Recently, Novartis announced that it will invest in establishing a new radiopharmaceutical production site in China, in order to accelerate the introduction of innovative radioligand therapy to China. After its completion, the production site will become Novartis' second innovative drug production base in China.

Similarly, in early October 2023, Eli Lilly announced its acquisition of Point Biopharma Global, a US clinical-stage targeted radiotherapy (isotope-linked pharmaceuticals) company, for $1.4 billion at a 68% premium. This acquisition marks Eli Lilly's formal entry into the competitive field of targeted radiotherapy in the metabolism sector, in which it has previously enjoyed great success.

According to VB Data, the global total financing amount for nuclear medicine enterprises in the first half of this year was RMB 3.047 billion. In the third quarter of this year, the financing performance of nuclear medicine companies in the primary market continued to be impressive, with a total financing amount of RMB 4.448 billion.

It can be seen that despite the capital winter, nuclear medicine does not seem to be affected. In the sluggish market environment of innovative drugs, the nuclear medicine field is still thriving.

Overview of the Nuclear Medicine Track

Nuclear medicine, also known as radiopharmaceuticals, are categorized by the clinical application of nuclear medicine into diagnostic and therapeutic nuclear medicine. Diagnostic nuclear medicine is a group of in vivo radiopharmaceuticals used to obtain images or functional parameters of target organs or lesion tissues for diagnosis. Therapeutic nuclear medicine involves selectively delivering radioactive isotopes with cytotoxic levels to the lesion site, using the ionizing radiation biological effects produced by the radiation of gamma or beta particles to kill diseased tissues or cells.

Since the first nuclear medicine, iodine [131I] sodium, was approved by the FDA for diagnosis and treatment of thyroid diseases in 1951, more than 100 radiopharmaceuticals have been marketed worldwide. Among them, diagnostic nuclear medicine accounts for the dominant position, while therapeutic nuclear medicine has grown strongly, mainly due to research and development in RDC (isotope-linked pharmaceuticals or targeted radiation therapy).

Similar to ADC (antibody-drug conjugates), RDC typically consists of four parts: targeting molecules, linkers, chelating agents, and radioactive isotopes. By linking different isotopes, diagnostic or therapeutic purposes are achieved. For example, fluorine [18F], gallium [68Ga] are linked to form diagnostic products, while alpha or beta particles (lutetium [177Lu], actinium [225Ac], iodine [I-131], radium [Ra-223], etc.) are linked to form therapeutic products.

Today, with the development of radioactive chemistry, nuclear medicine, molecular biology technology and multidisciplinary integration, nuclear medicine has become a hot field in global drug development, and the RDC track has attracted pharmaceutical companies both at home and abroad to layout their research and development.

MNCs Splurge Layout

Novartis

In October 2017, Novartis acquired the French innovative drug listing company Advanced Accelerator Applications (AAA) for $3.9 billion. AAA is a company focused on the research and production of radiopharmaceuticals. Through the acquisition of AAA, Novartis gained access to the radioligand therapy Lutathera and related technological platforms. In 2018, Novartis acquired Endocyte for $2.1 billion, further obtaining more radioligand therapies such as 177Lu-PSMA-617 and 255Ac-PSMA-617 for the treatment of prostate cancer.

These two acquisitions further solidified Novartis' leading position in the field of nuclear medicine. Currently, Novartis has two FDA-approved RDC products on the market, Lutathera and Pluvicto, as well as products under development such as 177Lu-FAP-2286, 177Lu-NeoBOMB1, and 225Ac-PSMA-617.

Lutathera (177Lu-DOTATATE) is a radioactive-labeled somatostatin analog that delivers the radioactive isotope Lu-177 to tumor cells by binding to somatostatin receptors on the surface of the cells, causing damage through emitted β-rays.

Lutathera was approved by the FDA in January 2018 for the treatment of gastroenteropancreatic neuroendocrine tumors (GEP-NETs) with somatostatin receptor-positive (SSTR) expression. It is worth mentioning that Lutathera is the first peptide receptor radionuclide therapy (PRRT) approved by the FDA. Since its launch, Lutathera has seen rapid sales growth, with sales reaching $167 million in 2018 and $441 million in 2019, a year-on-year increase of 167%.

Pluvicto (177Lu-PSMA-617) received FDA approval in March 2022 for the treatment of castration-resistant metastatic prostate cancer (mCRPC) with previous treatment with androgen receptor pathway inhibitors (ARPI) and taxane chemotherapy and positive expression of prostate-specific membrane antigen (PSMA). Phase III trial results showed that male patients who received Pluvicto in combination with the best standard treatment had a 38% reduction in the risk of death (4 months improvement in median overall survival) and a 60% reduction in the risk of imaging progression or death (5 months improvement in median radiographic progression-free survival) compared to those receiving monotherapy with the best standard treatment. Based on its excellent clinical efficacy, Pluvicto has high expectations from Novartis.

Due to the influence of Lutathera and Pluvicto, not only has there been a surge in RDC research and development in the industry, but it has also greatly promoted the development of nuclear medicine.

In the international market, apart from Novartis and Eli Lilly mentioned earlier, companies such as Bayer, Merck Sharp & Dohme, and AstraZeneca have also entered the field of nuclear medicine.

Bayer

Bayer is one of the companies that can rival Novartis in the field of nuclear medicine. In 2009, Bayer partnered with Algeta ASA to develop Xofigo (radium chloride-223). Xofigo was approved for marketing in 2013 for the treatment of castration-resistant prostate cancer with bone metastases. In 2014, Bayer completed the acquisition of Algeta ASA for $2.6 billion, gaining full control rights over Xofigo. In 2021, Bayer continued to invest in the RDC race by acquiring Noria Therapeutics and PSMA Therapeutics to further expand its presence in the RDC field. In May of this year, Bayer reached an agreement with Bicycle, leveraging Bicycle's synthetic peptide technology to collaborate on the development, manufacturing, and commercialization of RDC in the field of oncology. Currently, Bayer has 7 RDCs in the preclinical stage and 2 RDCs in the early clinical stage (BAY 3546828, BAY 3563254).

Merck Sharp & Dohme

In 2021, Merck Sharp & Dohme partnered with Canadian biopharmaceutical company Fusion Pharmaceuticals to conduct a clinical trial evaluating the efficacy of Fusion's targeted radiopharmaceutical FPI-1434 in combination with Merck's Keytruda for patients with solid tumors expressing insulin-like growth factor 1 receptor.

In March of this year, Merck Sharp & Dohme also reached an agreement with Ratio Therapeutics to provide multiple drug candidates and support their preclinical and CMC data for the Granzyme B-targeting drug used in PET imaging applications.

In addition to MSD, AstraZeneca and others are also cooperating with Fusion. In November 2020, AstraZeneca reached a collaboration with Fusion for the development and commercialization of next-generation α-emitting radiopharmaceuticals and combination therapy for cancer treatment.

In April this year, Fusion announced that its new drug [225Ac]-FPI-2068 (FPI-2068) and the accompanying molecular imaging drug [111In]-FPI-2107 (FPI-2107) have submitted or been accepted for the IND application, and they will be jointly developed with AstraZeneca.

Compared to these multinational corporations, domestic nuclear medicine research and development started relatively late and is currently in its early stages. However, the domestic market is experiencing a continuous upward trend in popularity.

Policy implementation accelerates the development of domestic nuclear medicine.

Due to the uniqueness of nuclear medicine, the nuclear materials are generally managed by the state. Acquiring nuclear materials requires a high level of production and management capabilities. Therefore, the field of nuclear medicine has always had high barriers to entry and a high degree of industry concentration.

The good news is that in 2021, eight ministries including the National Atomic Energy Agency, the Ministry of Science and Technology, the Ministry of Public Security, and the National Health Commission issued a heavyweight document titled "Medium - and Long Term Development Plan for Medical Isotopes (2021-2035)". The document clearly points out the goal of strongly supporting the development of the medical isotope industry. In the same year, in order to promote and standardize the research and development of radioactive in vivo diagnostic drugs in China, under the deployment of the National Medical Products Administration, the Drug Control Center organized the formulation of the "Technical Guidelines for Non Clinical Research of Radioactive in vivo Diagnostic Drugs".

The introduction of policies has accelerated the development of domestic nuclear medicine. At present, in addition to the duopoly of China Tongfu and Dongcheng Pharmaceutical in the field of nuclear medicine, there are also companies such as Ruidio, Xiantong Pharmaceuticals, Yuanda Pharmaceuticals, Hengrui Pharmaceuticals, Zhihe Biotechnology, Hexin Pharmaceuticals, and Jianyuan Pharmaceuticals in China. Public data shows that there are currently 75 research pipelines in China and nearly 7000 overseas pipelines entering clinical practice. Innovative nuclear drug research and development is entering a high production period.

However, the current nuclear drug market faces issues such as target homogenization (mainly concentrated in PSMA and SSTR) and concentrated indications (mostly prostate cancer and neuroendocrine tumors), and the phenomenon of homogenization is initially emerging. If latecomers want to quickly break through in the nuclear drug market, they need to carry out differentiated innovation in targets, indications, and nuclides. At present, the field of nuclear medicine is still in a high barrier stage, and domestic pharmaceutical companies that aspire to this should seize this window of opportunity.

Reference

1. Novartis official WeChat account: "Novartis announces investment in establishing a new production base in China to accelerate the introduction of innovative radioligand therapies"

2. Lilly official website and Point official website

3. Medical Mission: "Novartis, Bayer and other investment layouts, while Hengrui Pharmaceuticals, Yuanda Pharmaceuticals and others are also researching and developing. What are the prospects for the development of nuclear drugs?"

About the Author:

Yefenghong

Ye Fenghong, a medical editor specializing in oncology at a healthcare internet company, has conducted in-depth research on the pathogenesis and clinical treatment of lung cancer and breast cancer. She has previously been involved in the design and synthesis of anti-tumor drugs and has some experience in computer-aided drug design. She is currently devoted to introducing cutting-edge cancer treatment drugs to a wide range of readers, aiming to help more people avoid cancer pain and embrace good health.