On September 10, 2022 Adagene Inc. ("Adagene") (Nasdaq: ADAG), a company transforming the discovery and development of novel antibody-based therapies, reported the publication of data showing the best-in-class potential of ADG126, a masked, anti-CTLA-4 SAFEbody (Press release, Adagene, SEP 10, 2022, View Source [SID1234619402]). Interim results from the Phase 1 portion of an ongoing Phase 1b/2 trial of ADG126 are being presented at the European Society for Medical Oncology (ESMO) (Free ESMO Whitepaper) Congress 2022 in Paris, September 9 – 13, 2022.
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The poster, titled "Phase 1 Results Demonstrate Highly Differentiated Safety and PK Profile of ADG126, a Masked anti-CTLA-4 SAFEbody in Patients with Advanced Solid Tumors," reviewed data from the first-in-human, open label, phase 1 dose-escalation and dose expansion. The poster reports data on 26 patients with advanced metastatic solid tumors, the majority (58%) of whom received three or more lines of prior therapies and nearly half (42%) of whom progressed from prior immuno-oncology (IO) therapy.
Key findings include:
Safety: ADG126 monotherapy showed an unprecedented clinical safety profile at dosing levels up to 20 mg/kg when administered to this heavily pretreated patient population once every three weeks. ADG126 was well tolerated, with no dose-limiting toxicities or treatment-related Grade 3 or higher adverse events observed. The most frequent treatment related adverse events (TRAEs) (≥10%) were fatigue (12%), pruritis (12%), rash (12%) and diarrhea (12%). Dose escalation is completed at 20 mg/kg and dose expansion is ongoing at 10 mg/kg.
Antitumor Activity in Cold Tumors: With 18 cycles of treatment at 1 mg/kg, an ovarian cancer patient experienced significant, continued reduction of an established ovarian cancer biomarker, CA125, dropping 90% to within the normal range for full clinical benefit. As of cycle 16, the patient experienced a 22% decrease in target lesions. Previously, this patient had surgery and five prior lines of systemic therapies. At the data cut-off of August 17, 2022, the disease control rate was 39% (9/23 evaluable patients).
Pharmacokinetics: ADG126 plasma pharmacokinetics (PK) were approximately linear and activated ADG126 accumulated steadily during repeat dosing across different dose levels. This suggests prolonged exposures of activated ADG126 in the tumor microenvironment (TME), with cleaved ADG126 on average accumulating ≥3-fold during repeat dosing, resulting from an approximately 1.5-fold longer half-life of total ADG126 compared with its parental antibody.
"ADG126 continues to demonstrate a remarkable safety profile, highly differentiated from both the currently approved anti-CTLA-4 therapy and others in development, as well as antitumor activity in heavily pre-treated patients with cold tumors," said Dr. Gary Richardson, OAM, MBBS, FRACP, Group Director at Cabrini Health Research, Neil Beauglehall Endowed Chair, Medical Oncology Research, and Professor of Medicine at Monash University, Australia, said, "An intriguing case study of our poster is the experience of a patient with ovarian cancer, whose tumor reduced by 22 percent accompanied by normalization of an established clinical biomarker, CA125, dropping by tenfold after more than one year of treatment with ADG126 administered every three weeks at only 1 mg/kg. These data clearly demonstrate the monotherapy activity of this novel antibody, ADG126, supporting its ongoing evaluation as both monotherapy and in combination with anti-PD-1 agents."
Trials evaluating the combination of ADG126 and anti-PD-1 therapies are ongoing in patients with advanced, metastatic tumors in the US, China and Asia Pacific (APAC), evaluating optimized doses of ADG126 in targeted tumors.
ADG126 SAFEbody applies precision-masking technology to the parental anti-CTLA-4 antibody, ADG116, for conditional activation in the TME to expand the therapeutic index and further address safety concerns with existing CTLA-4 therapies. Binding to the same unique 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 in TME.