Currently, there is only one Bcl-2 inhibitor in the world, venetoclax, which is jointly developed by AbbVie and Roche. AbbVie's financial report shows that in 2023, venetoclax's revenue will reach US$2.28 billion (approximately RMB 16.5 billion), a year-on-year increase of 13.9%. Such an attractive golden big single product, the first domestic drug is about to usher in a breakthrough.

Recently, Ascent Pharmaceuticals announced that its independently developed new selective Bcl-2 inhibitor APG-2575's new drug application (NDA) has been accepted by the CDE and recommended for inclusion in the priority review process for the treatment of refractory or relapsed (r/r) chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL). This is the first domestic original Bcl-2 inhibitor to submit an NDA in China, and is expected to become the second Bcl-2 inhibitor to be listed in the world.

16.5 billion big drug, the first domestic product is accelerating to the finish line. The "strongest backing" of BTK inhibitors. Currently, there are 6 BTK inhibitors approved for marketing worldwide, including the first-generation covalent inhibitor ibrutinib, the second-generation covalent inhibitors acotinib, zanubrutinib, tirabrutinib and obeticholic acid, and the third-generation non-covalent inhibitor pirtobrutinib. They have achieved great success in hematological tumors such as chronic lymphocytic leukemia (CLL) and mantle cell lymphoma (MCL), especially ibrutinib, which has a far-leading sales due to its early listing time. In 2021, the market sales reached US$9.78 billion.

However, due to long-term continuous administration, BTK inhibitors are prone to BTK protein mutations, resulting in drug resistance and unacceptable toxicity. B-cell lymphoma-2 (Bcl-2) is a key apoptosis regulator protein highly expressed in hematological tumors. Bcl-2 inhibitors can specifically bind to BCL-2, blocking its function of inhibiting apoptosis, thereby triggering programmed cell death (apoptosis) of tumor cells to achieve the purpose of treatment.

Venetoclax is the world's first and only approved Bcl-2 inhibitor. Multiple clinical studies have shown the excellent efficacy of venetoclax combined with ibrutinib. In the Phase 2 CAPTIVATE trial exploring the efficacy of venetoclax and ibrutinib as first-line treatment for CLL, the venetoclax and ibrutinib group achieved its primary endpoint of complete remission (CR) rate, with a CR rate of 56% in patients with 17p deletion, significantly higher than the pre-set minimum rate of 37%. Among all treated people, the CR rate was 55%, and the 24-month PFS and OS rates were 95% and 98%, respectively.

In the GLOW randomized controlled clinical study of venetoclax and ibrutinib for first-line treatment of CLL/SLL, the PFS of the venetoclax and ibrutinib group was significantly longer than that of the chlorambucil-otuzumab group (hazard ratio, 0.216). On August 4, 2022, based on the above clinical results, the European Commission approved the expansion of venetoclax combined with ibrutinib as a first-line treatment for adult patients with CLL. The powerful combination of venetoclax and ibrutinib not only further increases venetoclax's sales, which will increase by 10.4% year-on-year to US$2.01 billion in 2022 and 13.9% year-on-year to US$2.288 billion in 2023, but also alleviates the sharp decline in sales of ibrutinib due to patent expiration and competition from other generations of BTK inhibitors, strengthening AbbVie's competition in the field of oncology.

Venetoclax is the first FDA-approved Bcl-2 inhibitor developed by AbbVie. It was launched in the United States on April 11, 2016, and then in December 2020, venetoclax was approved for marketing in China. Currently, Venetoclax has been approved for multiple indications, including single-agent or combined with Rituxan for the treatment of CLL patients with 17p deletion mutations who have received at least one previous therapy, combined with a hypomethylating agent or low-dose cytarabine (LD-AC) as first-line treatment for newly diagnosed elderly acute myeloid leukemia (AML) patients aged 75 years and above, and combined with obinutuzumab for the treatment of adult CLL patients who have not received previous treatment, etc.

In addition, Venetoclax is conducting multiple clinical trials, including a Phase 2 study to determine the efficacy of cirmtuzumab consolidation therapy in patients with measurable disease on Venetoclax (NCT04501939), a Phase 1b/2 study of Venetoclax combined with obinutuzumab and ibrutinib in patients with relapsed, refractory or previously untreated CLL (NCT02427451), a study evaluating adverse events and changes in disease activity in participants aged 19 years or older treated with oral Venetoclax tablets (NCT04826523), and a trial of Venetoclax, obinutuzumab and ibrutinib in patients with relapsed/refractory mantle cell lymphoma (OAsIs, NCT02558816).

What is the progress of Bcl-2 inhibitors in research? In addition to the already marketed Venetoclax, there are many Bcl-2 inhibitors under development worldwide, including APG-2575, Sonrotoclax, ICP-248, TQB3909 and S65487. APG-2575 is the second Bcl-2 inhibitor in the world and the first in China to see clear efficacy and enter the key registration clinical stage developed by Ascentage Pharmaceuticals. Similar to AbbVie's strategy, Ascentage is also developing combination therapies. Its APG-2575 combined with AstraZeneca's second-generation BTK covalent inhibitor acotinib received clinical trial approval from the NMPA Center for Drug Evaluation (CDE) on October 13, 2023 for the first-line treatment of patients with chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL).

APG-2575's clinical research data were presented at international conferences. For example, at the 2022ASH and 2023 AACR conferences, the objective response rate (ORR) of APG-2575 combined with acotinib in patients with relapsed/refractory (R/R) CLL/SLL reached 98%, and the ORR in patients with newly treated CLL/SLL reached 100%, and the safety was comparable to that of monotherapy. At this year's ASCO annual meeting, a phase 2 clinical study data of APG-2575 combined with azacitidine in patients with newly treated or relapsed/refractory (R/R) acute myeloid leukemia (AML) showed that in elderly (≥75 years old) or unfit newly treated AML patients (n=39), the ORR was 64.1%, and the composite complete remission rate (CRc=CR+CRi) was 51.3%.

Sonrotoclax is a potent and highly selective Bcl-2 inhibitor developed by BeiGene, and is another blockbuster blood cancer drug after zanubrutinib. Zebutinib, which beat AbbVie's ibrutinib in a head-to-head clinical trial, is a blockbuster drug of BeiGene. Zebutinib's global sales in the first three quarters of 2024 exceeded US$1.8 billion, and it is no surprise that it will exceed US$2 billion this year. A phase 1/2 clinical trial of Sonrotoclax and Zebutinib combined with venetoclax in patients with newly diagnosed chronic lymphocytic leukemia/small lymphocytic lymphoma (TN-CLL/SLL) showed good tolerability and achieved deep response. A total of 56 patients were evaluated for response. The ORR was 100%. At all doses, the CR rate increased over time, with an overall median CR time of 10.1 months. No progression was reported in either cohort.

Last October, BeiGene launched an open-label, randomized, controlled phase 3 study (NCT06073821) to evaluate the efficacy and safety of Sonrotoclax combined with Zebutinib versus venetoclax combined with obinutuzumab in the treatment of CLL. At this year's ASCO meeting, Mazyar et al. introduced a phase 3 trial design to compare the efficacy of sonrotoclax combined with zanubrutinib versus venetoclax combined with obinutuzumab in patients with TN CLL. The study plan is as follows: approximately 640 patients will be randomized in a 1:1 ratio to receive 3 cycles of zanubrutinib monotherapy (total daily dose of 320 mg, oral), followed by 12 cycles of sonrotoclax + zanubrutinib, or 12 cycles of standard venetoclax + obinutuzumab. The primary endpoint is PFS assessed by the independent review committee (IRC) according to the 2018 iwCLL guidelines.

ICP-248 is a novel oral highly selective Bcl-2 inhibitor developed by Innovent Biologics, designed to treat various hematological malignancies as a single agent or in combination. At last year's ASH meeting, the preliminary clinical phase 1/2 study results of ICP-248 in patients with relapsed or refractory B-cell malignancies showed good safety and efficacy. The study showed that ICP-248 has good bioavailability and PK distribution, and the drug exposure shows a clear linear relationship with the dosage. No dose-limiting toxicity (DLT) was observed, and there was no dose interruption or dose reduction directly caused by drug-related adverse events. No tumor lysis syndrome (TLS), including laboratory TLS, was observed in the study. In January this year, ICP-248 was approved by the FDA for clinical research. TQB3909 is a BCL-2 inhibitor developed by Zhengda Tianqing. At this year's ESMO conference, researchers first announced the results of the Phase 1 clinical study of TQB3909 in the form of an oral report.

The results showed that the ORR of TQB3909 in the treatment of R/R CLL/SLL patients was 88.9%, and the complete remission/complete remission with incomplete hematological recovery (CR/CRi) was 44.4%; the ORR of R/R CLL/SLL patients resistant to BTK inhibitors was 83.3%, and the CR/CRi was 41.7%. TQB3909 has been conducting a number of related clinical studies and has recently been granted implicit approval for two new clinical trials, which are intended to be used in combination with chemotherapy for the treatment of patients with acute lymphoblastic leukemia (ALL).

https://news.yaozh.com/archive/44562.html