Apeiron's GTA182 Shows 57% Response Rate in MTAP-Deleted Lung Cancer Phase 1 Trial
核心洞察
Apeiron Therapeutics (搜索) reported first-in-human data for GTA182, an oral brain-penetrant PRMT5 inhibitor, showing a 57.1% objective response rate in MTAP (搜索)-deleted non-small cell lung cancer patients.
The Phase 1 study enrolled 41 patients with MTAP (搜索)-deleted advanced solid tumors, demonstrating favorable safety profile with anemia as the most common side effect occurring in 51.2% of patients.
GTA182 showed robust PRMT5 pathway inhibition with plasma SDMA levels decreasing by 71.8% at active doses, and notably demonstrated intracranial activity in patients with brain metastases.
Apeiron Therapeutics (搜索) presented promising first-in-human clinical data for GTA182, an oral brain-penetrant PRMT5 inhibitor, at the ESMO Asia Congress 2025 in Singapore. The Phase 1 study demonstrated encouraging antitumor activity in patients with MTAP (搜索)-deleted advanced solid tumors, particularly showing a 57.1% objective response rate in non-small cell lung cancer (NSCLC) patients.
Study Design and Patient Population
The ongoing Phase 1 dose-escalation study enrolled 41 subjects with MTAP (搜索)-deleted advanced solid tumors as of the October 9, 2025 data cutoff. Patients received GTA182 at doses ranging from 20 to 450 mg once daily. The study population represented heavily pre-treated patients typical of this genomic setting, and the maximum tolerated dose had not been reached at the time of data presentation.
Shun Lu, M.D., Ph.D., Professor at Shanghai Chest Hospital and the leading principal investigator, presented the data in a mini-oral session at the congress.
Safety Profile
GTA182 demonstrated a generally well-tolerated safety profile across the dose range studied. The most frequent treatment-related adverse events included anemia (51.2%), decreased appetite (43.9%), and asthenia (39.0%). Grade ≥3 treatment-related adverse events occurred in 26.8% of subjects, which investigators noted was consistent with expectations for selective PRMT5 inhibition.
Pharmacokinetics and Target Engagement
Pharmacokinetic analyses revealed dose-proportional increases in exposure up to 450 mg, with low interpatient variability. The drug demonstrated robust PRMT5 pathway inhibition, with plasma SDMA levels decreasing by a mean of 71.8% (95% CI: 69.7%–73.8%) at active doses ranging from 100–450 mg. These pharmacodynamic effects correlated with systemic exposure and support ongoing dose optimization efforts.
Efficacy Results
Among 30 efficacy-evaluable subjects treated at active doses, GTA182 showed encouraging antitumor activity with an objective response rate (ORR) of 30.0% (95% CI: 14.7%–49.4%) and a disease control rate (DCR) of 83.3% (95% CI: 65.3%–94.4%).
The results were particularly notable in the MTAP (搜索)-deleted NSCLC subgroup (n=14), where the ORR reached 57.1% (95% CI: 28.9%–82.3%) and the DCR was 85.7% (95% CI: 57.2%–98.2%). Responses were observed across multiple dose levels in this patient population.
Brain Penetration and Intracranial Activity
Consistent with GTA182's brain-penetrant design, the study demonstrated evidence of intracranial activity. Two of three patients with baseline brain metastases experienced marked intracranial tumor shrinkage, highlighting the potential clinical benefit of the drug's ability to cross the blood-brain barrier.
Drug Development and Mechanism
GTA182 is a proprietary small molecule discovered through Apeiron's AI-guided drug discovery platform. The compound functions as an MTA-cooperative PRMT5 inhibitor designed specifically for MTAP (搜索)-deleted tumors. In preclinical studies, GTA182 demonstrated potent and selective inhibition of PRMT5, exhibiting over 100-fold selectivity for MTAP-deleted tumor cell lines compared to MTAP-intact cells.
"We are pleased to share the first clinical data for GTA182, which demonstrate strong target engagement, early tumor responses, and encouraging signs of intracranial activity in patients with MTAP (搜索)-deleted advanced solid tumors," said Mingxi Li, Ph.D., Chief Executive Officer of Apeiron Therapeutics (搜索). "These results highlight GTA182's differentiated profile as a brain-penetrant, MTA-cooperative PRMT5 inhibitor designed specifically for MTAP-deleted tumors."
Next Steps
The emerging safety, pharmacokinetic/pharmacodynamic, and antitumor activity data support continued dose exploration and advancement toward expansion cohorts. Li noted that the data "support continued dose exploration and advancement toward expansion cohorts."
The company has shown tumor growth inhibition and regression in preclinical in vivo models, including glioblastoma and various non-CNS cancer models with MTAP (搜索) deletions, suggesting potential applications beyond NSCLC.