Tegoprubart for Kidney Transplant Rejection

Enrolling by invitation at 40 trial locations

Age: 18+

Sex: Any

Trial Phase: Phase 2

Sponsor: Eledon Pharmaceuticals

Disqualifiers: Pregnant, Breastfeeding, others

No Placebo Group All trial participants will receive the active study treatment (no placebo)

Prior Safety Data This treatment has passed at least one previous human trial

Compensation: Varies

Number of Visits: Unknown

Duration: 48 months

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial tests a new treatment called AT-1501 (also known as Tegoprubart, an anti-CD40 ligand monoclonal antibody) to determine if it is safer and more effective than the usual medication, tacrolimus, for recent kidney transplant recipients. Researchers aim to ensure this new option can prevent the body from rejecting the transplanted kidney while remaining safe for long-term use. Participants should have completed a previous related study and not be part of any other trial to qualify. As a Phase 2 trial, this research focuses on measuring the treatment's effectiveness in an initial, smaller group, offering participants a chance to contribute to important advancements in kidney transplant care.

Do I need to stop my current medications for the trial?

The trial information does not specify whether you need to stop taking your current medications. It's best to discuss this with the study team for guidance.

Is there any evidence suggesting that this trial's treatments are likely to be safe?

Research has shown that AT-1501, also known as tegoprubart, has promising safety results. In animal studies, it was safe and improved kidney transplant outcomes, suggesting potential effectiveness in humans, though further research is needed to confirm this.

Other studies are encouraging, indicating that AT-1501 could be a safer option for preventing organ rejection, possibly with fewer side effects than some current treatments. Although it is still being tested in humans, reaching this stage indicates it is considered safe enough for further study.

Tacrolimus, the comparison drug in this study, is a well-known medication already used to prevent organ rejection in kidney transplant patients. Its safety is well-documented, but it can have side effects. Researchers hope AT-1501 might offer similar benefits with fewer issues.

Overall, evidence so far suggests AT-1501 is well-tolerated, but ongoing trials will provide more detailed information about its safety in humans. ^{1 2 3 4 5}

Why are researchers excited about this trial's treatments?

Unlike the standard of care for kidney transplant rejection, which typically involves drugs like Tacrolimus that suppress the immune system broadly, AT-1501 offers a novel approach. AT-1501 is an experimental treatment that targets a specific part of the immune system, potentially reducing the risk of rejection with fewer side effects. Researchers are excited because it uses a monoclonal antibody that selectively inhibits CD40L, a key player in immune response. This precision targeting could lead to more effective management of transplant rejection while minimizing the harm to other parts of the immune system.

What evidence suggests that this trial's treatments could be effective for kidney transplant rejection?

Research has shown that AT-1501, also known as tegoprubart, may help prevent kidney transplant rejection. In studies with animals similar to humans, AT-1501 improved the function and longevity of transplanted kidneys. Data from individuals who used tegoprubart for a year showed stable kidney health, with an eGFR of about 68, indicating good kidney function. In this trial, some participants will receive AT-1501, while others will receive Tacrolimus, an active comparator. This suggests that tegoprubart could serve as a promising alternative to current treatments for enhancing kidney transplant success in humans. ^{1 3 6 7 8}

Are You a Good Fit for This Trial?

This trial is for kidney transplant recipients who completed a prior study and consent to continue. They must understand the study, not join other trials, and if of childbearing potential, use effective contraception. Women must be sterile, postmenopausal or have a negative pregnancy test; men must also agree to contraception.

Inclusion Criteria

You promise not to join another research study while taking part in this treatment.

I am a man and agree to use effective birth control and not donate sperm for 90 days after the last dose of the study drug.

I am either not able to have children, past menopause, or will use effective birth control during the study.

Timeline for a Trial Participant

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment

Participants continue the treatment regimen from the Parent study, receiving either AT-1501 or tacrolimus

48 months

Follow-up

Participants are monitored for safety and effectiveness after treatment

48 months

Open-label extension

Participants may opt into continuation of treatment long-term to assess safety and efficacy

Long-term

What Are the Treatments Tested in This Trial?

Interventions

• AT-1501
• Tacrolimus

Trial Overview The trial compares long-term safety and effectiveness of two drugs in preventing kidney transplant rejection: Tegoprubart (AT-1501) versus Tacrolimus. Participants previously involved in related research will receive one of these treatments to determine which is better over time.

How Is the Trial Designed?

Group I: AT-1501 Experimental Treatment 1 Intervention

AT-1501 20 mg/kg administered every 3 weeks IV + MMF 1000 mg per os (orally) (PO) twice daily (BID) or MPS 720 mg PO BID + Corticosteroids 5 mg of prednisone PO once daily (QD) or equivalent

Group II: Tacrolimus Active Control 1 Intervention

Tacrolimus dosed PO BID with the dose titrated to maintain a trough concentration of 6-8 ng/mL+ MMF 1000 mg PO BID or MPS 720 mg PO BID + Corticosteroids 5 mg of prednisone PO QD or equivalent

Who Is Running the Clinical Trial?

Eledon Pharmaceuticals

Lead Sponsor

Trials

5

Recruited

300+

Published Research Related to This Trial

In a study involving Wistar rats as donors and male SD rats as recipients, the use of CD40L monoclonal antibody significantly reduced acute rejection of kidney transplants, with a mean rejection score of 0.63 in the therapy group compared to 3.72 in the control group.

The treatment was administered daily for four days following transplantation, demonstrating that CD40 blockade can effectively suppress acute renal graft rejection in this animal model.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

[Effect of CD40 blockade on acute renal graft rejection in rats]. Shi, XH., Liu, XY., Sun, XY., et al.[2017]

The monoclonal antibody AT-1501 (Tegoprubart) effectively promotes long-term survival of islet and kidney transplants in nonhuman primate models, demonstrating its potential as a safe immunosuppressive agent.

AT-1501 treatment resulted in improved metabolic outcomes, such as higher C-peptide levels and weight gain, along with a lower incidence of cytomegalovirus reactivation compared to traditional immunosuppressive therapies.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

The anti-CD40L monoclonal antibody AT-1501 promotes islet and kidney allograft survival and function in nonhuman primates. Anwar, IJ., Berman, DM., DeLaura, I., et al.[2023]

The novel anti-CD40 monoclonal antibody ASKP1240 significantly prolonged renal allograft survival in Cynomolgus monkeys, demonstrating its efficacy as a potential treatment for preventing organ rejection.

ASKP1240 was effective both as a monotherapy and in combination with low doses of other immunosuppressive drugs, without causing significant side effects or inducing cytokine release, suggesting a favorable safety profile.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Effects of ASKP1240 combined with tacrolimus or mycophenolate mofetil on renal allograft survival in Cynomolgus monkeys. Song, L., Ma, A., Dun, H., et al.[2021]

Both anti CD40 and anti CD40L (CD154) treatments effectively prevented acute and long-term kidney transplant rejection in nonhuman primates, with a significant increase in rejection-free survival compared to untreated animals (6 days).

Anti CD154 treatment showed a longer median rejection-free survival (352 days) compared to anti CD40 treatment (131 days), indicating that CD154 inhibition may provide a more durable solution for preventing transplant rejection.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

The Inhibition of CD40/CD154 Costimulatory Signaling in the Prevention of Renal Transplant Rejection in Nonhuman Primates: A Systematic Review and Meta Analysis. Perrin, S., Magill, M.[2022]

Switching from the twice-daily tacrolimus (Prograf) to the once-daily extended-release formulation (Advagraf) in 49 kidney transplant patients led to an increased openness about their transplant experience after 6 months, indicating a potential improvement in quality of life.

However, 8 out of the 49 patients had to switch back to the original formulation due to adverse events, suggesting that while the switch may have benefits, it also carries risks that need to be monitored.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Effects of switching from twice-daily to once-daily tacrolimus formulation on quality of life, anxiety, and transplant benefit perception after kidney transplantation. Calia, R., Lai, C., Aceto, P., et al.[2015]

The novel fully human anti-CD40 monoclonal antibody 4D11 significantly prolonged kidney graft survival in cynomolgus monkeys, with survival times ranging from 84 to 379 days depending on the dosage, compared to only 5-7 days in the control group.

4D11 demonstrated a favorable safety profile, as only one animal developed an anti-4D11 antibody, suggesting it may be a promising alternative for preventing organ rejection without the thromboembolic complications associated with anti-CD154 monoclonal antibodies.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

A novel fully human anti-CD40 monoclonal antibody, 4D11, for kidney transplantation in cynomolgus monkeys. Imai, A., Suzuki, T., Sugitani, A., et al.[2021]

The administration of a CD154-specific monoclonal antibody (hu5C8) in rhesus monkeys allowed successful kidney transplants without acute rejection, with effects lasting over 10 months after treatment ended.

This therapy does not require the depletion of T or B cells and shows promise for human transplantation, as treated monkeys remained healthy and maintained some immune response without harming the transplanted organ.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Treatment with humanized monoclonal antibody against CD154 prevents acute renal allograft rejection in nonhuman primates. Kirk, AD., Burkly, LC., Batty, DS., et al.[2022]

In a study of 28 adult kidney transplant patients, tacrolimus demonstrated high efficacy with a 100% patient and graft survival rate at 6 months, although acute rejection occurred in 17.8% of patients, particularly in those who were highly sensitized.

While tacrolimus is effective, it is associated with notable side effects, including infections (35.7% of patients), hypertension (14%), and metabolic issues like hyperglycemia (32%), indicating the need for careful monitoring and longer-term studies to evaluate its safety profile.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Single-center experience with tacrolimus-based immunosuppressive regimens in renal transplantation. Abou-Jaoude, MM., Almawi, WY.[2019]

A systematic review and network meta-analysis of 68 studies found that long-term outcomes, such as graft loss and patient mortality, are generally comparable between the once-daily tacrolimus formulation (Advagraf) and the twice-daily formulation (Prograf) in kidney transplant recipients.

The analysis showed that the rates of acute rejection and new-onset diabetes mellitus after transplantation varied by treatment, but both Advagraf and Prograf demonstrated similar effectiveness in preventing graft loss and mortality, indicating that either formulation can be a viable option for post-transplant care.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Efficacy and Safety of Tacrolimus-Based Maintenance Regimens in De Novo Kidney Transplant Recipients: A Systematic Review and Network Meta-Analysis of Randomized Controlled Trials. T A, M., Chng, R., Yau, WP.[2022]

The extended-release formulation of tacrolimus (Advagraf®/Astagraf XL®) shows similar efficacy to the immediate-release version (Prograf®) in kidney transplant recipients, with no significant differences in patient/graft survival, acute rejection rates, or renal function across studies involving over 2,500 patients.

Advagraf® significantly improves medication adherence compared to Prograf®, which is crucial for long-term transplant success, and it has also been associated with favorable outcomes when combined with mTOR inhibitors, potentially reducing the risk of late-onset cytomegalovirus infection.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Advagraf® with or without an induction therapy for de novo kidney-transplant recipients. Noble, J., Jouve, T., Rostaing, L., et al.[2021]

In a 5-year follow-up of the ADVANCE trial involving 1125 kidney transplant patients, overall graft survival rates were high at 88.1%, indicating that prolonged-release tacrolimus (PR-T) is effective for long-term immunosuppression.

Patient survival rates were also impressive at 94.4% after 5 years, with low rates of adverse drug reactions (1.5% likely related to tacrolimus), suggesting that PR-T is a safe option for kidney transplant recipients.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Long-term Prolonged-release Tacrolimus-based Immunosuppression in De Novo Kidney Transplant Recipients: 5-Y Prospective Follow-up of Patients in the ADVANCE Study. Pernin, V., Glyda, M., Viklický, O., et al.[2023]

Citations

1. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC10990482/

The anti-CD40L monoclonal antibody AT-1501 promotes islet ... These data support AT-1501 as a safe and effective agent to promote both islet and kidney allograft survival and function in non-human primate models.

2. ir.eledon.com ir.eledon.com/news-releases/news-release-details/eledon-presents-updated-data-ongoing-phase-1b-trial-evaluating-0

Eledon Presents Updated Data from Ongoing Phase 1b ... Data from patients who remained on tegoprubart for a year showed overall mean 12-month eGFR of approximately 68 mL/min/1.73 m² post- ...

3. journals.lww.com journals.lww.com/jasn/fulltext/2023/11001/tegoprubart_for_the_prevention_of_rejection_in.1140.aspx

Tegoprubart for the Prevention of Rejection in Kidney... Improved graft function may improve long term outcomes in kidney transplantation. It is postulated that tegoprubart could be an alternative therapy for ...

4. ir.eledon.com ir.eledon.com/news-releases/news-release-details/eledon-pharmaceuticals-present-results-phase-2-bestow-trial

Release Details Title: Efficacy and Safety of Tegoprubart for the Prevention of Rejection in Kidney Transplantation: Results from the Phase 2 BESTOW Trial

5. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC10287837/

CD40-CD40L Blockade: Update on Novel Investigational ... In this review, we discuss newer agents undergoing clinical trials to interrupt CD40/CD40L interactions in transplantation to prolong graft survival.

6. ir.eledon.com ir.eledon.com/news-releases/news-release-details/eledon-pharmaceuticals-announces-use-tegoprubart-key-component

Eledon Pharmaceuticals Announces Use of Tegoprubart ... Currently, tegoprubart is being evaluated in three global clinical studies for the prevention of organ rejection in patients receiving kidney ...

7. science.org science.org/doi/10.1126/scitranslmed.adf6376

The anti-CD40L monoclonal antibody AT-1501 promotes ... These data support AT-1501 as a safe and effective agent to promote both islet and kidney allograft survival and function in nonhuman primate ...

8. breakthrought1d.org breakthrought1d.org/grants/united-states/illinois/a-pilot-study-assessing-the-safety-of-using-a-monoclonal-antibody-against-cd40-ligand-to-achieve-a-calcineurin-inhibitor-free-immunosuppression-regimen-in-patients-with-type-1-diabetes-mellitus-t1d-2/

A pilot study assessing the safety of using a monoclonal ... A safer alternative that effectively prevents rejection without such side effects would significantly improve transplant outcomes and broaden access to this ...