AIMed: China BTK inhibitors leading on efficacy data

AIMed: China BTK inhibitors leading on efficacy data

AIMed: China BTK inhibitors leading on efficacy data.  AIMed: China’s BTK inhibitors debut in 2020ASH, leading the way in efficacy data

The 62nd Annual Meeting of the American Society of Hematology (ASH) will be held from December 5 to 8, 2020. According to the abstract and public information of the ASH Annual Meeting, many domestic companies such as BeiGene, Nuocheng Jianhua, Yasheng Pharmaceutical, Legend Biology and others will also appear at this conference and bring their own innovative therapies. The BTK inhibitors introduced in this article are one of them.

BTK (Bruton’s tyrosine kinase) is a non-receptor tyrosine kinase that plays a vital role in regulating the survival, proliferation, activation and differentiation of B cells. BTK is abundantly expressed in B-cell hematological malignancies and several autoimmune diseases. Therefore, BTK is considered as a potential target for the treatment of B-cell malignancies and certain autoimmune diseases.

At present, including China’s BeiGene, Nuocheng Jianhua, etc., many companies have developed BTK inhibitors for this target. The above two companies have brought their BTK inhibitor Zebu at this ASH annual meeting. The latest clinical data of tinib and abutinib [2].

Zebutinib is a new-generation BTK inhibitor developed by BeiGene. Compared with the first-generation BTK inhibitor, it has stronger selectivity, fewer off-targets, and fewer side effects. It is also the first independent research and development in China to obtain FDA approval. Marketed anti-tumor drugs. At present, Zebutinib has two indications, relapsed refractory mantle cell lymphoma (MCL) and relapsed refractory chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL) have been approved in China.

Obutinib was developed by Nuocheng Jianhua, and is currently undergoing multi-center, multi-indication clinical trials in China and the United States to study its efficacy and safety as a single drug and a combination drug. The marketing application for two indications of abutinib for CLL/SLL and MCL patients has been included in priority review by the National Medical Products Administration (NMPA) Drug Evaluation Center.

1. Zebutinib

01) The efficacy and safety of Zebutinib in the treatment of refractory/relapsed marginal zone lymphoma: initial results of the MAGNOLIA (BGB-3111-214) study

Study introduction: MAGNOLIA is a single-arm, multi-center phase II clinical study, which mainly includes adult patients with refractory/relapsed marginal zone lymphoma who have received at least first-line treatment (including at least one CD20 monoclonal antibody-related program) in the past .

The study included a total of 68 patients, with a median follow-up time of 6.8 months. The results of the study showed that the objective response rate (ORR) assessed by the investigator was 60%:

• Of which complete remission (CR) 15%,
• Partial remission (PR) 45%,
• Stable disease (SD) 27%;
• The median duration of remission (DOR) and median progression-free survival (PFS) have not yet been reached.

In this study, 30.9% of patients discontinued study treatment:

• The most important reason is disease progression (23.5%)
• The most common TEAE was diarrhea (19.1%)
• Bruises (17.6%)
• Constipation (13.2%)
• Fever (10.3%)
• Upper respiratory tract infection (10.3%)
• Nausea (10.3%).

02) Phase II clinical study of the safety and efficacy of BTK inhibitor Zebutinib in the treatment of patients with Waldenstrom’s macroglobulinemia

Study introduction: This study is a single-arm, multi-center phase II clinical study, mainly including refractory/relapsed Fahrenheit macroglobulinemia patients who have received at least first-line chemotherapy in the past. As of August 31, 2019, a total of about 44 patients were enrolled, with a median follow-up of 18.58 months. The median duration of remission (DOR) and median progression-free survival (PFS) had not yet been reached at the data cut-off date. The results of the study showed that among 43 evaluable patients, the main response rate (MMR, ≥PR) assessed by the investigator was as high as 69.8%. The patient was well tolerated, without atrial fibrillation and tumor lysis syndrome.

03) Phase II clinical study of Zebutinib in the treatment of patients with ibrutinib/acatinib intolerant of B-cell lymphoma

Study introduction: This study is a single-arm, multi-center phase II clinical study, mainly including lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL) patients who cannot tolerate BTK inhibitor treatment. As of June 1, 2020, the median zebutinib exposure time was 3.02 months. The results of the study showed that of the 31 cases of BTK inhibitor-related intolerable AEs that occurred, 30 cases (96.8%) did not recur. One case of atrial fibrillation AE decreased from grade 3 to grade 2, and the persistent event changed from 14 The days shrank to 3 days. 10 patients (58.8%) had AEs ≥1 grade, 2 patients (11.8%) had AEs ≥3 grade, 1 case of neutropenia, and 1 case of syncope. No AEs caused dose adjustment or interruption of treatment. Among the 10 patients with evaluable efficacy, all patients achieved remission above SD, and 60% of patients took zebutinib to deepen the remission.

04) The effectiveness and safety of Zebutinib in the treatment of untreated 17p-CLL/SLL patients: follow-up results of SEQUOIA study C group

Study introduction: This study is an open, multi-center phase III clinical study. Study C group mainly included patients with 17p-CLL/SLL who had not been treated before (eligible for treatment indication age ≥65 years or not suitable for FCR regimen chemotherapy). As of April 15, 2020, a total of 109 patients were enrolled, and the median follow-up time was 18.2 months. The results of the study showed that the ORR of the study was as high as 94.5%, and PFS, DOR and OS were not reached. The estimated 18-month PFS rate and OS rate were 88.6% and 95.1%, respectively. In terms of safety, Zebutinib was well tolerated, and only 4 patients (3.7%) discontinued the drug due to adverse events.

2.  Abutinib

01) The long-term safety and efficacy of abutinib monotherapy in Chinese patients with relapsed or refractory mantle cell lymphoma: a multicenter, open, phase II clinical study

Study introduction: This study is an open, multi-center phase II clinical study, which mainly includes patients with relapsed or refractory MCL. As of the data cutoff date, the median follow-up time for the study was 15.0 months. The results of the study showed that the ORR of the study was 87.9%, and the DCR was 93.9%. PFS, DOR and OS were not reached. The 12-month PFS rate and OS rate were 70.8% and 88.7%, respectively. In terms of safety, the common AE of grade ≥3 is thrombocytopenia. No treatment-related gastrointestinal and cardiotoxicity of grade ≥3 was observed, and no severe bleeding was observed.

02) The updated data of the Phase II study of Chinese patients with relapsed/refractory chronic lymphocytic leukemia/small lymphocytic lymphoma with abutinib monotherapy

Study introduction: This study is an open, multi-center phase II clinical study, which mainly includes patients with relapsed/refractory chronic lymphocytic leukemia/small lymphocytic lymphoma who have been introduced at least once in the past. As of the data cut-off date, a total of 80 patients were enrolled, and the median follow-up time was 14.3 months. The results of the study showed that the study’s ORR was 91.3%, CR was 10.0%, and PR was 63.8%. The median PFS and DOR were not reached, and the 12-month PFS rate and OS rate were 81.1% and 86.3%, respectively. In terms of safety, the most common AEs are hematological toxicity (including thrombocytopenia, neutropenia, and anemia), upper respiratory tract infection, pneumonia, and hypokalemia. There was no atrial fibrillation and secondary malignant tumors, no hypertension events of grade ≥3 were found, and only one case of diarrhea of ​​grade ≥3 was found.

3. Conclusion

With the vigorous development of China’s biomedical industry, more and more Biotech companies have been born. The growth of these companies has also developed a number of innovative drugs that are internationally competitive. BTK inhibitors are the above-mentioned drugs. one. It is believed that as Chinese pharmaceutical companies further tap their innovative potential, more and more innovative drugs will be displayed and participate in international competition.

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