On September 16, 2024 Adagene Inc. ("Adagene") (Nasdaq: ADAG), a company transforming the discovery and development of novel antibody-based therapies, reported new ADG126 clinical data presented at the ESMO (Free ESMO Whitepaper) Congress, taking place in Barcelona, Spain, September 13-17 (Press release, Adagene, SEP 16, 2024, View Source [SID1234646641]).

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The poster, titled Increased Therapeutic Index of Muzastotug (ADG126), a Masked Anti-CTLA-4 Antibody, in Combination with Pembrolizumab (Pembro) Enables Significant Clinical Benefits and Supports Further Clinical Development in Patients with Metastatic MSS CRC, reports data from an ongoing phase 1b/2 trial of Adagene’s masked anti-CTLA-4 SAFEbody in combination with Merck & Co., Inc., Rahway, NJ, USA’s anti-PD-1 therapy KEYTRUDA (pembrolizumab) (ADG126-P001; NCT05405595).

"I am delighted that the ESMO (Free ESMO Whitepaper) data show a promising overall response rate, progression-free survival (PFS) and early survival benefit from treatment with the immunotherapy (IO) doublet of ADG126 in combination with pembrolizumab for patients with advanced/metastatic MSS CRC, the largest segment of colorectal cancer with few treatment options," said Daneng Li, MD, Associate Professor in the Department of Medical Oncology & Therapeutics Research at the City of Hope Comprehensive Cancer Center, and a study investigator. "With a much higher dosing level than available anti-CTLA-4 therapies, these data reinforce the encouraging safety and efficacy profile for ADG126 administered repeatedly in MSS CRC."

Dr. Li continued, "Given the best-in-class potential for ADG126, this combination with pembrolizumab could address even broader patient populations, such as those with liver metastases, particularly if combined with standard of care to control early disease progression. Further, the safety profile of this immunotherapy doublet enables repeat cycles to achieve and sustain sufficient drug exposure that maximizes potential for a long-term survival benefit."

ADG126 is a masked anti-CTLA-4 SAFEbody targeting a unique epitope of CTLA-4 on regulatory T cells (Tregs) in tumor tissue which shows potential best-in-class safety and efficacy profiles in combination with pembrolizumab. The unique epitope of ADG126 alone has shown enhanced antibody-dependent cell mediated cytotoxicity without Fc engineering, which is associated with significantly increased toxicity. Further, it has shown minimal immunogenicity and anti-drug antibodies, with no impact on its pharmacokinetic (PK) profile.

Key highlights from the poster (July 30, 2024 data cutoff) include:

· ADG126 in combination with pembrolizumab continued to demonstrate a differentiated safety profile in dose escalation and dose expansion cohorts for heavily pre-treated advanced/metastatic patients with solid tumors (n=66):

o No dose-limiting toxicities (DLT) or Grade 4 or 5 TRAEs were observed at any dose up to 20 mg/kg Q3W, which was evaluated in dose escalation (n=6) to support an ongoing loading dose cohort.

o No Grade 3 colitis was observed at any dose, with limited use of infliximab to manage immune-mediated diarrhea/colitis in no more than 10% of patients.

o No significant late-onset toxicities were observed after repeat dosing at the 10 mg/kg dose level. TRAEs by week from treatment start are summarized in the poster.

o Grade 3 TRAEs occurred in only 6% of patients at the 10 mg/kg Q6W dose (1/17) and 16% of patients at the 10 mg/kg Q3W dose (6/37). Standard of care treatments are associated with higher rates of toxicities.

o Seven patients developed treatment related SAEs; however, the discontinuation rate remains low at 8% (5/66).

· ADG126 administered at 10 mg/kg Q6W or Q3W in combination with pembrolizumab (200 mg/Q3W) demonstrated an encouraging efficacy signal, durable disease control and an early survival benefit in MSS CRC patients, with dose-dependent efficacy and objective responses per RECIST criteria observed for the Q3W schedule:

o In the subset of efficacy evaluable patients without liver and peritoneal metastases (n=17) who received ADG126 10 mg/kg Q3W, an ORR of 24% was observed, including four confirmed PRs. These results are consistent with earlier ORR data published at ASCO (Free ASCO Whitepaper) GI 2024. Response rates for current standard of care treatments range from 1% to 6.3%*.

o An additional 11 patients had stable disease (SD) for an overall disease control rate (DCR) of 88% (15/17).

o Further, a median PFS of 8.5 months was observed in the subset at the ADG126 10 mg/kg Q3W dose and median PFS was 5.9 months for patients at the ADG126 10 mg/kg Q6W dose.

o The 12-month OS rates were 74% for those patients without liver metastases (n=36), and 82% in those without liver and peritoneal metastases (n=24) in the combined 10 mg/kg Q6W and Q3W cohorts.

o While the 10 mg/kg Q3W cohort demonstrated efficacy with RECIST responses and the Q6W did not, early OS rates appear comparable for both doses. This suggests that the Q6W could be used as a starting point for future combination trials, or as a dose modification strategy for safety management.

o Additionally, results in patients without liver metastases who received at least four cycles of the combination showed comparable OS rates to those without liver and peritoneal metastases, highlighting the importance of early disease control with standard of care to enable the IO doublet to drive a long-term survival benefit.

· In dose escalation, the 20 mg/kg Q3W dose level was tolerable for the initial cycle (n=6). Based upon the safety profile of the initial dose, 20 mg/kg is being evaluated as a loading dose in an expansion cohort that has enrolled 12 patients. This cohort is evaluating a single dose of ADG126 at 20 mg/kg followed by a 10 mg/kg Q3W maintenance dose in combination with pembrolizumab. Initial data for this cohort are expected later this year.

· Comprehensive PK and exposure response analyses were also conducted to provide insight on various dosing regimens and their correlation to safety and efficacy of the combination. These results reinforce the increased therapeutic index of ADG126, underscoring a key advantage of the SAFEbody precision masking technology. The extensive PK data also guide future clinical development and dose selection to meet FDA’s Project Optimus dose optimization requirements.

Commenting on these promising results, Peter Luo, Adagene’s CEO and President of R&D said, "We are thrilled that today’s update continues to reinforce the clinical benefits of the best-in-class therapeutic potential for ADG126 at the 10 mg/kg dose level in combination with pembrolizumab in MSS CRC. Armed with these results and the anticipated findings from our ongoing 20 mg/kg loading dose regimen, we are moving ahead with plans to evaluate ADG126 in MSS CRC at 10- to 20-fold higher doses than ipilimumab in a randomized, registration-oriented clinical program. With safety comparable to historical data for pembrolizumab monotherapy, these data provide a solid foundation for the potential of an IO doublet targeting CTLA-4 and PD-1 to move into earlier lines of therapy and broader patient populations, particularly when combined with standard of care aiming for a transformational improvement in patient outcomes."

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

SAFEbody is a registered trademark in the United States, China, Australia, Japan, Singapore, and the European Union.