Dose-Effect Curve

Currently, the global PSMA-targeted radiopharmaceutical landscape is intensely competitive, with the majority of R&D resources focused on optimizing and iterating novel proprietary ligands. However, a drug named [177Lu]Lu-PSMA-597 is attempting to break free from molecular-level homogenization to provide its own answer — not competing merely at the ligand level, but returning to a more upstream design logic. Using the therapeutic window as a fulcrum, it aims to lever a systemic reconstruction of the dosing paradigm, pursuing a highly distinct differentiated path. To understand why PSMA-597 has the confidence to challenge this rigid treatment paradigm, we must trace back to the origins of its molecular design.

The Instituto Nacional de Investigaciones Nucleares (ININ) is Mexico's core national nuclear research institution. It originated from the former Mexican National Nuclear Energy Commission (CNEN), which was restructured in 1979 into three entities: ININ, the Mexican Uranium Institute (URAMEX), and the National Commission for Nuclear Safety and Safeguards (CNSNS). This drug was born at ININ.

Around 2017, ININ collaborated with the nuclear medicine clinical department of Mexico's National Institute of Cancerology (INCan), with research funding from the National Council of Science and Technology (CONACyT), to establish the radiopharmaceutical chemistry development, radiolabeling, and clinical imaging evaluation modules for this drug. Together they completed the preparation, quality control, and systematic validation of the diagnostic molecular probe ⁹⁹ᵐTc-EDDA/HYNIC-Lys(Nal)-Urea-Glu (abbreviated as ⁹⁹ᵐTc-EDDA/HYNIC-iPSMA). This work, published in the journal Nuclear Medicine and Biology under the title "Clinical translation of a PSMA inhibitor for 99mTc-based SPECT," demonstrated through in vitro cell experiments and in vivo tumor-bearing animal studies that the probe could specifically bind to PSMA-high-expressing prostate cancer cells. Subsequent human studies were conducted: on one hand, the probe's normal tissue distribution patterns in healthy volunteers were examined; on the other, prostate cancer patients were enrolled for imaging to preliminarily assess lesion uptake and clinical detection potential. This became the starting point for all subsequent technical iterations of PSMA-597.

Head-to-head comparison in the same patient: ⁹⁹ᵐTc-SPECT vs. ⁶⁸Ga-PSMA-617 PET

Using the HYNIC-EDDA dual-chelator system for molecular modification to enhance the probe's binding affinity to the PSMA target, this study systematically validated the in vitro stability, targeting specificity, small-animal tissue distribution characteristics, and human biodistribution of this imaging probe. The study enrolled 3 healthy volunteers and 2 pathology-confirmed metastatic prostate cancer patients for preliminary human SPECT imaging; one patient also underwent a concurrent ⁶⁸Ga-PSMA-617 PET comparison scan, providing multi-angle evidence for the clinical translation value of this radiopharmaceutical.

Key study data showed: the lyophilized kit developed by the research team could complete radiolabeling in a single step, with radiochemical purity consistently exceeding 98%; in vitro cell experiments confirmed that the probe specifically recognized and bound only PSMA-positive prostate tumor cells, with minimal non-specific binding; in tumor-bearing nude mice, tumor uptake reached 10.22 %ID/g at 1 hour post-administration, with excellent tumor-to-normal organ uptake ratios and outstanding imaging contrast; no adverse events occurred throughout the human clinical trial; in healthy volunteers, images showed only physiological radioactive accumulation in the salivary glands and kidneys; in prostate cancer patients, both primary lesions and systemic metastases were clearly visualized, with detection efficacy essentially comparable to ⁶⁸Ga-PSMA-617 PET — laying the groundwork for the subsequent development of the therapeutic radiopharmaceutical.

Stage 2 (2017–2018): Therapeutic Radiopharmaceutical Debut and Patent Deployment

 

One year later, the research team published the first academic paper on PSMA-597 in October 2018 in the Journal of Radioanalytical and Nuclear Chemistry, titled "177Lu-DOTA-HYNIC-Lys(Nal)-Urea-Glu: synthesis and assessment of the ability to target the prostate specific membrane antigen." Building upon the 2017 imaging probe, the team completed molecular iterative optimization, developed DOTA-HYNIC-iPSMA, and successfully synthesized 177Lu-DOTA-HYNIC-Lys(Nal)-Urea-Glu (177Lu-iPSMA, i.e., PSMA-597). They comprehensively evaluated the therapeutic potential of this probe across multiple dimensions: molecular structural characterization, radiolabeling quality control, in vitro serum stability, cellular targeting and binding, receptor affinity properties, in vivo biodistribution in tumor-bearing mice, and small-animal tomographic imaging.

 

 

The results showed that the radiochemical purity of 177Lu-iPSMA after labeling was as high as 99.5%, and it maintained excellent stability after 24 hours in human serum. In vitro cell experiments confirmed that the probe's cellular uptake efficiency, internalization, and maximum receptor binding capacity were all significantly superior to the reference drug 177Lu-PSMA-617, with no statistically significant difference in PSMA target affinity between the two. In vivo animal distribution data showed that tumor uptake reached 11.06 %ID/g at 24 hours post-administration, demonstrating outstanding prolonged tumor retention. This 177Lu-targeted therapeutic radiopharmaceutical, paired with the ⁹⁹ᵐTc-EDDA/HYNIC-iPSMA diagnostic imaging probe developed by the same team in 2017, formed a complete theranostic pipeline from the same molecular origin.

 

Biodistribution in tumor-bearing mice

 

Approximately 7 months before this paper was published, the research team filed a patent priority application in Mexico, subsequently completing international patent布局 through the PCT system. The patent was published at the European Patent Office in January 2021. The patent claims cover all PSMA-positive solid tumors. Through the European patent route, the patent can take effect simultaneously in 38 European contracting states, extension states, and validation states — achieving broad intellectual property protection, completing its global commercialization patent barrier, and laying the foundation for subsequent commercial collaboration with Telix.

Stage 3 (2018–2025): Shelving and Strategic Restart

 

From the formal publication of the paper in 2018 to the launch of the OPTIMAL trial, more than seven years elapsed (October 2018 – June 2025).

 

Development Timeline of 177Lu-PSMA-617 (Brand Name: Pluvicto)

 

During these seven years, the PSMA-targeted radioligand therapy landscape underwent transformative change. The 177Lu-PSMA-617 that the research team had used as a reference comparator was developed by Novartis, receiving marketing approval in both the US and Europe in 2022 under the brand name Pluvicto. To this day, it continues to expand into earlier-line indications, firmly holding its position as the leading prostate-targeted radiopharmaceutical and continually pushing the clinical application boundaries of nuclear medicine. As early as January 2019, ANMI — a company already acquired by Telix Pharmaceuticals (hereafter "Telix") — completed a global patent license for iPSMA from ININ. The drug subsequently entered Telix's pipeline under the code name TLX597-Tx, positioned as a SPECT imaging companion reagent within the PSMA diagnostic matrix, targeting regions with limited PET infrastructure to capture differentiated commercial value.

 

2019 Phase I/II Single-Arm Open-Label Clinical Trial of TLX591-Tx

 

At that time, multiple similar small-molecule radiopharmaceuticals were being positioned in the PSMA space, and relying solely on "me-too" incremental molecular modifications could no longer establish a meaningful clinical barrier advantage. Although the patent license agreement covered the entire iPSMA platform (both diagnostic and therapeutic), constrained by the company's phased R&D strategic priorities, Telix concentrated resources on commercializing PSMA diagnostic products and developing TLX591-Tx. TLX597-Tx was therefore placed on hold, with only exploratory 225Ac work and subsequent patent filings continuing. Given that TLX597-Tx was still at an early development stage with considerable uncertainty surrounding its clinical value and commercial prospects, it could only be shelved, awaiting restart. Standing at the 2019 juncture, if Telix were to plan for TLX597, it would face a choice between two fundamentally different development paths: replicate the classic dosing model that had secured Novartis's 177Lu-PSMA-617 approval and compete within the existing market, or leverage the molecule's own differentiated characteristics for innovative breakthrough, creating an entirely new competitive dimension and reshaping the industry's competitive landscape.

 

Faced with the massive prostate cancer market, Telix ultimately chose the second path. But how could they win?

 

Against this backdrop, an innovative radiopharmaceutical treatment regimen of "intensive induction and maintenance therapy" emerged. Setting aside whether this novel dosing and treatment course system can be validated by clinical data and reshape the treatment paradigm for prostate cancer radioligand therapy, this major strategic announcement has already clearly signaled that Telix's core competitive logic has long transcended molecular structural innovation, advancing into a new era of end-to-end dosing strategy iteration and upgrading.

 

OPTIMAL Protocol Overview

 

OPTIMAL-PSMA (ID: ACTRN12625000971437) is an investigator-initiated Phase II, open-label, multicenter randomized controlled clinical trial led by Professor Louise Emmett at St Vincent's Hospital, Australia. This is the first randomized controlled trial in the field of PSMA radioligand therapy to systematically explore a flexible dosing regimen:

① Leveraging the radiation-induced DNA repair window mechanism, dense fractionated irradiation is completed on Day 1 and Day 3, fully exploiting the 96-hour DNA repair gap to enhance tumor killing efficiency;

② Flexible dose escalation, increasing the single administered activity from the conventional 7.4 GBq to 8.5 GBq to strengthen tumor radiation dose (the independent Data Safety Monitoring Board [DSMB] conducted an interim safety assessment for the first 10 patients in the experimental arm, found no safety risks, and approved escalation of the experimental arm's single-dose from 7.5 GBq to 8.5 GBq);

③ An adaptive efficacy assessment checkpoint is set at Week 8 of treatment, based on ⁶⁸Ga-PSMA PET imaging combined with PSA levels, enabling dynamic treatment course decision-making.

Distinct from the classic dosing model under which Novartis's 177Lu-PSMA-617 was approved, the ingenuity of this protocol lies in the following:

 

Data demonstrating that tumor uptake increases after the first 177Lu-PSMA treatment, while off-target uptake synchronously decreases.

 

Point 1: During Cycle 1, the strategy does not rush to kill tumor cells; instead, it first leverages radiation-induced upregulation of PSMA target expression on tumors. Preclinical studies have confirmed that PSMA-positive tumors exhibit up to 150% upregulation of cell-surface PSMA expression within 48–96 hours after radiation exposure. This means that following the radiation exposure from Cycle 1 dosing, the number of PSMA targets on tumor cell membranes increases significantly, allowing subsequent Cycle 2 drug to bind more targets, resulting in continually increased drug uptake. The OPTIMAL protocol precisely exploits this pattern, scheduling the second dose on Day 3 after the Cycle 1 dose, strictly timed within the optimal window of PSMA expression upregulation.

 

Imaging from Cycle 1 at 7.5 GBq: low salivary gland and kidney uptake, with high tumor uptake and prolonged retention.

 

Point 2: The dosing rhythm is precisely anchored to the DNA damage repair cycle, achieving a decisive strike. Radiation causes DNA double-strand breaks in tumor cells, and the peak of tumor DNA repair initiation occurs within 96 hours post-irradiation. If a second irradiation is delivered before DNA repair is complete, the probability of "mitotic catastrophe" (MC) is substantially increased, causing tumor cells to attempt division with incompletely repaired DNA, leading to cell death. The trial dosing schedule — Day 1, Day 3, and Day 15 — ensures that these three closely spaced doses comprehensively cover the full cycle of DNA damage initiation, damage repair, and tumor cell repopulation. No previous PSMA-targeted radioligand clinical trial has attempted repeat irradiation within the 96-hour DNA repair window, making OPTIMAL the world's first clinical trial to validate this strategy.

 

Key Organ Dose Comparison: PSMA-597 vs. PSMA-617

 

Point 3: Leveraging the drug's low off-target uptake, the protocol aggressively exploits the "dose budget" to maximize efficacy. Dense dosing means higher cumulative dose over a short period, increasing organ toxicity risk. Dosimetry data from 12 patients indicate that even under the intensive regimen of 3 doses within 15 days, cumulative organ radiation doses remain within safe limits.

Taking the kidneys as an example: under the escalated 8.5 GBq dose, the total activity of 3 doses over the first 15 days is 25.5 GBq, with cumulative renal dose of approximately 25.5 × 0.28 Gy/GBq = 7.1 Gy (only 31% of the 23 Gy limit). The subsequent maintenance phase adds 3 more doses, increasing the renal dose by another 7.1 Gy, for a total cumulative dose of approximately 14.2 Gy (62% of 23 Gy) — still within safe limits.

These data also reveal PSMA-597's core advantage: PSMA-617 has a renal dose coefficient of 0.58 Gy/GBq, and 6 doses × 7.4 GBq = cumulative 25.7 Gy, which already exceeds the 23 Gy threshold — this is precisely why the standard regimen is limited to 6 doses. For the tumor-to-kidney ratio: PSMA-597 is 9.74/0.28 = 34.8, while PSMA-617 is 3.60/0.58 = 6.2 (a 5.6-fold advantage). For the tumor-to-lacrimal gland ratio: PSMA-597 is 27.8 vs. PSMA-617 at 2.2 (a 12.6-fold advantage). All of these indicate that PSMA-597 possesses a wider therapeutic window, enabling effective application of the "dose budget" concept.

 

Hematological and renal function indicators remain stable after dense dosing, visually demonstrating the coexistence of efficacy and safety.

 

In summary, the elegance of this protocol lies in its tightly interlocked, self-reinforcing positive cycle. Radiation-induced upregulation increases the number of tumor PSMA targets, enhancing radiation dose delivery to tumors for the 2nd and 3rd doses; timing repeat irradiation within the tumor DNA repair window further amplifies the killing efficiency of dense dosing, achieving efficacy gains; and PSMA-597's wide therapeutic window ensures that the total radiation from the entire dense dosing regimen remains within normal organ tolerance limits, enabling the first two biological strategies to be executed. These three elements are indispensable: without the safety advantage of the wide therapeutic window, dense dosing would cause radiation overdose to critical organs such as the kidneys and salivary glands, with uncontrollable toxicity; without the dual reinforcement of target upregulation and DNA-targeted killing, dense dosing would amount to mere physical dose escalation, unlikely to achieve additional biological synergy or breakthrough efficacy.

 

The study received ethics approval on June 25, 2025, and as of July 2026, all 120 patients have been enrolled. It must be emphasized that clinical trial results have not yet been published; whether this flexible dosing regimen is superior to the standard regimen remains to be validated by data. The long-term safety of 3 closely spaced doses within 15 days, particularly delayed renal toxicity, requires longer follow-up to answer. The cost-effectiveness of the Week 8 PET adaptive decision-making will also need to be ultimately tested by Telix's future market performance. However, regardless of whether PSMA-597 ultimately achieves marketing approval, this end-to-end R&D logic — from molecular design to flexible dosing — has already provided the radiopharmaceutical industry with a reference paradigm for innovation.

 

Stage 4 (2025–): Frontline Advancement of the OPTIMAL Protocol

If the OPTIMAL study enabled PSMA-597 to achieve clinical breakthrough in the later-line mCRPC setting, then the OPTIMAL-E clinical trial (ID: ACTRN12626000034336) represents Telix's core strategic pivot to expand its commercialization footprint into the potentially more valuable frontline prostate cancer market. This trial is also led by Professor Louise Emmett and is designed as a single-arm, open-label study for men with metastatic hormone-sensitive prostate cancer (mHSPC). It extends the mature OPTIMAL dosing strategy from advanced mCRPC to frontline mHSPC, serving as a critical component of Telix's full-disease-course prostate cancer diagnosis and treatment layout.

 

 

The trial completed its first patient dosing on July 16, 2026, with planned enrollment of 20 mHSPC patients randomized 1:1 into two groups of 10 each, comparing in combination with two ARPIs — darolutamide and enzalutamide, respectively. The study follows the flexible 3/5/7-dose regimen with the dual-dimension assessment rule of Week 8 PSMA-PET combined with PSA levels, with the final number of doses determined by early efficacy signals. Overall, Telix has fully executed its development strategy of advancing from later-line breakthrough to frontline positioning, expanding the indication from mCRPC to mHSPC, and upgrading clinical trial design from single-arm exploration to dual-arm comparative design — relying on this unified flexible dosing system to complete systematic clinical validation across different prostate cancer disease stages.