AstraZeneca Launches Phase I/IIa Clinical Trial of Next-Generation PARP1-Selective Inhibitor AZD5305 in China

On March 3, AstraZeneca's PARP1 selective inhibitor AZD5305 registered and initiated clinical trials in China for the first time. This is the Chinese segment of the international multicenter Phase I/IIa clinical trial, the PETRA study, which plans to enroll 40 participants in China.

Source: Insight Database (http://db.dxy.cn/v5/home/)

AZD5305 is AstraZeneca's second PARP inhibitor. Unlike the marketed PARP1/2 inhibitor olaparib, AZD5305 has high selectivity for the PARP1 subtype, which is expected to overcome the side effects of currently available PARP inhibitors.

PARP Inhibitors Have Demonstrated Excellent Clinical Efficacy in Patients with Homologous Recombination Deficient Cancers, but Hematological Toxicity and Other Toxicities Limit Their Application Whether Used as Monotherapy or in Combination Therapy. Recent Literature Suggests That These Adverse Effects May Stem from the Inhibition of PARP2 by Approved PARP Inhibitors, While PARP2 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 Build the Next Generation of PARP Inhibitors.

AZD5305 Structure

At the 2021 AACR conference, AstraZeneca disclosed the structure and early data of AZD5305 for the first time. As a highly efficient PARP1 selective inhibitor, AZD5305 exhibits significant PARP1-DNA trapping activity without PARP2 activity or binding to any other members of the PARP family. The drug demonstrates excellent secondary pharmacology and physicochemical properties, and shows high oral bioavailability in preclinical animal models.

In preclinical toxicology models, AZD5305 demonstrated superior properties compared to olaparib. After 14 days of dosing at clinically equivalent doses in rats, olaparib (a PARP1/2 inhibitor) can lead to a reduction in hemoglobin by up to 50%, consistent with the anemia observed clinically; whereas under the same experimental conditions, AZD5305 had no effect on any hematological parameter when administered at the predicted clinically effective dose.

In vitro, AZD5305 selectively inhibits the growth of cell lines with defective DNA repair pathways, with an IC50 in the single-digit nM range, while showing little or no growth inhibition in other cells (IC50 >10 μM), indicating that AZD5305 has significant potential for an improved therapeutic index in clinical applications. Compared with olaparib 100 mg/kg QD, treatment with AZD5305 ≥ 0.1 mg/kg QD in PDX models resulted in deeper tumor regression and significantly prolonged duration of efficacy after cessation of dosing.

Based on these encouraging preclinical data, AZD5305 is expected to become the next-generation PARP inhibitor with stronger efficacy and safety compared to other PARP inhibitors. It also has various clinical development options as both a monotherapy and combination therapy, and is considered a potential successor to AstraZeneca's blockbuster drug, olaparib.

From the AACR Annual Meeting

According to the Insight database, AZD5305 launched the Phase I/IIa clinical PETRA study (NCT04644068) abroad for the first time in October 2020, which is the clinical trial announced in China today, recruiting 715 patients globally. Based on the progress disclosed in AstraZeneca's annual report, Phase II data is expected to be available after 2023.

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