Adagene Eyes Phase II Data for Masked CTLA-4 Therapy in MSS Colorectal Cancer

Key Points

• Adagene expects Phase II data in the first half of next year from a randomized trial testing two doses of masked anti-CTLA-4 therapy ADG126 with pembrolizumab in metastatic MSS colorectal cancer. Earlier Phase Ib cohorts showed response rates of 17% to 25%, with adverse-event discontinuation below 10%.
• ADG126 uses the SAFEbody platform to activate primarily in the tumor microenvironment, potentially enabling higher CTLA-4 doses while reducing toxicity. The company is also studying a loading-dose regimen in a neoadjuvant Singapore trial, with additional data expected in 2027.
• Adagene plans to consult the FDA about potential registrational development after Phase II results and is collaborating with Incyte on a combination involving a PD-1/TIGIT bispecific. The company says its cash runway extends into the second half of 2028.

Adagene NASDAQ: ADAG is advancing its masked anti-CTLA-4 antibody, ADG126, also known as muzastotug, in metastatic microsatellite-stable colorectal cancer (MSS CRC) and in a neoadjuvant investigator-sponsored trial in Singapore, Chief Strategy Officer Mickael Chane-Du said during a Chardan conference session.

The company’s ongoing randomized Phase II trial is evaluating two doses of ADG126 in combination with pembrolizumab under the FDA’s Project Optimus dose-optimization framework. Chane-Du said data from that study are expected in the first half of next year.

Masked CTLA-4 approach aims to widen therapeutic window

ADG126 is designed using Adagene’s SAFEbody masking platform, which is intended to keep the antibody inactive until it reaches the tumor microenvironment. According to Chane-Du, the approach is intended to enable higher CTLA-4 dosing while limiting the safety issues historically associated with CTLA-4 blockade.

“Thanks to our SAFEbody platform, we believe that we have this very, very high masking efficiency,” Chane-Du said. He added that the molecule requires high expression of CTLA-4 for activation, with CTLA-4 highly expressed on regulatory T cells, or Tregs.

In colorectal cancer, Chane-Du said ADG126’s activity is expected to result primarily from Treg depletion, while also contributing to immune-system priming. He said the antibody binds a different epitope than established CTLA-4 therapies such as ipilimumab and tremelimumab, and that its underlying binder, ADG116, has shown stronger antibody-dependent cellular cytotoxicity, or ADCC, than ipilimumab.

Chane-Du said patients have received ADG126 with PD-1 therapy at doses up to 20 mg/kg. He characterized that dose as substantially higher than the 1 mg/kg to 3 mg/kg dosing typically used for ipilimumab in combination regimens. In the Phase Ib setting, he said the discontinuation rate due to adverse events was below 10%.

Phase II trial tests two metastatic CRC regimens

Adagene’s Phase II program is testing 20 mg/kg every six weeks and a 15 mg/kg regimen against a 10 mg/kg regimen, each in combination with pembrolizumab. Chane-Du said the company selected the schedules based on Phase Ib findings and the potential importance of an initial higher-dose exposure for patients with rapidly progressing disease.

While a loading-dose approach was not carried into the metastatic Phase II trial, Chane-Du said the company continues to favor that strategy and is evaluating it in the neoadjuvant setting.

During the discussion, Chane-Du said pembrolizumab as a single agent has minimal activity in MSS CRC. He said Adagene reviewed patient baseline characteristics across earlier cohorts and believes dose was the main driver of differing response outcomes seen in the study, while acknowledging cohort sizes were small.

The company’s earlier Phase Ib results included response rates ranging from 17% to 25% for doses being studied in Phase II, according to the discussion. Chane-Du said it would be favorable for the Phase II study to replicate the Phase Ib findings.

On potential registrational development, Chane-Du said Adagene plans to meet with the FDA after Phase II data are available. In a best-case scenario, he said the next study could be a randomized Phase III trial using overall survival as the primary endpoint. Potential control therapies would depend on the treatment line and could include fruquintinib, regorafenib, TAS-102 plus bevacizumab, or physician’s choice of therapy.

Neoadjuvant study uses loading-dose schedule

Adagene also has an ongoing investigator-sponsored neoadjuvant CRC trial in Singapore. The study is evaluating ADG126 with pembrolizumab using a loading-dose strategy of 20 mg/kg followed by 10 mg/kg every three weeks, Chane-Du said.

The exact number of doses has not been disclosed, though Chane-Du said it is more than two and includes a loading-dose component. Time from the first dose to surgery is at least eight weeks, he said, adding that time to surgery is important for capturing responses.

Chane-Du said the company believes higher CTLA-4 doses, more cycles of CTLA-4 treatment and extended time before surgery could potentially differentiate the program, though he emphasized that data will be needed. He said additional information from the neoadjuvant study is expected in 2027.

Incyte collaboration and cash runway

Adagene is also collaborating with Incyte on a combination involving Incyte’s PD-1/TIGIT bispecific antibody. Chane-Du said the collaboration could explore whether ADG126’s CTLA-4 inhibition and Treg-depleting activity can improve outcomes when combined with the bispecific approach in MSS CRC.

Separately, Chane-Du said Adagene’s cash runway extends into the second half of 2028. He said a follow-on offering completed in April strengthened the company’s balance sheet.

About Adagene (NASDAQ:ADAG)

Adagene Inc is a clinical-stage biopharmaceutical company focused on developing antibody-based cancer immunotherapies. The company uses computational technologies and antibody-engineering capabilities to discover and develop therapies designed to activate the immune system against tumors while limiting activity in healthy tissues.

Adagene's proprietary SAFEbody technology is designed to conditionally mask antibody binding sites so that therapies are preferentially activated in the tumor microenvironment.

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