Novartis Submits NDA in China for $1B+ Radioligand Therapy Pluvicto and Companion Diagnostic Agent

On November 13, the latest announcement on the official website of the Center for Drug Evaluation (CDE) of the China National Medical Products Administration showed that the new drug marketing application of Novartis' Lutetium [177Lu] Texiveptide Injection had been accepted. Public information indicates that this is Pluvicto (formerly known as 177Lu-PSMA-617), a PSMA-targeted radioligand therapy developed by Novartis, which was previously approved by the U.S. FDA in March 2022 for the treatment of prostate cancer patients.

In China, the product was granted priority review by the CDE in September this year. It is indicated for the treatment of adult patients with metastatic castration-resistant prostate cancer (mCRPC) that is positive for prostate-specific membrane antigen (PSMA), and who have received androgen receptor pathway inhibitors and taxane-based chemotherapy.

At the same time, the marketing application of Novartis' radiopharmaceutical Gallium [68Ga] Gozetotide Injection for preparation has also been accepted and included in the priority review. After being radiolabeled with 68Ga, this product can be used as a radioactive diagnostic agent to identify PSMA-positive lesions in adult prostate cancer patients through Positron Emission Tomography (PET).

Pluvicto is a radioligand therapy that connects a small molecule compound targeting PSMA with the radioactive isotope (177Lu). It can bind to prostate cancer cells expressing PSMA, while 177Lu releases beta rays to precisely target and kill tumors. Due to the limited radiation range released by Pluvicto, the damage to surrounding healthy cells is minimal.

In March 2022, Novartis announced that the FDA had approved the company's Pluvicto for marketing, becoming the world's first targeted radioligand therapy for the treatment of PSMA-positive mCRPC patients. This approval also signifies that radiopharmaceuticals are beginning to be used to treat more common malignant tumors such as prostate cancer.

This FDA approval is based on the positive results of the pivotal phase 3 clinical trial, the VISION study. The study showed that, compared with standard treatment, Pluvicto reduced the risk of death by 38% and significantly decreased the risk of radiological disease progression or death. Additionally, among patients with evaluable disease at baseline, the overall response rate was 30% in the Pluvicto group, compared to 2% in the standard treatment control group.

At the 2023 European Society for Medical Oncology (ESMO) Congress, Novartis announced that the Phase 3 PSMAfore clinical trial of Pluvicto had met its primary endpoint of radiographic progression-free survival (rPFS). Compared to switching to another androgen receptor pathway inhibitor (ARPI), patients treated with Pluvicto experienced a 59% reduction in the risk of radiographic progression. After extending the data cutoff date to a median follow-up time of 8.6 months, an updated analysis of rPFS confirmed the product's sustained clinical benefit, with Pluvicto more than doubling rPFS compared to switching to another ARPI (median time: 12.0 months vs 5.6 months).

In terms of commercialization, the sales revenue of Pluvicto in 2023 was $921 million. In the first three quarters of 2024, the sales of Pluvicto have exceeded $1 billion, increasing by 47%. The main factor currently limiting the exponential growth of this product's sales is production capacity. Therefore, Novartis also invested in building a factory in Haiyan, Zhejiang, China last year to produce radiopharmaceuticals and solve manufacturing challenges.

Not only that, but Pluvicto has also been shortlisted for the 2024 Prix Galien Award for Best Pharmaceutical Agent, demonstrating its leading position in the field of prostate cancer treatment.

According to a press release issued by Novartis during the recent China International Import Expo, as part of its goal to target earlier stages of the disease, the company has two Phase 3 studies evaluating the role of Pluvicto in earlier treatment of PSMA-positive prostate cancer: the PSMAddition study is being conducted in the metastatic hormone-sensitive stage, and the PSMA-DC study is being prepared for the oligometastatic stage.

Radioligand Therapy (RLT), in fact, is a type of conjugated drug that couples a chelator of radionuclides with molecules capable of specifically binding to tumors, thereby precisely identifying and killing cancer cells.

Unlike traditional radiopharmaceuticals such as iodine-131 (sodium iodide) and radium-223 (radium chloride), the high targeting capability of radioligand therapy allows it to safely, precisely, and efficiently attack tumor cells throughout the body without harming normal cells.

At the same time, RLT and ADC are both conjugated drugs. However, due to the use of radionuclides as payloads, peptides as carriers, and a non-hydrolyzed linker method, RLT has demonstrated lower immunogenicity, better penetration, and optimized in vivo metabolism in clinical applications, showing stronger efficacy and higher safety.

Moreover, radiopharmaceuticals have a prominent feature: they can diagnose and treat simultaneously. Using the same tumor marker as the target, the tumor lesions are located through radioligand imaging (RLI) technology targeting the specific marker, and then precise attacks on cancer cells are carried out using radioligand therapy drugs targeting the same marker, achieving true "theranostics integration."

Based on the advantages of precision, efficiency, fewer side effects, and integrated diagnosis and treatment, RLT therapy has demonstrated significant clinical benefits globally, especially in the treatment of advanced metastatic prostate cancer, where it has notably improved patient survival rates. Additionally, RLT therapy can utilize different isotope and ligand combinations, showing potential for the diagnosis, monitoring, and treatment of various cancers, with broad application prospects.

Currently, RLT therapy has become one of the five major technology platforms that Novartis focuses on, together with chemotherapy, biologic therapy, gene and cell therapy, and xRNA therapy. Novartis holds a leading position in RLT, but capacity issues have limited the exponential growth of Pluvicto sales.

On the one hand, the raw materials for radioactive isotopes are facing a global shortage. Currently, isotopes are mainly produced using two methods: reactors and accelerators, with a large number of reactors concentrated in Europe and the United States. It is predicted that by 2030, multiple active reactors worldwide will be shut down, leading to a tight supply of medical isotopes globally.

On the other hand, limited by the half-life of radioactive isotopes, the drug's activity will decrease within a specific time period, thus requiring timely delivery and administration to patients. Due to the limited dosing time window, these drugs are typically produced in single-dose forms, taking into account transportation distance and cycle for drug delivery. This not only requires mature and complete upstream and downstream industries and nuclear pharmacy support but also necessitates the presence of medical institutions with qualifications for clinical use of nuclear medicine within a certain range.

In the first half of 2023, the global production and supply of Pluvicto encountered issues, leading to distribution delays and drug shortages. This caused patients to experience delays in receiving medication and hindered its promotion, resulting in a situation where "patients were queuing but unable to access the drug." It was not until the end of October that the FDA removed Pluvicto from the drug shortage list.

To address the imminent capacity issues, Novartis has accelerated the establishment of production bases in the past five years, including setting up radiopharmaceutical production sites in Italy, Spain, the United States, and China. In January this year, the FDA approved Novartis' Indianapolis facility for the commercial production of Pluvicto, which is currently Novartis’ largest radiopharmaceutical production base, capable of reaching patients across the U.S. within 12 hours. CEO Vas Narasimhan stated that Novartis aims to deliver over 250,000 doses annually by 2024 through the construction of four facilities.

Novartis is continuously strengthening its layout in the RLT field. At the end of April this year, Novartis collaborated with PeptiDream to develop cyclic peptide RDC drugs, with a total collaboration value of $2.99 billion. Immediately in May, Novartis completed the acquisition of Mariana Oncology and its radiopharmaceutical pipeline for $1.75 billion. In China, Novartis has initiated multiple clinical studies on RLT therapies, covering late-line and front-line prostate cancer treatments as well as other early pipeline products.

Not only Novartis, but also MNCs such as BMS and Eli Lilly are rushing into the field, aiming to establish influence in the radiopharmaceuticals sector. For instance, BMS completed a $4.1 billion acquisition of RayzeBio by the end of 2023, gaining access to its core pipeline RYZ101 and other early-stage drug candidates. In July this year, Eli Lilly signed an investment agreement with Radionetics Oncology, prepaying $140 million for the option to acquire the biotech company for $1 billion. Additionally, Sanofi has also begun venturing into the radiopharmaceutical space, reaching a licensing agreement worth $356 million with RadioMedix.

Industry analysis points out that the specialization of radiopharmaceuticals means that MNCs cannot simply buy the drug and discard the rest of the company, as they might in other Biotech asset transactions. In other words, going forward, more Big Pharma companies in this field are likely to shift from merely acquiring pipelines to pursuing full mergers and acquisitions.

In China, the widespread adoption of nuclear medicine is influenced by several factors. Currently, there are significant challenges in the supply of isotopes in China. Data shows that in recent years, domestically produced I-131 and Sr-89 can only meet 20% of domestic demand, while Lu-177 can only meet 5% of domestic demand. Other commonly used reactor-produced medical isotopes are entirely reliant on imports.

Moreover, the scaling-up of nuclear medicine requires extremely strong industrialization capabilities as support. In China, when drugs enter clinical use, medical institutions must possess relevant qualifications. In 2019, there were 770 nuclear medicine departments in China conducting radionuclide therapy, but there were only 2,544 radionuclide therapy beds. This is far from sufficient to meet patient demand. Even if drug production capacity catches up, patients not being able to find designated institutions for treatment remains a significant issue.

In the future, it remains to be seen how Novartis will continue its market success with Pluvicto. Meanwhile, we also look forward to more progress in China regarding the supply of radionuclides and qualification reviews, promoting the rise of China's nuclear medicine industry.

References:

1. "The Acquired and the Acquirers: Big Pharma Rushes to the 'Nuclear' Battlefield" — VCBeat

2, "2.5B+2.3B! Sanofi Doubles Down on Nuclear Medicine" — VCBeat