Adagene Announces Updated Data from Phase 1b/2 Study of Muzastotug in Combination with KEYTRUDA® (pembrolizumab) in Colorectal Cancer at ASCO Gastrointestinal Cancers Symposium

Rhea-AI Summary

Adagene (NASDAQ: ADAG) announced updated clinical data for their Phase 1b/2 study of Muzastotug (ADG126) in combination with KEYTRUDA® for colorectal cancer treatment. The study showed promising results with a 33% overall response rate in microsatellite stable colorectal cancer patients, achieving four confirmed partial responses out of twelve patients using a 20 mg/kg loading dose followed by 10 mg/kg Q3W + pembrolizumab.

The treatment demonstrated a favorable safety profile with no Grade 4/5 treatment-related adverse events and no discontinuations to date. Pruritus was the most common side effect, occurring in 25% of patients. The company plans to expand the study to include patients with liver metastases. All responding patients remain on treatment at maintenance doses of either 10 mg/kg Q3W or Q6W in combination with pembrolizumab.

Positive

• 33% overall response rate in microsatellite stable colorectal cancer patients
• Four confirmed partial responses out of twelve patients
• No treatment discontinuations reported
• No Grade 4/5 treatment-related adverse events observed
• All responders remain on treatment

Negative

• Higher Grade 2/3 treatment-related adverse events observed in loading dose cohort
• 25% of patients experienced pruritus as side effect

Insights

Clinical Research Analyst

The latest data from Adagene's Phase 1b/2 trial represents a significant advancement in treating microsatellite stable colorectal cancer (MSS CRC), a notoriously difficult-to-treat cancer subtype that typically shows poor response to immunotherapy. The 33% overall response rate achieved with the new loading dose regimen (20 mg/kg followed by 10 mg/kg Q3W) marks a substantial improvement over the previous 23% ORR.

The trial's innovative loading dose strategy appears to be key in optimizing the therapeutic window. This approach allows for higher initial drug exposure to establish anti-tumor activity, followed by a maintenance dose that balances efficacy with long-term tolerability. The fact that all responders remain on treatment suggests durable responses, a important factor in immunotherapy success.

ADG126's SAFEbody technology demonstrates a differentiated approach by enhancing intra-tumoral accumulation while minimizing systemic exposure. This is particularly relevant for CTLA-4 inhibition, where the therapeutic window has historically been narrow. The absence of Grade 4/5 adverse events and no treatment discontinuations, despite higher G2/G3 events in the loading dose cohort, suggests a manageable safety profile that could potentially enable broader clinical application.

The planned expansion to include patients with liver metastases could significantly broaden the addressable patient population, as liver metastases are common in CRC and typically associated with poor prognosis. The potential for combination with standard of care treatments could further enhance ADG126's clinical utility and market position.

Oncology Expert

The clinical data for muzastotug represents a potential breakthrough in MSS CRC treatment, where current immunotherapy approaches have shown success. The 33% response rate is particularly noteworthy given that MSS tumors are traditionally considered 'cold' tumors resistant to immunotherapy. The novel epitope binding and enhanced Treg depletion mechanism, achieved without Fc engineering, suggests a fundamental improvement over existing CTLA-4 inhibitors.

The safety profile is especially impressive in the context of CTLA-4 inhibition, where toxicity has historically been a major limiting factor. While the loading dose cohort showed increased G2/G3 events, the ability to manage these through dose modification rather than discontinuation is clinically significant. The 25% incidence of pruritus as the most common TRAE is notably lower than historical data for other CTLA-4 inhibitors.

The masking technology's ability to increase intra-tumoral accumulation while maintaining optimal plasma concentrations represents a sophisticated approach to the classic efficacy-toxicity trade-off in cancer immunotherapy. This could potentially enable more aggressive dosing strategies without compromising safety, a important factor for combination therapies in colorectal cancer treatment.

Muzastotug (ADG126), an Anti-CTLA-4 SAFEbody^® in Combination with pembrolizumab showed 33% overall response rate in microsatellite stable colorectal cancer

Four confirmed partial responses out of twelve patients with 20 mg/kg loading dose followed by 10 mg/kg Q3W + pembrolizumab

No Grade 4/5 treatment related adverse events were observed and no discontinuations occurred to date

SAN DIEGO and SUZHOU, China, Jan. 27, 2025 (GLOBE NEWSWIRE) -- Adagene Inc. (“Adagene”) (Nasdaq: ADAG), a company transforming the discovery and development of novel antibody-based therapies, announced updated clinical data from ADG126 in microsatellite stable colorectal cancer (MSS CRC) at the ASCO Gastrointestinal (GI) Cancers Symposium in San Francisco, CA.

“These data, from the loading dose expansion cohort of our Phase 1b/2 trial, continue to demonstrate ADG126’s potential for patients with colorectal cancer.  Seeing four confirmed partial responses out of twelve patients, with no treatment related discontinuations, also highlights the differentiated therapeutic index of ADG126. CTLA-4 is clinically validated with a known correlation between dose, efficacy and toxicity to improve outcomes with PD-1 inhibitors, and now we know that our SAFEbody can deliver benefit to patients in a safe and efficacious way,” said Peter Luo, Chairman, CEO & President of R&D at Adagene.

Dr. Marwan Fakih, Professor of Medical Oncology and Therapeutics Research at City of Hope added, “Masking technology, which leads to increased intra-tumoral accumulation of cleaved ADG126 and maintains an optimal plasma concentration following higher and repeat dosing of ADG126, as well as enhanced Treg depletion through binding to a novel epitope without Fc engineering, position ADG126 to be a best-in-class CTLA-4 inhibitor.”

This Phase 1b/2, open-label, multicenter dose escalation and expansion combination study of ADG126 in combination with Merck’s (known as MSD outside of the US and Canada) anti-PD-1 therapy, KEYTRUDA^® (pembrolizumab; 200 mg, Q3W) in MSS CRC with no liver and peritoneum metastases previously demonstrated efficacy at the 10 mg/kg Q3W dose, with overall response rate (ORR) of 23%, including four confirmed partial responses and one unconfirmed partial response. Newly shared data with the 20 mg/kg loading dose followed by 10 mg/kg Q3W in combination with pembrolizumab achieved an improved ORR of 33%, and all responders remain on treatment at a maintenance dose of 10 mg/kg Q3W or 10 mg/kg Q6W in combination with pembrolizumab. Per protocol, dose modifications were permitted to manage toxicity, enabling investigators to optimize each patient’s course of treatment to further improve the duration of responses. Time to event endpoints will be reported when the data mature in 2025. Due to the enhanced therapeutic index of ADG126 in combination with anti-PD-1, the Company plans to evaluate a broader patient population in the dose expansion cohort, including patients with liver metastases, with standard of care combinations.

No Grade 4/5 safety events were seen with ADG126 to date and pruritus (25%) was the most commonly observed treatment-related adverse event (TRAE). Higher G2/G3 TRAEs were observed in the loading dose cohort but were managed through dose modification and infrequent use of infliximab/medical intervention, resulting in no discontinuations to date. The totality of data to date supports that Adagene’s anti-CTLA-4, ADG126, plus pembrolizumab has potential to be a best-in-class treatment for patients with MSS CRC.

About Adagene
Adagene Inc. (Nasdaq: ADAG) is a platform-driven, clinical-stage biotechnology company committed to transforming the discovery and development of novel antibody-based cancer immunotherapies. Adagene combines computational biology and artificial intelligence to design novel antibodies that address globally unmet patient needs. The company has forged strategic collaborations with reputable global partners that leverage its SAFEbody^® precision masking technology in multiple approaches at the vanguard of science.

Powered by its proprietary Dynamic Precision Library (DPL) platform, composed of NEObody™, SAFEbody, and POWERbody™ technologies, Adagene’s highly differentiated pipeline features novel immunotherapy programs. The company’s SAFEbody technology is designed to address safety and tolerability challenges associated with many antibody therapeutics by using precision masking technology to shield the binding domain of the biologic therapy. Through activation in the tumor microenvironment, this allows for tumor-specific targeting of antibodies in tumor microenvironment, while minimizing on-target off-tumor toxicity in healthy tissues.

Adagene’s lead clinical program, ADG126 (muzastotug), is a masked, anti-CTLA-4 SAFEbody that targets a unique epitope of CTLA-4 in regulatory T cells (Tregs) in the tumor microenvironment. ADG126 is currently in phase 1b/2 clinical studies in combination with anti-PD-1 therapy, particularly focused on Metastatic Microsatellite-stable (MSS) Colorectal Cancer (CRC). Validated by ongoing clinical research, the SAFEbody platform can be applied to a wide variety of antibody-based therapeutic modalities, including Fc empowered antibodies, antibody-drug conjugates, and bi/multispecific T-cell engagers.

For more information, please visit: https://investor.adagene.com.
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SAFEbody^® is a registered trademark in the United States, China, Australia, Japan, Singapore, and the European Union.

KEYTRUDA^® is a registered trademark of Merck Sharp & Dohme LLC, a subsidiary of Merck & Co., Inc., Rahway, NJ, USA.

Safe Harbor Statement
This press release contains forward-looking statements, including statements regarding certain clinical results of ADG126, the potential implications of clinical data for patients, and Adagene’s advancement of, and anticipated preclinical activities, clinical development, regulatory milestones, and commercialization of its product candidates. Actual results may differ materially from those indicated in the forward-looking statements as a result of various important factors, including but not limited to Adagene’s ability to demonstrate the safety and efficacy of its drug candidates; the clinical results for its drug candidates, which may not support further development or regulatory approval; the content and timing of decisions made by the relevant regulatory authorities regarding regulatory approval of Adagene’s drug candidates; Adagene’s ability to achieve commercial success for its drug candidates, if approved; Adagene’s ability to obtain and maintain protection of intellectual property for its technology and drugs; Adagene’s reliance on third parties to conduct drug development, manufacturing and other services; Adagene’s limited operating history and Adagene’s ability to obtain additional funding for operations and to complete the development and commercialization of its drug candidates; Adagene’s ability to enter into additional collaboration agreements beyond its existing strategic partnerships or collaborations, and the impact of the COVID-19 pandemic on Adagene’s clinical development, commercial and other operations, as well as those risks more fully discussed in the “Risk Factors” section in Adagene’s filings with the U.S. Securities and Exchange Commission. All forward-looking statements are based on information currently available to Adagene, and Adagene undertakes no obligation to publicly update or revise any forward-looking statements, whether as a result of new information, future events or otherwise, except as may be required by law.

Investor Contact:

Bruce Mackle
LifeSci Advisors
bmackle@lifesciadvisors.com

FAQ

What is the overall response rate for Muzastotug combined with KEYTRUDA in colorectal cancer patients?

The combination therapy showed a 33% overall response rate in microsatellite stable colorectal cancer patients, with four confirmed partial responses out of twelve patients.

What are the main side effects reported in the ADAG Phase 1b/2 trial?

The main side effect was pruritus, affecting 25% of patients. While higher Grade 2/3 treatment-related adverse events were observed in the loading dose cohort, no Grade 4/5 events were reported.

What is the dosing regimen for Muzastotug in the ADAG clinical trial?

The trial used a 20 mg/kg loading dose followed by 10 mg/kg Q3W maintenance dose, combined with pembrolizumab (200 mg, Q3W).

What are Adagene's (ADAG) future plans for the Muzastotug clinical trial?

Adagene plans to evaluate a broader patient population in the dose expansion cohort, including patients with liver metastases, with standard of care combinations.

When will the complete time-to-event data for ADAG's Muzastotug trial be available?

The complete time-to-event endpoints data will be reported when the data mature in 2025.