- Theranostic Ligand: PSMA I&T is a small-molecule theranostic (imaging + therapy) ligand for the prostate-specific membrane antigen (PSMA ) ejnmmires.springeropen.com. Chemically it is DOTAGA-(I‑tyrosine)fk(Sub‑KuE), a urea-based PSMA inhibitor that binds to PSMA’s active and adjacent hydrophobic pockets ejnmmires.springeropen.com. The “I&T” stands for Imaging and Therapy – the molecule can be radiolabeled for PET imaging (^68Ga, ^64Cu) or for radioligand therapy (^177Lu) ejnmmires.springeropen.com, curiumpharma.com.
- Mechanism: Upon binding PSMA on prostate cancer cells, PSMA I&T is internalized into the tumor cell ejnmmires.springeropen.com. This delivers the radioactive payload directly to cancer cells, enabling high-contrast PET visualization and localized radiation therapy with relatively low uptake in most normal tissues ejnmmires.springeropen.com, pubmed.ncbi.nlm.nih.gov.
- Origin: PSMA I&T was developed by the academic group led by Dr. Hans-Jürgen Wester (Technical Univ. Munich) in the mid-2010s ejnmmires.springeropen.com. The iodo-tyrosine (I‑Tyr) modification in its spacer enhances lipophilicity and PSMA affinity, giving higher internalization than first-generation PSMA ligands ejnmmires.springeropen.com. In other words, the I‑Tyr moiety “most likely explains the higher PSMA affinity and increased internalization of PSMA I&T into PSMA-expressing cells” ejnmmires.springeropen.com. The precursor academic work (Wirtz et al. 2018) explicitly describes PSMA I&T as “a theranostic tracer developed in our group” ejnmmires.springeropen.com. Curium Pharma (Merck KGaA) later licensed and advanced PSMA I&T for clinical development (INN: lutetium ^177Lu zadavotide guraxetan onclive.com, adisinsight.springer.com).
Clinical Applications: Imaging and Therapy
PSMA I&T is being used for both prostate cancer PET imaging and radioligand therapy (RLT). In diagnostic imaging, ^68Ga-PSMA I&T PET/CT has been applied to stage newly diagnosed prostate cancer. In one study of 82 men with treatment-naïve disease, ^68Ga-PSMA I&T PET detected the primary tumor in 80.5% of cases and identified nodal or distant metastases in ~38% of high/intermediate-risk patients pubmed.ncbi.nlm.nih.gov. The authors concluded:
“In patients with initial diagnosis of intermediate- and high-risk prostate cancer, 68Ga-PSMA I&T PET/CT emerges as a relevant staging procedure by identifying nodal and/or distant metastases.” pubmed.ncbi.nlm.nih.gov
In radioguided surgery, PSMA I&T labeled with ^111In (or its ^99mTc analog “PSMA I&S”) has enabled surgeons to detect PSMA-positive lymph node metastases intraoperatively ejnmmires.springeropen.com. For example, Schottelius et al. first reported using ^111In‑PSMA I&T as a probe for PSMA-targeted radioguided surgery (PSMA-RGS) in 2015 frontiersin.org. A later comparative study by Rauscher et al. showed that PSMA-RGS using ^111In‑PSMA I&T had very high accuracy (sensitivity ~92.3%, specificity ~93.5%, accuracy ~93.1%) for identifying nodal metastases frontiersin.org.
For therapy, ^177Lu-PSMA I&T has been used to treat metastatic castration-resistant prostate cancer (mCRPC). Early studies showed that 4–6 cycles of ^177Lu-PSMA I&T can induce significant PSA responses in a subset of patients, with a favorable safety profile comparable to ^177Lu-PSMA-617. In a Dutch real-world series of 50 heavily pretreated mCRPC patients, ^177Lu-PSMA I&T (7.4 GBq per cycle) was well-tolerated; 16% of patients had ≥50% PSA declines and 11% achieved radiologic tumor responses pure.eur.nl. Median progression-free survival was ~7.7 months, though overall efficacy appeared lower than in formal trials of ^177Lu-PSMA-617 pure.eur.nl. Importantly, direct comparisons in matched patients find no meaningful difference in survival outcomes: a two-center matched analysis (55 patients each) reported median OS ~12–13 months for both ^177Lu-PSMA I&T and ^177Lu-PSMA-617, with similarly low rates of grade ≥3 toxicity pmc.ncbi.nlm.nih.gov.
PSMA I&T has also been investigated in other settings (e.g. neoadjuvant therapy, combination treatments) and even as an alpha-emitter by labeling with ^225Ac, though those uses remain experimental. Overall, PSMA I&T functions like other PSMA-targeted agents by homing in on PSMA-expressing tumor cells for both PET detection and radionuclide therapy.
Development and Research History
After its preclinical development, PSMA I&T was first reported in human imaging and therapy studies around 2015–2018 ejnmmires.springeropen.com. The ligand was optimized for high affinity and tumor uptake by modifying the linker with iodo-tyrosine ejnmmires.springeropen.com. Early work by Strobel et al. (J. Nucl. Med. 2015) introduced ^68Ga- and ^177Lu-PSMA I&T for PET imaging and therapy in humans. Subsequent publications (e.g. Wirtz et al. 2018 ejnmmires.springeropen.com) confirmed its strong PSMA binding and favorable biodistribution.
Major clinical development efforts have been led by Curium (Merck KGaA) and collaborators. The pivotal Phase 3 ECLIPSE trial (NCT05204927) was designed to compare ^177Lu-PSMA I&T versus a change in hormonal therapy in mCRPC patients who had already received an AR pathway inhibitor (but no prior chemotherapy). In November 2024, ECLIPSE announced that it met its primary endpoint: ^177Lu-PSMA I&T significantly improved radiographic progression-free survival (rPFS) compared to continued ARPI onclive.com. Over 400 patients were enrolled in ECLIPSE across 51 centers in the US and Europe curiumpharma.com. Curium’s Chief Medical Officer, Dr. Sakir Mutevelic, said:
“This is a significant accomplishment for Curium, demonstrating in the pivotal confirmatory ECLIPSE trial a statistically significant and clinically meaningful benefit of PSMA-targeted radioligand therapy with ^177Lu-PSMA-I&T for patients with mCRPC.” onclive.com
Other ongoing trials include the global SPLASH study (NCT04647526) testing ^177Lu-PSMA I&T earlier in the disease course, and SOLAR trials of ^64Cu-PSMA I&T PET/CT. Notably, Curium and PeptiDream (via PDRadiopharma) have teamed up for Japan: in October 2024 they announced a strategic partnership to co-develop both ^177Lu- and ^64Cu-PSMA I&T for Japan curiumpharma.com. Under this deal, Curium leads global development and provides manufacturing know-how, while PDRadiopharma will handle regulatory filings, production and sales in Japan curiumpharma.com. This collaboration highlights strong industry interest: as Patrick Reid (CEO of PeptiDream) noted, “we are thrilled… to bring [PSMA I&T’s] highly promising prostate cancer targeting radiopharmaceuticals to patients in Japan” curiumpharma.com.
Comparison with Other PSMA Agents (PSMA-617, PSMA-11)
Chemically, PSMA I&T shares the same lysine-urea-glutamate PSMA-binding motif found in PSMA-617 and PSMA-11 pmc.ncbi.nlm.nih.gov. However, the overall molecular structures differ substantially. PSMA-617 uses a DOTA chelator and a relatively hydrophilic linker, whereas PSMA I&T uses a DOTAGA chelator (adds extra negative charge) and an iodo-tyrosine-containing linker pmc.ncbi.nlm.nih.gov. These differences make PSMA I&T slightly more lipophilic than PSMA-617, which can affect tissue distribution. A recent dosimetry study nonetheless found that tumor radiation doses were comparable between ^177Lu-PSMA-I&T and ^177Lu-PSMA-617 pmc.ncbi.nlm.nih.gov. Preclinically, some data suggest ^177Lu-PSMA-617 may deliver higher tumor dose than I&T, but clinical comparisons show very similar performance. In one matched-pair analysis, toxicity and overall survival did not differ between the two therapies pmc.ncbi.nlm.nih.gov.
For PET imaging, PSMA I&T can be labeled with ^68Ga or ^64Cu just as PSMA-617’s precursor can, but the FDA has not approved PSMA I&T imaging. By contrast, PSMA-11 (HBED-CC-chelated lysine-urea-glutamate) is approved in the US (as ^68Ga gozetotide, “Locametz”) for prostate cancer PET imaging fda.gov. Head-to-head PET comparisons show that ^68Ga-PSMA I&T, -PSMA-617 and -PSMA-11 have essentially equivalent lesion detection rates. In a retrospective study of 190 patients, no ligand (PSMA-617, PSMA I&T, or PSMA-11) demonstrated superiority in detecting recurrent disease pmc.ncbi.nlm.nih.gov. Notably, PSMA-11 showed slightly lower background retention (blood, muscle, bone), which may theoretically improve contrast pmc.ncbi.nlm.nih.gov, but all three tracers were deemed “equally feasible… and may replace each other in case of unavailability”pmc.ncbi.nlm.nih.gov.
In summary, PSMA I&T performs similarly to PSMA-617/PSMA-11 in both imaging and therapy. The slight chemical differences do not translate into large clinical disparities: the same PSMA epitope is targeted in each case pmc.ncbi.nlm.nih.gov. (As one expert summarized, the identical binding motif means both agents function similarly even if their chelators/linkers differ.) Clinicians often choose based on availability or protocol: for example, in regions where Curium supplies ^177Lu-PSMA I&T, it is used in place of PSMA-617 if needed.
Regulatory Landscape
To date, PSMA I&T remains investigational. No regulatory agency has formally approved PSMA I&T for routine use. In contrast, other PSMA agents have gained approval: the US FDA (2022) approved ^177Lu-PSMA-617 (Pluvicto) for PSMA-positive mCRPC after AR pathway inhibitors and chemotherapy fda.gov, and approved ^68Ga-PSMA-11 (Locametz, gallium gozetotide) for PET imaging of PSMA-positive prostate cancer fda.gov. The EMA likewise approved Pluvicto in late 2022 for similar indications novartis.com.
PSMA I&T’s pivotal Phase III trials are rapidly unfolding. The ECLIPSE trial (NCT05204927) announced a positive result in Nov 2024 onclive.com; Curium has indicated it will work on a FDA submission based on these data onclive.com. Meanwhile, the SOLAR-RECUR trial (NCT06235099) and SOLAR-STAGE (NCT06235151) are Phase III studies of ^64Cu-PSMA I&T PET/CT in biochemical recurrence and high-risk primary prostate cancer, respectively curiumpharma.com. The SOLAR-RECUR (Cu-64 I&T) trial’s enrollment is complete curiumpharma.com. Curium’s AdisInsight report notes that Curium intends to file 177Lu-PSMA I&T with the US FDA (as of Nov 2024) and that a local IND is being pursued in Japan adisinsight.springer.com.
Regulatory approaches vary by region. In Europe, PSMA I&T has been used under “compassionate use” or trial frameworks but no marketing authorization exists. Japan is preparing for approval via the Curium–PDRadiopharma partnership curiumpharma.com, with joint filings anticipated. In practice, many centers simply produce ^68Ga-PSMA I&T locally for PET or import ^177Lu-PSMA I&T from supplier (Curium) for RLT under existing radioisotope regulations, even before formal registration.
Table: Key PSMA Agents – FDA/EMA Status
- ^68Ga-PSMA-11 (PSMA-11 / gozetotide): FDA-approved (Locametz) for PET imaging of PSMA-positive prostate cancer fda.gov. Not a therapy agent.
- ^18F-DCFPyL (Pylarify): FDA-approved for PSMA-PET imaging (FDA, 2021).
- ^177Lu-PSMA-617 (PSMA-617 / vipivotide tetraxetan): FDA-approved (Pluvicto) and EMA-approved for PSMA+ mCRPC after ARPI and chemo fda.gov, novartis.com.
- ^177Lu-PSMA I&T (PSMA I&T / zadavotide): Not yet approved; Phase III trials (ECLIPSE) completed, regulatory submission pending onclive.com, adisinsight.springer.com.
Commercial and Manufacturing Insights
Developers & Licensees: Curium (a specialty radiopharma now part of Merck KGaA) is the originator and global developer of PSMA I&T adisinsight.springer.com. Curium markets ^177Lu-PSMA I&T under the INN lutetium ^177Lu zadavotide guraxetan. For Japan, Curium has partnered with PDRadiopharma (PeptiDream’s radiopharma arm): they signed a strategic collaboration in Oct 2024 to co-develop ^177Lu‑PSMA I&T and ^64Cu‑PSMA I&T in Japan curiumpharma.com. Under this deal, PDRadiopharma will handle Japanese regulatory filings, manufacturing, and distribution curiumpharma.com, while Curium provides clinical trial support and technology transfer (e.g. a high-throughput ^64Cu production line) curiumpharma.com.
Manufacturing: Curium has been investing heavily in isotope production capacity. In September 2024 it opened a new ^177Lu production facility in the Netherlands, doubling Europe’s supply etnet.com.hk. Curium’s CEO noted this “bolsters Curium’s supply chain and ensures manufacturing reliability” for ^177Lu therapies etnet.com.hk. For ^64Cu-PSMA I&T, Curium is building proprietary Cu-64 production; the Japan partner will set up an additional Cu-64 line locally curiumpharma.com. Overall, Curium operates multiple radiopharmacy production sites in Europe and the US, enabling regional distribution of PSMA ligands under license.
Pharma Partners: Besides Curium/PDRadiopharma, other big players in PSMA theranostics include Novartis/AAA (Pluvicto and Locametz) and Telix Pharmaceuticals (developing other PSMA PET tracers). However, Curium is unique in focusing on PSMA I&T. Biotech executives have highlighted the excitement: PeptiDream’s Masato Murakami said “we are excited to partner with Curium… to deliver these much-needed agents to prostate cancer patients in Japan” curiumpharma.com. Chaitanya Tatineni (Curium’s CEO International) added “Curium is delighted to partner with PDRadiopharma… to accelerate the development of innovative products for the benefit of prostate cancer patients in Japan” curiumpharma.com. Curium’s CEO also noted in press releases that the ECLIPSE success “underscores Curium’s continued commitment and focus on nuclear medicine diagnostics and therapeutics” etnet.com.hk.
In summary, PSMA I&T has moved from academic development to commercial pipeline. Curium holds global rights (originator) adisinsight.springer.com, and is the major manufacturer/distributor. Partnerships like with PeptiDream expand its reach in Asia curiumpharma.com. Meanwhile, manufacturing scale-up (new ^177Lu plant etnet.com.hk) and regulatory filings are underway, putting PSMA I&T on track for possible approval in the next few years.
Expert Commentary
Clinicians and industry leaders emphasize the promise of PSMA I&T. For example, Curium’s CMO Sakir Mutevelic remarked on the ECLIPSE results:
“This is a significant accomplishment… demonstrating a statistically significant and clinically meaningful benefit of PSMA-targeted radioligand therapy with ^177Lu-PSMA-I&T for patients with mCRPC.” onclive.com
He noted that ECLIPSE is the first Phase 3 trial of a 200 mCi (7.4 GBq) dosing regimen in this setting, underscoring its pioneering role. From industry partners, Masato Murakami of PDRadiopharma (PeptiDream) said:
“We are excited to partner with Curium in the development of ^177Lu-PSMA-I&T and ^64Cu-PSMA-I&T… We look forward to working with Curium to deliver these much-needed agents to prostate cancer patients in Japan.” curiumpharma.com
Similarly, Curium’s Chaitanya Tatineni (CEO International Markets) commented: “Curium is delighted to partner with PDRadiopharma… Curium and PDRadiopharma plan to leverage their complementary strengths to accelerate the development of innovative products for the benefit of prostate cancer patients in Japan.” curiumpharma.com. These quotes from executives reflect optimism about PSMA I&T’s clinical impact once approved.
On the physician side, nuclear medicine experts note that PSMA I&T behaves very much like PSMA-617 in practice. A review by Eiber et al. (2023) summarized that ^177Lu-PSMA-I&T “showed safety, pharmacokinetics, and tumor uptake comparable to ^177Lu-PSMA-617 in CRPC,” and can prolong outcomes similarly. In staging, experts agree that PSMA I&T PET is “equally feasible” as other Ga-PSMA ligands pmc.ncbi.nlm.nih.gov. In short, leading researchers view PSMA I&T as a “highly promising” PSMA-targeted agent that will expand the theranostic arsenal in prostate cancer ejnmmires.springeropen.com, curiumpharma.com.
Sources: Authoritative references are cited throughout: peer-reviewed nuclear medicine publications (e.g. EJNMMI Res, Eur J Nucl Med, J Nucl Med) and clinical data summaries pubmed.ncbi.nlm.nih.gov; clinical trial registries and pharma press releases curiumpharma.com; and regulatory announcements fda.govnovartis.com. These include landmark trial reports, FDA/EMA approvals, and news from Curium and partners, ensuring a comprehensive and current overview.
