NGM621 is a Potent Inhibitory Anti-Complement C3 Antibody in - PowerPoint PPT Presentation

Poster # B0267 NGM621 is a Potent Inhibitory Anti-Complement C3 Antibody in Development for Treatment of Geographic Atrophy Alexander Loktev, Iris Ngan, Kalyani Mondal, Yan Wang, Jian Luo, Darrin Lindhout, Bin Fan, Raj Haldankar, Jie Tang, Husam Younis, David Shen, Hui Tian, and Zhonghao Liu NGM Biopharmaceuticals, South San Francisco, CA, USA

Poster # B0267 Financial Disclosures: All authors are employees of NGM Biopharmaceuticals, South San Francisco, CA, USA

Geographic Atrophy (GA) is an Advanced Form of AMD Early AMD Intermediate AMD Advanced AMD Choroidal Neovascularization Geographic Atrophy Small or intermediate drusen, Larger or more numerous +/- pigmentary changes drusen, +/- pigmentary changes • GA is characterized by progressive and irreversible loss of photoreceptors, retinal pigment epithelium (RPE) and choriocapillaris • GA is typically bilateral and lesion enlargement results in irreversible blindness • GA affects ~5 million people globally and ~ 1 million people in the US • Currently there are no effective treatments for GA CNV = choroidal neovascularization Fleckenstein et al, Ophthalmology 2018, 125(3): 369-390; Friedman et al, Arch Ophthalmol. 2004, 122: 564-572 3

� � � � � � � � � Complement Activation is Associated with Development of Advanced AMD CFH CFI C9 C2/CFB C3 a ARMS2-HTRA1 CFH C2/CFB-SKIV2L 800 SLC16A8 SYN3-TIMP3 APOE 600 CETP 400 C3 200 ADAMTS9-AS NPLOC4-TSPAN10 C20orf85 20 CTRB2-CTRB1 VEGFA CF1 MIR6130-RORB KMT2E-SRPK2 LIPC TNFRSF10A COL8A1 PILRB-PILRA C9 TMEM97-VTN 15 RDH5-CD63 ARHGAP21 B3GALTL RAD51B –log 10 ( P ) MMP9 TGFBR1 TRPM3 ABCA1 ACAD10 SPEF2 COL4A3 CNN2 10 5 0 1 3 5 7 9 11 13 15 17 19 21 X MT 2 4 6 8 10 12 14 16 18 20 22 Y Chromosome b c Variants in the complement pathway account for the majority of the known genetic risk for AMD Fritsche et al. Nat Genet 2016 4

Pathological Dysregulation of Complement System Provides Rationale for Total Complement Inhibition for Treatment of GA Complement Deposition on Photoreceptors Simultaneous Inhibition of Classical and Alternative Precedes their Degeneration in Human GA Complement Pathways is Protective in Rodent Retinal Degeneration Model non-atrophic GA lesion border Katschke et al. Sci. Reports 2018 Katschke et al. Sci. Reports 2018 • Preclinical retinal degeneration models show greatest • Pathological activation of complement system is strongly benefit from inhibition of both classical and alternative implicated in development and progression of GA complement pathways secondary of AMD Ø Unsuccessful late stage clinical trials with alternative pathway complement inhibitors in GA provide rationale for developing inhibitors of all complement activation pathways 5 ��������������������������������� ��������������������������������� ��������������������������������� ���������������������������������

NGM621 Targets Complement C3, Blocking All Three Pathways of Complement Activation Classical Alternative Lectin Pathway Pathway Pathway Alternative pathway inhibitors do C4 Factor B not block classical/lectin pathway Factor D C2 Inhibition at C3 may provide superior efficacy for treatment of GA NGM621 C3 • Phagocytosis C3a • Tissue recruitment C3b Opsonization • Inflammation • Ag presentation • Chemotaxis • Vascular permeability Anti-C5 Abs do not block all C5 C5 convertase activities mediated by C3b / C3a C5a Membrane Attack Complex (MAC) Cell lysis 6

Discovery and Engineering of NGM621: A Potent Anti-Complement C3 Antibody NGM Hybridoma Antibody Discovery Platform NGM621 is a humanized monoclonal antibody selected for • Ø High affinity binding to intact C3 determined by surface plasmon resonance (SPR) Ø Complete and potent inhibition of C3a release in biochemical assay Ø Completed and potent inhibition of complement activation via alternative and classical pathways in hemolytic assays Fc receptor effector function eliminated • • Inhibitory activity is identical for common C3 SNPs (A80G and P292G) • Favorable biophysical properties High solubility and low viscosity • • Excellent long-term stability Binding by SPR C3a Release Assay Complement Hemolytic Assays rc e n t ly s is n o rm to n o in h ib itio 3.0 0 0 0 0 0 mAb 1 Response (RLU x 10 5 ) 3 8 G 10 mAb 1 1 0 0 3 8 G 10 mAb 2 Hemolysis (%) 3 D 8 mAb 2 3 D 8 2.0 mAb 3 0 0 0 0 0 1 5 C 1 2 mAb 3 1 5 C 1 2 5 0 1.0 0 0 0 0 0 0 -1 0 1 2 3 0 0 .0 0 1 0 .0 1 0 .1 1 1 0 1 0 0 1 0 0 0 1 0 0 0 0 [Antibody] Log(nM) [Antibody] (nM) 7

NGM621 Binds to Intact Human and Cynomolgus Monkey C3 with High Affinity Binding to Human C3 at 37 ° C Binding to Cyno C3 at 37 ° C K D = 0.34 nM K D = 0.4 nM 2 5 0 2 0 0 R e s p o n s e [R U ] 2 0 0 Response (RU) Response (RU) R e s p o n s e [R U ] 1 5 0 1 5 0 1 0 0 1 0 0 5 0 5 0 0 0 0 2 0 0 4 0 0 6 0 0 8 0 0 1 0 0 0 0 2 0 0 4 0 0 6 0 0 8 0 0 1 0 0 0 Time (s) Time (s) T im e (s ) T im e (s ) Binding affinity between NGM621 and human or cynomolgus monkey C3 measured by SPR at 37 ° C 8

NGM621 Affinity to C3 Cleavage Fragments is Significantly Lower Compared to Affinity to Intact C3 • During complement activation, and inactivation by host factors, C3 is sequentially proteolyzed into fragments C3a, C3b/iC3b, C3c and C3d • C3 fragments play role physiological functions including inflammation, activation of adaptive immune system, opsonization, phagocytosis and cell lysis • NGM621 is >100 fold selective for intact C3 over C3b and other C3 proteolytic products NGM621 Binding to Human C3 and C3b Response (RU) Time (s) 9

NGM621 Potently Inhibits Classical and Alternative Complement Activation Pathways • Canonical hemolytic assays allow for functional analysis of complement inhibitors • C3 concentration in vitreous humor of GA patients was reported to be 150 nM ( Loyet, K. M., et al., 2012) Alternative Classical Lectin Pathway Pathway Pathway NGM621 Inhibition of Classical Pathway NGM621 Inhibition of Alternative C4 (CP) Hemolytic Assay Pathway (AP) Hemolytic Assay Factor B • C3 depleted human serum supplemented C2 C3 depleted human serum supplemented • Factor D with 150 nM human C3 with 150 nM human C3 Lysis of sheep erythrocytes coated with • Lysis of rabbit erythrocytes • anti-sheep IgM Requires Mg++ and chelation of Ca++ C3 • Requires Mg++ and Ca++ • C3 convertase C3a NGM621 CP NGM621 AP 120 120 C3b IC 50 = 74.1 nM IC 50 = 37 nM Hemolysis (%) 100 100 Hemolysis (%) 80 80 C5 C5 convertase 60 C5a 60 40 40 MAC 20 20 0 0 0 1 2 3 4 -20 -20 0 1 2 3 4 Log Concentration (nM) Log Concentration (nM) Hemolysis 10

Intravitreally Administered NGM621 Inhibits LPS-mediated Complement Activation in Cynomolgus Monkey • Durability and in vivo efficacy of NGM621 after intravitreal injection (IVT) in Cynomolgus Monkey eye was assessed based on inhibition of C3a release, a proximal product of complement C3 proteolysis • C3a protein concentration was measured in aqueous humor (AH) samples • In the healthy eye baseline levels of C3 proteolysis and C3a production are low • A carefully optimized low dose of LPS was used to transiently activate complement Testing NGM621 in vivo Activity in the Eye of NGM621 Inhibits Complement Activation up to Cynomolgus Monkeys 4 Weeks in Cynomolgus Monkey Eyes Treatment groups (n=12 eyes per treatment group) Vehicle or NGM621 8 mg/eye • 16 ✱✱ ✱ ✱ AH samples collected prospectively • AH C3a (fold change 8 from baseline) Vehicle NGM621 IVT LPS IVT NGM621 8 mg/eye 4 AH AH AH AH 2 Day 1 22 23 28 1 Day -3 Baseline 0.5 Day 22 Day 23 Day 28 C3a concentration in AH samples were measured by ELISA and normalized to baseline (day -3) concentration LPS IVT 11

NGM621: A Potent Anti-Complement C3 Antibody NGM621 Molecule Attributes Type Humanized IgG1 monoclonal antibody Target Binds & inhibits Complement C3 Molecular Weight ~150 kDa Affinity (Biacore binding) K D = 0.34 nM, >100 specific to C3 over C3b Potency (hemolytic assays) AP IC 50 =37nM; CP IC 50 =74nM (150 nM C3 concentration) Effector Function 2-point mutations in the Fc region eliminate effector function Concentration 15mg, 100ul IVT dose (150 mg/mL) Formulation Liquid Route of Administration IVT Injection • Currently completing the first-in-human open-label single dose (SD) and multidose (MD) Phase 1 study of 15 GA patients (NCT04014777) • Favorable safety and tolerability supports continued development of the maximum tolerated dose in Phase 2b study in GA • Preclinical evidence suggest anti-angiogenic effect of C3 inhibition – see ARVO Abstract/Video Presentation # B0268 12

Poster # B0267 Thank you! Contact information: Zhonghao Liu: zlui@ngmbio.com Novel Biology. Powerful Medicines. Transformative Impact.