What's Still Missing for Innovative Radiopharmaceuticals to Succeed? Insights from Xiantong Pharmaceuticals' IPO Filing

In the past two years, radiopharmaceuticals have attracted more cross-sector participants, gradually breaking out of their niche market.

On Tuesday, VCBeat once again hosted a VB Insight Session themed around radiopharmaceuticals. In collaboration with Xiantong Pharma, the event invited experts from clinical practice, investment, and upstream and downstream sectors of the industry to discuss the advantages of radiopharmaceuticals in diagnosis and therapy, as well as strategic considerations for their advancement. Discussions covered in-depth topics including R&D, clinical trials, regulatory submission and registration, the industrial supply chain, and sector development trends.

Guests participating in the discussion include:

Liu Chuanwen | Managing Director, Neovision Capital

Wu Haowei | CEO of Midu Bio: One-Stop Service for Radiopharmaceutical R&D

Wang Peng | Vice President, Xiantong Medicine

Xu Bailing | Xiantong Pharma, CMO of Diagnostic Products

How are radiopharmaceuticals performing clinically in precision diagnosis and therapy? What concerns do stakeholders still have regarding their clinical application in precision medicine, and how can these concerns be gradually addressed?

Wang Peng | Vice President, Xiantong Pharma:Taking several products from Xiantong as examples, such as diagnostic radiopharmaceuticals, we have a PET agent targeting amyloid-beta (Aβ) and another targeting tau protein for the diagnosis of Alzheimer’s disease (AD). In the past, AD could only be definitively diagnosed through postmortem examination of affected brain tissue; prior to that, cases were merely suspected AD. However, Aβ and tau PET imaging can visually reveal the presence and location of plaques in the brain, and even quantitatively assess plaque density, thereby assisting physicians in making more accurate diagnoses. Similarly, certain cardiac diagnostic agents can intuitively and quantitatively display the extent of myocardial ischemia and the amount of viable myocardium remaining, helping clinicians make precise treatment decisions.

Compared with other drugs, the precision of radiopharmaceuticals is reflected in two aspects: one is their visualizability, and the other is their quantifiability. For instance, it allows for accurate visualization of tumor location while simultaneously calculating the absorbed dose after administration. This helps physicians adjust patient dosing to maximize tumor cell kill while minimizing adverse reactions. A key advantage of radiopharmaceuticals is termed “see and treat”; however, this also presents a challenge: identifying the problem must be followed by finding effective therapeutic interventions.

For radiopharmaceuticals, a common challenge in clinical practice is the pervasive fear of radiation. However, a high-quality product that truly addresses clinical needs—such as Lutathera, which extends patients’ progression-free survival from 12 months to nearly 30 months and delivers substantial clinical benefit—can gradually alleviate concerns about radiopharmaceuticals through ongoing communication and education with physicians and patients.

What is the current landscape of diagnostic and therapeutic radiopharmaceutical pipelines on the market? What is the portfolio strategy for Xiantong’s diagnostic radiopharmaceutical products, and what is the logical framework for their future development?

Liu Chuanwen | Managing Director, Neovision Capital:We can observe that most companies developing radiopharmaceuticals in the market are pursuing integrated theranostics, unless an approved diagnostic agent is already available. Therapeutic and diagnostic development are conducted almost simultaneously, with a potential stagger of only three to six months. This parallel approach accelerates the overall R&D process, enables data synergy, and thereby reduces total development costs.

Xu Bailing | Xiantong Pharma, CMO of Diagnostic Products:Xiantong has adopted a “start with the easier, then tackle the more difficult” development strategy for radiopharmaceutical R&D. This approach effectively reduces R&D risks, accelerates the market launch in China of products already approved abroad, and enables rapid accumulation of R&D expertise. Taking Xiantong’s first New Drug Application (NDA) submission—the florbetaben PET Aβ amyloid imaging agent—as an example, this product had already been marketed in Europe and the United States since 2014. After acquiring the development rights for China, Xiantong promptly advanced bridging clinical trials in the country. These trials demonstrated that florbetaben exhibits comparable safety and efficacy in the Chinese population to that observed in Western populations, thereby meeting regulatory requirements for NDA submission, which was filed in the first half of 2022.

Xiantong Medicine has accumulated valuable experience from bridging clinical trials, laying a solid foundation for the clinical development of two Class I cardiovascular products (one PET myocardial fatty acid metabolism imaging agent and one PET myocardial perfusion imaging agent) and one Class I neurological product (a PET tau protein imaging agent for Alzheimer’s disease diagnosis). The two cardiovascular products are expected to complete Phase II clinical trials in the first half of 2023 and sequentially initiate Phase III clinical trials in the second half. The overall clinical trial progress is highly streamlined, with Phase I clinical trials for the Class I neurological product also scheduled to commence shortly.

Wang Peng | Vice President, Xiantong Medicine:Prior to formally embarking on the R&D of diagnostic radiopharmaceuticals, Xiantong had already recognized that the future market belongs to therapeutic products. Of course, we are also acutely aware that every step of radiopharmaceutical R&D is fraught with various pitfalls. For therapeutic radiopharmaceuticals, we adhere to a product pipeline layout and R&D logic that proceeds from the easier to the more challenging. Initially, we focused on developing generic versions of marketed products to accumulate experience in areas such as CMC, non-clinical radionuclide supply, and product transportation, while also building our talent pool. This foundational work ultimately paved the way for clinical development, laying the groundwork for our subsequent therapeutic products. The second step involves exploring new molecules and novel compounds targeting indications that have already been validated abroad. For instance, recognizing that PSMA is a well-established target for radiopharmaceuticals, we licensed a novel PSMA compound from the U.S. National Institutes of Health (NIH) to conduct innovative research on this mature target.

Next, we turn to entirely novel targets and compounds. Globally, the number of validated targets for radiopharmaceuticals remains relatively limited, raising the question of what directions should be pursued next. On one hand, there is a need to develop first-in-class therapies, which requires a profound understanding of the medical and biological aspects of radiopharmaceuticals. On the other hand, consideration should be given to novel radionuclides, such as alpha-emitting isotopes. Additionally, combination therapies with other drug classes, such as immune checkpoint inhibitors and PARP inhibitors, hold considerable promise.

What are some “forethought-driven” recommendations for regulatory submissions and clinical trials of radiopharmaceuticals? What experiences or pitfalls can serve as references?

Wu Haowei | CEO, Midu Biotech:China’s current regulatory guidelines for radiopharmaceuticals are more complex than those in Europe and the United States. A key consideration during the submission process is whether to file exclusively in China or to pursue dual filings in both China and the United States. The vast majority of therapeutic products we encounter opt for the dual filing strategy. However, dual filing is not merely a matter of translating study content and compiling a separate set of registration documents. There are significant differences between China and the United States in quality standards, as well as in the design of non-clinical and clinical trials.

Furthermore, radiopharmaceuticals possess unique characteristics that necessitate specialized facilities for their production, quality control, and transportation. Due to their relatively short shelf life, the viable transportation radius for these agents is limited. Consequently, there are very few suppliers in China capable of undertaking such contract manufacturing. When selecting a contract manufacturing organization (CMO), several key factors must be considered. First is production throughput: to accommodate large-scale patient enrollment in clinical trials, it is essential to understand the manufacturer’s production frequency and available time slots. Second is the usage quota for radionuclides, particularly therapeutic ones. Apart from Class A facilities, annual allowances for radioactive nuclide usage are strictly limited; therefore, prior due diligence on the facility is mandatory to determine the total annual allocation and the portion available for the specific project. Third is the proximity to other trial sites, which impacts logistical convenience and helps minimize losses during transit.

Next is the issue of quality control by the contract manufacturer. Based on experimental requirements, it is highly likely that compliance with both GMP and GLP, or GMP and GCP, will be required. Therefore, it is essential to assess whether the supplier can provide radioactive drug production quality control and transportation standards that meet R&D needs.

Wang Peng | Vice President, Xiantong Pharma:Two recommendations. First, the regulatory guideline framework for radiopharmaceuticals remains incomplete and immature, both domestically and internationally, with very few successful precedents. However, this also presents an advantage by allowing greater flexibility in radiopharmaceutical research. By engaging in communication with the Center for Drug Evaluation (CDE) and clearly articulating the rationale, logic, and specific issues, many proposals can gain CDE’s acceptance.

Second, radiopharmaceuticals are, at their core, pharmaceutical products. Communication with the Center for Drug Evaluation (CDE) should first proceed from a pharmaceutical perspective, ensuring that the drug meets the requisite standards for safety, efficacy, and quality controllability; only thereafter should the unique characteristics of radiopharmaceuticals be addressed. Prioritizing the specific attributes of radiopharmaceuticals while neglecting their fundamental pharmaceutical commonalities poses significant challenges for regulatory authorities.

What progress has been made in the domestic supply chain for radiopharmaceuticals? What are the weak points?

Wang Peng | Vice President, Xiantong Pharma:The radiopharmaceutical supply chain is highly complex, with numerous upstream and downstream segments; any deficiency in a single link can lead to project delays or even significant issues. Examples include the timeliness of radionuclide supply, availability of synthesizers and accelerators required for production, kit manufacturing challenges, CDMO services for precursors, transportation of radionuclide products, customs clearance for imported goods, and domestic air freight logistics, among others.

Wu Haowei | CEO, Midu Bio:Radiopharmaceutical companies excel at conjugating radionuclides with drugs, but molecular development is not a core strength for many of them. In recent years, it has been encouraging to see ADC (Antibody-Drug Conjugate) and PDC (Peptide-Drug Conjugate) developers entering the radiopharmaceutical space, bringing their deep expertise in molecular development, particularly in antibodies and peptides. The current trend of collaboration or joint development between ADC companies and radiopharmaceutical firms is a highly positive development.

Liu Chuanwen | Managing Director, Neovision Capital:Weaknesses at both ends of the radiopharmaceutical industry chain remain to be addressed. One is the upstream production and supply of radionuclides, which still relies heavily on imports; therapeutic radionuclides, in particular, are almost entirely imported. Although many domestic teams are engaged in this area, it will indeed take time to achieve self-sufficiency. This is, of course, a global challenge, with conditions being somewhat more favorable in Europe and the United States. The second issue concerns hospitals, especially those with a long history. If such facilities previously lacked the necessary infrastructure or qualifications to add new capabilities, they will face objective difficulties in clinical implementation.

What Is the Most Pressing Issue for Innovative Radiopharmaceuticals to Navigate the “Deep Water Zone”?

Wang Peng | Vice President, Xiantong Medicine:I believe that for therapeutic radiopharmaceuticals, there is an urgent need to address the recurring patterns underlying successful development. Currently, apart from local administration and the treatment of hematologic malignancies, there are only two successful cases of therapeutic radiopharmaceuticals for solid tumors. A significant challenge lies in extending the success of these two cases to other tumor types, molecular targets, and indications. Which tumors may be suitable for radiopharmaceutical therapy? Which molecular formats might be more advantageous—peptides, antibodies, or small molecules? Peptides have achieved success thus far, but they face inherent limitations, such as a relatively limited number of druggable targets and significant renal clearance. Antibodies, on the other hand, are characterized by their large molecular weight, slow tissue penetration, and excessively long half-life.

Liu Chuanwen | Managing Director, Neovision Capital:I believe we need to build and solidify the entire radiopharmaceutical industry chain from the source. I am not overly concerned about the downstream drug manufacturing and clinical application segments. Although they face their own challenges and obstacles, excellent teams and talent are flowing in. I am confident that these issues will be gradually resolved, leading to increasing standardization in the radiopharmaceutical sector and its steady penetration into clinical practice.

However, if the root causes are not addressed and the supply of raw materials cannot be guaranteed, the industry will find itself in a passive predicament akin to “trying to cook without rice.” Therefore, I call on more outstanding pharmaceutical teams and talents in advanced manufacturing to engage in the upstream sector of radionuclide production and fundamentally transform this industry. Current practices resemble laboratory-scale operations rather than rigorous industrial-scale manufacturing.

Xu Bailing | CMO, Diagnostic Products, Xiantong Medicine:Domestic regulatory authorities can adopt a more scientific approach to the regulation of radiopharmaceuticals. Currently, regulatory complexities pose significant obstacles to our clinical trials. The use of radionuclides in radiopharmaceuticals entails a protracted approval process for expanding the scope and volume of services within nuclear medicine departments when initiating clinical trials. Furthermore, regulators require annual usage plans for the following year to be finalized at the end of the current year; any mid-year adjustments to increase planned usage involve an excessively lengthy administrative procedure. These regulatory complexities hinder the normal conduct of clinical trials. Domestic regulatory authorities should draw greater reference from the scientific regulatory practices of Western countries, thereby creating more favorable conditions for the conduct of clinical trials involving radiopharmaceuticals.

Wu Haowei | CEO of Midu Bio:R&D inevitably involves a variety of problems and challenges, sometimes even approached in somewhat irrational ways. We believe that by conducting substantial preparatory work upfront, solutions to many of these issues can be identified.

Organizer Introduction:

About Xiantong Medicine

Beijing Xiantong International Technology Co., Ltd. is a leading innovative nuclear medicine enterprise rooted in China and oriented toward global development. The company officially commenced research and development of next-generation radiopharmaceuticals in 2014. Headquartered in Beijing, the capital of China, it operates modern intelligent manufacturing bases for radiopharmaceuticals in Jiangsu, Guangdong, and Sichuan provinces, maintains a branch in the United States, and has established business collaborations with more than ten multinational pharmaceutical companies. Leveraging globally leading R&D resources for precise diagnosis and therapy using radiopharmaceuticals, Xiantong has pioneered the development of multiple targeted therapeutic and precision diagnostic radiopharmaceuticals in the fields of oncology, neurodegenerative diseases, and cardiovascular disorders. These products are either undergoing or have completed clinical trials and are scheduled for sequential market launch in the coming years. Since April 2020, Xiantong Medicine has successfully raised nearly RMB 1 billion in financing, gaining favor from major institutional investors, and plans to list on major capital markets in the near future.

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