myopia, ✔ ✔ BCVA RVO NEI VFQ-25 -- -- ✔ ✔ Blood draw -- -- for genetics 11