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

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

Jun 15, 2023 366 likes •507 views

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,

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SLIDE 1

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

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SLIDE 2

Financial Disclosures:

All authors are employees of NGM Biopharmaceuticals, South San Francisco, CA, USA

Poster # B0267

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SLIDE 3

Geographic Atrophy (GA) is an Advanced Form of AMD

3

Choroidal Neovascularization Geographic Atrophy

Advanced AMD Intermediate AMD

Larger or more numerous drusen, +/- pigmentary changes

Early AMD

Small or intermediate 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

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SLIDE 4

4

Complement Activation is Associated with Development of Advanced AMD

Fritsche et al. Nat Genet 2016

  • a

COL4A3 COL8A1 SPEF2 VEGFA KMT2E-SRPK2 PILRB-PILRA TNFRSF10A MIR6130-RORB TRPM3 TGFBR1 RDH5-CD63 ACAD10 B3GALTL RAD51B LIPC CETP CTRB2-CTRB1 NPLOC4-TSPAN10 TMEM97-VTN C3 APOE MMP9 C20orf85 SLC16A8 SYN3-TIMP3 CNN2 ABCA1 ARHGAP21 ARMS2-HTRA1 CF1 C9 ADAMTS9-AS C2/CFB-SKIV2L

800 600 400 200 20 15 –log10 (P) 10 5 1 2 3 4 5 6 7 9 11 13 15 17 19 21 X MT 8 10 Chromosome 12 14 16 18 20 22 Y

CFH

b c

  • Variants in the complement pathway account for the majority of the known genetic risk for AMD

CFH C9 C2/CFB C3 CFI

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SLIDE 5

Pathological Dysregulation of Complement System Provides Rationale for Total Complement Inhibition for Treatment of GA

  • 5
  • Simultaneous Inhibition of Classical and Alternative

Complement Pathways is Protective in Rodent Retinal Degeneration Model Complement Deposition on Photoreceptors Precedes their Degeneration in Human GA

non-atrophic GA lesion border

Ø Unsuccessful late stage clinical trials with alternative pathway complement inhibitors in GA provide rationale for developing inhibitors of all complement activation pathways

Katschke et al. Sci. Reports 2018 Katschke et al. Sci. Reports 2018

  • Pathological activation of complement system is strongly

implicated in development and progression of GA secondary of AMD

  • Preclinical retinal degeneration models show greatest

benefit from inhibition of both classical and alternative complement pathways

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SLIDE 6

NGM621 Targets Complement C3, Blocking All Three Pathways of Complement Activation

6

C2 C4

Classical Pathway Lectin Pathway Alternative Pathway

Factor B Factor D C3b C5 C5 convertase C3a C5a

  • Inflammation
  • Chemotaxis
  • Vascular permeability
  • Phagocytosis
  • Tissue recruitment
  • Ag presentation

Cell lysis

NGM621

Inhibition at C3 may provide superior efficacy for treatment of GA

C3

Membrane Attack Complex (MAC)

Anti-C5 Abs do not block all activities mediated by C3b / C3a

Alternative pathway inhibitors do not block classical/lectin pathway

Opsonization

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SLIDE 7

Discovery and Engineering of NGM621: A Potent Anti-Complement C3 Antibody

7

  • 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

NGM Hybridoma Antibody Discovery Platform

[Antibody] Log(nM) Hemolysis (%)

Complement Hemolytic Assays

  • 1

1 2 3 5 0 1 0 0

rc e n t ly s is n o rm to n o in h ib itio 3 8 G 10 3 D 8 1 5 C 1 2

mAb 1 mAb 2 mAb 3

Binding by SPR

[Antibody] (nM)

3.0

Response (RLU x 105)

2.0 1.0

C3a Release Assay

0 .0 0 1 0 .0 1 0 .1 1 1 0 1 0 0 1 0 0 0 1 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0

3 8 G 10 3 D 8 1 5 C 1 2

mAb 1 mAb 2 mAb 3

  • 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
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SLIDE 8

NGM621 Binds to Intact Human and Cynomolgus Monkey C3 with High Affinity

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Binding to Cyno C3 at 37°C

2 0 0 4 0 0 6 0 0 8 0 0 1 0 0 0 5 0 1 0 0 1 5 0 2 0 0 2 5 0

T im e (s ) R e s p o n s e [R U ]

Time (s) Response (RU)

2 0 0 4 0 0 6 0 0 8 0 0 1 0 0 0 5 0 1 0 0 1 5 0 2 0 0

T im e (s ) R e s p o n s e [R U ]

Time (s) Response (RU)

KD = 0.34 nM KD = 0.4 nM

Binding affinity between NGM621 and human or cynomolgus monkey C3 measured by SPR at 37°C

Binding to Human C3 at 37°C

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SLIDE 9

NGM621 Affinity to C3 Cleavage Fragments is Significantly Lower Compared to Affinity to Intact C3

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  • 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

Time (s) Response (RU)

NGM621 Binding to Human C3 and C3b

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SLIDE 10

NGM621 Potently Inhibits Classical and Alternative Complement Activation Pathways

10

1 2 3 4

  • 20

20 40 60 80 100 120

Log Concentration (nM) Hemolysis (%) NGM621 CP IC50 = 74.1 nM NGM621 Inhibition of Classical Pathway (CP) Hemolytic Assay

  • C3 depleted human serum supplemented

with 150 nM human C3

  • Lysis of sheep erythrocytes coated with

anti-sheep IgM

  • Requires Mg++ and Ca++

1 2 3 4

  • 20

20 40 60 80 100 120

NGM621 Inhibition of Alternative Pathway (AP) Hemolytic Assay

  • C3 depleted human serum supplemented

with 150 nM human C3

  • Lysis of rabbit erythrocytes
  • Requires Mg++ and chelation of Ca++

NGM621 AP IC50 = 37 nM Log Concentration (nM) Hemolysis (%)

  • 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)

C2 C4

Classical Pathway Lectin Pathway Alternative Pathway

C3b C5 C5 convertase C3a C5a

C3

Factor B Factor D

MAC Hemolysis

C3 convertase

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SLIDE 11

Intravitreally Administered NGM621 Inhibits LPS-mediated Complement Activation in Cynomolgus Monkey

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  • 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

Treatment groups (n=12 eyes per treatment group)

  • Vehicle or NGM621 8 mg/eye
  • AH samples collected prospectively

C3a concentration in AH samples were measured by ELISA and normalized to baseline (day -3) concentration

Testing NGM621 in vivo Activity in the Eye of Cynomolgus Monkeys

Day -3 Baseline AH Day 1 NGM621 IVT 22 23 28 AH AH AH LPS IVT

AH C3a (fold change from baseline)

NGM621 Inhibits Complement Activation up to 4 Weeks in Cynomolgus Monkey Eyes

LPS IVT

Day 22 Day 23 Day 28 0.5 1 2 4 8 16

Vehicle NGM621 8 mg/eye

✱✱ ✱ ✱

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SLIDE 12

NGM621: A Potent Anti-Complement C3 Antibody

12

NGM621 Molecule Attributes

Type

Humanized IgG1 monoclonal antibody

Target

Binds & inhibits Complement C3

Molecular Weight

~150 kDa

Affinity (Biacore binding)

KD = 0.34 nM, >100 specific to C3 over C3b

Potency (hemolytic assays)

AP IC50 =37nM; CP IC50 =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
  • f 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

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SLIDE 13

Thank you! Contact information:

Zhonghao Liu: zlui@ngmbio.com

Poster # B0267

Novel Biology. Powerful Medicines. Transformative Impact.