Announcement • Aug 06
Acrivon Therapeutics Advances Acr-2316 into Randomized Dose Expansion in Ongoing Phase 1/2 Study
Acrivon Therapeutics, Inc. has advanced ACR-2316 into the randomized dose expansion portion of its ongoing Phase 1/2 study. The advancement is supported by the differentiated favorable safety profile and clinical activity observed during dose escalation, including tumor shrinkage and partial responses (PRs) with durable clinical benefit in multiple subjects. Acrivon has selected 120 mg and 160 mg administered orally once daily (QD) on a 3d on/4d off weekly schedule for further dose optimization and final dose selection. Oral weekly regimen (3 days on/4 days off) at 120 mg and 160 mg QD dose levels were selected for randomized dose optimization across AP3-informed solid tumor populations. Dose expansion will evaluate biomarker-selected small cell lung cancer (SCLC), squamous non-small cell lung cancer (sqNSCLC), lung adenocarcinoma (adNSCLC), as well as endometrial, cervical, and esophago-gastric junction cancers. Two weekly (3d on /4d off QD and 2d on /5d off QD) oral dosing regimens have been established, while a bi-weekly (3d on /11d off QD) oral dosing regimen was evaluated, but deprioritized. A total of 35 subjects received ACR-2316 across 6 dose levels ranging from 30 to 240 mg QD in the two weekly oral dosing schedules. Amongst the subjects treated with ACR-2316 at =120 mg QD in the weekly schedules, tumor shrinkage with long-lasting clinical benefit were observed across multiple tumor types, including PRs in lung cancer and endometrial cancer. In the 7 efficacy-evaluable subjects (median 3 prior lines of systemic therapy) with SCLC, sqNSCLC, and adNSCLC, AP3-predicted tumor types not previously shown to be sensitive to clinical single agent WEE1 or PKMYT1 inhibitors, a disease control rate of 86% (2 PRs, 4 SD, and 1 PD) was observed. Ongoing durable clinical benefit observed in 3 heavily pretreated lung cancer subjects remaining on treatment for over one year. In the selected 3d on /4d off dosing regimen, the 120 mg QD and 160 mg QD doses were well tolerated, with a favorable, differentiated safety profile; no grade =4 treatment-related adverse events (TRAEs) were reported, and grade 3 TRAEs were limited to primarily transient, mechanism-based hematologic events, predominantly neutropenia. These observations support further evaluation of ACR-2316 in the selected 3d on /4d off QD regimen in a randomized dose expansion study of AP3-informed tumor types. The dose expansion will evaluate ACR-2316 in subjects with SCLC, sqNSCLC and adNSCLC, as well as endometrial cancer, cervical cancer, and esophago-gastric junction carcinoma, all with AP3-identified biomarker signatures associated with pathway vulnerability, including loss or mutation of TP53 or FBXW7, or overexpression or amplification of CCNE1 or CCNB1, or HPV+ in the case of cervical cancer. The expansion utilizes a 3d on /4d off weekly administration schedule and will include stratification by lung cancer versus non-lung cancer tumor types, with 1:1 randomization within each group to the 120 mg QD or 160 mg QD dose level. The two selected doses are candidate doses for final recommended phase 2 dose selection. The ACR-2316 dose escalation and expansion study adheres to the principles of the FDA’s Project Optimus, which emphasize dose selection based on the totality of efficacy, safety, tolerability, pharmacokinetic and pharmacodynamic data, and specifically stipulate randomized evaluation of multiple doses rather than routine selection of the maximum tolerated dose. Acrivon is currently advancing its lead program, ACR-368 (also known as prexasertib), a selective small molecule inhibitor targeting CHK1 and CHK2 in a potentially registrational Phase 2 trial for endometrial cancer. The company has received Fast Track designation from the Food and Drug Administration, or FDA, for the investigation of ACR-368 as a monotherapy based on OncoSignature-predicted sensitivity in patients with endometrial cancer. The FDA has granted a Breakthrough Device designation for the ACR-368 OncoSignature assay for the identification of patients with endometrial cancer who may benefit from ACR-368 treatment. In addition to ACR-368, Acrivon is also leveraging its proprietary Generative AI-driven Phosphoproteomics AP3 platform for developing its co-crystallography-driven, internally discovered pipeline programs. These include ACR-2316, a novel, potent, selective WEE1/PKMYT1 inhibitor designed for superior single-agent activity. The Phase 1/2 trial of ACR-2316 is advancing in an oral weekly dose expansion study. Initial data has shown a highly differentiated, favorable safety profile primarily limited to only transient, mechanism-based hematological adverse events, predominantly only neutropenia. Clinical activity has been observed across multiple tumor types, including SCLC, squamous NSCLC and lung adenocarcinoma, tumor types not shown sensitive to current single agent WEE1 or PKMYT1 inhibitors. Durable clinical activity has been observed, with certain lung cancer subjects remaining on treatment more than one year. In addition, the company is in early IND-enabling studies with several potential first-in-class development candidates targeting CDK11.
