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Sprinting to $10 billion market, new PARP inhibitor products coming online, old products with expanding indications

AstraZeneca has announced that its PARP inhibitor Lynparza (olaparib, olaparib), co-developed with Merck Sharp & Dohme, has been approved by the FDA as an adjuvant therapy for the treatment of patients with high-risk HER2-negative early-stage breast cancer carrying a germline BRCA mutation (gBRCAm).

Previously, Lynparza has received several approvals in the United States for.

○ 2014.12 Patients with advanced ovarian cancer with germline BRCA mutations who have failed at least 3 prior chemotherapy treatments.

○ 2017.08 Maintenance treatment of adult patients with recurrent epithelial ovarian, fallopian tube, or primary peritoneal cancer who are in complete or partial remission after prior platinum-based chemotherapy.

○ 2018.01 Patients with progressive disease after receiving chemotherapy (including neoadjuvant chemotherapy, adjuvant chemotherapy, or cancer metastasis chemotherapy) and carrying a deleterious or suspected deleterious BRCA mutation, human epidermal growth factor receptor 2-negative (HER2-) metastatic breast cancer.

o 2018.12 Use as a maintenance therapy for patients with advanced epithelial ovarian, fallopian tube, or primary peritoneal cancer who carry a deleterious or suspected deleterious germline or somatic BRCA mutation (gBRCAm or sBRCAm) as confirmed by testing with one of the FDA-approved companion diagnostic kits.

o 2019.12 Adult patients with metastatic pancreatic cancer who have received first-line platinum-based chemotherapy regimens for at least 16 weeks without progression and who harbor a germline BRCA mutation (gBRCAm) as single-agent first-line maintenance therapy.

○ 2020.05 Adult patients with advanced ovarian cancer (epithelial ovarian cancer, fallopian tube cancer, primary peritoneal cancer) receiving first-line bevacizumab in combination with first-line platinum-containing chemotherapy who have achieved complete remission or partial remission and are HRD-positive as defined by deleterious or suspected deleterious BRCA mutations and/or genomic instability.

o 2020.05 Progressive disease after treatment with the novel hormonal therapies enzalutamide (enzalutamide) or abiraterone (abiraterone), carrying a deleterious or suspected deleterious germline or somatic homologous recombination repair mutation (HRRm), metastatic debulking resistant prostate cancer (mCRPC) (2020.05).

With the approval of new indications and expansion of approvals, Lynparza annual sales climb yearly to reach $3,337 million in 2021.

PARP inhibitors are currently a hot area of drug development. In addition to Lynparza, five others have been approved in the global regulatory section, namely Clovis’ lucaparib, GSK/Redin Pharma’s niraparib, Pfizer’s talazoparib, Hengrui Pharma’s fludozoparib, and PepsiCo’s parmiparib. It is worth mentioning that there are two PARP inhibitors independently developed by Chinese pharmaceutical companies. And China’s four approved PARP inhibitors are through the health insurance negotiations into the national health insurance in 2021.

In terms of indications, Rubraca has received three approvals in the United States: (1) as a monotherapy for the maintenance treatment of adult patients with recurrent ovarian epithelial, fallopian tube or primary peritoneal cancer in partial or complete remission from platinum-containing chemotherapy; (2) as a monotherapy for adult patients who have received two or more prior chemotherapies and carry deleterious BRCA mutations (germline and/or somatic) associated with adult patients with ovarian epithelial, fallopian tube or primary peritoneal cancer who have received 2 or more prior chemotherapies and carry a deleterious BRCA mutation (germline and/or somatic). (3) As a monotherapy for the treatment of adult patients with androgen receptor (AR)-directed therapy and paclitaxel chemotherapy who harbor a deleterious BRCA mutation (germline and/or somatic) associated with metastatic debulking resistant prostate cancer (mCRPC).

Zejula received 2 approvals in the United States (1) for the maintenance treatment of patients with recurrent epithelial ovarian, fallopian tube, or primary peritoneal cancer in complete or partial remission on platinum-containing chemotherapy and (2) for patients with advanced ovarian, fallopian tube, or primary peritoneal cancer who have received 3 or more prior chemotherapy regimens and whose cancer is associated with a homologous recombination defect (HRD) positive status as defined by one of the following 2 conditions Primary peritoneal cancer in patients with (a) deleterious or suspected deleterious BRCA mutations; (b) genomic instability (GIS) and progression of disease for more than 6 months after responding to the last platinum-containing chemotherapy.

Talzenna received 1 approval in the U.S. for the treatment of patients with harmful or suspected harmful germline BRCA mutations (gBRCAm) and HER2-negative locally advanced or metastatic breast cancer (MBC).

Hengrui Pharma’s fluazopalli received two approvals in China: (1) for the treatment of recurrent ovarian cancer with BRCA1/2 deleterious or suspected deleterious mutations after previous second-line chemotherapy or higher; and (2) for the maintenance treatment of platinum-sensitive recurrent epithelial ovarian cancer, fallopian tube cancer or primary peritoneal cancer after achieving complete remission or partial remission with platinum-containing chemotherapy.

Baekje Shenju has received 1 domestic approval for pamiparib for the treatment of patients with advanced ovarian, fallopian tube or primary peritoneal cancer with germline BRCA (gBRCA) mutations who have received at least two prior lines of chemotherapy.

In terms of sales, Lynparza is the highest-selling PARP inhibitor and the only PARP inhibitor currently in the heavyweight category. Overall, the global market for PARP inhibitors continues to expand, with Lynparza (olaparib) performing well both in terms of indications and sales. However, according to the CDE patent registration platform, the compound patent of Olaparib will expire in March 2024, the formulation patent will expire in October 2029, and the use patent will expire in November 2024. Currently, Qilu Pharmaceutical and Xuantai Pharmaceutical have successively submitted domestic applications for the marketing of generic versions of Olaparib in Class 4.

In addition, there are several PARP inhibitors under development worldwide, as detailed in the table below. Among them, Elpida Pharmaceuticals’ Senaparib and AbbViriparib are progressing faster and have entered Phase III clinical trials.

► Senaparib (IMP4297) is a PARP inhibitor independently developed by EiPharma, which has conducted clinical phase II/III studies for ovarian cancer, prostate cancer, small cell lung cancer and other indications worldwide including China, including two registrational clinical studies. Early data show that Senaparib has the potential to be the best-in-class drug with a superior safety profile and a wider therapeutic window than comparable drugs.

► Veliparib is an oral PARP-1 and PARP-2 inhibitor developed by AbbVie and previously granted orphan drug designation by the FDA for the treatment of progressive squamous lung cancer in combination with chemotherapy or radiation therapy. A phase III randomized placebo-controlled trial (BROCADE3) showed that adding veriparib to carboplatin/paclitaxel significantly improved PFS in patients with advanced, unresectable, HER2-negative, germline BRCA1/2 mutated breast cancer.

► Mefurpiride (CVL218) is a new second-generation PARP inhibitor obtained by using natural-like dominant structure for drug design and a series of structural optimization, which is expected to make up for the poor water solubility, low bioavailability, low tissue distribution, mostly unable to cross the blood-brain barrier, unstable formulation and safety risks of the first-generation PARP inhibitors. Currently, Mefuropiri has entered the phase II clinical stage and is expected to become the “best-in-class” second-generation PARP inhibitor in the future.

AZD5305 is a second-generation PARP inhibitor developed by AstraZeneca with excellent secondary pharmacological and physicochemical properties and has demonstrated high oral bioavailability in preclinical animal models. Data from early studies show that AZD5305 possesses significant PARP1-DNA capture activity without PARP2 activity and does not bind other members of the PARP family.

► TSL-1502 is a PARP inhibitor with independent intellectual property rights developed by Tianshi Li Diyi Pharmaceutical, intended for the treatment of ovarian cancer, breast cancer, prostate cancer, gastric cancer, lung cancer and other tumor diseases. Data from preclinical studies show that this drug has a clear mechanism of action, is highly sensitive to a variety of tumors with DNA repair defects, and has certain advantages in terms of safety and efficacy when compared with drugs of the same target whose structures have been disclosed.

PARP is a class of cytosolic enzymes that catalyze the ribosylation of ADP. A variety of tumors, including ovarian, breast, pancreatic, and prostate cancers, have been shown to respond to PARP inhibitors. The market for PARP inhibitors continues to grow in size as the number of approvals and indications for PARP inhibitors increases. According to Frost & Sullivan, the global market for PARP inhibitors is growing rapidly, reaching $2.4 billion in 2020, and is expected to grow at a CAGR of 38.3% in the future to reach $12.3 billion in 2025. According to the current research progress of PARP drugs under development, it is expected that new products will be approved and marketed in the future, which will continuously expand the market size of PARP inhibitors.

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