Investigational Drug
REGN5678
HealthScout AI Analysis
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Overview
REGN5678 (nezastomig) is a first‑in‑class, human IgG4 PSMA×CD28 costimulatory bispecific antibody being developed by Regeneron for prostate cancers, primarily metastatic castration‑resistant prostate cancer (mCRPC). It is being tested alone and in combination with the PD‑1 inhibitor cemiplimab (Libtayo) in an ongoing first‑in‑human phase 1/2 study (NCT03972657). Additional studies include combination with the PSMA×CD3 bispecific REGN4336 (NCT05125016) and a presurgical pilot in high‑risk localized disease (NCT06085664). Recent conference materials and registries also refer to REGN5678 by the nonproprietary/USAN name “nezastomig.” (ascopubs.org)
Mechanism of action
Nezastomig binds PSMA on tumor cells and CD28 on T cells to deliver a localized costimulatory “signal 2,” intended to amplify T‑cell activation in the tumor microenvironment. Preclinical work established the CD28‑bispecific concept and showed that tumor‑antigen×CD28 bispecifics can enhance antitumor activity when combined with T‑cell–activating therapies, while showing limited activity alone and avoiding the systemic activation seen with historical CD28 superagonists. The clinical program often combines nezastomig with PD‑1 blockade (cemiplimab) to further augment T‑cell responses. (science.org)
Efficacy
- AACR 2025 (late‑breaking abstract, data cutoff Feb 16, 2024): Among 78 patients with mCRPC treated with nezastomig plus cemiplimab, clinical activity was confined to nezastomig dose levels ≥30 mg weekly (n=61). At these doses, PSA50 responses occurred in 25% (15/61) and PSA90 in 16% (10/61). Median radiographic PFS was 5.0 months (95% CI, 2.1–12.0) at ≥30 mg versus 2.1 months (1.9–3.5) at <30 mg. With longer follow‑up (data cutoff Jul 19, 2024), median OS was 17.3 months (95% CI, 11.0–NE) for ≥30 mg versus 10.3 months (3.7–12.6) for <30 mg. (aacrjournals.org)
- Earlier presentations showed radiographic responses at higher dose levels, including a confirmed complete response at 30 mg and partial responses at 100–300 mg in dose‑escalation cohorts. PSA declines ≥99% were also observed at 100–300 mg in some patients. (ovid.com)
Overall, these early data suggest dose‑dependent activity for nezastomig plus cemiplimab in heavily pretreated mCRPC, a setting typically resistant to PD‑1 monotherapy. (onclive.com)
Safety
- AACR 2025 update (nezastomig + cemiplimab; n=78): Treatment‑related adverse events (any grade) in 77%; common events included fatigue (27%), cytokine release syndrome (CRS; 13%, mostly grade 1) and nausea (13%). Immune‑mediated adverse reactions (imARs) grade ≥3 occurred in 14% (11/78), predominantly in patients with PSA50 responses (8/11). Two grade 5 imARs (hemophagocytic lymphohistiocytosis and hepatitis) were reported. Notably, all grade ≥3 imARs occurred after addition of cemiplimab. (aacrjournals.org)
- Earlier dose‑escalation experience identified dose‑limiting toxicities including grade 3 pain and Guillain–Barré syndrome at higher dose levels; grade 3 encephalitis, seizure, and mucositis were also reported in responding patients. The signal of activity appeared correlated with higher‑grade immune‑related toxicity. (ovid.com)
An amendment to the clinical program is exploring nezastomig monotherapy and other combinations to optimize the activity–toxicity balance, and evaluation in clear cell renal cell carcinoma has been noted. (urotoday.com)
Further reading
- Phase 1/2 nezastomig (REGN5678) + cemiplimab in mCRPC: updated results and survival analyses (AACR 2025, Abstract CT064). (aacrjournals.org)
- Preliminary results from the phase 1/2 study (ASCO GU 2023 abstract 154). (ovid.com)
- Study design: first‑in‑human REGN5678 ± cemiplimab in mCRPC (ASCO 2020/2021 TPS abstracts; NCT03972657). (ascopubs.org)
- Early activity summary and dose‑level details (news/secondary reports). (onclive.com)
- Concept and preclinical rationale for CD28 costimulatory bispecifics. (science.org)
- Ongoing related trials: REGN4336 (PSMA×CD3) ± nezastomig (NCT05125016) and presurgical trial in localized disease (NCT06085664). (ascopubs.org)
Notes - Nezastomig/REGN5678 remains investigational; no regulatory approvals to date. (investor.regeneron.com)
Last updated: Oct 2025
Active trials using REGN5678
Found 3 active trials using this drug:
HealthScout AI summary: Men with metastatic castration‑resistant prostate cancer progressing after ≥2 prior systemic regimens (including a next‑generation AR pathway inhibitor), ECOG 0–1, and adequate organ function; prior PSMA‑targeted therapy and immunotherapy allowed. Treatment is REGN5678 (nezastomig), a PSMA×CD28 T‑cell costimulatory bispecific antibody with a weekly lead‑in then q3w dosing, combined q3w with the PD‑1 inhibitor cemiplimab.
ClinicalTrials.gov ID: NCT06826768
HealthScout AI summary: Adults with metastatic castration-resistant prostate adenocarcinoma (progressed after ≥2 prior systemic regimens including a second‑generation AR‑targeted agent; PSA ≥4; progression within 6 months) receive the investigational PSMA×CD3 T‑cell–redirecting bispecific REGN4336 alone or combined with cemiplimab (anti–PD‑1) or REGN5678/nezastomig (PSMA×CD28 costimulatory bispecific), with step‑up dosing and optional IL‑6 blockade to mitigate CRS. Prior PSMA radioligand therapy is allowed; PSMA‑targeted non‑radioligand therapies are excluded.
ClinicalTrials.gov ID: NCT05125016
HealthScout AI summary: Adults with PSMA-expressing tumors, primarily mCRPC post–ARPI (and including a post–177Lu‑PSMA‑617 cohort) and previously treated metastatic ccRCC, receive REGN5678 (nezastomig), a PSMA×CD28 costimulatory bispecific antibody, as monotherapy or with the PD‑1 inhibitor cemiplimab. Aims include identifying active/safe doses and assessing responses, with combination use tempered by prior immune‑related toxicities.
ClinicalTrials.gov ID: NCT03972657
