AstraZeneca's Next-Generation PARP1-Selective Inhibitor AZD5305 Granted IND Approval in China for Advanced Solid Tumors

On September 7, the official website of the CDE indicated that AstraZeneca's PARP1-selective inhibitor has received clinical trial approval for advanced malignant solid tumors.

Notably, this is a selective PARP1 inhibitor. Compared with AstraZeneca’s marketed PARP1/2 inhibitor olaparib, AZD5305 is expected to overcome the adverse effects associated with currently marketed PARP inhibitors.

Source: CDE Official Website

PARP inhibitors have demonstrated excellent clinical efficacy in patients with homologous recombination deficiency (HRD) cancers. However, hematological and other toxicities associated with both monotherapy and combination therapy have limited the clinical application of these agents. Recent literature indicates that these adverse effects may stem from PARP2 inhibition by currently marketed PARP inhibitors, which is not essential for therapeutic efficacy. Therefore, AstraZeneca has developed the selective inhibitor AZD5305, aiming to overcome the side effects of existing PARP inhibitors and establish a next-generation PARP inhibitor.

At the 2021 AACR Annual Meeting, AstraZeneca first disclosed the structure and early data of AZD5305. As a highly potent and selective PARP1 inhibitor, AZD5305 exhibits significant PARP1–DNA trapping activity while lacking PARP2 activity, and does not bind to any other members of the PARP family. The drug demonstrates excellent secondary pharmacology and physicochemical properties, along with high oral bioavailability in preclinical animal models.

In preclinical toxicology models, AZD5305 demonstrated a more favorable profile than olaparib. When administered to rats at clinically equivalent doses for 14 days, olaparib (a PARP1/2 inhibitor) reduced hemoglobin levels by up to 50%, consistent with clinically observed anemia; whereas under the same experimental conditions, when administered at the predicted clinically effective dose, AZD5305 had no effect on any hematological parameters.

In vitro, AZD5305 selectively inhibited the growth of DNA repair pathway–deficient cell lines, with IC50 values in the single-digit nM range, while exhibiting little to no growth inhibition in other cell lines (IC50 > 10 μM). This indicates that AZD5305 holds significant potential for an improved therapeutic index in clinical settings. Compared with olaparib at 100 mg/kg QD, treatment of PDX models with AZD5305 at ≥0.1 mg/kg QD resulted in deeper tumor regression and a significantly prolonged duration of response following treatment cessation.

From the AACR Annual Meeting

According to the Insight database, AZD5305 first initiated the Phase I clinical PETRA study (NCT04644068) overseas in October 2020; meanwhile, in China, this new drug received clinical trial approval for the first time today.

From the Insight Global New Drug Database (http://db.dxy.cn/v5/home/)

Note: The original text has been abridged.