Qilu Pharmaceutical's Palbociclib Capsules, the First Domestic Generic of a CDK4/6 Inhibitor, Approved by NMPA

On December 18, Qilu Pharmaceutical’s palbociclib capsules (Acceptance No.: CYHS1800441) were approved for marketing by the NMPA, becoming the first generic version of Pfizer’s blockbuster breast cancer drug, Ibrance.

The incidence of breast cancer has been rising year by year, and its treatment is receiving increasing attention from physicians. In China’s national tumor registry areas, the annual incidence of new breast cancer cases is 545.29 per 100,000 population, with higher rates in urban areas than in rural areas. Among newly diagnosed breast cancer patients, 6%–7% present with advanced-stage disease at initial diagnosis. Furthermore, among those initially diagnosed with early-stage breast cancer, 30% will ultimately experience recurrence and metastasis despite receiving adjuvant therapy. This implies that in the coming years, the proportion of advanced breast cancer cases in China will increase, resulting in a substantial patient population.

Breast cancer can be classified into five subtypes based on molecular profiling: Luminal A, Luminal B, human epidermal growth factor receptor 2 (HER2)-positive, triple-negative, and normal breast-like. Luminal A breast cancer, also known as hormone receptor-positive breast cancer, accounts for approximately 60% of all breast cancer cases. It is more common in women aged over 50 years. This subtype is characterized by sensitivity to endocrine therapy, a favorable prognosis, and lower sensitivity to chemotherapy compared to other subtypes, making it the most prevalent type of breast cancer. The immunohistochemical (IHC) profile of Luminal A breast cancer is defined as estrogen receptor (ER)-positive and progesterone receptor (PR)-positive with high PR expression (≥20%), HER2-negative, and low Ki-67 expression.

Cyclin-dependent kinases (CDKs) are members of the serine/threonine protein kinase family and play a crucial role in cell cycle regulation. Among the various CDKs, CDK4/6 forms complexes with cyclin D to phosphorylate the retinoblastoma protein (Rb), thereby releasing the transcription factor E2F. This promotes the transcription of cell cycle-related genes and triggers the transition from the G1 phase (pre-DNA synthesis phase) to the S phase (DNA replication phase). Overexpression of CDK4/6 is observed in various cancers, leading to uncontrolled cell division. Palbociclib inhibits cancer cell proliferation by arresting tumor cells at the G1-to-S phase transition.

Palbociclib, developed by Pfizer, is the first CDK4/6 inhibitor approved globally. In February 2015, it was first approved in the United States for use in combination with letrozole as initial endocrine therapy for postmenopausal women with ER-positive/HER2-negative advanced breast cancer, and three additional indications have since been sequentially added.

The efficacy of palbociclib as first-line treatment for ER-positive/HER2-negative recurrent breast cancer was validated in a phase III clinical trial. The phase III PALOMA-2 trial enrolled a total of 666 postmenopausal Asian patients with ER-positive/HER2-negative breast cancer. The results showed that the median progression-free survival (PFS) was longer in the palbociclib plus letrozole group than in the placebo plus letrozole group (25.7 vs. 13.9 months).

Multiple studies have demonstrated that palbociclib in combination with fulvestrant represents a new second-line treatment option for postmenopausal patients with HR-positive, HER2-negative advanced breast cancer. The Phase III PALOMA-3 clinical trial enrolled patients with HR-positive, HER2-negative advanced breast cancer who had progressed during prior endocrine therapy. The results showed that the median progression-free survival (PFS) was 9.5 months in the palbociclib plus fulvestrant group and 4.6 months in the placebo plus fulvestrant group. Another study indicated that the median overall survival (OS) for patients treated with palbociclib plus fulvestrant versus fulvestrant monotherapy was 34.9 months and 28.0 months, respectively; although this represented a survival benefit of 6.9 months for the combination therapy, the difference was not statistically significant.

As a first-in-class CDK4/6 inhibitor, palbociclib has captured a significant market share by virtue of its first-mover advantage, with global sales revenue reaching $4.961 billion in 2019.

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Pfizer’s original palbociclib capsules were approved for import by the NMPA in July 2018, for use in combination with aromatase inhibitors as initial endocrine therapy for postmenopausal women with locally advanced or metastatic HR-positive, HER2-negative breast cancer. The compound patent for palbociclib in China is set to expire on January 10, 2023. In addition to the recent approval granted to Qilu Pharmaceutical, Simcere Pharmaceutical has also submitted a marketing application, while 15 other companies, including Hengrui Medicine, Fosun Pharma, and Hisun Pharma, have laid out their generic drug strategies for this product.

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Qilu Pharmaceutical’s Abbreviated New Drug Application (ANDA) for Palbociclib Capsules in the United States has received tentative approval, and the product will be officially launched in the U.S. market upon the expiration of the drug’s patent period.

As a star target, CDK4/6 has attracted many companies to develop me-too innovative drugs in China. In addition to Eli Lilly's abemaciclib and Novartis's ribociclib, Hengrui's SHR6390 is progressing the fastest and is currently in Phase III clinical trials.

Source: PharmaCube PharmaGo