DRUG DEVELOPMENT - Targeting the CD40L Pathway to Improve Immunosuppression Therapy & Help Organ Transplants Last Longer

ADDRESSING THE NATIONAL DONOR ORGAN SHORTAGE

Kidney transplants are a life-saving option for about 25,000 Americans per year suffering from end-stage renal disease (ESRD), but due to the ongoing shortage of available kidneys, transplants are not available for every­one who needs them.¹ In the US, for every five people who receive a kidney transplant, one person dies waiting for a kidney that never materializes. Moreover, for the 90,000 Americans on the Kidney Transplant Waitlist, most will see their health continue to decline as they wait, often for years, for a kidney.² Efforts to encourage more people to become organ donors or to salvage more organs, while important, have been unable to address this critical shortage.

In cases where someone is fortunate enough to find a suitable match and receive a kidney transplant, the fact that most transplanted kidneys typically fail after only about 10 to 15 years is both a harsh reality and another factor that reduces the number of kidneys available.³ Given that kidney transplant recipients in the US are in their 50s on average, many eventually need a second or even third transplant to last a normal lifespan. Indeed, one in six patients on the Kidney Transplant Waitlist is awaiting a repeat transplant. While it is possible for some patients to return to dialysis once a transplanted kidney fails, this is not an ideal alternative. Dialysis is a grueling, cumbersome, and costly treatment option, with many pa­tients continuing to bear a high burden of disease and low quality of life. The survival span for patients on dial­ysis is only 5 years on average.⁴

While efforts to increase the number of available organs continue, another focus is emerging that could play a central role in addressing the donor challenge. Researchers are targeting strategies in immunosup­pression that can help donated kidneys remain healthy and viable for much longer post-transplant, thus alleviating the need for repeat trans­plants and making more organs available for first-time transplant recip­ients.

TARGETING CD40L TO INCREASE TRANSPLANT FUNCTION & LONGEVITY

One promising avenue of research involves targeting a pathway called CD40 ligand (CD40L, also known as CD154) that has been shown to play a central role in immune system activation and control­ling inflammation in the body.⁵ By blocking CD40L, we may be able to inhibit multiple co-stimulatory receptors, including CD40 and CD11, key components of how im­mune cells communicate with one another, and increase polarization of lymphocytes into “T-regs,” a specialized subpopulation of T cells that act to suppress immune re­sponse.⁶ The central role of CD40L signal­ing in generating pro-inflammatory responses makes it a highly attractive can­didate for therapeutic intervention in the protection of transplanted organs and pre­vention of transplant rejection. Based on research conducted thus far, inhibiting CD40L has the potential for better efficacy and improved safety, including reduced risk of lymphopenia, diabetes, hyperten­sion, and other side effects associated with many current immunosuppressive drugs, including the current standard of care, cal­cineurin inhibitors (CNIs).^7,8

Advances in research are especially encouraging because there has not been much innovation in chronic transplant im­munosuppression during the past 30 years. Throughout that time, CNIs, such as tacrolimus, have been positioned as the standard of care to reduce the risk of organ rejection. While tacrolimus is con­sidered to have a positive risk-benefit pro­file, it has some significant limitations. Research shows that tacrolimus can be toxic to kidney cells and is associated with side effects, including risk of diabetes and hypertension – the very conditions that lead most patients to require a kidney transplant in the first place.^7,8

Innovation in immunosuppression therapy and strategies to better protect transplanted organs while reducing the risk of potentially harmful side effects could represent a major advance in patient care in the years ahead while also helping to make kidney transplants available to more patients who need them. If we can reduce the risk of organ failure or rejection, we can make additional organs available for other patients on the waiting list.

THE POTENTIAL OF TEGOPRUBART, A NOVEL CD40L INHIBITOR

The research team at Eledon Pharma­ceuticals is advancing development of tegoprubart, a novel anti-CD40L antibody with high affinity for CD40L. The goal in treatment is to inhibit or “turn off” both the CD40-CD40L pathway necessary for adaptive (ie, T and B cells) and innate (eg, macrophages and dendritic cells) immune cell activation and function. Tegoprubart is the first anti-CD40L antibody to enter mul­tiple clinical trials for patients undergoing transplantation, including kidney trans­plants. Promising data from both preclini­cal and clinical studies to date demonstrate the significant potential of tegoprubart to prevent transplant rejection safely and effectively and improve out­comes in patients.

In June 2024, at the American Trans­plant Congress (ATC), researchers pre­sented updated results from 13 participants from an ongoing Phase 1b clinical trial showing that mean eGFR was above 60 mL/min/1.73m² at each reported time point after day 30, with an overall mean eGFR of 70.5 mL/min/1.73m² for all the reported time points after day 30 post-transplant.⁹ These levels are approximately 20% to 40% above the historical averages seen with tacrolimus. Historical studies have re­ported average eGFRs generally in the low 50 mL/min/1.73m² range during the first year after kidney transplant using standard of care immunosuppression drugs.¹⁰

Two participants completed 12 months on therapy post-transplant, and both demonstrated mean eGFRs above 90 mL/min/1.73m² at one-year post-trans­plant.⁹ This includes a 77-year-old woman with diabetes who had been on hemodial­ysis before receiving a kidney transplant from a deceased donor, who had an eGFR of 91 mL/min/1.73m² – about 80% above historical levels with tacrolimus and higher than what might typically be expected in a woman her age without diabetes and with two native working kidneys.¹¹

Importantly, results also showed tego­prubart was generally safe and well toler­ated in patients undergoing kidney transplantation, with no cases of hyper­glycemia, new onset diabetes, or tremor commonly seen with CNIs.^7-9 There were no cases of graft loss or death.

Tegoprubart continues to be evalu­ated in the ongoing Phase 1b , Phase 2 BESTOW, and long-term safety and effi­cacy extension studies, with BESTOW reaching its target enrollment of 120 par­ticipants in September 2024.¹² BESTOW is a multicenter, two-arm, active comparator Phase 2 study designed to assess the safety, pharmacokinetics, and efficacy of tegoprubart compared to tacrolimus for the prevention of organ rejection in pa­tients undergoing kidney transplantation in the US and other countries. The study’s pri­mary endpoint will assess the potential su­periority of tegoprubart versus tacrolimus in post-kidney transplant kidney function at 12 months as measured by eGFR.

Tegoprubart has also demonstrated its potential applications in preventing graft rejection in people undergoing islet cell allotransplants. This type of transplant is an experimental treatment for type 1 di­abetes that involves injecting patients with healthy islet cells from a donor pancreas that can produce insulin, with the goal of improving blood glucose levels, preventing severe hypoglycemia, and eliminating the need for insulin injections.¹³

Tegoprubart is being assessed in an investigator-led clinical trial at the Univer­sity of Chicago Medicine Transplant Insti­tute for its potential to prevent islet transplant rejection in people with type 1 diabetes. In October 2024, positive initial data from this trial demonstrated that the first two islet transplant recipients achieved insulin independence and normal hemo­globin A1C levels, a measure of average blood glucose control.¹⁴ The third patient, who only recently received an islet trans­plant, decreased insulin use by more than 60% three days post-transplant and con­tinues on an insulin independence trajec­tory.

These collective data in kidney and islet cell transplantation reinforce the ad­vances being made in immunosuppres­sion research and the potential of an anti-CD40L antibody such as tegoprubart to play a role in modulating the immune system to help protect and improve the viability of transplanted organs. As research continues to advance, these efforts are helping bring the field closer to a new era in transplant medicine where patients have better outcomes and will be more likely to live a full lifespan after their organ trans­plant. This research can be positioned as an important element in a holistic strategy to improve access to organ transplantation for all patients who need them.

ADVANCES IN XENOTRANSPLANTATION

One additional potential strategy to address the “organ gap” that has gained traction in recent months is to identify an­other workable source of donor organs. Xenotransplantation, or transplanting or­gans from one species to another (eg, an­imals to humans), may be a promising option, with recent developments marking a historic turning point in research. The faculty from the University of Maryland School of Medicine at the University of Maryland Medical Center performed for the first-time transplantation of genetically modified pig hearts into two humans. In the second procedure, performed in Sep­tember 2023, tegoprubart was used as the cornerstone of the immunosuppressive regimen administered, along with conven­tional anti-rejection drugs.¹⁵ Also in March 2024, tegoprubart was used as a compo­nent of the immunosuppressive treatment regimen following the first-ever transplant of a kidney from a genetically modified pig to a human, which was performed at Mas­sachusetts General Hospital.¹⁶

While xenotransplantation is still in relatively early days, this option could someday lead to an additional supply of organs for people who need transplants. Support for xenotransplantation will re­quire continued innovation in multiple areas, including immunosuppression, gene editing, surgical training, and patient management, to improve both safety and access to xenografts in the years ahead.

THE FUTURE OF ORGAN TRANSPLANTATION

The global need for organ trans­plants, including kidney transplants, is projected to more than double in the next decade, highlighting the urgent need to take steps to address the donor organ shortage and improve patient outcomes.¹⁷ Without viable solutions, the cycle of ESRD, kidney failure, dialysis, kidney transplant, and back to kidney failure will continue. Too many patients go through this cycle, in some cases more than once during their lifetime, transitioning between dialysis to transplantation and back again. This cycle puts a tremendous burden on transplant recipients and their families and represents millions of dollars in costs for healthcare systems. Continued investment in innova­tive science is key to advance these efforts as rapidly as possible for patients who de­serve broader access to donor organs and better outcomes.

REFERENCES

1. Health Resources & Services Administration. (Updated 2022, Decem­ber 31). Organ Donation and Transplantation: National Level Data. https://data.hrsa.gov/topics/health-systems/organ-donation.
2. Penn Medicine. (2020, December 16). Too Many Donor Kidneys Are Discarded in U.S. Before Transplantation. Penn Medicine News. https://www.pennmedicine.org/news/news-releases/2020/december/too-many-donor-kidneys-are-discarded-in-us-before-transplantation.
3. American Kidney Fund. (Updated 2023, April 18). Deceased donor kidney transplants. https://www.kidneyfund.org/kidney-donation-and-transplant/deceased-donor-kidney-transplants.
4. Himmelfarb, J., Vanholder, R., Mehrotra, R., and Tonelli, M. (2020). The current and future landscape of dialysis. Nat Rev Nephrol 16, 573–585. https://doi.org/10.1038/s41581-020-0315-4.
5. Elgueta, R., Benson, M.J., de Vries, V.C., Wasiuk, A., Guo, Y., and Noelle, R.J. (2009). Molecular mechanism and function of CD40/CD40L engagement in the immune system. Immunol Rev, 229(1),152-72. doi: 10.1111/j.1600-065X.2009.00782.x.
6. Perrin, S. and Magill, M. (2022). The Inhibition of CD40/CD154 Cos­timulatory Signaling in the Prevention of Renal Transplant Rejection in Nonhuman Primates: A Systematic Review and Meta Analysis. Front Im­munol, 13:861471. doi: 10.3389/fimmu.2022.861471.
7. Chakkera, H.A. and Mandarino, L.J. (2013). Calcineurin inhibition and new-onset diabetes mellitus after transplantation. Transplantation, 95(5):647-52. doi: 10.1097/TP.0b013e31826e592e.
8. Safarini, O.A., Keshavamurthy, C. and Patel, P. (2023, Nov 12). Cal­cineurin Inhibitors. StatPearls Publishing. https://www.ncbi.nlm.nih.gov/books/NBK558995.
9. Eledon Pharmaceuticals, Inc. (2024, June 3). Eledon Presents Updated Data from Ongoing Phase 1b Trial Evaluating Tegoprubart for Preven­tion of Rejection in Kidney Transplantation. https://ir.eledon.com/news-releases/news-release-details/eledon-presents-updated-data-ongoing-phase-1b-trial-evaluating.
10. Pernin, V. et al. (2023). Long-term Prolonged-release Tacrolimus-based Immunosuppression in De Novo Kidney Transplant Recipients: 5-Y Prospective Follow-up of Patients in the ADVANCE Study. Trans­plantation Direct, 9(3):p e1432. doi: 10.1097/TXD.0000000000001432.
11. National Kidney Foundation. (2022). Estimated Glomerular Filtration Rate (eGFR): A key to understanding how well your kidneys are work­ing. https://www.kidney.org/sites/default/files/11-10-1813_esti­mated_glomerular_filtration_rate.pdf.
12. Eledon Pharmaceuticals, Inc. (2024, September 4). Eledon Announces Completion of Enrollment in Phase 2 BESTOW Clinical Trial Assessing Tegoprubart for Prevention of Organ Rejection in Kidney Transplant Patients. https://ir.eledon.com/news-releases/news-release-details/ele­don-announces-completion-enrollment-phase-2-bestow-clinical.
13. National Institute of Diabetes and Digestive and Kidney Diseases. (2018 Oct). Insulin, Medicines, & Other Diabetes Treatments: Pancre­atic Islet Transplantation. National Institutes of Health. https://www.niddk.nih.gov/health-information/diabetes/overview/in­sulin-medicines-treatments/pancreatic-islet-transplantation.
14. Eledon Pharmaceuticals, Inc. (2024, October 29). Eledon Pharmaceu­ticals Announces Positive Initial Data from Subjects with Type 1 Dia­betes Treated with Tegoprubart as Part of an Immunosuppression Regimen Following Islet Transplantation in Investigator-Initiated Trial at UChicago Medicine. https://ir.eledon.com/news-releases/news-re­lease-details/eledon-pharmaceuticals-announces-positive-initial-data-subjects.
15. Eledon Pharmaceuticals, Inc. (2023, Sept 25). Eledon Pharmaceuti ­cals Announces Use of Tegoprubart anti-CD40L Antibody in Second-ever Transplant of Genetically Modified Heart from a Pig to a Human. https://ir.eledon.com/news-releases/news-release-details/eledon-pharmaceuticals-announces-use-tegoprubart-anti-cd40l. https://www.precedenceresearch.com/transplantation-market.
16. Eledon Pharmaceuticals, Inc. (2024, March 21). Eledon Pharmaceuti­cals Announces Use of Tegoprubart in First-ever Transplant of Geneti­cally Modified Kidney from a Pig to a Human. https://ir.eledon.com/news-releases/news-release-details/eledon-pharmaceuticals-announces-use-tegoprubart-first-ever.
17. Precedence Research. (2023 March). Transplantation Market Size, Share and Growth Analysis, By Product Type (Immunosuppressive Drugs, Tissue Products, and Preservation Solution), By Application (Tissue Transplantation and Organ Transplantation), By End-use (Transplant Centers, Hospitals, and Others) – Global Industry Analysis, Trends, Regional Outlook and Forecast 2023 – 2032. https://www.precedenceresearch.com/transplantation-market.

Dr. David-Alexandre C. Gros is Chief Executive Officer and a member of the Board of Directors at Eledon Pharmaceuticals, Inc. He joined Eledon from Imbria Pharmaceuticals, where he served as Co-Founder, Chief Executive Officer, and Chairman of the Board of Directors. Prior, he was President and Chief Operating Officer of Neurocrine Biosciences, Chief Business and Principal Financial Officer of Alnylam Pharmaceuticals, and Chief Strategy Officer of Sanofi, S.A. Before joining Sanofi, he held leadership positions in healthcare investment banking at Centerview Partners, LLC, and Merrill Lynch, Pierce, Fenner & Smith Inc., and in healthcare consulting at McKinsey & Company. He previously served on the Board of Directors of Eliem Therapeutics, a biotechnology company he also co-founded. He earned his MD from The Johns Hopkins University School of Medicine, MBA from Harvard Business School, and BA from Dartmouth College.