September 22 is International CML Day. CML is the abbreviation for chronic myeloid leukemia, also known as chronic myelogenous leukemia. The selection of this date holds special significance, derived from the pathogenic mechanism of CML, which is caused by the fusion gene resulting from the translocation of the ends of chromosomes 9 and 22 in the body. The 2018 film "Dying to Survive," which touched countless people, brought CML and the anti-cancer drug imatinib (Gleevec®) into the public spotlight, rapidly breaking out of niche awareness.

Just a few days ago, Olverembatinib (耐立克®), a domestic Class 1 new drug independently developed by Ascentage Pharma, representing an iterative upgrade of imatinib and filling a clinical gap in China, officially passed the formal review for the 2022 National Reimbursement Drug List adjustment. It can be seen that both the medical insurance authorities and pharmaceutical companies are accelerating efforts to improve the accessibility of innovative drugs for CML through medical insurance, aiming to avoid a repeat of the situation where CML patients desperately sought imatinib in the past.

01. From Incurable Disease to Manageable "Chronic Condition": Targeted Drugs Cannot Escape the "Curse" of Drug Resistance

CML is a malignant disorder of hematopoietic stem cells characterized by myeloid proliferation. Patients often present with leukocytosis with or without splenomegaly, immature myeloid cells in the peripheral blood, and the presence of the Philadelphia chromosome and/or BCR-ABL fusion gene. Data from "Cancer Statistics in China & US" 2020, published by the National Cancer Center/Cancer Hospital, Chinese Academy of Medical Sciences, showed that there were 88,249 new cases of leukemia in China, with CML accounting for approximately 15%.

In the past, CML was considered an "incurable disease." Treatments such as chemotherapy, interferon therapy, and bone marrow transplantation were once mainstream, but the treatment outcomes were not ideal. It wasn't until the 1990s, with the advent of tyrosine kinase inhibitors (TKIs) like imatinib targeting the BCR-ABL fusion gene, that the treatment paradigm for CML was revolutionized. Since then, CML has transformed from an "incurable disease" into a controllable chronic condition, similar to hypertension or diabetes, earning it the title of the "most 'fortunate' leukemia."

Statistics show that the advent of targeted drugs has increased the five-year survival rate for CML patients from less than 50% to over 90%. Most patients can achieve long-term survival and even clinical cure. However, it is important to note that with the widespread use of targeted drugs and disease progression, CML patients inevitably face the "curse" of acquired drug resistance, which has become a thorny issue in clinical practice. Data indicates that over 50% of resistance cases are caused by mutations in the BCR-ABL kinase domain. Among these, the T315I mutation is the most common, accounting for approximately 10%-30% of all mutations.

For a long period, CML patients with the T315I mutation in China lacked effective treatment options, facing a dilemma with no available drugs. Due to the high mutation rate, which causes resistance to both first- and second-generation TKIs and leads to rapid disease progression, the survival prognosis for these patients is significantly worse than for other CML patients, representing a substantial unmet clinical need. However, these CML patients have once again been favored by "luck." With policy support, Ascentage Pharma, a leading domestic innovative drug company that emerged during this period, focused its R&D efforts on CML drug resistance, breaking the treatment deadlock for patients with the T315I mutation using an original Class 1 new drug.

02. From 0 to 1, Filling a Domestic Treatment Gap: Clinical Data Demonstrates Best-in-Class Potential

In November 2021, China's National Medical Products Administration granted conditional approval for the marketing of Ascentage Pharma's Class 1 innovative drug Olverembatinib Tablets through a priority review and approval process, filling the treatment gap for CML patients with the T315I mutation in China. As the first and currently only approved third-generation BCR-ABL inhibitor in China, Olverembatinib provides an effective treatment option for patients who develop resistance due to the T315I mutation. Its clinical data demonstrates best-in-class therapeutic potential.

Data from the pivotal Phase II clinical trial for marketing authorization showed that Olverembatinib is highly effective in CML patients with drug resistance. Among chronic phase (CP) patients, the 24-month progression-free survival (PFS) rate was 92%, and the 24-month overall survival (OS) rate was 95%. Among accelerated phase (AP) patients, the 24-month PFS rate was 62%, and the 24-month OS rate was 69%. Just before International CML Day, more positive news emerged for Olverembatinib: results from its Phase I and II clinical studies for resistant CML were published in the prestigious international oncology journal *Journal of Hematology & Oncology*, further validating its durable efficacy and safety in CML patients and supporting its best-in-class potential. Leveraging its data advantages from Chinese patients and breakthrough therapeutic effects, Olverembatinib has become a preferred treatment option for physicians and patients since its approval. It has also been recommended in the latest clinical guidelines, including the 2022 CSCO Guidelines for the Diagnosis and Treatment of Malignant Leukemia and the 2022 CACA Guidelines for Integrated Management of Hematological Malignancies.

Ascentage Pharma is actively advancing the global clinical development of Olverembatinib, with over 450 patients enrolled in global clinical trials. In the first half of this year, Olverembatinib received a Clinical Trial Application (CTA) approval from Health Canada to conduct a Phase Ib clinical study for the treatment of resistant CML and Philadelphia chromosome-positive acute lymphoblastic leukemia (Ph+ ALL). Previously, clinical studies for Olverembatinib were conducted in multiple countries including the United States, Russia, and across Europe. This approval marks Ascentage Pharma's first clinical study in Canada and further expands its global strategic footprint.

Notably, Olverembatinib's clinical progress has been featured as an oral presentation at the American Society of Hematology (ASH) Annual Meeting for four consecutive years since 2018, and was nominated for "Best Research" at the 2019 ASH Annual Meeting. Currently, Olverembatinib has received one Fast Track Designation from the U.S. Food and Drug Administration (FDA), three Orphan Drug Designations from the FDA, and one Orphan Drug Designation from the European Medicines Agency (EMA). In China, Olverembatinib has twice been granted priority review status by the Center for Drug Evaluation (CDE) of the NMPA and has been designated as a Breakthrough Therapy.

In July of this year, the marketing application for Olverembatinib for the treatment of chronic phase chronic myeloid leukemia (CML-CP) patients resistant and/or intolerant to first- and second-generation TKIs was accepted by the CDE and granted priority review. In the industry's view, this represents another significant milestone following the drug's conditional approval in 2021, supporting its potential for full approval and accelerating broader access for more CML patients in China.

03. Clinical Value Demonstrates Global Competitiveness: Olverembatinib's Cost-Effectiveness is Becoming Evident

In fact, the differentiated clinical value and global independent intellectual property rights of a domestic innovative drug not only allow it to fill domestic treatment gaps but also endow the drug with global competitiveness.

For resistant CML, especially in patients with the T315I mutation, aside from Olverembatinib developed by Ascentage Pharma, two other drugs have been approved for use by global regulatory authorities: Ponatinib, the world's first third-generation BCR-ABL inhibitor developed by Takeda, and Asciminib, an ABL1 allosteric inhibitor developed by Novartis. The former is not yet approved in China. Although the latter has been made available at Ruijin Hospital Hainan Branch through the Hainan Boao Lecheng "pilot" policy, its high cost places significant pressure on drug accessibility.

In contrast, the situation for Olverembatinib, which is formally and uniquely approved in China, is distinctly different, and its cost-effectiveness is becoming increasingly apparent. With Olverembatinib officially shortlisted for formal review in the 2022 National Reimbursement Drug List adjustment, Ascentage Pharma is actively preparing for the upcoming reimbursement negotiations. Industry observers believe that leveraging its uniqueness, excellent clinical efficacy, favorable safety profile, and innovative clinical value, this domestic original innovative drug holds considerable promise.

Ma Aixia, Director of the Center for Pharmacoeconomic Evaluation at China Pharmaceutical University and Professor at the International Pharmaceutical Business School, has also stated that Olverembatinib is the only third-generation TKI approved in China, and available clinical data suggest it has a higher safety profile compared to similar drugs. Therefore, there is no particularly suitable comparator drug for pharmacoeconomic evaluation of Olverembatinib. However, data from its pivotal Phase II clinical trial demonstrate outstanding efficacy. "Based on this, it is recommended to conduct the pharmacoeconomic evaluation of Olverembatinib using relatively flexible research assumptions, or to assign a higher price compared to alternative treatment options based on other supporting evidence."

Data indicates that 26 anti-tumor drugs not currently on the list passed the preliminary medical insurance review this year, including 3 non-exclusive drugs and 23 exclusive drugs. Notably, among these drugs, most of the shortlisted ones are imported innovative anti-tumor drugs, while only 9 are domestic innovative anti-tumor drugs. Furthermore, only 5 are "first-in-class" drugs approved in China, a small number that includes Olverembatinib.

By potentially serving as an alternative to bone marrow transplantation, ineffective chemotherapy, and palliative care, thereby freeing up clinical and medical insurance resources, Olverembatinib aligns with the "basic coverage" principle of China's medical insurance system. Additionally, its advantages in filling gaps in the current list and reducing clinical management difficulty will also facilitate its faster entry into the medical insurance system. The industry generally believes that the support of medical insurance coverage is undeniably crucial for further improving patient access to innovative drugs.