J&J Reports Four Patient Deaths in Phase I Trial of Novel hK2-Targeted Radiopharmaceutical JNJ-6420 for mCRPC

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Recently, Johnson & Johnson unveiled its radioligand therapy JNJ-69086420 for the first time at the ASCO meeting.（JNJ-6420）For metastatic castration-resistant prostate cancer（mCRPC）Phase I study data.

JNJ-6420 is the first radioactive ligand therapy targeting hK2, where hK2 refers to human tissue kallikrein 2.（human kallikrein 2）——A protein expressed in prostate tissue, with higher expression levels in prostate cancer cells and limited expression in other areas.

Leveraging the targeting function of the hK2 antibody, JNJ-6420 can specifically bind to the hK2 protein on the surface of prostate cancer cells, emitting high-energy short-range α particles, 225Ac, towards prostate cancer cells.

According to the oral abstract information on the ASCO official website, the participants in this Phase I dose-escalation trial were all heavily pretreated mCRPC patients who were not screened by biomarkers, and these patients had received at least one androgen receptor pathway inhibitor treatment before enrollment. The trial explored doses ranging from 50 millicuries via intravenous injection.(mCi)Increase to 400μCi, administered once every 8-12 weeks.

As of January 5, 2024, a total of 67 patients had received ≥1 dose of JNJ-6420 treatment in this Phase I clinical trial.But from the data disclosed this time, the safety of JNJ-6420 is not as expected.

It was reported that, throughout the trial, a total of 9 patients experienced treatment-related adverse events.(TRAEs)Discontinuation of treatment, and four patients died due to TRAE. Full data shows that the deaths of two of these patients were related to interstitial lung disease.（ILD）Related, one case was related to respiratory failure caused by COVID-19, and the other was related to anorexia and hypotension.

ILD is a common adverse event in cancer treatment, which leads to gradual scarring of lung tissue. Patients initially experience symptoms such as shortness of breath, cough, and fatigue, and in severe cases, it can be life-threatening.

The abstract mentions that currently, 9% of the subjects have developed ILD, and all cases of ILD occurred in patients whose cumulative dose reached or exceeded 500 μCi before the implementation of pulmonary function monitoring.

In addition, in the preliminary study, the researchers examined 57 individuals who had received ≥150μCiThe treatment outcomes of patients receiving JNJ-6420 were analyzed. Approximately two-thirds of the patients experienced grade 3 or higher treatment-related adverse events.(TEAEs, including thrombocytopenia, interstitial lung disease, lymphocytopenia, leukocytopenia), and nearly one-third of the patients experienced severe TEAE.

From a positive perspective, JNJ-6420 has already shown initial effectiveness.，And demonstrated significant and sustained biochemical and imaging responses.According to the abstract disclosure, among all 57 patients receiving ≥150μCi of JNJ-6420, half of the patients were observed to have a 50% decrease in prostate-specific antigen levels. At the time of interim analysis, the objective response rate（PR）was 12.5%, with one patient showing complete remission, and the disease control rate（DCR）Reaching 28.1%.

Safety is one of the important thresholds for a drug to be marketed. The performance of JNJ-6420 in the current trial protocol is clearly substandard and requires further adjustment of the trial protocol. At the upcoming ASCO meeting, Johnson & Johnson will continue to release more data related to JNJ-6420 trials.

Returning to JNJ-6420 itself, as mentioned above, JNJ-6420 is an α-radioactive ligand therapy targeting hK2.

From the perspective of targets, hK2 is indeed a niche target. According to the PatSnap database, there are currently no products targeting this point on the market. In the clinical stage, apart from JNJ-6420, there is only one small molecule drug developed by Vidac Pharma Ltd., which is currently in Phase II clinical trials.

Moreover, the isotope of this drug is Actinium-225.（225Ac）, which belongs to α radionuclides.

In the history of nuclear medicine development, β radionuclides have always been at the forefront, including Novartis' Pluvicto and Lutathera, both of which chose 177Lu — a β radionuclide. It was not until 2013 that the world's first α radionuclide drug emerged.(Radium Chloride²²³）Just received FDA approval for marketing, used to treat bone metastases in prostate cancer.

In terms of physical properties, α-emitting radionuclides are superior to β-emitting radionuclides in treatment. This is because α particles have relatively weaker penetration, with a range typically within a few cell diameters, thus causing less damage to surrounding normal tissues. However, the short range also determines that these radionuclides are less effective in treating deep or widely metastatic tumors. Additionally, correspondingly, the production and handling of α-emitting radionuclides are more challenging compared to β-emitting radionuclides.

In several recent radiopharmaceutical-related transactions, α radionuclides have appeared frequently.

In December 2023, BMS for $3.6 billion(Price after deducting the acquired party's cash on hand)Acquisition of RayzeBio, RayzeBio's Core PipelineRYZ101The payload is also actinium-based and is under development for gastrointestinal pancreatic neuroendocrine tumors and small cell lung cancer.

In addition, in March 2024, FPI-2265, the core pipeline of Fusion acquired by AstraZeneca for up to 2.4 billion dollars, is also an actinium-based candidate drug, used for treating mCRPC patients.

Summary

The fruit of nuclear medicine is not easy to pick.

From the perspective of the R&D process, due to the involvement of multiple disciplines such as pharmaceuticals, radiation dosimetry, and radiation biology, there is a relatively high demand for the accumulation of experience among research talents. Meanwhile, because it contains radioactive isotopes, its production, use, and distribution are subject to very strict policy supervision, further increasing costs and R&D difficulties.

Currently, a group of MNCs are placing their bets; who will be the one to secure an approved nuclear medicine product?

References:

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3.ASCO Official Website

4.Other Public Information

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