Recently, the official website of China's State Food and Drug Administration showed that the third-generation Bcr-Abl inhibitor Orebatinib tablets (Olverembatinib, HQP1351, formerly known as nectinib and oribatinib) were applied for marketing (accepted) No.: CXHS2000038) has been in the "administrative approval" stage and will be approved for listing in the near future. It is intended for use in chronic myelogenous leukemia (CML) patients who are resistant to any tyrosine kinase inhibitor and accompanied by T315I mutation. Orebatinib is ASUN's first product that is about to enter the commercialization stage, and it is also expected to become the first third-generation Bcr-Abl inhibitor to be marketed in China.

CML is a malignant tumor related to white blood cells. CML is generally divided into three stages: chronic phase (CP), accelerated phase (AP) and blast phase (BP). The course of the disease can last for many years, but once CML enters the blast phase, it often dies within half a year. With the launch of TKI drugs targeting BCR-ABL, the treatment of CML has been innovated. Although the first-generation BCR-ABL inhibitor Imatinib (Gleevec) and several subsequent second-generation drugs have significant clinical benefits for the treatment of CML, acquired resistance has always been the main challenge for CML treatment. Mutations in the kinase region of BCR-ABL are one of the important mechanisms of acquired drug resistance. Among them, T315I mutation is one of the common types of drug-resistant mutations, and the incidence rate in drug-resistant CML is as high as about 25%. CML patients with T315I mutations are resistant to all current first- and second-generation BCR-ABL inhibitors, so there is an urgent need for effective new-generation therapeutic drugs in clinical practice.

Orebatinib is an original class 1 new drug under research by Ascent Pharmaceuticals. It is an oral third-generation BCR-ABL inhibitor. It is China’s first third-generation BCR-ABL targeted drug-resistant CML treatment drug. It is resistant to BCR-ABL and A variety of BCR-ABL mutants, including the T315I mutation, have outstanding effects. In October 2020, the marketing application of Orebatinib was formally included in the priority review because it was in compliance with the review and approval procedures for clinically urgently needed new drugs.

Code-named HQP1351-CC201 and HQP1351-CC202 are an open, single-arm, multi-center key registration phase II clinical study conducted in China, respectively, which evaluated the resistance of oribatinib to TKI (BCR-ABL1T315I mutation). The safety and effectiveness of CML-CP and CML-AP in adult subjects. Oribatinib is administered 40 mg orally, every other day, 28 days as a cycle.

The ASH2021 summary data released by Ascent Pharmaceuticals shows: As of August 25, 2020, of the 41 CML-CP patient studies (HQP1351-CC201) enrolled, 32 (78%) completed ≥12 cycles of treatment. The follow-up time was 13 (3.1-16.3) months. Subjects who did not respond at baseline had a complete hematological response (CHR) of 100% after ≥12 treatment cycles. Major cytogenetic response (MCyR) was 75.6% (31/41), complete molecular genetic response (CCyR) was 68.3% (28/41), and major molecular response (MMR) was 56.1% (23/41). The PFS rate of the subjects at the 12th month was 89.3%, and the overall survival (OS) rate was 100%.

As of July 27, 2020, among the 23 CML-AP patient studies (HQP1351-CC202) enrolled, 14 patients (61%) completed ≥12 cycles, and the median follow-up time was 13.5 (1.4-15.2) moon. In subjects who did not respond at baseline, after ≥12 treatment cycles, the hematological depth response rate (MaHR) reached 73.9% (17/23), MCyR was 52.2% (12/23), and CCyR was 47.8%% (11 /23), MMR is 39.1% (9/23). The PFS rate of the subjects at the 12th month was 74.1%, and the OS rate was 91.3%.

In terms of safety, the most common grade 3/4 treatment-related adverse reaction (TRAE) in HQP1351-CC201 was thrombocytopenia (48.8%), and no treatment-related deaths occurred. The most common grade 3/4 TRAE in HQP1351-CC202 is thrombocytopenia (56.5%).