Content guidance and source: Peter K . Kaiser, MD; *Editorially independent content supported by advertising from GenentechRETINA PIPELINE

A VIEW INTO ONGOING INNOVATION

November/December 2019

Tyrosine Kinase cascade

Therapeutic Protein

VEGF-R1

VEGF-AVEGF-BPLGF

VEGF-AVEGF-C

VEGF-CVEGF-D

VEGF-R2 VEGF-R3

Tyrosine Kinase inhibitor (TKi) Pathways

OTX-TKi (Ocular Therapeutix)RTKi-MPP (Kala)GB-102 (Graybug)PAN 90806 (Panoptica)SK 1011 (Sanwa Kagaku)sutent (x-82) (Tyrogenex)axitinib (Clearside Biomedical) AR-13503 (Aerie Pharmaceuticals) Caveolin subdomain downstream inhibitorCVX-51401 (CavtheRx)

W E T A M D

Gene Therapy

Extended Duration Options

RGX-314 (RegenxBio)ADVM-022 (Adverum)HMR59 (Hemera)

DNA Genome

Nuclear Pore

Therapeutic GeneSURVIVAL

DIFFERENTIATION

PROLIFERATION

SHCGRB2 AKT

RAS

ERKSOS

RAS

RAF

MEK

ERK

ranibizumab Port Delivery System (PDS)

PETER K. KAISER, MD | Medical Advisor, Retina Today; Cole Eye Institute, Cleveland Clinic; Cleveland, Ohio

Keeping an eye on drug development in AMD is difficult. Therapeutic options move from one phase to the next at different times and at different rates, and drugs may start their path in one disease only to find success treating another. We hope you use this poster to understand where we stand in clinical development for AMD treatment as we enter 2020.

Ang1Ang2Ang 3/4

TIE2 Receptor

© 2019 by The Angiogenesis Foundation, Inc., All Rights Reserved

Integrin Receptors

TIE2 Activation Pathways

faricimab (Genentech/Roche)AXT107 (AsclepiX Therapeutics)

PDGF-AAPDGF-BBPDGF-ABPDGF-CCPDGF-DD

PDGF Receptor

Pericyte

Clearside Suprachoroidal injection

Clearside Biomedical

Genentech

Polymer Extended Release:

OTX-TKI (Ocular Therapeutix) GB-102 (Graybug Vision) KSI-301 (Kodiak Sciences) AR-13503 (Aerie Pharmaceuticals)

Kodiak Sciences

PLGF D C B AVEGF

Extracellular VEGF Pathways

pegaptanib (Valeant)ranibizumab (Genentech/Roche)bevacizumab (Genentech/Roche)brolucizumab (Novartis) abicipar pegol (Allergan)KSI-301 (Kodiak Sciences)FYB201 (biosimilar) (Formycon/Bioeq)PF582 (biosimilar) (Pfenex/Pfizer)razumab (biosimilar) (Intas)CHS3551 (biosimilar) (Coherus Biosciences)SB-11 (biosimilar) (Samsung Bioepis)FYB201 (biosimilar) (Formycon/Bioeq)ONS-510 (biosimilar) (Outlook Therapeutics)Xlucane (biosimilar) (Xbrane)CHS3551 (biosimilar) (Coherus Biosciences)PD807 (biosimilar) (Biopharm)SBS7001 (biosimilar) (Siam Bioscience)aflibercept (Regeneron/Bayer)conbercept (Kanghong Biotech)CHS-2020 (biosimilar) (Coherus Biosciences)SOK583A1 (biosimilar) (Sandoz/Hexal)MYL1710 (biosimilar) (Mylan/Momenta)ALT-L9 (biosimilar) (Alteogen)OPT-302 (Opthea)

Integrin Pathways

risuteganib (Allegro/Senju)THR-687 (Oxurion)

volociximab (IVERIC bio)SF0166 drop (SciFluor)AXT107 (AsclepiX Therapeutics)

PAN

axitinib (Clearside Biomedical)RGX-314 (RegenxBio)

FDA-APPROVED

FDA-APPROVED

OFF-LABEL

FDA-APPROVED

FDA-APPROVED

RETINA PIPELINE A VIEW INTO ONGOING INNOVATION

D RY A M D

Dry AMD Emerging Treatment Strategies

Prevent photoreceptor and RPE loss • Neuroprotection • Reduce toxic by-product accumulation • Visual cycle modulation • Stem CellsSuppress inflammationOther approaches

Other approaches

Inflammasome Inhibitionkamuvudine (Inflammasome Therapeutics) Xiflam (OcuNexus)Matrix Modulation HtrA1 inhibitordoxycycline (Oracea) FHTR2163 (Genentech/Roche)

Neuroprotection

Repair mitochondrial dysfunction/ oxidative stresselamipretide (Stealth)risuteganib (Allegro)photobiomodulation (LumiThera)brimonidine tartrate (Allergan)

NT-501 - ciliary neurotrophic factor (Neurotech)tandospirone (Alcon)OT-551 (Othera)FA

ILED

Stem Cells

Human embryonic stem cells (hESCs) (Lineage Cell Therapeutics)(Regenerative Patch Technologies)Umbilical stem cells (hUTCs) Human retinal progenitor cells ( jCyte)

Reduce toxic by-product accumulation

Prevents Amyloid Aβ oligomer assemblyGAL-101 (Galimedix) ALZ-801 (Alzheon)Reduce DHA peroxidationRT011 (Retrotope)

Glatiramer acetate (Copaxone, FDA approved, Teva)RN6G (Pfizer)GSK933776 (GSK)FA

ILED

Visual cycle modulation

ALK-001 (Alkeus) fenretinide (Sytera)emixustat (Acucela)OT-551 (Othera)FA

ILED

Content guidance and source: Peter K . Kaiser, MD; *Editorially independent content supported by advertising from Genentech

MBL

C4

C2

C3C3

C3

Factor B

Properdin

Factor D

C3b

C5C5b

MAC

C6

C7

C8

C9

C5a C5a

C3a

C3a

C3b or iC3b

Chemotatic or anaphylactic peptides

Convertases

Alternative pathway

Lectin pathway

Classical pathways

MAC proteins

C5 Convertase(C4b2a3b, C3bBbC3b)

C4b2aC3bBb

C1r + C1s

Host Cell

Host Cell(non-activating surface)

Host Cell

Host Cell

MASPs

C1qSuppress inflammation

PETER K. KAISER, MD• Medical Advisor, Retina Today• Cole Eye Institute, Cleveland Clinic• Cleveland, Ohio

Complement inhibition location and molecule ANX007 (Annexon) APL-2 (Apellis) CB2782 (Catalyst) Zimura (IVERIC bio) ALXN1720 (Alexion) HMR59 (Hemera) danicopan (Achillion) CR2-fH Ionis-FB-LRX (Ionis)

Alternative

Lectin Classical

• Opsonization, phagocytosis• IC solubilization• B cell activation (CR2 and C3dg)• Clearance of debris and apoptotic cells

• Activation of T Cells and APCs• Tissue regeneration• Leukocyte recruitment and activation• Inflammasome activation

• Cell activation• Killing and/or

target damage

• Activation of T cells and APCs

Amplification Loop

Modified by Dr. Kaiser from M Walport . Complement. First of two parts. NEJM. 2001;344(14):1058-1066 and other sources.

November/December 2019

t FA I L E D eculizumab (Alexion) tesidolumab (Novartis) lampalizumab (Genentech/Roche) CLG561 (Novartis)