Could Eledon’s Anti-CD40L Change Transplant Medicine?

Post-transplantation immunosuppression has come a long way: the first immunosuppressive, azathioprine, was developed in the 1960s and had one-year survival rates of 50-60%. Calcineurin inhibitors came along in the 1980s, with Sandoz’s (now Novartis) cyclosporine increasing one-year kidney graft survival to roughly 70%. The approval of Fujisawa Pharmaceutical Co.’s (now Astellas Pharma) tacrolimus in 1994 further lengthened organ survival rates, lifting one-year graft survival to 90%. 

However, there have been limited innovations in post-transplant immunosuppression since tacrolimus’s advent, and the drug remains the standard of care despite a litany of side effects, including organ damage. 

Now, Irvine, California-based Eledon Pharmaceuticals, Inc. believes their lead asset could be the next step in the evolution of transplant medicine. 

“We’re no longer looking at how well we do at one year, but how we do at 10-12 years and now, in our case, hopefully at 15-20 years,” the company’s CEO, David-Alexandre Gros, told In Vivo. 

Eledon Pharmaceuticals

Eledon’s pipeline centerpiece, tegoprubart, is a CD40 Ligand blocker. CD40L signaling is central to both adaptive and innate immune cell activation and function, and regulating CD40L can prevent transplant rejection. 

Tegoprubart was originally developed at the ALS Therapy Development Institute to treat amyotrophic lateral sclerosis. When Eledon acquired it from the organization, it indeed set forth down that therapeutic path, but the focus has since shifted to post-transplant organ rejection. 

The global need for organ transplants is expected to double in the next decade and there are over 100,000 people in the US waiting for a kidney transplant at any given time, with 5,000 succumbing during that wait. The average kidney transplant recipient experiences kidney failure within 10-12 years of transplant, returning them to the transplant waiting list for a second – or third, or fourth – transplant. 

Focus On Kidney Transplant For Now

Eledon is gathering data to support tegoprubart’s use in kidney transplant patients, the largest transplant population. The numbers to date are small, but more data are expected this year. 

Findings from 11 participants in an ongoing single-arm, open-label Phase Ib trial showed tegoprubart was generally safe and well tolerated and reduced the risk of organ rejection as part of a maintenance immunosuppressive regimen including mycophenolate and a corticosteroid taper, which is the standard regimen, with the exception that it typically includes tacrolimus. The company will be presenting interim clinical data from the study in June and has begun enrolling patients in a 52-week Phase II BESTOW trial, comparing it to the same regimen as above, with tacrolimus. The company expects to complete enrolment for the 120-patient study this year. 

Moving Xenotransplantation Forward

Tegoprubart was employed in two historic xenotransplantations – transplants of non-human organs to humans – that made a splash in media outlets worldwide. The drug was administered in the first-ever pig-to-human kidney xenotransplant and in the second-ever pig-to-human heart transplant. The heart transplant patient died following organ rejection, but the 62-year old recipient of the pig kidney was discharged from hospital only days after the procedure, which was performed on 16 March 2024 at Massachusetts General Hospital in Boston.

“It’s an exhilarating time to be in transplant medicine,” said Gros. “The success of xenotransplantation is thanks to lots of technology, from medical devices to CRISPR to better immunosuppressive medications, like ours.” 

Given the need for more organs and the chronic shortage of organs for donation, the number of xenotransplants are expected to grow. Changing organ donation systems from an opt-in to an opt-out approach, as it is in many parts of the world, including the US, would face cultural resistance, and it does not always increase the supply of organs. 

More notably, advances in gene editing means organs can be made more human-like than ever. Porcine organs in particular are the best option for organ transplant for several reasons: their organs are the most similar to human organs, they mature quickly, and they are already farmed for food and other products, and thus are subject to fewer ethical concerns if they were to be farmed for their organs.  

However, even the most human-like porcine organs face a higher risk of rejection than human organs. Tacrolimus, Gros said, is “not sufficiently strong to protect pig organs from rejection.” 

As attested by the success of the recent pig-to-human kidney transplant using tegoprubart in the immunosuppression regimen, the agent could fill that gap. Eledon has studied the drug also in non-human primate xenotransplants – including kidneys transplanted from pigs to non-human primates – and found that, compared to tacrolimus-based regimens, kidneys survived at least nine times longer in the non-human primate recipients when tegoprubart was used.

The results, which Gros says is, “some of the best preclinical xenotransplantation data,” in xenograft preservation, have attracted clinical collaborators, such as the organ engineering companies eGenesis and United Therapeutics Corporation, a biotech with a rare disease-focused drug pipeline but a growing interest in the xenotransplantation field. And the results are bringing in investment, with Eledon raising up to $185m via private placement, subject to achieving clinical development milestones, to advance the tegoprubart clinical trials program in mid-2023.

Improving Organ Survival And Function

With 16% of those awaiting a transplant already living with a failed transplanted organ, Gros believes Eledon’s drug could be an important factor in alleviating demand on the transplant system. 

“Part of the problem of the shortage of kidney transplants is that there are not enough kidneys to transplant, but another is that kidneys aren’t surviving long enough,” said Gros. “If you’re 60, in order to live to 80, you might need two or more kidney transplants.” 

Tegoprubart has shown it can improve kidney function, measured using estimated glomerular filtration rate (eGFR), and thus, presumably, lead to longer graft survival. In their Phase Ib kidney transplantation study, aggregate mean eGFR was over 70 milliliters per minute per 1.73 meter2 at all reported time points after day 90. In the one patient that had been followed up to one year, eGFR at that time was 91/ml/min/1.73 m2. In contrast, according to one meta-analysis of over 13,660 kidney transplant recipients, eGFR at 12 months has historically been a median of 50 ml/min/1.73m2.    

Gros touts tegoprubart’s favorable safety profile, particularly compared to tacrolimus. The latter drug can cause, among other adverse effects, nephrotoxicity in significant numbers of kidney transplant patients, as well as hypertension and new-onset diabetes, both of which are risk factors for kidney disease. While Eledon’s Phase 1b data are limited, there have been no cases of new-onset diabetes or nephrotoxicity. The most common adverse effects with the drug are gastrointestinal and there is a higher risk of infections. 

Because CD40L plays a central role in pro-inflammatory processes, it could ultimately be a candidate for autoimmune diseases and neuroinflammation, and indeed the company is studying it in a Phase II trial of patients with ALS, the neuroinflammatory disease it was initially designed for. 

A Narrow Focus In The Face Of Big Pharma

In terms of strategy, Eledon is being shrewd about its ambitions. There are other anti-CD40L agents in development across the industry: UCB S.A.’s dapirolizumab pegol is being tested for systemic lupus erythematosus, and Sanofi’s frexalimab recently fared well in a Phase II multiple sclerosis study. Eledon, in contrast, is focusing on the transplant indication for now. 

“As a smaller biotech, we’ve chosen to go after a niche,” said Gros, noting in the same breath that the global organ transplant immunosuppressant market size is estimated at over $5.3bn. 

The niche focus does not mean Gros’s aspirations are limited. 

“Our vision is ultimately for tegoprubart to be used as the cornerstone immunosuppressant regardless of the organ type, whether it’s human or non-human, and regardless of whether it’s liver, lung, or kidney,” he said. 

If Eledon’s tegoprubart in fact improves transplant outcomes, reduces transplant wait times and lessens the supply-demand gap, Eledon may take its seat at the table of companies that have shaped the field of transplant medicine.