FDA Grants Orphan Drug Designation to HQP1351 for Chronic Myeloid Leukemia

The FDA granted orphan drug designation to Ascentage Pharma’s HQP1351 for the treatment of chronic myeloid leukemia.

The FDA granted HQP1351 orphan drug designation for the treatment of patients with chronic myeloid leukemia (CML), according to Ascentage Pharma, the drug’s developer.1

HQP1351 is a novel, orally active, potent third generation BCR-ABL inhibitor designed to target BCR-ABL mutants, including T3151. Further, the agent is being developed for the treatment of patients with CML resistant to first- and second-generation tyrosine kinase inhibitors (TKIs). 

"There is significant unmet clinical need in the treatment of CML globally. This ODD from FDA marks a major milestone for HQP1351 which will bring about the incentives and support that will enable us to further accelerate the global development and commercialization of this drug candidate," Dajun Yang, PhD, chairman and chief executive officer of Ascentage Pharma, said in a press release. "Given the favorable safety and efficacy data obtained thus far, we will expedite the development and are hopeful that HQP1351 will soon benefit patients worldwide."

In July 2019, HQP1351 was cleared by the FDA to enter a phase Ib study. Currently, the drug candidate is being evaluated in a pivotal phase II study in China, and Ascentage indicated that they plan to submit a new drug application for HQP1351 sometime this year. 

Data from the phase I clinical study of HQP1351 were selected for oral presentations at the American Society of Hematology (ASH) Annual Meetings 2 years in a row and was a finalist of "Best of ASH" research in 2019. The open-label, dose escalation, and expansion trial was designed to determine the maximum tolerated dose (MTD) and to identify dose-limiting toxicities (DLTs) in patients with CML in the chronic phase or accelerated phase resistant or intolerant to ≥2 prior TKIs or those with T3151 mutation after ≥1 prior TKI.2

Trial participants were administered HQP1351 orally once every other day in 28-day cycles in 11 dose cohorts ranging from 1 mg to 60 mg. Blood samples were collected at certain time points on day 1-2 and day 27-28 during cycle 1 for PK analyses.

From October 26, 2016 to May 27, 2019, researchers treated 101 patients with HQP1351, including 87 patients who were chronic phase and 14 who were accelerated phase. Moreover, 83 (83.8%) patients had received ≥2 prior lines of TKI-therapy and 62 (61.4%) harbored T3151 mutation. Median interval from CML diagnosis to starting HQP1351 treatment was 5.8 (range, 0.3-15.2) years and the median duration of follow-up was 12.8 (range, 1.2-31.5) months.

Overall, 17 patients were initially assigned to the dose escalation cohorts ranging from 1 mg to 20 mg moved to 30 mg or higher dose cohorts. Additionally, 56 patients were enrolled in the dose expansion part of the trial, including 30 mg, 40 mg, and 50 mg dose cohorts. Further, 2 out of 3 patients treated at 60 mg experienced DLT and 50 mg once every other day was considered to be the MTD.

During the follow-up period, HQP1351 was found to be well-tolerated in each dose cohort, except for the 60 mg cohort. However, all patients experienced ≥1 treatment related adverse events (TRAEs), and most of the non-hematologic TRAEs were reported as grade 1 or grade 2. The most common hematologic TRAE of grade 3 or 4 was thrombocytopenia (49.5%). Moreover, the incidences of TRAEs tended to be dose-dependent and no death or grade 5 AEs occurred. 

HQP1351 also demonstrated potent anti-leukemic activities in patients with CML. Of the 68 evaluable patients with non-complete hematologic response (CHR) at baseline, 63 (92.6%) achieved CHR, including 52 out of 55 (94.5%) chronic phase patients and 11 out of 13 (84.6%) accelerated phase patients, respectively. Even further, of the 95 evaluable patients with non-complete cytogenetic response (CCyR) at baseline, 56 out of 81 (69.1%) chronic phase patients achieved major cytogenetic response (MCyR) including 49 (60.5%) CCyR and 6 out of 14 (42.9%) accelerated phase patients achieved MCyR, including 5 (35.7%) CCyR, respectively.

Of the 100 evaluable patients, 32 out of 86 (37.2%) chronic phase patients and 5 out of 14 (35.7%) accelerated phase patients achieved a major molecular response (MMR), respectively. In addition, HQP1351 showed highly efficacious in the patients with T315I mutation. As of the cut-off date of May 27, 2019, 9 patients (5 chronic phase and 4 accelerated phase) had withdrawn from the study, including progression to accelerated phase or blast phase (n = 5), intolerant AEs (n = 2), consent withdrawal (n = 1), and newly diagnosis of breast cancer (n = 1). The progression free survival rate at 18-months was 94% in the chronic phase patients and 61% in the accelerated phase patients.


1. Ascentage Pharma's Core Drug Candidate HQP1351 Granted Orphan Drug Designation by the US FDA for the Treatment of Patients with Chronic Myeloid Leukemia [news release]. Suzhou, China and Rockville, MD. Published May 4, 2020. prnmedia.prnewswire.com/news-releases/ascentage-pharma-s-core-drug-candidate-hqp1351-granted-orphan-drug-designation-by-the-us-fda-for-the-treatment-of-patients-with-chronic-myeloid-leukemia-868803015.html. Accessed May 4, 2020. 

2. Jiang Q, Huang X, Chen Z, et al. An Updated Safety and Efficacy Results of Phase 1 Study of HQP1351, a Novel 3rdGeneration of BCR-ABL Tyrosine Kinase Inhibitor (TKI), in Patients with TKI Resistant Chronic Myeloid Leukemia. Blood. doi:10.1182/blood-2019-124295.