A drug called felzartamab is changing what doctors thought was possible in kidney transplant medicine. In a phase 2 trial published in the New England Journal of Medicine in May 2024, felzartamab resolved antibody-mediated rejection in 82 percent of treated patients, compared to just 20 percent on placebo — a 62 percentage-point difference that caught the transplant community off guard. The drug works by targeting CD38, a protein found on the surface of plasma cells that produce the very antibodies responsible for attacking a transplanted kidney. By depleting these cells through an entirely new mechanism, felzartamab addresses a form of late rejection that existing immunosuppressants have largely failed to control. For readers of this site who follow brain health and dementia research, the relevance is not abstract.
Chronic kidney disease is an established risk factor for cognitive decline and vascular dementia, and the immunosuppressive drugs that transplant recipients take for life — particularly calcineurin inhibitors like tacrolimus — carry their own neurological side effects, including tremor, confusion, and in rare cases, posterior reversible encephalopathy syndrome. Any advance that improves kidney graft survival or reduces the toxic burden of standard immunosuppression has downstream implications for brain health in this population. Felzartamab is not the only drug pursuing a new path. This article covers four novel therapies — felzartamab, tegoprubart, the belatacept-dazodalibep combination, and riliprubart — each attacking transplant rejection through a different biological mechanism. We will look at what the clinical data actually shows, where these drugs fall short, and what they could mean for the hundreds of thousands of people living with kidney transplants who remain at risk of graft failure.
Table of Contents
- How Does Felzartamab Reduce Kidney Transplant Rejection Through a New Mechanism?
- Tegoprubart and the Push to Eliminate Tacrolimus Entirely
- A Combination Approach That Could Replace Standard Immunosuppression
- How Riliprubart Targets the Complement System to Prevent Graft Damage
- The Neurological Stakes of Transplant Immunosuppression
- What Breakthrough Therapy Designation Actually Means for Patients
- Where Transplant Rejection Therapy Goes from Here
- Conclusion
- Frequently Asked Questions
How Does Felzartamab Reduce Kidney Transplant Rejection Through a New Mechanism?
Traditional anti-rejection drugs suppress the immune system broadly. Calcineurin inhibitors block T-cell activation. Mycophenolate interferes with lymphocyte proliferation. Steroids dampen inflammation across the board. The problem with all of these is that they do nothing to stop plasma cells — long-lived immune cells that sit in the bone marrow and continuously produce donor-specific antibodies. These antibodies attack the blood vessels inside the transplanted kidney, causing antibody-mediated rejection, which is the leading cause of late graft loss. Until now, there has been no approved therapy that directly targets this process. Felzartamab is a monoclonal antibody directed against CD38, a surface marker highly expressed on plasma cells. By binding to CD38, the drug marks these cells for destruction by the patient’s own immune system.
In the phase 2 trial, 22 kidney transplant recipients with active antibody-mediated rejection were randomized to receive either felzartamab at 16 mg/kg intravenously — nine infusions over six months — or placebo. The results were striking. Among felzartamab-treated patients, the median microvascular inflammation score dropped to zero, compared to 2.5 in the placebo group. The molecular probability score for antibody-mediated rejection fell to 0.17 versus 0.77 on placebo. Donor-derived cell-free DNA, a biomarker of graft injury, measured 0.31 percent versus 0.82 percent. No felzartamab patients lost their graft during the study; one placebo patient did. The FDA granted felzartamab both Breakthrough Therapy Designation and Orphan Drug Designation, which are regulatory signals that the agency considers this drug to address a serious unmet need. Biogen, which is developing felzartamab, began enrolling its phase 3 TRANSCEND trial in the first quarter of 2025 for late antibody-mediated rejection. One important caveat emerged from the phase 2 data: at week 52, three of the nine felzartamab responders saw their rejection recur, suggesting that a single course of treatment may not be permanently curative and that maintenance dosing or repeated courses might be necessary.
Tegoprubart and the Push to Eliminate Tacrolimus Entirely
Among transplant nephrologists, there is a long-standing frustration with tacrolimus. It works — it remains the backbone of most anti-rejection regimens — but it exacts a serious toll. Tacrolimus is nephrotoxic, meaning the very drug meant to protect the transplanted kidney also damages it over time. It causes tremor in roughly a quarter of patients, raises blood pressure, and dramatically increases the risk of new-onset diabetes after transplant. For patients and families already managing cognitive decline or dementia risk factors, these metabolic and neurological side effects are especially concerning. Tegoprubart, developed by Eledon Pharmaceuticals, is a humanized monoclonal antibody designed to replace tacrolimus by blocking a completely different immune pathway — the CD40-CD40L costimulatory signal that T cells need to mount a full attack on foreign tissue. The phase 2 BESTOW trial randomized 127 kidney transplant recipients across 44 global sites: 63 received tegoprubart and 64 received tacrolimus. At 12 months, kidney function was comparable between the two groups — eGFR of 69 versus 66 mL/min/1.73 m², a difference that was not statistically significant.
The drug did not outperform tacrolimus on efficacy, and the trial technically missed its primary endpoint. However, the safety data told a different story. New-onset diabetes occurred in just 1 of 47 tegoprubart patients compared to 1 in 6 tacrolimus patients. Tremor affected 1.6 percent of the tegoprubart group versus 25 percent on tacrolimus. Rates of hypertension, heart failure, sepsis, and delayed graft function were all lower with tegoprubart. There were zero cases of post-transplant lymphoproliferative disorder or progressive multifocal leukoencephalopathy in either group. The implication is significant: if tegoprubart can match tacrolimus on rejection prevention while eliminating the metabolic and neurological toxicity, it could become the preferred option for transplant recipients who are older, diabetic, or at elevated risk for cognitive impairment. Eledon is advancing tegoprubart to a phase 3 trial based on this safety profile, even though the efficacy bar was not cleared in phase 2 — a decision that will face scrutiny from regulators.
A Combination Approach That Could Replace Standard Immunosuppression
Researchers at the University of California, San Francisco published results in February 2026 in the American Journal of Transplantation describing a combination of two biologic proteins — belatacept and dazodalibep — that selectively disrupt immune attack on the transplanted kidney without affecting non-immune cells. This distinction matters because conventional immunosuppressants suppress the entire immune system indiscriminately, leaving patients vulnerable to infections, cancers, and organ damage that has nothing to do with rejection. In the phase 2 pilot study, 23 kidney transplant patients received infusions of both drugs while their standard immunosuppressants were discontinued by day 28. Over 48 weeks, kidney function improved in every patient who completed the study, and there were zero cases of antibody-mediated rejection — the very complication that felzartamab was designed to treat after the fact.
This is a fundamentally different strategy: rather than rescuing a kidney that is already under immune attack, the UCSF approach aims to prevent that attack from ever happening by using targeted immune modulation from the start. The limitations are real. Only 13 of the 23 participants completed the study, with some withdrawing due to complications. The sample size is small, and the lack of a control group makes it difficult to draw firm conclusions about how this combination would compare to standard immunosuppression in a larger, randomized trial. Still, the concept of eliminating calcineurin inhibitors, steroids, and broad-spectrum immunosuppressants in favor of two targeted infusions is the kind of paradigm shift that transplant medicine has been chasing for decades.
How Riliprubart Targets the Complement System to Prevent Graft Damage
A fourth drug in development, riliprubart (also known as BIVV020), takes yet another angle on transplant rejection. Developed by Sanofi, riliprubart is an IgG4 humanized monoclonal antibody that selectively inhibits activated complement component C1s. The complement system is part of the innate immune response — it is older and more primitive than the adaptive immune system that T cells and B cells belong to — and its role in transplant rejection has been underappreciated until recently. When donor-specific antibodies bind to the graft’s blood vessels, they activate the complement cascade, which punches holes in endothelial cells and triggers inflammatory damage. C4d deposition on a kidney biopsy is the classic histological signature of this process, and it is strongly associated with poor graft outcomes.
Early data from riliprubart’s phase 2 clinical trial showed that the drug was well tolerated and led to reduced or eliminated C4d deposition in kidney biopsies after just five weeks. This is encouraging, but the data remains limited. Unlike felzartamab, which has a published randomized trial in the New England Journal of Medicine, riliprubart’s evidence base is still at an early stage. The comparison that matters is whether blocking complement at C1s is more effective, safer, or more durable than depleting plasma cells with an anti-CD38 approach, and that question has not been answered head-to-head. For patients and caregivers weighing these options, the practical tradeoff is between a drug that removes the source of harmful antibodies (felzartamab) versus one that blocks the downstream damage those antibodies cause (riliprubart). Both approaches could eventually be used together, and there is growing interest in combination strategies that target rejection at multiple points in the immune cascade.
The Neurological Stakes of Transplant Immunosuppression
The connection between kidney transplant medicine and brain health is more than incidental. Chronic kidney disease accelerates cerebrovascular disease, and patients who receive a transplant generally see improvements in cognitive function compared to those who remain on dialysis. But the immunosuppressive drugs required to maintain that transplant introduce their own neurological risks. Tacrolimus, the current standard, causes tremor in approximately 25 percent of recipients — a rate confirmed in the BESTOW trial’s control arm. It also causes headache, insomnia, and in rare but well-documented cases, posterior reversible encephalopathy syndrome, which presents with seizures, visual disturbances, and altered consciousness. For older transplant recipients, who are the fastest-growing segment of the transplant population, these neurological side effects overlap with and can be mistaken for early signs of cognitive decline or dementia.
A 68-year-old kidney transplant recipient who develops new tremor and word-finding difficulty may be experiencing tacrolimus neurotoxicity, early Parkinson’s disease, or Alzheimer’s — and distinguishing among these requires careful clinical evaluation. The prospect of replacing tacrolimus with a drug like tegoprubart, which caused tremor in only 1.6 percent of patients and new-onset diabetes in just 1 of 47, could meaningfully reduce this diagnostic confusion and improve quality of life for older transplant recipients. There is a caveat, however. Novel immunosuppressants that are less toxic to the brain could carry other risks that only emerge with longer follow-up. Progressive multifocal leukoencephalopathy, caused by JC virus reactivation, is a devastating brain infection that has occurred with some immunosuppressive biologics. Neither the tegoprubart nor the felzartamab trials reported any cases of PML, but the follow-up periods have been short and the patient numbers small. Long-term pharmacovigilance will be essential.
What Breakthrough Therapy Designation Actually Means for Patients
When the FDA granted felzartamab Breakthrough Therapy Designation, it did not mean the drug was approved or that its safety had been fully established. Breakthrough Therapy Designation is a regulatory pathway that provides more intensive FDA guidance, rolling review of the application, and potentially faster approval — but it is not a stamp of proven efficacy. The designation requires preliminary clinical evidence showing substantial improvement over existing therapy for a serious condition.
In felzartamab’s case, the 82 percent resolution rate versus 20 percent on placebo clearly met that bar. The additional Orphan Drug Designation provides financial incentives to Biogen, including tax credits and market exclusivity, reflecting the relatively small number of patients affected by late antibody-mediated rejection. For patients and families, the practical meaning is that felzartamab is likely to reach the market faster than it would through the standard regulatory pathway — but phase 3 results from the TRANSCEND trial will still be required before approval. No timeline has been publicly committed, and patients currently experiencing antibody-mediated rejection should discuss clinical trial eligibility with their transplant centers rather than waiting for commercial availability.
Where Transplant Rejection Therapy Goes from Here
The four drugs discussed here represent a genuine inflection point in transplant medicine. For the first time, there are multiple credible strategies for addressing rejection through mechanisms other than broad immune suppression — plasma cell depletion, costimulatory blockade, selective immune modulation, and complement inhibition. If even one or two of these approaches succeed in phase 3 trials, the standard of care for kidney transplant recipients could look very different within the next five years.
The implications extend beyond the transplant itself. A kidney graft that lasts longer means fewer years on dialysis, fewer retransplants, and less cumulative exposure to toxic immunosuppressive drugs — all of which reduce the vascular and neurological burden that contributes to cognitive decline. For families managing both organ transplant and dementia risk, these are not separate medical stories. They are the same story, told through different organ systems, and the drugs emerging from these trials may end up improving outcomes for both.
Conclusion
Felzartamab, tegoprubart, the belatacept-dazodalibep combination, and riliprubart each offer a fundamentally different approach to preventing or treating kidney transplant rejection. Felzartamab’s phase 2 results — 82 percent resolution of antibody-mediated rejection versus 20 percent on placebo — set a new benchmark, while tegoprubart’s dramatically lower rates of tremor, diabetes, and infection point toward a future where tacrolimus may no longer be the default. The UCSF combination trial demonstrated that complete withdrawal of standard immunosuppression is at least feasible, and riliprubart’s complement-targeting approach adds yet another option to the pipeline.
For readers concerned with brain health and cognitive preservation, these advances matter directly. Every reduction in tacrolimus exposure is a reduction in neurotoxic risk. Every year of preserved graft function is a year off dialysis and its associated cognitive toll. The phase 3 trials now underway will determine which of these drugs reaches clinical practice first, but the direction of travel is clear: transplant immunosuppression is moving from blunt-force immune suppression toward targeted, mechanism-specific therapies that protect the graft while sparing the rest of the body — brain included.
Frequently Asked Questions
What is antibody-mediated rejection in kidney transplants?
Antibody-mediated rejection occurs when the recipient’s immune system produces antibodies that attack the blood vessels of the transplanted kidney. It is driven by plasma cells and is the leading cause of late kidney graft loss. Unlike T-cell-mediated rejection, which responds to standard immunosuppressive drugs, antibody-mediated rejection has had no approved targeted therapy until drugs like felzartamab entered clinical trials.
How is felzartamab different from current anti-rejection medications?
Current anti-rejection drugs like tacrolimus and mycophenolate suppress T cells and lymphocytes broadly but do not target the plasma cells that produce donor-specific antibodies. Felzartamab is an anti-CD38 monoclonal antibody that directly depletes these plasma cells, addressing the root cause of antibody-mediated rejection rather than suppressing the immune system as a whole.
Can tegoprubart fully replace tacrolimus after a kidney transplant?
The phase 2 BESTOW trial showed that tegoprubart preserved kidney function comparably to tacrolimus at 12 months, with dramatically fewer side effects — new-onset diabetes in 1 of 47 patients versus 1 in 6 on tacrolimus, and tremor in 1.6 percent versus 25 percent. However, the trial did not demonstrate statistical superiority in efficacy, and a phase 3 trial is needed before tegoprubart could be used as a tacrolimus replacement in clinical practice.
Do these new transplant drugs affect brain health or dementia risk?
Indirectly, yes. Tacrolimus, the current standard immunosuppressant, causes tremor in about 25 percent of patients and carries risks of neurotoxicity. Chronic kidney disease itself accelerates cognitive decline. Drugs that reduce tacrolimus dependence or extend graft survival could lower the cumulative neurological burden on transplant recipients, particularly older patients who are already at higher risk for dementia.
Are any of these drugs currently available to patients?
As of early 2026, none of these four drugs are FDA-approved for transplant rejection. Felzartamab is the furthest along, with Breakthrough Therapy Designation and a phase 3 trial (TRANSCEND) actively enrolling. Patients interested in accessing these treatments should ask their transplant team about clinical trial eligibility at their center.
What happened in the UCSF trial when standard immunosuppressants were stopped?
In the phase 2 pilot study of belatacept plus dazodalibep, standard immunosuppressants were discontinued by day 28 and replaced with targeted infusions. Kidney function improved in all patients who completed the 48-week study, and there were zero cases of antibody-mediated rejection. However, only 13 of 23 participants finished the study, with some withdrawing due to complications, so the approach needs validation in larger trials.
