China Innovation Talk | Ascentage's Dajun Yang on the true path to biotech "shore"

The Bcl-2 protein is often called the "ultimate gatekeeper" of apoptosis. Since its discovery in 1985, scientists worldwide have relentlessly pursued this target, yet repeatedly faltered. The protein is deeply embedded within the double-membrane structure of the mitochondria, the cell's powerhouse, requiring drugs to navigate significant barriers to reach it. Furthermore, its mechanism of action involves protein-protein interactions (PPI). The binding interface is as large as "two open palms," making it notoriously difficult for small molecules to precisely block. For nearly 40 years, only AbbVie's venetoclax had reached the market globally, leaving Chinese patients in a prolonged state of having a critical treatment remain out of reach.

To pursue Bcl-2 was to choose the hardest path.

At that time, the three-dimensional structure of the Bcl-2 protein remained unsolved, and the prevailing academic view was that "protein-protein interactions are undruggable." In 1995, Dr. Dajun Yang and Dr. Shaomeng Wang initiated their research in a laboratory at Georgetown University in the United States. "We thought at the time that synthesizing compounds in the lab was the whole task. We later realized it was merely the first step of a Long March," Dr. Yang remarked wryly.

In 1996, American scientists successfully resolved the hydrophobic binding pocket of the Bcl-2 protein. Over the next two years, Dr. Yang and his team utilized computer modeling and structural analysis to screen small molecules. By 2001, they filed their first patent for AT-101.

AT-101 originated from gossypol, a natural compound used in China during the 1970s and 1980s for male oral contraception. This chapter, akin to Tu Youyou's discovery of artemisinin, represents a story of repurposing an old compound for a new target in the United States—much like the story of Paclitaxel.

In 2003, Dr. Yang and his colleagues established Ascenta Therapeutics in the U.S. Following a Series A financing of $5.5 million, they advanced AT-101 into Phase I clinical trials. However, the program ultimately did not succeed in Phase II trials. Coupled with the U.S. financial crisis at the time, the project was discontinued.

Despite this, the startup achieved notable milestones: from 2003 to 2007, it raised a cumulative total of $85 million, with key investors including the prestigious Soros Fund Management. It was once ranked among the 15 most promising companies in the U.S. biopharmaceutical sector, and its molecular structures and other R&D achievements gained significant recognition within the industry.

Indeed, innovative drug development is inherently challenging. Dr. Dajun Yang and his team subsequently embarked on the development of a second Bcl-2-targeting drug, APG-1252, which is currently undergoing multiple clinical trials.

In 2014, they initiated the design of their third compound, APG-2575 (commercially known as 利生妥® Lishengtuo/lisaftoclax). This molecule demonstrated 1,000-fold greater potency than AT-101 while maintaining a molecular weight of approximately 800 Daltons, ensuring favorable oral bioavailability.

Reportedly, tumor lysis syndrome (TLS) is the most significant safety risk associated with Venclexta (venetoclax), the world's first approved Bcl-2 inhibitor, necessitating a five-week dose-escalation protocol that results in a slow onset of action for patients.

To address this, Ascentage Pharma proposed a groundbreaking solution: an innovative daily dose-escalation regimen. This approach reaches the therapeutic window within just 5 days of dose escalation! It not only enables rapid dose titration, allowing patients to achieve therapeutic levels in a short timeframe, but also helps reduce hospital stays, improve treatment adherence, and deliver a faster response for patients.

Dr. Yang noted that this dose-escalation regimen initially faced skepticism but ultimately demonstrated its safety profile with solid clinical data.

Multiple clinical studies for lisaftoclax have shown an extremely low incidence of TLS. In the pivotal registrational Phase II clinical trial (APG2575CC201) supporting its approval, no clinical or even laboratory TLS events were observed, eliminating the need for complex monitoring and highlighting its favorable short-term safety profile. Compared to venetoclax, lisaftoclax exhibits a milder hematological toxicity profile, with significantly reduced side effects such as neutropenia and thrombocytopenia. This effectively lowers the risks of infection and bleeding, thereby enhancing the long-term safety of treatment.

Observers have described this as a victory rooted in scientific courage, but it equally represents the culmination of the researchers' collective wisdom and relentless dedication. Although Ascentage was not the first to enter the clinic with a Bcl-2 inhibitor, its initial design already established clear differentiation in mechanism and strategy. It directly addresses key clinical challenges, ultimately delivering greater benefit to patients.

Lisaftoclax has garnered recognition from multiple clinical experts. Professor Li Jianyong, Director of the Lymphoma Center at Jiangsu Provincial People's Hospital, highlighted its distinctive profile, particularly its very short half-life. "For Bcl-2 inhibitors, the most serious side effect is TLS, which in severe cases can be fatal. The safety improvements demonstrated by this drug represent a highly significant contribution to the entire drug class."

Secondly, the rapid dose-escalation regimen of lisaftoclax is particularly important in the context of China's policy to "reduce the average length of hospital stays." This feature can improve bed turnover efficiency and alleviate pressure on limited hospital bed resources in major medical centers.

Furthermore, lisaftoclax achieves its target dose within just five days of dose escalation, making it especially suitable for patients who have developed resistance after prior BTK inhibitor therapy. Disease progression in these patients is often rapid. Therefore, the ability to reach an effective dose quickly and exert therapeutic efficacy promptly is crucial for disease control.

The launch of lisaftoclax is not the finish line for Ascentage Pharma. Dr. Dajun Yang and his team now face a new challenge: commercialization.

For an innovative pharmaceutical company, commercial execution capability directly determines its survival and growth. In a previous discussion with VCBeat, Dr. Yang clearly pointed out that the greatest weakness for Chinese biotechs lies not in science, but in commercialization.

Ascentage's first product, olverembatinib (Chinese brand name: 耐立克®), was approved in November 2021. At the time, it was the only third-generation "Gleevec®-like" kinase inhibitor approved in China. Its initial approved indication was relatively niche—limited to patients with chronic myeloid leukemia (CML) carrying the T315I mutation and resistant to prior therapies. The full commercial rollout of olverembatinib began in 2022. As its approved indications have progressively expanded, the drug was included in China's National Reimbursement Drug List (NRDL) in both 2022 and 2024.

Upon the approval of olverembatinib, Ascentage Pharma entered into a co-promotion agreement with Innovent Biologics. According to the terms, Innovent paid Ascentage an upfront fee of $30 million for the collaboration on olverembatinib. Furthermore, Ascentage is eligible to receive up to an additional $115 million in milestone payments, contingent upon the drug achieving certain development, regulatory, and sales milestones.

To date, this remains the largest collaboration agreement between two domestic biopharmaceutical companies in China. "At that time, we secured an upfront payment and structured milestone payments. Most crucially, we adopted a co-promotion model. On one hand, the cash infusion mitigated our risk. On the other, it allowed us to leverage our partner's commercial team to promote the drug, while we retained half of the market share. We also began building our own commercial team in parallel," explained Dr. Yang.

For lisaftoclax, the commercial strategy marks a return to building an in-house team.

"The hematologic oncology sector in China has a distinct characteristic: treatment is highly concentrated in one, two, or three major centers per city. This means we don't require a sales force numbering in the thousands, as would be necessary for lung or breast cancer. Therefore, we can establish a relatively small yet highly efficient commercial team," stated Dr. Yang. He expressed confidence, based on past experience, in building a team capable of growing and strengthening the product's presence in China.

Dr. Yang is also optimistic about the prospects for lisaftoclax, given the broad therapeutic potential of the Bcl-2 target, often referred to as the "small-molecule PD-1." Beyond chronic lymphocytic leukemia (CLL), it has shown significant activity in various hematologic malignancies, including acute myeloid leukemia (AML), myelodysplastic syndromes (MDS), and multiple myeloma (MM). It can be used either as a monotherapy or in combination with agents like BTK inhibitors, indicating substantial market potential.

Venetoclax, which targets the same Bcl-2 pathway, has been on the market for nine years. It achieved sales of $2.6 billion in 2024, with projections exceeding $3 billion this year.

"Following its launch, lisaftoclax holds significant future potential. The clinical data for its combination with our earlier drug, olverembatinib, is also very promising," stated Dr. Yang. "Both are targeted oral therapies. If we can achieve long-term safety and efficacy, the first step would be to realize a chemotherapy-free approach. The second step would be to transform acute hematologic diseases into chronic, manageable conditions, and chronic ones into states where treatment can be stopped without disease progression. The ultimate goal in CLL is that, through the combination of these two drugs, clinical cure could be achieved in at least a subset of patients—defined as being treatment-free and without relapse for five years. This is our long-term objective in hematologic oncology."

To date, lisaftoclax has received a total of five Orphan Drug Designations (ODD) from the U.S. Food and Drug Administration (FDA) for indications including Waldenström's macroglobulinemia (WM), chronic lymphocytic leukemia (CLL), multiple myeloma (MM), acute myeloid leukemia (AML), and follicular lymphoma (FL).

Lisaftoclax is Ascentage Pharma's second commercialized product. In early 2025, the company also went public in the United States. Furthermore, its business development (BD) collaboration with Takeda, with a total potential value of $1.3 billion, set a new record for out-licensing of a China-discovered small-molecule drug.

Ascentage Pharma is progressing toward a stronger position. Concurrently, the capital market for Chinese innovative drugs appears to be showing signs of a "thaw." Innovative drug stocks in Hong Kong have hit record highs, with share prices surging 2 to 3 times, or even up to 5 times. The primary market also exhibits a clear trend of "capital returning."

BD transactions are occurring frequently. According to incomplete statistics from industry media, as of the end of June 2025, 52 out-licensing deals have been completed. Among these, 18 deals have a total potential value exceeding $1 billion, with the combined disclosed value surpassing $64.7 billion.

Regarding this, Dr. Dajun Yang maintains a clear-eyed perspective. "The capital winter and industry challenges that began around mid-2021 have persisted for over three to four years. During this process, some companies survived, while others did not. Truly good companies and products will ultimately gain recognition from the market and capital. This is a process of elimination. The positive aspect is that genuine gold can survive and endure."

Dr. Yang candidly stated that around early 2021, there was indeed a significant bubble in the Hong Kong stock market for biotech listings. Many companies that went public before that period saw their shares fall below the offering price. The current phase is, in fact, one of valuation correction, underpinned by the clinical value of products and their ability to generate commercial returns.

"The recent rebound is primarily based on clinical data and the survival of companies through BD deals. Because of these successes, the capital markets—both public and private—have begun to refocus on biopharma. The situation is much better compared to two years ago, so the perception of a thaw is natural."

When VCBeat asked if Ascentage Pharma had truly "reached the shore," Dr. Dajun Yang responded with a definitive "no."

In fact, "reaching the shore" has become one of the hottest buzzwords in the Biotech circle in 2025. Dr. Yang offered his own definition: company-level profitability, where sales profits cover all R&D, administrative, and sales expenses. True "reaching the shore" means using product sales profits to fund the next cycle of R&D, rather than perpetually relying on financing or BD deals.

"The fundamental difference between a pharmaceutical company (Pharma) and a biotechnology company (Biotech) is this: a true major pharma must support its R&D investments with profits generated from its own product sales. It's not merely having a product and sales that makes a company a Pharma. In this sense, Ascentage has not yet 'reached the shore.' We aim to achieve profitability and break-even for the entire company by 2027, but the process is not an easy one," Dr. Yang pointed out.

In Dr. Yang's view, the sustainable development of innovative drugs, beyond capital market support, hinges most critically on commercial success: only when the market provides reasonable pricing, generating stable sales and profits, can a company sustain its innovation. The century-long trajectory of multinational pharmaceutical giants demonstrates that a closed loop where product profits feed back into R&D constitutes the true meaning of "reaching the shore."

Ascentage Pharma aims to achieve company-wide profitability and a breakeven point by 2027. In the future, we may witness innovative drug companies, including Ascentage, truly "reaching the shore."