ON November 3, 2023 Adagene Inc. ("Adagene") (Nasdaq: ADAG), a company transforming the discovery and development of novel antibody-based therapies, reported new data on its masked, anti-CTLA-4 SAFEbody ADG126 at the Society for Immunotherapy of Cancer (SITC) (Free SITC Whitepaper) 38th Annual Meeting taking place in San Diego (Press release, Adagene, NOV 3, 2023, View Source [SID1234636873]). The poster presentation, Optimal Dose Selection of ADG126 (Masked Anti-CTLA-4 SAFEbody) with Significantly Widened Therapeutic Index Compared to Ipilimumab in Combination with anti-PD-1 Antibodies Informed by QSP Modeling, is available on the company’s website.

Schedule your 30 min Free 1stOncology Demo!
Discover why more than 1,500 members use 1stOncology™ to excel in:

Early/Late Stage Pipeline Development - Target Scouting - Clinical Biomarkers - Indication Selection & Expansion - BD&L Contacts - Conference Reports - Combinatorial Drug Settings - Companion Diagnostics - Drug Repositioning - First-in-class Analysis - Competitive Analysis - Deals & Licensing

                  Schedule Your 30 min Free Demo!

The data, which integrate clinical results with physiologically based pharmacokinetic and quantitative systems pharmacology modeling, demonstrated that Adagene’s lead SAFEbody candidate, ADG126, is effective at targeting CTLA-4 within the tumor microenvironment (TME). This resulted in an approximately 30-fold projected pharmacokinetic difference at 10 mg/kg every three weeks (Q3W) in the TME indicating a wider therapeutic index (TI) compared to ipilimumab at 1 mg/kg Q6W, when either is combined with anti-PD-1 therapies.

The enhanced TI of ADG126 enables higher, more frequent and repeat dosing of ADG126 in combination with anti-PD-1, resulting in significantly increased CTLA-4 engagement by activated ADG126 at steady state in tumors versus circulating blood. Analyses also demonstrated that the optimal dose of ADG126 at 10 mg/kg Q3W plus pembrolizumab results in a dose-dependent efficacy profile, without a significant increase in treatment related adverse events (TRAEs).

Importantly, a clinical case example presented for the first time from an ongoing dose expansion cohort in advanced/metastatic MSS CRC* patients free of liver metastases showed that ADG126 10 mg/kg Q3W plus pembrolizumab resulted in a confirmed PR after four cycles (i.e., 12 weeks). The patient was previously treated with two lines of therapy (bevacizumab plus FOLFOX; aflibercept plus FOLFIRI) and experienced manageable Grade 3 TRAEs consistent with known adverse events from immunotherapy.

The poster concluded that initial clinical data from the SAFEbody ADG126 program support that ADG126 may provide greater clinical benefit than ipilimumab in combination with anti-PD-1 in both ‘hot’ and ‘cold’ tumors, including MSS CRC, driven by better target engagement in the TME and a favorable safety profile that enables higher, more frequent and repeat dosing.

ADG126 SAFEbody is the most advanced clinical stage anti-CTLA-4 candidate integrating masking technology and Treg depletion for superior safety and efficacy profiles. A phase 2 dose expansion cohort is ongoing to evaluate ADG126 plus pembrolizumab in patients with MSS CRC without liver metastases.

About ADG126 & SAFEbody Technology

SAFEbody technology is designed to address safety and tolerability challenges of antibody therapeutics by minimizing on-target off-tumor toxicity in healthy tissues. ADG126 is a masked anti-CTLA-4 therapy that applies the SAFEbody precision-masking technology to its parental antibody, ADG116, for conditional activation in the TME to expand the therapeutic index by addressing dose dependent toxicity issues that severely limit the dosage and dosing cycles for effective anti-CTLA-4 therapies.

Binding to the same distinct and highly conserved epitope as ADG116, the masked ADG126 is designed to provide enhanced safety and efficacy profiles due to the combination of the potent Treg depletion in the TME and partial ligand blocking by the activated ADG126, which is accumulated steadily for the prolonged tumor killing effect.

Clinical results together with detailed pharmacokinetic analyses support the unique mechanism of action for ADG126 and its profile as a potential best-in-class anti-CTLA-4 therapy.

* Microsatellite stable colorectal cancer (MSS CRC) accounts for approximately 95% of metastatic colorectal cancer patients. MSS tumors are referred to as ‘cold’ tumors, which means they don’t typically trigger a strong response from the body’s immune system. There is no currently approved immune-oncology treatment for MSS CRC.