Tens of billions of dollars market! The leader of AstraZeneca has two hands: Olapalli has received a new indication, and the next generation of products has been laid out in a variety of ways

On September 19, NMPA issued an approval document showing that AstraZeneca Orapalil new indications were approved for listing in China (acceptance numbers: JXHS2101103, JXHS2101104), and it is speculated that the approved indications may bevacizumab as a first-line maintenance therapy for newly diagnosed patients with advanced ovarian cancer who
receive complete or partial remission after platinum chemotherapy.

From: NMPA website

Lynparza has previously been approved for several indications in China, including maintenance therapy for platinum-sensitive recurrent ovarian cancer, fallopian tube cancer or primary peritoneal cancer, first-line maintenance therapy for advanced ovarian cancer with BRCA mutation, fallopian tube cancer or primary peritoneal cancer, and metastatic castration-resistant prostate cancer monotherapy with BRCA mutation and disease progression after previous novel hormonal drug therapy
.

Previously, in August 2019, AstraZeneca announced that in a clinical study called PAOLA-1, Orapaparl had reached the primary study endpoint
of progression-free survival (PFS).

At this year's ESMO meeting, AstraZeneca further disclosed the results of the long-term follow-up update of the PAOLA-1 phase III trial: olapari plus bevacizumab significantly extended the 5-year survival rate of patients with homologous recombination defects (HRD) to 65.

PAOLA-1 test results

From: Insight Database Web

Sales of the first PARP inhibitor, Orapali, are all the way up: annual revenue exceeds 2 billion

Developed by AstraZeneca and Merck, Orapalil was first approved by the FDA in 2014 for use in patients with advanced ovarian cancer with
BRCA mutations.

A key node in the Olapalli global project

From: Insight Database Web (http://db.

As the world's first approved PARP inhibitor, Orapali is a well-deserved blockbuster drug, and since its approval, its sales have continued to soar, and the successive listings of similar products have not shaken its king
.

Olapalli sales revenue and cooperation income

From: AstraZeneca Financial Report PPT

In China, Olapalli's results can also be said to be good
.

Trailblazers AstraZeneca: The next generation of PARP inhibitors set sail

According to Frost & Sullivan, the global PARP inhibitor market is growing rapidly, reaching $2.

At present, PARP inhibitors have shown excellent clinical efficacy, but whether used alone or in combination, hematologic toxicity and other toxicities limit the use of
such drugs.

AZD5305

AZD5305 is the successor product of Olaparli, and AstraZeneca published structural and preclinical data
of AZD5305 at the AACR in 2021.
AZD5305 has significant PARP1-DNA capture activity without PARP2 activity and does not bind to any other member of
the PARP family.
In addition, AZD5305 has excellent secondary pharmacological and physicochemical properties and exhibits high oral bioavailability
in preclinical animal models.

AZD5305 structure

AZD5305 has initiated the Phase I/IIa Phase I/IIa Phase I Clinical PETRA Study (NCT04644068) abroad in October 2020, an open, multicenter, modular phase I/IIa clinical study evaluating the safety, tolerability, pharmacokinetics, pharmacodynamics and initial efficacy of AZD5305 dose-increasing monotherapy and combination therapy with anticancer agents in patients with advanced solid malignancy, with a global enrollment of 715 patients
。 In March 2022, the China section (CTR20220423) has also been publicly announced in China, and it is expected that Phase II data
will be obtained after 2023.

AZD5305 domestic development progress

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

Previously, some data from the AZD5305 PETRA study was first disclosed at AACR in 2022, and 46 subjects had been included in the study at the time of the data, and the results showed that AZD5305 showed good safety and clinical activity in different tumor patients compared with the first generation of PARPi
.

From: Insight Database Web

In addition, at this year's AACR, AstraZeneca also published preclinical data
on AZD5305 combined with the HER2 ADC star drug Enhertu (DS-8201, T-Dxd).

AstraZeneca believes that PARP1 inhibitors kill cancer cells by targeting the DNA damage repair mechanism of tumor cells, which makes it have the potential
to be used in conjunction with drugs such as ADCs that stimulate DNA damage.
Preclinical data have preliminarily demonstrated the antitumor effects
of Enhertu in combination with DDR drugs, including PARP1-selective inhibitors.

AZD5305 related abstracts in AACR 2022

From: 2022 AACR

AZD9574

AZD9574 is a novel brain-translucent PARP1 inhibitor
.
In the 2022 AACR, AstraZeneca disclosed its drug discovery process and preclinical data
for the first time.
The results showed that AZD9574 was more than 8000 times more selective for PARP1 than other members of the PARP2 and PARP families, and that AZD9574 inhibited PARP1 activity in all tested cell lines with an IC50 range of 0.
3-2nM
, regardless of HRR status.

AstraZeneca evaluated the efficacy of AZD9574 in an intracranial xenograft model of breast cancer brain metastasis, and preliminary results showed that 3 mg/kg AZ9574 showed significant tumor growth inhibition in animal models of intracranial lesions, significantly prolonged the survival of tumor-bearing mice, and is expected to provide a new treatment plan
for HRD+ breast cancer brain metastases.

AZD9574 related abstracts in 2022 AACR

From: 2022 AACR