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

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

Dec 20, 2023 102 likes •238 views

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

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Jay M. Stewart, MD University of California, San Francisco

A new clinical trial for geographic atrophy: 10 reasons it might work Disclosures

  • None

A B C

Mechanisms

  • Complement components found in

drusen

  • Genetic studies implicate complement

system (CFH)

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AMD treatments directed toward complement system

Rhoades et al, Clin Ophth 2015;9:1049-56

Complement

  • Lampalizumab – anti-factor D
  • MAHALO (phase 2)

– 18 months: 20.4% reduction in mean change from baseline – Larger effect with biomarkers

  • Phase 3 (CHROMA/SPECTRI):

q4-6 week injections

Brimonidine

  • Brimonidine: phase 2 data

– 22g injection at baseline and 6 months – 12 months: 19% and 28% reduction in progression rate in low- and high-dose groups – Neuroprotection

  • Phase 2b (BEACON): q3 months
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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 pathogenesis Reported action of metformin Oxidative stress

Kaarniranta et al, Autophagy 2013

Aspect of geographic atrophy pathogenesis Reported action of metformin Oxidative stress Reduces oxidative stress

✔

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Aspect of geographic atrophy pathogenesis Reported action of metformin Oxidative stress Reduces oxidative stress

✔

mTOR signaling pathway in lysosomal dysregulation and autophagy

RPE hypertrophy and dedifferentiation due to mTOR activation

Aspect of geographic atrophy pathogenesis Reported action of metformin Oxidative stress Reduces oxidative stress

✔

mTOR signaling pathway in lysosomal dysregulation and autophagy Inhibits mTOR pathway

✔

Aspect of geographic atrophy pathogenesis Reported action of metformin Oxidative stress Reduces oxidative stress

✔

mTOR signaling pathway in lysosomal dysregulation and autophagy Inhibits mTOR pathway

✔

Mitochondrial stress; production

  • f ROS by complex I

Ricci et al, Cell Death & Differentiation 2003

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Aspect of geographic atrophy pathogenesis Reported action of metformin Oxidative stress Reduces oxidative stress

✔

mTOR signaling pathway in lysosomal dysregulation and autophagy Inhibits mTOR pathway

✔

Mitochondrial stress; production

  • f ROS by complex I

Inhibits mitochondrial complex I

✔

Aspect of geographic atrophy pathogenesis Reported action of metformin Oxidative stress Reduces oxidative stress

✔

mTOR signaling pathway in lysosomal dysregulation and autophagy Inhibits mTOR pathway

✔

Mitochondrial stress; production

  • f ROS by complex I

Inhibits mitochondrial complex I

✔

C-reactive protein elevated in choroid and drusen, and gene variant associated with AMD

CRP staining pink (left) and white (right) HH (homozygous for Y to H mutation) shows a lot of staining for CRP in both samples

CFH Polymorphism

  • Higher levels of C-reactive protein seen

in choroid and drusen

Johnson, PNAS 2006

High C-reactive protein levels

  • Odds ratio = 9 for advanced AMD

Seddon, Ophthalmology 2010

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Aspect of geographic atrophy pathogenesis Reported action of metformin Oxidative stress Reduces oxidative stress

✔

mTOR signaling pathway in lysosomal dysregulation and autophagy Inhibits mTOR pathway

✔

Mitochondrial stress; production

  • f ROS by complex I

Inhibits mitochondrial complex I

✔

C-reactive protein elevated in choroid and drusen, and gene variant associated with AMD Reduces C-reactive protein

✔

Aspect of geographic atrophy pathogenesis Reported action of metformin Oxidative stress Reduces oxidative stress

✔

mTOR signaling pathway in lysosomal dysregulation and autophagy Inhibits mTOR pathway

✔

Mitochondrial stress; production

  • f ROS by complex I

Inhibits mitochondrial complex I

✔

C-reactive protein elevated in choroid and drusen, and gene variant associated with AMD Reduces C-reactive protein

✔

Chronic inflammation

Saisho Y, Endocr Metab Immune Disord Drug Targets 2015

Aspect of geographic atrophy pathogenesis Reported action of metformin Oxidative stress Reduces oxidative stress

✔

mTOR signaling pathway in lysosomal dysregulation and autophagy Inhibits mTOR pathway

✔

Mitochondrial stress; production

  • f ROS by complex I

Inhibits mitochondrial complex I

✔

C-reactive protein elevated in choroid and drusen, and gene variant associated with AMD Reduces C-reactive protein

✔

Chronic inflammation Suppresses inflammation via NFk-B

✔

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Aspect of geographic atrophy pathogenesis Reported action of metformin Oxidative stress Reduces oxidative stress

✔

mTOR signaling pathway in lysosomal dysregulation and autophagy Inhibits mTOR pathway

✔

Mitochondrial stress; production

  • f ROS by complex I

Inhibits mitochondrial complex I

✔

C-reactive protein elevated in choroid and drusen, and gene variant associated with AMD Reduces C-reactive protein

✔

Chronic inflammation Suppresses inflammation via NFk-B

✔

Activation of RAGE (receptor for advanced glycation end-products)

Rauvala, Biochim Biophys Acta 2010 Receptor for Advanced Glycation Endproducts (RAGE)

Aspect of geographic atrophy pathogenesis Reported action of metformin Oxidative stress Reduces oxidative stress

✔

mTOR signaling pathway in lysosomal dysregulation and autophagy Inhibits mTOR pathway

✔

Mitochondrial stress; production

  • f ROS by complex I

Inhibits mitochondrial complex I

✔

C-reactive protein elevated in choroid and drusen, and gene variant associated with AMD Reduces C-reactive protein

✔

Chronic inflammation Suppresses inflammation via NFk-B

✔

Activation of RAGE (receptor for advanced glycation end-products) Reduces RAGE expression; reduces AGE-induced apoptosis

✔

Aspect of geographic atrophy pathogenesis Reported action of metformin RPE cell senescence

Cao et al, IOVS 2013

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Aspect of geographic atrophy pathogenesis Reported action of metformin RPE cell senescence Prevents senescence by various mechanisms including AMPK activation

✔

Aspect of geographic atrophy pathogenesis Reported action of metformin RPE cell senescence Prevents senescence by various mechanisms including AMPK activation

✔

DICER1 loss and inflammasome activation

Kim et al, PNAS 2014

Aspect of geographic atrophy pathogenesis Reported action of metformin RPE cell senescence Prevents senescence by various mechanisms including AMPK activation

✔

DICER1 loss and inflammasome activation Increases DICER1; inhibits inflammasome activation

✔

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Aspect of geographic atrophy pathogenesis Reported action of metformin RPE cell senescence Prevents senescence by various mechanisms including AMPK activation

✔

DICER1 loss and inflammasome activation Increases DICER1; inhibits inflammasome activation

✔

Amyloid-beta activation of complement and inflammation

Amyloid-containing vesicles Johnson et al, PNAS 2002 Green = Amyloid beta Red = iC3b, an activation-specific fragment of complement C3

Aspect of geographic atrophy pathogenesis Reported action of metformin RPE cell senescence Prevents senescence by various mechanisms including AMPK activation

✔

DICER1 loss and inflammasome activation Increases DICER1; inhibits inflammasome activation

✔

Amyloid-beta activation of complement and inflammation Increases beta-amyloid clearance; dephosphorylates tau43 and reduces the main amyloidogenic protein, BACE14

✔

Aspect of geographic atrophy pathogenesis Reported action of metformin RPE cell senescence Prevents senescence by various mechanisms including AMPK activation

✔

DICER1 loss and inflammasome activation Increases DICER1; inhibits inflammasome activation

✔

Amyloid-beta activation of complement and inflammation Increases beta-amyloid clearance; dephosphorylates tau43 and reduces the main amyloidogenic protein, BACE14

✔

Mast cell degranulation

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Flat mount of choroid from subject with geographic atrophy Degranulated mast cells Bhutto et al, BJO 2016

Aspect of geographic atrophy pathogenesis Reported action of metformin RPE cell senescence Prevents senescence by various mechanisms including AMPK activation

✔

DICER1 loss and inflammasome activation Increases DICER1; inhibits inflammasome activation

✔

Amyloid-beta activation of complement and inflammation Increases beta-amyloid clearance; dephosphorylates tau43 and reduces the main amyloidogenic protein, BACE14

✔

Mast cell degranulation Attenuates activation of mast cells via AMPK

✔

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)

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Randomized trial

  • Oral metformin vs. observation (1:1)
  • Target enrollment = 100 subjects total

Inclusion Criteria

  • AMD with GA area between 0.5 and 7

disc areas

  • VA 20/20 to 20/400
  • Normal kidney function

Exclusion Criteria

  • Diabetes
  • Active CNV or anti-VEGF injections in

the past 12 months

  • Potentially confounding retinal

conditions such as pathologic myopia, RVO

Visit schedule

Baseline 6 months 12 months 18 months Spectralis FAF ✔ ✔ ✔ ✔ Spectralis OCT ✔ ✔ ✔ ✔ Fundus photography ✔ ✔ ✔ ✔ ETDRS BCVA ✔ ✔ ✔ ✔ NEI VFQ-25 ✔

  • ✔

Blood draw for genetics ✔

  • ✔
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Outcomes

  • Primary: rate of change in GA area
  • Secondary: vision and NEI VFQ-25

DSMC

  • Jeremy Keenan – UCSF/Proctor
  • Phoebe Lin – OHSU/Casey Eye Institute
  • Steven Yeh – Emory Eye Center

Sites

  • UCSF – enrolling
  • 9 others – pending IRB

Contact

  • eyestudy@ucsf.edu