FDA Grants Orphan Drug Designation to Novel Bcl-2 inhibitor in CLL

A novel Bcl-2 inhibitor, APG-2575, has been granted an Orphan Drug designation by the FDA for the treatment of patients with chronic lymphocytic leukemia.

A novel Bcl-2 inhibitor, APG-2575, has been granted an Orphan Drug designation (ODD) by the FDA for the treatment of patients with chronic lymphocytic leukemia (CLL), announced Ascentage Pharma in a press release.1

This marks the second ODD for APG-2575, after 1 was granted to the drug in July 2020 for the treatment of Waldenström Macroglobulinemia (WM).2

“At present, CLL still presents considerable unmet medical needs. APG-2575 is a key drug candidate in Ascentage Pharma's pipeline targeting apoptosis. The APG-2575 received this ODD from the FDA shortly after the first ODD in WM, and this designation will be helpful in enhancing our communication with the FDA and expediting our development of APG-2575 in these rare cancer diseases," said Yifan Zhai, MD, PhD, chief medical officer, Ascentage Pharma, in a statement.1 “All the policy support and incentives as a result of this ODD will help us accelerate the global clinical development of APG-2575, which we hope will soon offer additional treatment options for patients with CLL."

In hematologic malignancies, APG-2575 may selectively block Bcl-2 as a way to renew the apoptosis process in cancer cells. The first study of APG-2575 in CLL, as well as in small lymphocytic leukemia (SLL), is currently recruiting 35 patients with relapsed or refractory disease. In the phase 1b dose-escalation study (NCT04215809), patients will receive APG-2575 alone or in combination with other therapeutic agents. The primary end point of the study is dose-limiting toxicity, and the secondary end point is the maximum tolerated dose of APG-2575.

The study will follow a non-randomized 3 + 3 design at a starting dose of 200 mg given on day 1 of a 28-day cycle. The dose will be increased to 400 mg, followed by 600 mg, 800 mg, and 1200 mg.

To be included in the trial, patients must be 18 years or older with a histologically confirmed diagnosis of CLL/SLL, and ECOG performance status of 2 or lower, adequate bone marrow function, and a serum creatinine level of ≤1.5×upper limit of normal. In part 1, patients will be eligible for dose escalation if they have received 3 or fewer prior lines of systemic therapy. Female patients are required to be postmenopausal for 2 years or surgically sterile prior to beginning treatment in the study.

Patients are excluded from this study if they have undergone allogeneic stem cell transplant within 90 days of joining the study, have active graft-versus-host-disease or are in need of immunosuppressive therapy, and/or have Richter's syndrome. The study also excludes patients with certain prior therapies and comorbidities that may interfere with APG-2575 treatment.

Multiple cancer centers in the United States are involved in the phase 1b study of APG-2575 including the Mayo Clinic in Scottsdale Arizona, City of Hope in Duarte, California, Dana-Farber Cancer Institute in Boston, Massachusetts, Novant Health in Charlotte, North Carolina, Grabrail Cancer Center in Canton, Ohio, Cleveland Clinic in Cleveland, Ohio, and Swedish Health in Seattle, Washington.

Outside of the realm CLL/SLL, APG-2575 is being investigated in other hematologic malignancies like WM, AML, and T-cell prolymphocytic leukemia. Studies of APG-2575 in these disease states are currently recruiting patients in centers in the United States, Australia, and China.


1. Ascentage Pharma's Bcl-2 inhibitor apg-2575 granted Orphan Drug designation by the FDA for the treatment of chronic lymphocytic leukemia. News release. Ascentage Pharmaceuticals. September 7, 2020. Accessed September 8, 2020. https://prn.to/2ZiOqFJ

2. Ascentage Pharma’s Bcl-2 inhibitor apg-2575 granted Orphan Drug Designation by the FDA for the treatment of waldenström macroglobulinemia. News release. Ascentage Pharmaceuticals. July 15, 2020. Accessed September 8, 2020. https://bit.ly/329A5gL