RENGEVITY-201 Trial: Pegrizeprument Takes On Tacrolimus

RENGEVITY-201 trial dosing has begun, Veloxis says, with the first participant now treated. The Phase 2 study plans to randomise up to 120 kidney-transplant recipients across two pegrizeprument doses and tacrolimus. The announcement contains no outcome data, while the public registry still lists the study as not yet recruiting.

Veloxis reported on 31 August 2026 that the first participant had been dosed in the RENGEVITY-201 trial. The company did not identify the site, dosing date, assigned arm or dose level.

The undisclosed treatment arm limits what the RENGEVITY-201 trial announcement proves. A tacrolimus control is built into the study, so the release does not establish that anyone has yet received pegrizeprument. It also does not say whether the participant had been randomised. As with a first-participant milestone in PULSE-LHD, trial activity is not efficacy evidence.

The NCT07290777 record remains at Version 1. It was last updated on 18 December 2025, still says “not yet recruiting,” and lists no locations. The sponsor announcement is eight months newer. That makes the release the current source for first dosing and the registry the source for the disclosed design. No safety, rejection, graft-function or infection results are available.

01 What happened in the RENGEVITY-201 trial

Veloxis has reported one dosing milestone in the RENGEVITY-201 trial, but it has not identified the assigned treatment or said that pegrizeprument was administered.

The uncertainty comes from the three-arm design. One-third of the planned allocation is an active-control group receiving immediate-release tacrolimus. Until Veloxis identifies the arm, the first participant could be in either experimental dose group or the control group.

The RENGEVITY-201 trial registry is also behind the announcement. Its estimated start was July 2026, but the record has not moved since December 2025. No site, country, principal investigator or recruitment location is visible. Until the registry is updated, those details remain unknown.

02 How the RENGEVITY-201 trial is designed

The RENGEVITY-201 trial is a multicentre Phase 2 study in adults receiving a new kidney transplant. Participants are assigned equally across two pegrizeprument dose levels and one tacrolimus comparator.

Every group also receives rATG, corticosteroids and mycophenolate. The RENGEVITY-201 trial therefore compares complete immunosuppressive regimens, not pegrizeprument monotherapy with tacrolimus monotherapy. Early rejection and infection outcomes will reflect the full regimen.

The registry labels masking as double, but the description is more limited. Participants and investigators are masked only to whether the low or high pegrizeprument dose is used. They are not masked to tacrolimus versus pegrizeprument. No outcome-assessor or data-analyst masking is listed.

03 RENGEVITY-201 trial endpoints

The official title calls the RENGEVITY-201 trial dose-ranging and says it will evaluate “preliminary efficacy.” That wording matches the endpoint hierarchy.

Serious adverse events and treatment-emergent adverse events are primary outcomes. The rest of the primary set measures drug exposure, anti-drug and neutralising antibodies, and CD28 receptor occupancy. Together, these measures compare exposure, immunogenicity and CD28 engagement across the two doses.

The clinical efficacy measures sit in the secondary tier. The main composite counts death, graft failure or biopsy-proven acute rejection by Month 12. The trial also tracks the eGFR slope, delayed graft function, renal-replacement therapy and new-onset diabetes after transplantation.

No public statistical analysis plan explains the sample-size calculation, hypothesis, multiplicity control or decision rule. The RENGEVITY-201 trial should therefore be read as a controlled dose-selection and signal-finding study. Its 120-person design may produce useful comparative estimates, but the public record does not describe a definitive superiority or non-inferiority test.

04 Why the RENGEVITY-201 trial uses tacrolimus

Tacrolimus remains the efficacy benchmark because it suppresses early rejection reliably. The still-hosted KDIGO kidney-transplant guideline suggests tacrolimus as the first-line calcineurin inhibitor. That recommendation dates from 2009, but the comparator choice in the RENGEVITY-201 trial shows how durable the standard has been.

The trade-off is written into the current U.S. tacrolimus label: acute or chronic nephrotoxicity, new-onset diabetes, neurotoxicity, hyperkalaemia, hypertension, drug interactions and the need for therapeutic-drug monitoring. Those recognised risks create the clinical case for a calcineurin-inhibitor alternative.

A replacement must protect the graft well enough to justify any measurable gain in kidney function, metabolic burden or monitoring convenience. The RENGEVITY-201 trial puts that question against an active comparator rather than a placebo.

05 What the RENGEVITY-201 trial is testing

Pegrizeprument, previously called VEL-101 and FR104, is a pegylated monovalent antibody fragment. It binds CD28, a costimulatory receptor used in T-cell activation. The molecule is designed to block the activating CD28 signal while leaving the inhibitory CTLA-4 pathway available.

That is the mechanistic distinction under study in the RENGEVITY-201 trial. Belatacept, the approved costimulation blocker in kidney transplantation, binds CD80 and CD86 rather than CD28 itself. It provides clinical precedent for costimulation blockade, but its trial history includes more early acute rejection alongside better kidney-function measures.

In the pivotal BENEFIT study, the less-intensive belatacept regimen produced 97% patient-and-graft survival at one year versus 93% with cyclosporine, while acute rejection occurred in 17% versus 7%. The comparator was cyclosporine, not tacrolimus. A separate direct randomised study against tacrolimus enrolled only 40 recipients and reported biopsy-proven acute rejection in 55% with belatacept versus 10% with tacrolimus.

Pegrizeprument is not belatacept, and those results cannot be transferred to it. They explain why preserving CTLA-4 is biologically interesting and why rejection remains the clinical test. The OX40 registry analysis offers a parallel from another immune pathway, where a persuasive mechanism failed to translate into clinical superiority.

06 Evidence before the RENGEVITY-201 trial

The strongest published pegrizeprument evidence is a randomised Phase 1 study in 60 healthy participants. They were assigned 3:1 across seven dose levels or placebo and followed for 50 days. Two dose levels were intravenous and five were subcutaneous.

Most adverse events were mild or moderate, with injection-site pain reported most often. One grade 3 serious adverse event, rhabdomyolysis, resolved with supportive care. No clinically elevated cytokines or cytokine-release syndrome was observed. Exposure increased with dose, and the paper reported sustained CD28 receptor occupancy in the ranges selected for further development.

That study supports single-dose tolerability, pharmacokinetics and receptor engagement. It did not include transplant recipients, combination immunosuppression, rejection endpoints or long-term dosing. The subcutaneous route used there should not be assigned to the RENGEVITY-201 trial because the current Phase 2 record does not disclose its route.

The earlier FIRsT Phase 1/2 study moved FR104 into kidney transplantation. Ten candidates were enrolled; eight were transplanted and analysable. The group was selected for low rejection risk, treated at one site without randomisation or a control group, and received tacrolimus alongside FR104 for the first six months.

An investigator and company conference report said the eight patients completed one year, with no acute rejection, donor-specific antibody or FR104 safety alert observed. The report observed no rejection after tacrolimus withdrawal, but eight selected patients cannot support a comparative rate estimate. Tacrolimus overlap during the first six months also prevents isolation of FR104’s effect from the rest of the regimen.

07 Competition around the RENGEVITY-201 trial

The RENGEVITY-201 trial enters a field that already includes approved belatacept and later-stage investigational programmes. Belatacept is available to eligible adult kidney-transplant recipients, although its label is restricted to EBV-seropositive patients and carries PTLD and serious-infection warnings.

Two investigational anti-CD40L programmes are further along. Sanofi’s frexalimab study NCT07412470 is a recruiting 526-person Phase 2/3 comparison with tacrolimus. Eledon’s tegoprubart BESTOW study enrolled 127 participants in Phase 2, and Health Canada authorised a separate Phase 3 protocol in August 2026; that new record still says not yet recruiting.

These are different molecules and pathways, so mechanism alone cannot rank them. Development timing can: frexalimab has entered a larger seamless study, while tegoprubart has completed randomised Phase 2 enrolment. The RENGEVITY-201 trial starts behind both programmes in development stage.

08 What the RENGEVITY-201 trial does not disclose

The RENGEVITY-201 trial is registered, but its public record is thin for a study that has reportedly started. Without the dose, route, tacrolimus target and statistical plan, readers cannot reproduce or fully interpret the comparison.

The trial also excludes several populations that often make transplant evidence harder to interpret: recipients with current or historical donor-specific antibodies, positive crossmatches, very high panel-reactive antibodies, donor KDPI above 85%, CMV D-positive/R-negative status and EBV-seronegative status, among others.

Those exclusions reduce clinical heterogeneity but narrow generalisability. A result in selected lower-risk recipients would not establish performance in sensitised, EBV-negative or otherwise high-risk patients.

09 For Academics: a citation-safe study map

Academics can cite the RENGEVITY-201 trial design and the sponsor-reported dosing milestone separately. The following description reflects the public record as checked on 1 September 2026.

Five questions should guide any academic reading of the RENGEVITY-201 trial results:

• Does receptor occupancy show a usable dose-response? A pharmacodynamic gradient would support dose selection, but it is not a substitute for rejection control.
  2 doses
• How is the clinical composite distributed? Death, graft failure, T-cell-mediated rejection and antibody-mediated rejection should be reported separately as well as together.
  Month 12
• What does the background regimen contribute? rATG, corticosteroids and mycophenolate affect early rejection and infection in every arm; regimen-level conclusions are required.
  3 co-therapies
• Does kidney function improve without a rejection penalty? eGFR should be read beside biopsy-proven rejection, graft failure, delayed graft function and renal-replacement therapy.
  eGFR + BPAR
• Who is missing from the sample? High immunological-risk, EBV-negative and CMV D-positive/R-negative recipients are among the excluded groups.
  Limited scope

The RENGEVITY-201 trial can presently be cited as a randomised, dose-ranging, active-controlled Phase 2 study that has reportedly begun. It cannot be cited as evidence that pegrizeprument prevents rejection, improves eGFR, reduces tacrolimus toxicity or is safer than an approved regimen.

10 RENGEVITY-201 trial risk score

The score is not a prediction of rejection, patient harm, trial failure or regulatory refusal. It measures how much uncertainty remains around the programme using the public evidence available on 1 September 2026.

11 What to watch in the RENGEVITY-201 trial

• A new ClinicalTrials.gov version. Recruitment status, sites and locations should move beyond the December 2025 record now that first dosing has been reported.
  Version 1
• The actual VEL-101 regimen. Dose amounts, route, frequency, duration and tacrolimus exposure targets are needed to reproduce the comparison.
  Not public
• Completion of the planned sample. Equal allocation implies about 40 participants per arm before discontinuations and missing data.
  120
• The Month-12 clinical composite. Death, graft failure, T-cell-mediated rejection and antibody-mediated rejection should be shown separately.
  BPAR
• Infection and malignancy signals. BK, CMV and EBV viraemia, PTLD and malignancies are named adverse events of special interest.
  Month 12
• Whether one dose advances. Dose selection will require arm-level exposure, receptor-occupancy, rejection and tolerability data.
  Low vs high

12 Verdict on the RENGEVITY-201 trial

The RENGEVITY-201 trial asks whether selective CD28 blockade can support a kidney-transplant regimen that competes with tacrolimus.

The active comparator, three-way randomisation and 12-month outcomes give pegrizeprument its first controlled transplant test beyond the small FIRsT cohort. Because clinical efficacy outcomes are secondary, this is primarily a safety, dose and pharmacology study.

First dosing marks execution progress; the evidence base remains unchanged until arm-level results appear. The decisive evidence will be rejection, graft function, infection, immunogenicity and discontinuation data, not receptor occupancy by itself.

For now, the evidence gap is clear: prior transplant experience comprises eight analysable recipients, while the RENGEVITY-201 trial plans a 120-person randomised comparison with tacrolimus.

13 RENGEVITY-201 trial FAQs

What is the RENGEVITY-201 trial?

The RENGEVITY-201 trial is a randomised, partially blinded, active-controlled Phase 2 study of pegrizeprument in up to 120 adult kidney-transplant recipients. Two pegrizeprument dose groups are compared with immediate-release tacrolimus, with rATG, corticosteroids and mycophenolate also named across the study.

Has the first RENGEVITY-201 participant received pegrizeprument?

That has not been disclosed. Veloxis says the first trial participant has been dosed, but the study includes a tacrolimus control arm and the company did not identify the participant’s allocation.

Is pegrizeprument approved by the FDA?

No FDA or EMA marketing authorisation for pegrizeprument was found as of 1 September 2026. FDA Fast Track status reported for kidney-transplant development and orphan designations for liver and heart transplantation do not approve the medicine or the kidney indication.

What are the primary outcomes of the RENGEVITY-201 trial?

The primary outcomes assess serious and treatment-emergent adverse events, pharmacokinetics, immunogenicity and CD28 receptor occupancy. The Month-12 composite of death, graft failure or biopsy-proven acute rejection is a secondary outcome.

What did earlier pegrizeprument studies show?

A randomised Phase 1 study in 60 healthy participants supported single-dose tolerability, dose-related exposure and CD28 receptor occupancy. The uncontrolled FIRsT transplant study had eight analysable low-risk recipients and reported no acute rejection through one year, with tacrolimus used during the first six months.

When could RENGEVITY-201 trial results be available?

The registry estimates primary and overall study completion in October 2028. That date may change, and no interim readout schedule is public.

Why does the RENGEVITY-201 trial registry still say not yet recruiting?

The public ClinicalTrials.gov record has not been updated since 18 December 2025. Veloxis’s first-dose announcement is dated 31 August 2026. The difference is best treated as a dated public-record lag until the sponsor posts a newer registry version.