Adagene : Immuno-Oncology 360⁰ Summit 2025 Presentation

Published: 2025-04-03 14:25:05 ET ADAG

ADG126 SAFEbody® :

Targeting CTLA-4+ Tregs to Overcome MSS CRC Resistance

Peter Luo, PhD

CEO & President of R&D, Adagene

March 2025

MSS CRC is a Major Unmet Medical Need: Current Immunotherapy is Ineffective from Early to Late Stage

3L+ MSS CRC Without Liver Metastases is a Substantial Initial Opportunity

• Patients with no liver metastases (NLM) show responses to IO therapy, representing ~30% of MSS mCRC patients

• Several companies are conducing registration trials in 3L+ MSS mCRC NLM

• Thanks to its safety profile, ADG126/pembrolizumab is being studied in neoadjuvant settings (NCT06846268), and in combination with the current standard of care (e.g., TAS-102 and bevacizumab)

Source from: Cerner/Envisa 2022 Drug Treated Patients and CancerMpact Treatment Architecture

* US/EU5 patients treated annually

Immune-Suppressive Tumor Microenvironment in Metastatic MSS versus MSI-H mCRC: Treg, TILs, and PD-L1 Expression

High Tregs 3

Minimal TILs 2, 3

Negative/Low PD-L1 Expression 2

25%

22%

20% 15% 10% 5%

14%

MSS MSI

Treg/CD3+%

FOXP3

CD8

TIL and stroma

PD-L1

Invasive front

cells/0.25mm2

Source from:1.S Michel et al. High density of FOXP3-positive T cells infiltrating colorectal cancers with microsatellite instability. British Journal of Cancer 2008; 99, 1867-1873. DOI:

MSI-H1

MSS1

CD3+

CD8+

(T cell) FoxP3+

(CTL)

(Treg)

10.1038/sj.bjc.6604756

2. Le et al. PD-1 blockade in tumors with mismatch repair deficiency. N Engl J Med 2015; 372:2509-20. DOI: 10.1056/NEJMoa1500596

3. NJ Llosa et al. The Vigorous Immune Microenvironment of Microsatellite Instable Colon Cancer Is Balanced by Multiple Counter-Inhibitory Checkpoints. Cancer Discov 2014; 5(1) 43-51.

DOI: 10.1158/2159-8290

Targeting Intra-Tumoral CTLA-4+ Treg Depletion for Immune-Resistant MSS mCRC with Masked Anti-CTLA-4 SAFEbody, ADG126

a Deplete CTLA-4+ Tregs in TME by epitope-enhanced ADCC/P anti-CTLA-4

01 Recruit TILs Cells into Tumors

02 Up-Regulate PD-L1 in TME

Enrich/activate ADG126 in TME while minimizing cleaved ADG126 in circulation

Source from: 1. Xu, S. et al. (2020). Distribution of PD-L1 expression level across major tumor types. Journal of Clinical Oncology

Dynamic Precision Library Technology Widens Therapeutic Window for Two Cross-Reactive Anti-CTLA-4 Antibodies

Masking peptide

IgG1 wild-type

▪ 20X higher dosing level over ipi, consistent with GLP-tox over ipi

▪ Masking results in higher activated ADG126 in TME vs blood

▪ Dose-dependent CTLA-4-mediated Treg depletion in TME

ADG126 SAFEbody®ADG116 NEObody

KD (nM)

ADG116

Human

2.8

Cyno Monkey

1.2

Mouse

2.4

Rat

1.8

IgG1 wild-type

▪ 10X higher ADCC than ipi w/o Fc engineering

▪ Targets a unique/conserved epitope of CTLA-4 across different species

▪ ≥ 5X higher potency and 3X improved GLP-tox over ipi

(Activated ADG126)

ADG126 Has a Higher Safety Margin Over ADG116 and Ipilimumab in Cyno Tox Study

BMS CytomX

Adagene

Cyno Tox Study

Ipilimumab$

Ipilimumab Probody

(BMS-986249)$

ADCC-enhanced

Ipilimumab

Probody (BMS-986288)$

NEObody

ADG116

SAFEbody

ADG126

Highest Non-severely Toxic

Dose (QW, 1 month)

10 mg/kg

50 mg/kg

10 mg/kg

30 mg/kg

200 mg/kg

RP2D*

1 mg/kg Q6W +

Nivo Repeat dosing

3 mg/kg Q3/6W +

PD-1

10 or 20 mg/kg Q6W + Pembro

* Not head-to-head comparison

$ John Engelhardt, et al. Preclinical characterization of novel anti-CTLA-4 prodrug antibodies with an enhanced therapeutic index. AACR 2020. Poster 4551.

Immunotherapy in Comparison with the Current SOC for 3L+ MSS CRC

Fruquintinib Compounds

Sunlight TAS102 plus Avastin w/o Liver mets with Liver mets

ADG126 Dose Level + Pembro 200mg Q3W

10 mg/kg Q6W

10 mg/kg Q3W

20 mg/kg x1 +10 mg/kg Q3W

ORR (%)

Discontinuation

Rate

13%

15-20%

≥G3 TRAEs

72%

6.1

4.3

4.9

0*a

23*b

33*C

20%

42%

10%

36-46%

Source from: Josep Tabernero et al. 2023 ASCO Gastrointestinal; Gerald W. Prager et al. N Engl J Med 2023 May 04;388(18); Shukui Qin et al. 2019 CSCO; Jin Li et al. JAMA. 2018;319(24):2486-2496;

* NLPM group; a, One patient with target lesion assessed as "PR", overall assessment as "PD" due to new lesion. b. Including one unconfirmed PR (10 mg/kg Q3W). c. all PRs are confirmed.

The Addition of Ipilimumab to Nivolumab Resulted in a Disproportionate Increase in Toxicity with Limited Improvement in Response Rates

Ipi Monotherapy

Data in Melanoma across Trials

Ipi + Nivo Combo

Data in Melanoma across Trials

ORR%

Ipi dose (mg/kg, Q3W)

* Ipi at 1mpk Q6W was graphed as 0.5mpk Q3W

✓ Efficacy outcomes with ipilimumab were significantly improved when combined with anti-PD-1 (nivolumab).

✓

However, the incidence of severe adverse events leading to discontinuations also rose substantially, even with a threefold reduction in the dose of ipilimumab

%EArT 3G ≥

Combo (+Nivo) ≥ G3 TRAE

Combo (+Nivo) ORR

Treatment Discontinuation

Treatment discontinuation rate

Ipi Monothera

Combo (+Nivo ≥1 mpk

✓ Combination tox is similar at >3-fold lower Ipi dose to mono

✓

The discontinuation rate remains low for EXP cohorts (6%) for ADG126 + Pembro in MSS CRC (01/15/2025 data cut across all studied cohorts).

Literature data were digitized; each symbol represent one data point from each study; the shaded area represent 90% confidence interval for nonlinear regression of the data (when applicable)

Combining Efficacy and Safety Data with PK Modeling Drives Dosing Regimen Design - Reaching Efficacy Faster Without Sacrificing Safety

• Using a 20 mpk loading dose allows us to quickly exceed the target concentration in tumor while keeping cleaved drug in plasma below the concentration at which Gr3 events begin to emerge

The percentage of patients who reach the target concentration at a given dosing regimen

84 time

105 126 147 168

Source from: Minchinton, A., Tannock, I. Drug penetration in solid tumours. Nat Rev Cancer 6, 583-592 (2006).https://doi.org/10.1038/nrc1893

Epitope-Enhanced ADCC/P for Treg Depletion in TME

CTLA-4+ Treg depletion via epitope-enhanced ADCC/P of ADG116 vs ipilimumab

RLU

Changes of Intramoral Treg

Changes of intratumoral Treg

***

% Treg in CD4+ T

-3

-2

-1

Log(Ab)[nM]

MC38 Colon Cancer Model

MC38 colon cancer model

Tumor Volume (MeanSEM, mm3)

Vehicle

ADG116 (10 mg/kg)

ADG116-siFc (10 mg/kg)

Dosing

Days Post Tumor Inoculation

Source from: 1. Martineau R, Susini S, Marabelle A. Fc Effector Function of Immune Checkpoint Blocking Antibodies in Oncology. Immunol Rev. 2024 Nov;328(1):334-349. doi: 10.1111/imr.13427. 2. Aurélien Marabelle, presentation at SITC Webinar, Intratumoral Anti CTLA-4: Checkpoint Blockade and/or Treg Depletion ?

Disclaimer

Adagene Inc. published this content on April 02, 2025, and is solely responsible for the information contained herein. Distributed via , unedited and unaltered, on April 03, 2025 at 18:24 UTC.