Ascentage Pharma, a globally focused biotechnology company engaged in developing novel therapies for cancers, chronic hepatitis B (CHB), and age-related diseases, announced that the US Food and Drug Administration (FDA) recently granted an Orphan Drug Designation (ODD) to the company's MDM2-p53 inhibitor, APG-115 (alrizomadlin), for the treatment of stage IIB-IV melanoma. This marks the fifth ODD granted to alrizomadlin, after those for the treatment of gastric cancer, acute myeloid leukemia, soft tissue sarcoma, and retinoblastoma. To date, Ascentage Pharma has obtained a total of twelve ODDs from the FDA, continuing to set the record for the number of ODDs granted to any Chinese biopharmaceutical company.

The term "orphan drugs" refers to pharmaceutical products developed for the prevention, diagnosis, and treatment of rare diseases or conditions. In the United States, an orphan indication is defined as a disease or condition with a prevalence of less than 200,000 patients in the country. Since the Orphan Drug Act was passed in 1983, the US government has provided incentives and policy support to encourage development of orphan drugs. This ODD by the FDA qualifies alrizomadlin for a range of development incentives, including a tax credit on expenditures incurred in clinical studies, a waiver of the New Drug Application (NDA) fee, possible research grant awarded by the FDA, and most importantly, 7 years of US market exclusivity upon approval.

Melanoma is a potentially deadly dermatologic malignancy that has been increasingly prevalent globally. The current lifetime risk of developing melanoma is 1 in 63 in the US1. In 2019, an estimated 96,480 patients have been diagnosed with melanoma and about 7230 patients with melanoma have died in the United States2. The prognosis of patients with of melanoma is closely associated with the stage of the disease at diagnosis. A US Surveillance, Epidemiology, and End Results (SEER) database review of melanoma cases from 2011 to 2015 identified approximately 75% of patients were diagnosed at stage I, 15% at stage II, 7.5% at stage III, and 2.5% at stage IV3.

Since 2011, remarkable progress has been achieved in the clinical treatment of patients with metastatic or unresectable melanoma. Targeted therapies such as mitogen-activated protein (MAP) kinase inhibitors and immunotherapies have dramatically improved patients' overall survival and quality of life4-6. Immunotherapies, namely immune checkpoint inhibitors (ICIs) such as anti-CTLA-4, anti-PD-1, and anti-PD-L1 monoclonal antibodies have been extensively studied and broadly used in clinical treatment. However, significant number of patients will eventually develop resistance to ICIs, and there is no approved treatment yet for patients with ICI-resistant melanoma.

Being developed by Ascentage Pharma, alrizomadlin is an orally administered, selective, small-molecule MDM2-p53 inhibitor. Preclinical studies showed that alrizomadlin combined with PD-1 blockade enhances antitumor activities by triggering adaptive antitumor immunity. At the 2021 American Society of Clinical Oncology (ASCO) Annual Meeting, Ascentage Pharma reported updated results from a Phase II study of alrizomadlin in combination with pembrolizumab that demonstrated promising antitumor activity and safety. The PD-1/PD-L1 inhibitor-resistant melanoma cohort which was treated with alrizomadlin plus pembrolizumab reported 1 patient with complete response, an objective response rate (ORR) of 24.1%, and a disease control rate of 55.2%. These results signified the synergy between alrizomadlin and immune-oncologic drugs, and a potential regimen that could bring hope to patients with ICI-resistant melanoma.

"At present, there is a large unmet medical need for the treatment of melanoma. Therefore, this ODD for alrizomadlin bears tremendous significance," said Dr. Yifan Zhai, Chief Medical Officer of Ascentage Pharma. "As the fifth ODD granted to alrizomadlin, and the twelfth obtained by Ascentage Pharma, this designation reaffirms Ascentage Pharma's leadership in the number of ODDs granted to any Chinese biopharmaceutical company, demonstrating our capabilities in global innovation. Moving forward, we will continue to pursue our mission of addressing unmet medical needs in China and around the world. The FDA's supporting policy for orphan drug development will help us to further accelerate the clinical development of alrizomadlin and other drug candidates in our pipeline and hopefully we can bring these potential novel therapies to patients as soon as possible."

References

1. Stephanie C, Christy S, Jessica W. Epidemiology and Risk Factors of Melanoma. Surg Clin North Am. 2020 Feb;100(1):1-12.

2. Cancer Facts & Figures 2019. American Cancer Society. Link: https://www.cancer.org/research/cancer-facts-statistics/all-cancer-facts-figures/cancer-facts-figures-2019.html

3. Andrew P, Jason L. Considering adjuvant therapy for stage II melanoma. Cancer. 2020 Mar 15;126(6):1166-1174.

4. GV Long, Victoria A, Jonathan C, et al. Standard-dose pembrolizumab in combination with reduced-dose ipilimumab for patients with advanced melanoma (KEYNOTE-029): an open-label, phase 1b trial. Lancet Oncol. 2017 Sep;18(9):1202-1210.

5. Jacob S, Antoni R, Georgina L, et al. Pembrolizumab versus ipilimumab for advanced melanoma: final overall survival results of a multicentre, randomised, open-label phase 3 study (KEYNOTE-006). The Lancet. 2017 Oct 21;390(10105):1853-1862.   

6. Wolchok JD, Chiarion-Sileni V, Gonzalez R, et al. Overall Survival with Combined Nivolumab and Ipilimumab in Advanced Melanoma. N Engl J Med. 2017 Oct 5;377(14):1345-1356.

About Ascentage Pharma

Ascentage Pharma (6855.HK) is a globally focused biopharmaceutical company engaged in developing novel therapies for cancers, chronic hepatitis B, and age-related diseases. On October 28, 2019, Ascentage Pharma was listed on the Main Board of the Stock Exchange of Hong Kong, S.A.R., China Limited with the stock code: 6855.HK.

Ascentage Pharma focuses on developing therapeutics that inhibit protein-protein interactions to restore apoptosis, or programmed cell death. The company has built a pipeline of eight clinical drug candidates, including novel, highly potent Bcl-2, and dual Bcl-2/Bcl-xL inhibitors, as well as candidates aimed at IAP and MDM2-p53 pathways, and next-generation tyrosine kinase inhibitors (TKIs). Ascentage Pharma is also the only company in the world with active clinical programs targeting all three known classes of key apoptosis regulators. The company is conducting more than 40 Phase I/II clinical trials in the US, Australia, Europe, and China. Ascentage Pharma has been designated for multiple Major National R&D Projects, including five Major New Drug Projects, one New Drug Incubator status, four Innovative Drug Programs, and one Major Project for the Prevention and Treatment of Infectious Diseases. HQP1351, the company's core drug candidate developed for the treatment of drug-resistant chronic myeloid leukemia (CML), has been granted an Orphan Drug Designation (ODD) and a Fast Track Designation (FTD) by the US FDA. A New Drug Application (NDA) for HQP1351 has been submitted and subsequently granted Priority Review status and a Breakthrough Therapy Designation (BTD) by the Center for Drug Evaluation (CDE) in China. To date, Ascentage Pharma has obtained a total of 12 ODDs from the US FDA for 4 of the company's investigational drug candidates.

Leveraging its robust R&D capabilities, Ascentage Pharma has built a portfolio of global intellectual property rights, and entered into global partnerships with numerous renowned biotechnology and pharmaceutical companies and research institutes such as UNITY Biotechnology, MD Anderson Cancer Center, Mayo Clinic, Dana-Farber Cancer Institute, MSD, and AstraZeneca. The company has built a talented team with global experience in the discovery and development of innovative drugs, and is setting up its world-class commercial manufacturing and Sales & Marketing teams. Ascentage Pharma aims to continuously strengthen its R&D capabilities and accelerate its clinical development programs to fulfil its mission of 'addressing unmet clinical needs in China and around the world' for the benefit of more patients.