Tegoprubart for Kidney Transplant Rejection
Recruiting in Palo Alto (17 mi)
+56 other locations
Age: 18+
Sex: Any
Travel: May Be Covered
Time Reimbursement: Varies
Trial Phase: Phase 2
Waitlist Available
Sponsor: Eledon Pharmaceuticals
No Placebo Group
Prior Safety Data
Trial Summary
What is the purpose of this trial?This study will evaluate the safety and efficacy of AT-1501 compared with tacrolimus in patients undergoing kidney transplantation.
Do I have to stop taking my current medications for the trial?
Yes, you must stop taking any systemic immunosuppressive medications and corticosteroids, except for topical or inhaled ones, to participate in the trial.
What data supports the idea that Tegoprubart for Kidney Transplant Rejection is an effective treatment?
The available research shows that Tegoprubart, also known as AT-1501, is effective in preventing kidney transplant rejection in nonhuman primates. In studies, Tegoprubart led to long-term survival of transplanted kidneys, indicating its potential as a treatment. Compared to conventional treatments, Tegoprubart resulted in better outcomes, such as higher levels of certain proteins that indicate kidney function and fewer complications like viral reactivation. This suggests that Tegoprubart could be a safer and more effective option for kidney transplant patients.
12345What safety data is available for Tegoprubart in kidney transplant rejection?
The provided research primarily discusses the safety and efficacy of tacrolimus (also known as FK506, Prograf, Advagraf, Astagraf XL) in kidney transplantation. Tacrolimus is a calcineurin inhibitor used in immunosuppressive regimens. Safety data from these studies indicate that tacrolimus is effective but associated with side effects such as hypertension, hyperglycemia, hypercholesterolemia, and infections, including CMV. The studies also compare different formulations of tacrolimus, showing similar patient and graft survival rates, with some variations in acute rejection and new-onset diabetes mellitus. However, none of the studies specifically address Tegoprubart (also known as AT-1501 or Anti-CD40 ligand monoclonal antibody) for kidney transplant rejection, so additional research would be needed to find specific safety data for Tegoprubart.
678910Is the drug AT-1501 (Tegoprubart) a promising treatment for preventing kidney transplant rejection?
Yes, AT-1501 (Tegoprubart) is a promising drug for preventing kidney transplant rejection. It has shown success in nonhuman primates by helping transplanted kidneys survive longer and function better. This drug works by blocking a specific pathway that can lead to rejection, and it has been engineered to reduce certain risks seen in earlier treatments. These positive results suggest it could be effective in humans too.
123411Eligibility Criteria
This trial is for adults (18+) who are receiving their first kidney transplant from a living or deceased donor and agree to follow contraception rules post-treatment. It's not for those on chronic steroids/immunosuppressants, with clotting disorders, needing long-term anticoagulation, or previous severe reactions to similar drugs.Inclusion Criteria
I am 18 years old or older.
I have received my first kidney transplant.
Agree to comply with contraception requirements during and for at least 90 days after the last administration of study drug
Exclusion Criteria
I am planned to receive a specific initial immune system treatment other than rATG.
I am currently taking corticosteroids that are not just for skin or breathing.
My kidney transplant will involve a delay over 30 hours before implantation.
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Participant Groups
The study compares the safety and effectiveness of a new drug called Tegoprubart (AT-1501) with Tacrolimus in preventing organ rejection after kidney transplantation. Participants will be randomly assigned to receive one of these treatments.
2Treatment groups
Experimental Treatment
Active Control
Group I: InvestigativeExperimental Treatment1 Intervention
AT-1501 monoclonal antibody targeting CD40L given as an IV infusion
Group II: ComparatorActive Control1 Intervention
Tacrolimus administered BID, targeting a whole blood trough concentration of 6-12 ng/mL until Month 6, and 6-8 ng/mL thereafter
Find a Clinic Near You
Research Locations NearbySelect from list below to view details:
Brigham and Women's HospitalBoston, MA
Johns Hopkins UniversityBaltimore, MD
Loyola University Medical CenterMaywood, IL
UT SouthwesternDallas, TX
More Trial Locations
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Who Is Running the Clinical Trial?
Eledon PharmaceuticalsLead Sponsor
References
The Inhibition of CD40/CD154 Costimulatory Signaling in the Prevention of Renal Transplant Rejection in Nonhuman Primates: A Systematic Review and Meta Analysis. [2022]The prevention of allograft transplant rejection by inhibition of the CD40/CD40L costimulatory pathway has been described in several species. We searched pubmed for studies reporting the prevention of kidney transplant rejection in nonhuman primates utilizing either anti CD40 or anti CD40L (CD154) treatment. Inclusion of data required treatment with anti CD40 or anti CD154 as monotherapy treatment arms, full text available, studies conducted in nonhuman primate species, the transplant was renal transplantation, sufficient duration of treatment to assess long term rejection, and the reporting of individual graft survival or survival duration. Eleven publications were included in the study. Rejection free survival was calculated using the Kaplan-Meier (KM) life test methods to estimate the survival functions. The 95% CI for the medians was also calculated. A log-rank test was used to test the equality of the survival curves between control and treatment arms (CD40 and CD154). The hazard ratio for CD154 compared to CD40 and 95% CI was calculated using a Cox proportional-hazards model including treatment as the covariate to assess the magnitude of the treatment effect. Both anti CD40 and anti CD154 treatments prevented acute and long term graft rejection. The median (95% CI) rejection free survival was 131 days (84,169 days) in the anti CD40 treated animals and 352 days (173,710 days) in the anti CD154 treated animals. Median survival in the untreated animals was 6 days. The inhibition of transplant rejection was more durable in the anti CD154 group compared to the anti CD40 group after cessation of treatment. The median (95% CI) rejection free survival after cessation of treatment was 60 days (21,80 days) in the anti CD40 treated animals and 230 days (84,552 days) in the anti CD154 treated animals.
The anti-CD40L monoclonal antibody AT-1501 promotes islet and kidney allograft survival and function in nonhuman primates. [2023]Prior studies of anti-CD40 ligand (CD40L)-based immunosuppression demonstrated effective prevention of islet and kidney allograft rejection in nonhuman primate models; however, clinical development was halted because of thromboembolic complications. An anti-CD40L-specific monoclonal antibody, AT-1501 (Tegoprubart), was engineered to minimize risk of thromboembolic complications by reducing binding to Fcγ receptors expressed on platelets while preserving binding to CD40L. AT-1501 was tested in both a cynomolgus macaque model of intrahepatic islet allotransplantation and a rhesus macaque model of kidney allotransplantation. AT-1501 monotherapy led to long-term graft survival in both islet and kidney transplant models, confirming its immunosuppressive potential. Furthermore, AT-1501-based regimens after islet transplant resulted in higher C-peptide, greater appetite leading to weight gain, and reduced occurrence of cytomegalovirus reactivation compared with conventional immunosuppression. These data support AT-1501 as a safe and effective agent to promote both islet and kidney allograft survival and function in nonhuman primate models, warranting further testing in clinical trials.
Effects of ASKP1240 combined with tacrolimus or mycophenolate mofetil on renal allograft survival in Cynomolgus monkeys. [2021]Blocking the CD40-CD154 signal pathway has previously shown promise as a strategy to prevent allograft rejection. In this study, the efficacy of a novel fully human anti-CD40 monoclonal antibody-ASKP1240, administered as a monotherapy or combination therapy (subtherapeutic dose of tacrolimus or mycophenolate mofetil), on the prevention of renal allograft rejection was evaluated in Cynomolgus monkeys.
Treatment with humanized monoclonal antibody against CD154 prevents acute renal allograft rejection in nonhuman primates. [2022]CD154 is the ligand for the receptor CD40. This ligand-receptor pair mediates endothelial and antigen-presenting cell activation, and facilitates the interaction of these cells with T cells and platelets. We demonstrate here that administration of a CD154-specific monoclonal antibody (hu5C8) allows for renal allotransplantation in outbred, MHC-mismatched rhesus monkeys without acute rejection. The effect persisted for more than 10 months after therapy termination, and no additional drug was required to achieve extended graft survival. Indeed, the use of tacrolimus or chronic steroids seemed to antagonize the anti-rejection effect. Monkeys treated with antibody against CD154 remained healthy during and after therapy. The mechanism of action does not require global depletion of T or B cells. Long-term survivors lost their mixed lymphocyte reactivity in a donor-specific manner, but still formed donor-specific antibody and generated T cells that infiltrated the grafted organ without any obvious effect on graft function. Thus, therapy with antibody against CD154 is a promising agent for clinical use in human allotransplantation.
[Effect of CD40 blockade on acute renal graft rejection in rats]. [2017]To explore the effect of CD40 blockade in suppressing acute rejection of renal graft in rats.
Single-center experience with tacrolimus-based immunosuppressive regimens in renal transplantation. [2019]The efficacy and safety of tacrolimus (FK506; Prograf) were determined in 28 adult kidney transplant patients (20 males and 8 females), aged 18-68 years (mean+/-S.D.: 46.9+/-4.03 years). Induction therapy was ATG-F (n=23), daclizumab (n=3), or none (n=2), and maintenance immunosuppression consisted of tacrolimus, combined with mycophenolate mofetil (MMF; n=26) or azathioprine (AZA; n=2) and prednisone (Pred). In seven patients, cyclosporine A microemulsion (Neoral) was replaced by tacrolimus for acute rejection (AR; three patients), slow graft function (SGF, two patients) and Neoral side effects (two patients). Acute rejection occurred in five patients (17.8%), three of whom were steroid-resistant treated with a second course of ATG-F. Infection occurred in 10 patients (35.7%) with a total of 15 infectious episodes, comprising bacterial (73%) and viral (27%) infections related to CMV. Other side effects related to tacrolimus were hypertension in four patients (14%) and post-transplantation hyperglycemia in nine patients (32%), three of whom required insulin therapy. In addition, hypercholesterolemia and hypertriglyceridemia occurred in six (21%) and eight patients (28.5%), respectively. The patient's hospital stay was 12.7+/-1.3 days (range: 8-24 days), and mean serum creatinine upon discharge, and at 1, 3 and 6 months following transplantation were: 2.1+/-0.5, 1.47+/-0.21, 1.41+/-0.53 and 1.23+/-0.11 mg/dl, respectively. The 6-month actuarial patient and graft survival rates were 100%. While tacrolimus is an effective calcineurin inhibitor for kidney transplantation (KT), severe acute rejection seen is related to highly sensitized patients, and the CMV infections noted were related to the presence of more CMV-negative recipients receiving kidneys from CMV-positive donors. Longer follow-up with a larger patient sample is needed to fully assess both the efficacy and safety of tacrolimus, including its metabolic effects.
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. [2022]BACKGROUND Tacrolimus is an established component of immunosuppressive regimens for kidney transplant recipients (KTRs); however, data comparing long-term outcomes between formulations are lacking. We conducted a systematic literature review and network meta-analysis assessing tacrolimus (primarily Advagraf [once-daily] and Prograf [twice-daily])-based maintenance regimens. MATERIAL AND METHODS Embase, MEDLINE, and Cochrane databases and congress proceedings were searched to identify studies of adult de novo KTRs who received tacrolimus-based therapy in phase II/III randomized controlled trials. Outcomes were acute rejection, graft/patient survival, and incidence of new-onset diabetes mellitus after transplantation (NODAT) and cytomegalovirus (CMV) infection. Bayesian network meta-analysis was used to analyze treatment effects on graft/patient survival. RESULTS Sixty-eight publications (61 primary) were included. Of 21 publications reporting graft rejection following Advagraf or Prograf treatment in ≥1 study arm, 12-month biopsy-proven acute rejection (BPAR) ranged from 3.3% with Prograf to 55.0% with mycophenolic acid (MPA)+corticosteroids (CS); >24 month BPAR ranged from 0% to 58.7% (the latter with bleselumab-based therapy). Fourteen publications reported graft loss following Advagraf (0-9.6%) or Prograf (0-7.5%). Patient mortality ≤24 months after transplantation (14 publications) ranged from 0% to 8.1% with Advagraf or Prograf. Advagraf+MPA+CS and reference treatment, Prograf+MPA+CS, were associated with a similar risk of graft loss (odds ratio 1.19; 95% credible-interval 0.51, 3.06) and mortality (odds ratio 1.21; 95% credible-interval 0.1557, 9.03). Incidence of NODAT and CMV varied by treatment arm. CONCLUSIONS Graft loss and patient mortality rates were generally comparable between Advagraf- and Prograf-based regimens. Further prospective studies are needed to evaluate longer-term outcomes.
Long-term Prolonged-release Tacrolimus-based Immunosuppression in De Novo Kidney Transplant Recipients: 5-Y Prospective Follow-up of Patients in the ADVANCE Study. [2023]Although prolonged-release tacrolimus (PR-T) is widely approved for posttransplantation immunosuppression in kidney recipients, large-scale studies are required to assess long-term outcomes. We present follow-up data from the Advagraf-based Immunosuppression Regimen Examining New Onset Diabetes Mellitus in Kidney Transplant Recipients (ADVANCE) trial, in which kidney transplant patients (KTPs) received corticosteroid minimization with PR-T.
Advagraf® with or without an induction therapy for de novo kidney-transplant recipients. [2021]Cornerstone immunosuppressive therapy currently relies on immediate-release tacrolimus, a calcineurin inhibitor (CNI) that is potentially nephrotoxic and is more diabetogenic than cyclosporine A. Two new formulations of tacrolimus have been launched: an extended-release formulation (Advagraf®/Astagraf XL®, Astellas company) and a long-lasting formulation (Envarsus®, Veloxis company). Area covered: Herein, we assess the efficacy of an extended-release formulation of tacrolimus (Advagraf®/Astagraf XL®) used in conjunction with or without an induction therapy (i.e., basiliximab) in de novo kidney-transplant recipients. To achieve this, we searched for suitable articles through PubMed. Expert commentary: Phases-III and -IV studies comparing Advagraf®/Astagraf XL® to Prograf® in association with mycophenolate mofetil (more than 2,500 patients) have demonstrated overall similar results with regards to patient/graft survival, biopsy-proven acute-rejection rate, and renal function (p > 0.05). A randomized controlled study in maintenance kidney transplant patients has shown (using electronic monitoring) that, as compared to Prograf®, Advagraf® significantly improved adherence to medication. Other studies report that Advagraf®-treated patients receiving a mTOR-inhibitor agent (sirolimus or everolimus) instead of MMF: this was associated with good allograft outcome, and might also prevent late-onset cytomegalovirus infection. Advagraf®-based immunosuppression given to de novo kidney-transplant recipients, with or without an induction therapy, provided excellent results compared to Prograf®; it also increased patients' adherence to treatment.
Effects of switching from twice-daily to once-daily tacrolimus formulation on quality of life, anxiety, and transplant benefit perception after kidney transplantation. [2015]This study investigated whether switching from the twice-daily (Prograf; TAC) to the once-daily formulation of tacrolimus with extended release (Advagraf; XL) affected quality of life, anxiety, and transplant benefit perception after allogeneic kidney transplantation.
A novel fully human anti-CD40 monoclonal antibody, 4D11, for kidney transplantation in cynomolgus monkeys. [2021]CD40-CD154 pathway blockade by anti-CD154 monoclonal antibodies (mAbs) significantly prolongs allograft survival in nonhuman primates. However, thromboembolic complications have prevented clinical application. Thus, blockade of the counter molecule by a novel fully human anti-CD40 mAb, 4D11, is an attractive alternative.