Everything can be connected!

Not long ago, Novartis announced that its targeted radioligand therapy Pluvicto (lutetiumLu177vipivotidetetraxetan, 177Lu-PSMA-617) was approved by the FDA for the treatment of PSMA positive, and after taxane chemotherapy and androgen receptor signaling pathway inhibitors Treatment of patients with metastatic castration-resistant prostate cancer (mCRPC)
.
This is also the first FDA-approved targeted radioligand-targeted therapy for the treatment of this type of mCRPC patient
.
"Everything can be coupled"! In the field of conjugated drugs, in addition to the well-known antibody drug conjugates (ADC), there are many members, including the new track of conjugation where Pluvicto is located - radionuclide drug conjugates (RDC)
.
What is RDC? I believe that everyone is no stranger to tumor radiotherapy (commonly known as: radiotherapy), which has a powerful killing effect on tumors, but the safety issues that cannot be ignored also limit its clinical application
.
The birth of radioisotope (nuclide) drugs brings new possibilities for making good use of the "double-edged sword" of radiotherapy
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Before discussing the advantages of nuclide drugs, let us first understand the concept of "radioimmunotherapy"
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Radioimmunotherapy (RIT) uses monoclonal antibodies as carriers and radionuclides as warheads to specifically bind tumor cells with positive antigen expression through antibodies, targeting high-energy ray-producing radionuclides to tumor cells, and interacting with tumors.
Cell-specific binding to achieve brachytherapy of tumors, also known as targeted radionuclide therapy
.
With the monoclonal antibody as the "guide", the radionuclide-labeled drugs are concentrated in the tumor lesions, and after reaching the special battlefield of the tumor, the two cooperate to "cross-fire" to fight against the tumor cells, so as to achieve the purpose of treatment
.
Nuclide-coupled drug (RDC) is a kind of nuclide drug, mainly composed of targeting ligand (Ligand), linker (linker), chelator (Chelator) and nuclide (Radioisotope)
.
Similar to ADC drugs, antibodies or small molecules are used to mediate specific targeting, and cytotoxic molecules or imaging molecules such as radionuclides are delivered to the target site, so that the radiation generated by the radioisotope can be concentrated on the local tissue, which is efficient and accurate.
Treatment while reducing damage to other tissues from systemic exposure
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The energy produced by the radioactive rays brought by the nuclide can damage the chromosomes of the cells, causing the cells to stop growing, thereby destroying the rapidly dividing and growing cancer cells
.
Unlike ADC drugs, RDC payloads are radionuclides that can be used for both diagnostic and therapeutic functions
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In terms of composition, RDCs are also slightly different, requiring the addition of a specific functional group structure (Chelator) that chelates toxins
.
Currently commonly used ligands include small molecules (such as PSMA-617), antibodies, etc.
, and radioisotopes include 68Ga, 64Cu as tracers, and 177Lu, 213Bi, etc.
for therapy
.
Breaking the curse, the most difficult target PSMA is successfully developed.
Although RDC is not as hot as ADC drugs, there have been many successful cases of new drug development
.
Among them, LUTATHERA is the first FDA-approved radiopharmaceutical for the treatment of gastroenteropancreatic neuroendocrine tumors, with sales of US$441 million in 2019, a year-on-year increase of 167%
.
The product has submitted a clinical application in China in July 2020
.
Another FDA-approved RDC drug is GALLIUMGA68PSMA-11 developed by the University of California, the first drug for PET imaging of prostate-specific membrane antigen (PSMA)-positive lesions in patients with suspected prostate cancer metastases, and Elevated serum PSA in patients with suspected prostate cancer recurrence
.
In terms of targets, most of the RDC drugs currently under development are projects targeting PSMA
.
PSMA is an important molecular target in prostate cancer and has been extensively studied in the past 20 years
.
At the diagnostic level, PSMAPET-CT has demonstrated its superiority in detecting metastases more accurately, thereby changing the treatment options for patients
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However, in the past period of time, the development of drugs based on PSMA targets has not been smooth
.
For example, APVO414 was discontinued due to its immunogenicity, AMG160 had limited efficacy, and P-PSMA-101 was once suspended due to safety issues.
.
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until the emergence of Pluvicto broke the spell of PSMA's failure for the first time
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The approval of Pluvicto is based on the positive results of its Phase 3 clinical trial VISION: in patients with second-line PSMA-positive mCRPC (metastatic castration-resistant prostate cancer), 617+ best standard of care (SOC) vs SOC, median OS reached 15.
3 months vs 11.
3 months, reducing the patient's risk of death by 38%; rPFS (radiographic progression-free survival) reached 8.
7 months vs 3.
4 months; and the 617+SOC group The PR/CR of the SOC group reached 29.
8%, and the PR of the SOC group was only 1.
7%
.
Currently, in the treatment of mCRPC, the best clinical regimen is the PARP inhibitor olaparib
.
When olaparib was approved for second-line mCRPC indications in May 2020, the data from the PROfound study showed that olaparib alone, compared with enzalutamide, or abiraterone + prednisone, was in BRCA1/prednisone in group A.
2 or ATM mutations, OS of 19.
1 months vs 14.
7 months and mPFS of 7.
4 months vs 3.
6 months were achieved
.
Comparing the above data, it can be seen that the efficacy data disclosed by Pluvicto is slightly better than olaparib in mPFS, and the OS is comparable; the safety data is basically the same, and even the incidence of adverse reactions is slightly lower
.
RDC may become a golden track in the future With the successive approvals of products under development, the RDC drug market has ushered in new growth in recent years
.
According to incomplete statistics, there are currently a number of products under development that are already in the critical clinical stage
.
For example: PNT2002 (177Lu-PSMA-I&T), another targeted radioligand therapy for mCRPC developed by overseas POINTBiopharma, is currently in phase 3 clinical trials.
The PSMA ligand used in this therapy is different from Pluvicto
.
Previous clinical trials have shown that the drug's radiation dose to normal tissue is within a safe range, and the low radiation to red pulp is promising for combination therapy
.
The 227Th-Pelgifatamab Corixetan developed by Bayer targets PSMA for the treatment of mCRPC and is currently in Phase 1 clinical research
.
Unlike Novartis and POINTBiopharma using 177Lu to produce beta particles, Bayer's 227Th produces alpha particles that can produce stronger killing effects on tumors in a shorter distance of action
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In addition, Bayer acquired Noria Therapeutics and PSMA Therapeutics in June 2021, and obtained its 225Ac radiotherapy targeting PSMA, which is in the preclinical research stage
.
Grand Pharma is a leading RDC company in China, and it started to deploy RDC product pipeline earlier
.
In the product pipeline, Grand Pharma has introduced a number of RDC drugs developed by Telix, including TLX591-CDx, TLX250-CDx, TLX599-CDx for diagnosis and TLX591, TLX250, TLX101 for treatment in Greater China (including China Hong Kong, Macau, China Taiwan) exclusive commercialization rights
.
Among them, TLX591-CDx for the diagnosis of prostate cancer has been approved for marketing in the United States and Australia, and has been specially authorized in Brazil to be sold before the official approval; TLX250-CDx for the diagnosis of clear cell renal cell carcinoma has been approved by the FDA for breakthrough Sex therapy and the first patient dosed in Phase 1 clinical study in Australia; TLX101 for the treatment of glioblastoma has been granted orphan drug designation by the FDA; TLX591 for the treatment of prostate cancer has been approved for Phase 3 clinical trials in Australia Research
.
In addition, the registration of a number of RDC drugs in China is also actively advancing, among which TLX591-CDx is expected to submit a clinical investigation application (IND) to the NMPA in the first quarter of 2022
.
On December 27, 2021, Grand Pharma also reached a product strategic cooperation with ITMIsotope TechnologiesMunichSE in Germany, paying no more than 520 million euros in licensing fees and milestone payments to obtain the ITM company's development of the diagnosis of gastroenteropancreatic neuroendocrine tumors.
TOCscan® (68Ga-Edotreotide), 3 RDC products including ITM-11 (nca177Lu-Edotreotide) for the treatment of gastroenteropancreatic neuroendocrine tumors and ITM-41 (nca177Lu-Zoledronate) for the treatment of malignant bone metastases Exclusive development, production and commercialization rights in Greater China (Mainland China, Hong Kong, Macau, Taiwan) further expand the company's RDC product pipeline
.
Conclusion There are very few radionuclide conjugated drugs approved in the world, and the projects in clinical research are also relatively scarce
.
With the participation of international pharmaceutical giants and the gradual deployment of major capitals, RDC drugs are expected to become an emerging track with rapid development
.