The Latest “Battle” of CDK4/6 inhibitors: Big Three Equally Matched

SHIRLEY, NY, UNITED STATES - Jul 4, 2018 - On June 13th, Beida Pharmaceutical announced that its self-developed BPI-16350 capsule has approved clinical trial application for breast cancer by China FDA. BPI-16350 capsule is a new anti-tumor drug that is independently developed by Beida Pharmaceutical. The target is cyclin-dependent kinase 4/6 (CDK4/6).

CDK4/6 inhibitors have become a new and hot target in recent years. In 2015, the world's first CDK4/6 inhibitor, Pfizer's Palbociclib (trade name: Ibrance), was approved by the US FDA. Currently, the US FDA has approved a total of three CDK4/6 inhibitor drugs, the remaining two are Novartis' Ribociclib (Rebosini, trade name: Kisqali) and Lilly's Abemaciclib (trade name: Verzenio).

None of the above three drugs have been approved for marketing in China, and there are currently no other CDK4/6 inhibitors is used for the treatment of patients with advanced breast cancer.

Development of CDK inhibitors

In the past 20 years, the development of three generations of CDK inhibitors has not been smooth. The first generation of CDK inhibitors is represented by flavopiridol. Due to its poor selectivity to various protein kinases of the CDK family, the drug is highly toxic, and related clinical trials are terminated due to the narrow treatment window, which has not been marketed.

The second-generation of CDK inhibitors is represented by dinaciclib, which is more novel in structure, more active, and more selective. They have stronger inhibitory effects on CDK 1, 2, 5 and 9. Dinaciclib has now entered Phase III clinical research phase for refractory chronic lymphoma. Dinaciclib is not optimistic about the efficacy of solid tumors, and its phase II clinical trial for the treatment of advanced breast cancer has been discontinued.

Three generations of oral CDK inhibitors is represented by Palbociclib, which is more selective for CDK4/6. By inhibiting phosphorylation of Rb protein, the CDK4/6-Rb pathway is blocked, thereby inducing tumor cells to arrest in G1 phase. CDK4/6 (cyclin-dependent kinase 4/6) is a key factor regulating the cell cycle and triggers the transition of the cell cycle from the growth phase (G1 phase) to the DNA replication phase (S phase). The cycle is blocked in the G1 phase, thereby inhibiting the proliferation of tumor cells.

Big three equally matched

The three small molecule drugs Palbociclib, Ribociclib and Abemaciclib have similar similarities in chemical structure and activity, and the research methods in clinical trials are similar, and they have all received accelerated approval from the FDA.

But the first-mover advantage of Palbociclib is still very obvious. It is understood that in 2017, Palbociclib, Ribociclib and Abemaciclib have global sales of $31.26, $0.76, and $0.21 million, respectively.

At the ASCO 2018 annual meeting, we ushered in good news. Pfizer, Novartis and Eli Lilly have published Phase III clinical trial data on their respective CDK4/6 inhibitors for hormone receptor + Her2 - breast cancer patients, and currently have evidence for the treatment of premenopausal patients.

Breast cancer has three major endocrine therapies - letrozole, anastrozole and exemestane, which compete with each other, and now there are three CDK4/6 inhibitor competitions.

Data from the study showed that all CDK4/6 inhibitors significantly improved objective efficiency and prolonged progression-free survival (PFS) in either first- or second-line, premenopausal or postmenopausal. Especially in first-line treatment, all three CDK4/6 inhibitors can prolong PFS for more than 10 months. In second-line treatment, the efficacy of three CDK4 / 6 inhibitors is surprisingly consistent, the risk ratio is between 0.5 and 0.6, which can reduce the risk of disease progression by about 40% to 50%.

Breast cancer is one of the most common cancers among women worldwide, and its market potential is self-evident. Looking forward to the near future, CDK4/6 inhibitors will not only bring more surprises in other areas than breast cancer.

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