AbbVie's Venetoclax Tablets Nearing Approval in China with Projected Annual Sales Exceeding $1 Billion

Recently, the marketing application (JXHS2000002/3/4) for AbbVie’s BCL-2 inhibitor “Venetoclax Tablets” has entered the administrative approval stage, indicating that the drug is imminent to be approved in China. The approved indication is: in combination with azacitidine, or decitabine, or low-dose cytarabine for the treatment of newly diagnosed adult patients with acute myeloid leukemia (AML) who are aged 75 years or older, or who have comorbidities that preclude the use of intensive induction chemotherapy.

Venetoclax is a selective B-cell lymphoma-2 (BCL-2) inhibitor co-developed by AbbVie and Genentech. BCL-2 plays a critical role in apoptosis (programmed cell death) by preventing the apoptosis of certain cells, including lymphocytes, and is overexpressed in certain types of cancer, contributing to the development of drug resistance. Venetoclax is designed to selectively inhibit BCL-2 function, restore cellular signaling pathways, and induce cancer cell self-destruction, thereby achieving the goal of tumor treatment.

In April 2016, venetoclax, marketed under the brand name Venclexta, was approved by the U.S. Food and Drug Administration (FDA) for the treatment of patients with chronic lymphocytic leukemia (CLL) harboring a 17p deletion who had received at least one prior therapy, becoming the first BCL-2 inhibitor approved by the FDA. In October 2016, the drug was approved in the European Union under the brand name Venclyxto. AbbVie and Roche are jointly responsible for the commercialization of the drug in the U.S. market, while AbbVie is responsible for its commercialization in markets outside the United States.

To date, venetoclax has been approved for marketing in numerous countries worldwide, with indications including chronic lymphocytic leukemia (CLL), small lymphocytic lymphoma (SLL), and acute myeloid leukemia (AML). According to AbbVie’s financial reports, annual sales of Venclexta have increased year over year. Its global sales reached $344 million in 2018 and $792 million in 2019. Sales for the first three quarters of 2019 alone amounted to $972 million, with expectations that full-year sales would surpass the $1 billion mark, establishing Venclexta as a blockbuster product for AbbVie.

The indication for venetoclax that is about to be approved in China was previously granted accelerated approval by the FDA in 2018 and received full approval from the FDA this October. The approval of this indication is based on data from the Phase 3 studies VIALE-A (M5-656) and VIALE-C (M16-043), the Phase 1b study M14-358, and the Phase 1/2 study M14-387.

The VIALE-A study was conducted in patients with newly diagnosed acute myeloid leukemia (AML) who were untreated and ineligible for intensive conventional chemotherapy, comparing the efficacy and safety of placebo plus azacitidine (AZA, a hypomethylating agent) versus venetoclax plus azacitidine. The results demonstrated that venetoclax plus azacitidine significantly prolonged overall survival (OS) compared with placebo plus azacitidine.

Specific efficacy data are as follows: (1) Compared with the azacitidine + placebo group, the venetoclax + azacitidine treatment group demonstrated a significantly prolonged overall survival (OS) (median OS: 14.7 months vs. 9.6 months) and a 34% reduction in the risk of death (HR=0.66; 95% CI: 0.52–0.85; p<0.001). (2) Compared with the azacitidine + placebo group, the composite complete response rate (CR+CRi) in the venetoclax + azacitidine treatment group was more than doubled (66.4% vs. 28.3%, p<0.001). Furthermore, the study also met the secondary endpoint of CR+CRh (complete response + complete response with partial hematologic recovery): the CR+CRh rate was 64.7% in the venetoclax + azacitidine treatment group versus 22.8% in the azacitidine + placebo group.

The VIALE-C study was conducted in patients with newly diagnosed acute myeloid leukemia (AML) who were ineligible for intensive chemotherapy. In this study, patients were randomized to compare the efficacy and safety of venetoclax plus low-dose cytarabine (LDAC) versus placebo plus LDAC (n=68). The primary efficacy endpoint was overall survival (OS) comparison between the two groups. Although the study did not meet its primary endpoint of significantly improving OS, the complete remission rate was significantly higher in the experimental group (27%) than in the control group (7.4%). The median time to complete remission also increased from 8.3 months to 11.1 months.

Acute myeloid leukemia (AML) is a cancer caused by the abnormal proliferation of myeloblasts and immature myeloid cells in the bone marrow and peripheral blood, predominantly affecting older adults. Currently, the standard treatment for AML involves intensive induction chemotherapy followed by consolidation chemotherapy or allogeneic stem cell transplantation. However, due to factors such as advanced age, comorbidities, and the presence of adverse genetic mutations, many elderly patients are unable to tolerate standard chemotherapy or develop resistance to it. Consequently, these patients are often limited to hypomethylating agents (e.g., azacitidine) and low-dose chemotherapy, with median overall survival typically less than one year.

According to statistics, there are approximately 40,000 new cases of acute myeloid leukemia (AML) in China each year, exceeding the total number of new cases in Europe, the United States, and Japan combined. It is anticipated that venetoclax will soon receive regulatory approval in China, thereby benefiting Chinese patients with AML. Furthermore, according to the Insight database, venetoclax is also under development in China for the treatment of chronic lymphocytic leukemia and multiple myeloma, as detailed in the table below.

In addition to venetoclax, there are currently multiple Bcl-2 inhibitors under development in China, such as Ascentage Pharma’s APG-1252 (a Bcl-2/Bcl-xL inhibitor), APG-2575 (a selective Bcl-2 inhibitor), and AT-101 (a pan-inhibitor of Bcl-2/Bcl-xL/Mcl-1); BeiGene’s BGB-11417; Fosun Pharma’s FCN-338; and Lupeng Pharmaceuticals’ LP-108. Among these, Ascentage Pharma’s APG-2575 has been granted orphan drug designation by the FDA for the treatment of Waldenström’s macroglobulinemia. Notably, in October this year, Fosun Pharma exclusively licensed the global rights to FCN-338 outside mainland China, Hong Kong, and Macau to Eli Lilly, in a deal valued at up to $440 million.