Adagene Spotlights ADG126 Strategy as Masked CTLA-4 Trial Advances in Colorectal Cancer

Key Points

• Adagene’s lead drug ADG126 (muzastotug) is a masked anti-CTLA-4 antibody designed to improve the therapeutic index of CTLA-4 inhibition. The company says its SAFEbody masking technology and differentiated epitope may allow higher dosing with less off-target binding than earlier drugs like ipilimumab.
• The company is focusing on late-line microsatellite-stable colorectal cancer, especially patients without liver metastases, where it sees a major unmet need. Early data suggest higher ADG126 doses may produce better response rates, with a randomized Phase 2 trial now comparing 10 mg/kg every three weeks versus 20 mg/kg every six weeks, both with pembrolizumab.
• Adagene says the program has shown a favorable safety profile relative to peers and is advancing through collaborations with Incyte and Sanofi in additional combinations. The company also recently raised $70 million, extending its cash runway into the second half of 2028 and fully funding the randomized Phase 2 study.

Adagene NASDAQ: ADAG Chief Strategy Officer Mickael Chane-Du outlined the company’s clinical strategy for its lead antibody program, ADG126, during a discussion with Stifel senior biotech analyst Stephen Willey, emphasizing the company’s focus on improving the therapeutic index of CTLA-4 inhibition through its proprietary masking technology.

Chane-Du described Adagene as a global biotechnology company developing novel antibodies, including monoclonal antibodies, T-cell engagers, antibody-drug conjugates and masked versions of those formats. Its lead program, ADG126, also known as muzastotug, is a masked anti-CTLA-4 antibody that the company believes has shown preliminary evidence of an improved therapeutic index compared with first-generation anti-CTLA-4 therapies.

ADG126 Designed to Differentiate From Earlier CTLA-4 Drugs

Chane-Du said ADG126 incorporates two key design features. First, he said the anti-CTLA-4 binder is proprietary and targets a differentiated epitope, which Adagene believes results in stronger antibody-dependent cellular cytotoxicity and potency compared with ipilimumab, without Fc engineering. Second, the antibody uses Adagene’s SAFEbody masking technology, which is designed to reduce target binding while the mask remains uncleaved.

“What really stands out is … the masking efficiency,” Chane-Du said, adding that the company believes the antibody is less likely to bind CTLA-4 while intact and uncleaved. He said cleavage sensitivity and specificity are also important factors for masked antibody approaches.

Chane-Du pointed to the company’s ability to dose ADG126 at up to 20 mg/kg in colorectal cancer patients, including in combination with PD-1 therapy, as evidence supporting the masking approach. By comparison, he said ipilimumab has been given up to 10 mg/kg as monotherapy, while in combination with nivolumab physicians are generally more comfortable with lower doses, often around 1 mg/kg.

Colorectal Cancer Focus Centers on MSS Patients Without Liver Metastases

The discussion focused heavily on Adagene’s development of ADG126 in late-line microsatellite-stable colorectal cancer, or MSS-CRC, particularly in patients without liver metastases. Chane-Du said the unmet need remains substantial, with current standard-of-care options producing mid-single-digit response rates and overall survival in the low-teens range in patients without liver metastases.

He said first-generation checkpoint blocker combinations have not worked well in MSS colorectal cancer, citing prior experience with PD-1 and CTLA-4 approaches. He characterized MSS colorectal cancer as a “very cold tumor,” with high rates of PD-L1 negativity and substantial regulatory T-cell presence.

Chane-Du said patients without liver metastases may be more responsive to immunotherapy approaches. He described a working hypothesis that liver metastases may draw effector T cells from circulation and suppress them while activating suppressive immune cells such as Tregs, MDSCs and macrophages.

Company Highlights Dose Dependence and Safety Profile

Chane-Du said Adagene believes CTLA-4 inhibition is a highly dose-dependent mechanism, based on experience with ipilimumab and the company’s own data. He said lower doses of ADG126 at 10 mg/kg produced response rates between 0% and 17% in combination with pembrolizumab among MSS-CRC patients without liver metastases. At higher doses up to 20 mg/kg, he said response rates were 25% to 36% in combination with pembrolizumab.

The company is attempting to balance higher concentrations of activated, cleaved ADG126 in the tumor microenvironment with limited peripheral exposure, Chane-Du said. He added that Adagene has conducted pharmacokinetic and modeling work and believes clinical data support that balance.

“When you look at our rate of serious adverse events, dose discontinuation, dose modification, utilization of infliximab, it’s significantly lower than our peers,” Chane-Du said. He acknowledged that severe adverse events seen with the drug are consistent with immune-mediated adverse events associated with CTLA-4 antagonism.

When asked what de-risks a registrational effort, Chane-Du said no single data point was sufficient. Instead, he cited the totality of the data, including the ability to dose at high levels, low discontinuation despite higher dosing, higher response rates versus first-generation PD-1/CTLA-4 combinations and an encouraging overall survival trend.

Randomized Phase 2 Trial Underway

Adagene has initiated a randomized Phase 2 trial intended to help satisfy the U.S. Food and Drug Administration’s Project Optimus expectations. Chane-Du said the trial will randomize 60 patients one-to-one, with 30 patients in each arm, testing two ADG126 dose levels in combination with full-dose pembrolizumab.

• ADG126 10 mg/kg every three weeks plus pembrolizumab
• ADG126 20 mg/kg every six weeks plus pembrolizumab
• Primary endpoint: response rate

Chane-Du said the results are expected to inform the design of a future registrational or Phase 3 trial. If designed today, he said a Phase 3 trial would likely be randomized, enroll approximately 400 to 500 patients and use overall survival as the primary endpoint, with physician’s choice of therapy as the control arm. He also described an “upside scenario” in which response rate could serve as a co-primary endpoint with overall survival and potentially support an interim analysis and accelerated approval.

Collaborations With Incyte and Sanofi Expand Development Options

Chane-Du also discussed early combination efforts beyond pembrolizumab. At AACR, Adagene presented preliminary data combining ADG126 and pembrolizumab with fruquintinib. He said the small dataset suggested the triplet could be safely combined and that higher ADG126 dosing remained associated with higher response rates, though he cautioned that the sample size was limited.

Adagene recently entered a clinical collaboration with Incyte to evaluate ADG126 with Incyte’s PD-1/TGF-beta receptor II bispecific. Chane-Du said Adagene believes ADG126 could potentially address mechanisms of resistance related to Tregs and CTLA-4 regulation. He noted that Incyte has generated monotherapy data in late-line MSS-CRC, including patients with liver metastases, and said the goal is to generate comparable data in the same setting.

Chane-Du also described Adagene’s relationship with Sanofi, which began in 2022 as a discovery collaboration involving Adagene’s SAFEbody technology. He said the relationship later deepened with a Sanofi corporate equity investment in July of last year and a trial collaboration evaluating ADG126 with Sanofi’s PD-1/IL-15 conjugate in more than 100 solid tumor patients. He said Sanofi controls the timing of any data release, and no guidance was provided.

In hepatocellular carcinoma, Chane-Du said Adagene presented small-patient-number data evaluating ADG126 with atezolizumab and bevacizumab. He said the company observed a trend toward better response, progression-free survival and overall survival with the triplet, using a lower ADG126 dose of 6 mg/kg every six weeks. He also identified first-line liver cancer and non-small cell lung cancer as tumor types investors should watch, while emphasizing that Adagene has made no near-term commitment to move forward in NSCLC.

On financing, Chane-Du said Adagene recently raised $70 million from U.S.-based biotech investors. He said the capital extends the company’s runway into the second half of 2028 and fully funds execution of the randomized Phase 2 trial, with the potential to support smaller Phase 1 trials and partially fund a randomized Phase 2 trial in late-line MSS-CRC.

About Adagene NASDAQ: ADAG

Adagene Inc, headquartered in Suzhou, China, is a clinical-stage biopharmaceutical company specializing in the discovery and development of antibody-based therapeutics for cancer and immune-related diseases. Founded in 2017, the company leverages its proprietary immunome technology platform to mine human antibody repertoires and engineer novel monospecific and bispecific antibodies. Adagene's pipeline includes multiple candidates in preclinical and early clinical development, with a focus on targeting tumor microenvironments and modulating immune checkpoints to enhance anti-tumor efficacy.

At the core of Adagene's research and development efforts is its Bihanc™ antibody platform, which combines combinatorial phage display, structure-based design and artificial intelligence to optimize binding affinity, specificity and developability.

This instant news alert was generated by narrative science technology and financial data from MarketBeat in order to provide readers with the fastest reporting and unbiased coverage. Please send any questions or comments about this story to contact@marketbeat.com.