CONVERGE-01: A Patient’s Guide to Ac-225 Rosopatamab Tetraxetan (CONV01-α)
Understanding the realities of the next-generation alpha-emitting radioantibody for PSMA-positive mCRPC
Bottom Line Up Front (BLUF)
CONV01-α (Ac-225 rosopatamab tetraxetan, formerly 225Ac-J591) is an investigational radioantibody that delivers the alpha emitter Actinium-225 to prostate cancer cells via a monoclonal antibody targeting PSMA. It represents a fundamentally different approach from Pluvicto (Lu-177-PSMA-617): instead of a small-molecule ligand carrying a beta emitter, it uses a full-sized antibody carrying an alpha emitter. This matters because (1) alpha particles are far more destructive to cancer DNA than beta particles, and (2) the antibody is too large to penetrate salivary glands, kidneys, and small bowel—the organs that take the worst beating from small-molecule PSMA therapies.
Across Phase I trials at Weill Cornell Medicine enrolling over 120 patients, CONV01-α produced PSA declines of ≥50% in 47–68% of heavily pretreated mCRPC patients, including those who had already failed Lu-177-PSMA therapy. The dominant toxicity was transient, manageable thrombocytopenia. Quality of life was preserved. The drug is now in the Phase II CONVERGE-01 trial at nine U.S. sites, including UCSD Moores Cancer Center under PI Rana McKay, MD. Convergent Therapeutics has secured $130 million in Series A funding and locked in Actinium-225 manufacturing supply through a partnership with NorthStar Medical Radioisotopes.
For IPCSG members: This is one of the most closely watched drugs in the alpha radiopharmaceutical pipeline. If CONVERGE-01 confirms the Phase I response rates, a pivotal (registration) trial is planned, which could eventually lead to FDA approval of the first alpha-emitting radioantibody for prostate cancer.
1. What Is CONV01-α and How Does It Work?
CONV01-α consists of two components working together:
The antibody (rosopatamab): This is a humanized monoclonal antibody called J591 that targets PSMA (prostate-specific membrane antigen), a protein massively overexpressed on the surface of prostate cancer cells. J591 was developed by Dr. Neil Bander at Weill Cornell Medicine over two decades of research. It binds to an external region of the PSMA protein, gets internalized into the cancer cell, and drags its radioactive payload inside.
The radionuclide (Actinium-225): Ac-225 is an alpha-emitting isotope with a half-life of approximately 10 days. When it decays, it releases four alpha particles in rapid succession before reaching stable Bismuth-209. Each alpha particle delivers massive energy over a very short distance—only about 50–85 micrometers, or roughly 2–10 cell diameters. This is enough to shatter DNA double strands beyond repair, killing the cell regardless of whether it is actively dividing, in a resistant phase, or in a low-oxygen environment where conventional radiation often fails.
The chelator (tetraxetan/DOTA): This is the chemical “cage” that locks the Actinium-225 onto the antibody. Stable chelation is essential to prevent the radioactive isotope from detaching and depositing in bone or other organs.
Why does the delivery vehicle matter? Small-molecule PSMA ligands (like PSMA-617 in Pluvicto, or PSMA-I&T) are tiny and can penetrate virtually any tissue—including salivary glands, lacrimal (tear) glands, kidneys, and small bowel, all of which naturally express some PSMA. This causes the signature side effects of small-molecule PSMA therapy: severe dry mouth (xerostomia), dry eyes, kidney damage, and GI toxicity.
The J591 antibody is far too large to enter these organs efficiently. At ASCO GU 2025, Dr. Michael Morris (Memorial Sloan Kettering) showed imaging data confirming that CONV01-α has no detectable uptake in salivary or lacrimal glands and follows a hepatobiliary excretion pathway that minimizes kidney exposure. This is a clinically meaningful difference: it means the organs most vulnerable to Pluvicto-type damage are largely spared.
Alpha vs. Beta: Why the Physics Matter
| Property | Alpha Particles (Ac-225) | Beta Particles (Lu-177 in Pluvicto) |
|---|---|---|
| Energy transfer (LET) | ~100 keV/μm (very high) | ~0.2 keV/μm (low) |
| Range in tissue | 50–85 μm (2–10 cell diameters) | ~2 mm (hundreds of cells) |
| DNA damage type | Irreparable double-strand breaks & cluster damage | Single-strand breaks (often repairable) |
| Effectiveness in hypoxic tumors | Fully effective | Reduced effectiveness |
| Particles per decay | 4 alpha particles (nanogenerator effect) | 1 beta particle |
| Half-life | ~10 days | ~6.7 days |
The practical implication: alpha particles are estimated to be 500–1,000 times more cytotoxic per particle track than beta particles. And because Ac-225 generates four alphas per decay, the effective kill-per-atom is extraordinary. The tradeoff is that you need precise targeting—alpha particles won’t reach far enough to hit tumors they aren’t attached to. That’s where the antibody’s targeting and internalization come in.
2. Clinical Trial Evidence: What Do We Know So Far?
Phase I Single-Dose Escalation (NCT03276572)
Published by Tagawa et al. in the Journal of Clinical Oncology in March 2024, this was the first-in-human study of 225Ac-J591. Thirty-two patients with progressive mCRPC who had failed AR pathway inhibitors and chemotherapy (or were ineligible) received a single IV infusion at one of seven dose levels from 13.3 to 93.3 KBq/kg. Patients were not pre-selected for PSMA expression.
• PSA decline ≥50%: 46.9% of patients (34.4% confirmed by PCWG3 criteria)
• Any PSA decline: 69% of evaluable patients
• CTC response: 59.1% (13/22 evaluable) converted to favorable CTC counts
• Maximum tolerated dose: Not reached. Recommended Phase II dose: 93.3 KBq/kg
• Dose-limiting toxicity: 1 of 22 patients (cohort 6, 80 KBq/kg) had Grade 4 anemia + thrombocytopenia. No DLTs at the highest dose level.
Phase I Fractionated-Dose Trial (NCT04886986) — The Basis for CONVERGE-01
This study, also led by Tagawa and Nauseef at Weill Cornell, tested the Day 1 + Day 15 fractionated dosing schedule—the same regimen used in CONVERGE-01. Two parallel cohorts were enrolled: fractionated (dose-dense, single cycle) and multiple-cycle (every 6 weeks).
• PSA decline ≥50%: 68% in the fractionated arm (vs. 28% in the multiple-cycle arm)
• Recommended Phase II dose: 60 KBq/kg × 2 doses (fractionated)
• Multiple-cycle arm: Not advanced due to thrombocytopenia-related delays
• Quality of life (FACT-P): Preserved or improved in the fractionated arm; median scores rose from 116 to 123. No significant deterioration.
• FACT-RNT (radiotherapy-specific QoL): Stable across all timepoints and dose levels
At ESMO 2025, Tagawa concluded that the fractionated regimen appeared safe with preliminary efficacy and that the multiple-cycle (every 6 weeks) approach should not be pursued due to nadir timing.
Combination Therapy: 225Ac-J591 + 177Lu-PSMA-I&T
A separate Phase I/II trial combined CONV01-α with the beta-emitting radioligand 177Lu-PSMA-I&T, exploiting complementary mechanisms: the alpha particles deliver focused kill to PSMA-expressing cells, while the longer-range beta particles address neighboring cells in the tumor microenvironment.
• PSA decline: 94% of patients had any PSA decline; 64% had ≥50% decline
• Median overall survival: 29.8 months (95% CI: 7.4 – not reached) in 18 heavily pretreated patients
• Recommended Phase II dose of 225Ac-J591: 35 KBq/kg when combined with Lu-177
• DLTs: 2 of 6 patients at 40 KBq/kg experienced thrombocytopenia-related DLTs
A separate retrospective analysis presented at AUA 2025 compared monotherapy versus combination 225Ac-J591 across the Weill Cornell experience. Combination therapy showed higher PSA50 response rates (57% vs. 48%, p=0.4) and significantly better progression-free survival (5.7 vs. 3.9 months) and overall survival (20.6 vs. 11.2 months, p<0.01). Acute adverse events were generally low grade.
3. Side Effects: What to Expect
• Fatigue (extreme tiredness) — the most common;
reported in 77–95% of patients across trials, generally Grade 1–2 and
resolving within several weeks
• Thrombocytopenia (low platelets) — the dose-limiting toxicity; nadir typically at weeks 4–6 post-infusion
• Nausea — mostly low-grade
• Anorexia (loss of appetite)
• Pain
• Xerostomia (dry mouth) — reported in 69% of
fractionated-dose patients but generally low-grade and far milder than
with small-molecule Ac-225-PSMA compounds
• Anemia (low red blood cells)
• Neutropenia (low white blood cells)
• Dizziness
• Weight loss
The hematologic toxicity pattern deserves special attention. Across all Phase I data, the primary dose-limiting concern was thrombocytopenia (low platelets). In the single-dose Phase I, only 1 of 32 patients experienced Grade 4 hematologic toxicity (at the 80 KBq/kg dose level). In the fractionated-dose trial, 2 of 6 patients at the highest tested dose (65 KBq/kg ×2, or a cohort combining with Lu-177) had DLTs related to low platelets. The platelet nadir typically occurs around weeks 4–6 after infusion, which is why the CONVERGE-01 DLT assessment window runs from Day 1 through Week 6.
Importantly for patients who have had Pluvicto: The xerostomia profile is markedly different. Small-molecule Ac-225-PSMA-617 (the South African/Pretoria experience with “free” Ac-225 on a PSMA small molecule) produces severe, often irreversible salivary gland damage because the small molecule concentrates heavily in the glands. With the J591 antibody, salivary gland uptake is minimal. In a telling comparison, only one patient reported xerostomia in the earlier Lu-177-J591 antibody trials. In the Ac-225-J591 fractionated trial, the 69% xerostomia rate was predominantly Grade 1 (mild dry mouth, manageable) and did not produce the debilitating permanent dry mouth seen with small-molecule approaches.
4. CONVERGE-01: The Current Trial
CONVERGE-01 (NCT06549465) is a Phase II, open-label, multicenter, three-part study sponsored by Convergent Therapeutics and conducted at approximately nine U.S. sites. The study is designed to establish the safety, dosimetry, dose optimization, and efficacy of CONV01-α monotherapy in PSMA PET-positive mCRPC.
| Feature | Details |
|---|---|
| Part 1 | Biodistribution study: first 5 participants receive Indium-111-rosopatamab tetraxetan to image where the drug goes in the body |
| Part 2 | Dose optimization in Lu-177-PSMA-naïve patients (no prior Pluvicto/PSMA radioligand therapy) |
| Part 3 | Dose escalation in patients with prior Lu-177-PSMA exposure (post-Pluvicto or post-Lu-177-PSMA-I&T) |
| Dosing schedule | Single fractionated cycle: two IV infusions on Day 1 and Day 15 |
| Study drug | Ac-225 rosopatamab tetraxetan (CONV01-α) |
| Study design | Open-label (no placebo); you and your doctor know what you’re getting |
| Target enrollment | ~60 patients (Parts 2 & 3) + up to 12 in Part 3a |
| Key endpoints | Safety, PSA response, radiographic response, PFS, OS, pharmacokinetics |
| PI at UCSD | Rana McKay, MD (listed on consent; note: original PI was Yu-Wei Chen, MD) |
| Infusion location | UC San Diego Medical Center — Hillcrest, Nuclear Medicine |
| IRB | Advarra IRB (Pro00076969); ICF version dated 29 May 2025, revised 5 Aug 2025 |
5. Corporate and Supply Chain Developments
Convergent Therapeutics was founded in 2020 by Dr. Philip Kantoff (CEO) and Dr. Neil Bander (CSO) and is based in Cambridge, Massachusetts. The company holds an exclusive license from Weill Cornell Medicine for the J591 antibody platform.
Funding: Convergent has raised $130 million in Series A financing: $90 million in May 2023 (led by OrbiMed and RA Capital Management) and a $40 million extension in September 2024 from Novo Holdings (the investment arm of the Novo Nordisk Foundation). In September 2024, the company also appointed Dr. Richard Messmann as Chief Medical Officer; he previously led Fusion Pharmaceuticals’ actinium program (FPI-2265) and Amgen’s xaluritamig (AMG 509) development.
Manufacturing and Ac-225 supply: In January 2026, Convergent and NorthStar Medical Radioisotopes announced an expanded partnership establishing dedicated CONV01-α manufacturing suites on NorthStar’s campus in Beloit, Wisconsin. This co-location integrates Ac-225 isotope production with drug product manufacturing, addressing the historically critical supply constraint for Actinium-225. Convergent also has a supply agreement with Cardinal Health for Ac-225 shipments supporting CONVERGE-01, and a separate partnership with IONETIX for additional Ac-225 supply.
Regulatory pathway: The FDA cleared Convergent’s IND application for CONV01-α in April 2024. CEO Kantoff has stated publicly that CONVERGE-01 is intended to confirm the high response rate and durability of CONV01-α monotherapy to solidify the path forward to a pivotal (registrational) trial. The company is also planning additional trials in earlier stages of prostate cancer and in combination with other therapeutics.
Patent and litigation status: As of April 2026, no patent litigation or court filings involving Convergent Therapeutics or CONV01-α have been identified in public records.
6. Context for IPCSG Members: Where Does This Fit?
For patients in the mCRPC setting who have already been through AR pathway inhibitors (enzalutamide, abiraterone), chemotherapy (docetaxel, cabazitaxel), and potentially Pluvicto (Lu-177-PSMA-617), the options narrow considerably. CONV01-α addresses several specific unmet needs:
Post-Pluvicto failure: The fractionated-dose Phase I data showed comparable PSA response rates regardless of prior Lu-177-PSMA exposure. This is critical—it means PSMA targeting with an antibody-alpha construct can work even after the tumor has progressed through small-molecule-beta PSMA therapy. CONVERGE-01 Part 3 is specifically designed for this population.
Salivary gland sparing: For patients who already have dry mouth from prior Pluvicto, the antibody delivery mechanism offers a meaningful advantage. The drug simply does not reach the salivary glands in clinically significant concentrations.
Bone lesion targeting: At ASCO GU 2025, Morris highlighted CONV01-α’s potentially superior uptake and retention in bone and small-volume lesions compared to small-molecule radioligands. This is relevant for the many mCRPC patients whose dominant disease burden is skeletal.
The broader Ac-225 landscape: CONV01-α is not the only Ac-225-PSMA approach in development. However, most other Ac-225-PSMA programs use small-molecule ligands (e.g., Ac-225-PSMA-617), which inherit the salivary/renal toxicity problems. The antibody delivery platform is what distinguishes CONV01-α in this crowded field.
ENZA-p context: At ASCO GU 2025, the ENZA-p trial showed that adding Lu-177-PSMA-617 to enzalutamide in first-line mCRPC improved overall survival (34 vs. 26 months, HR 0.55, p=0.005). While this involves a different drug and earlier setting, it signals growing acceptance of PSMA radioligand therapy moving earlier in the treatment sequence—a trend that could eventually benefit alpha-antibody approaches like CONV01-α as well.
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