Reports

San Diego – The complement cascade is a key component of the immune system that plays an important role in recognizing pathogens and mounting an appropriate defence. When activated in the wrong contexts or misdirected against inappropriate tissues, it can lead to various disease pathologies, our understanding of which is continually evolving. In the kidney, complement-mediated injury has long been established as a driver of atypical hemolytic uremic syndrome (aHUS), and more recently, a role for complement has been recognized in IgA nephropathy (IgAN). At the recent Kidney Week meeting of the American Society of Nephrology, several clinical and real-world studies investigated the impact of using complement inhibitors in these two conditions. This report summarizes the most relevant findings and provides perspective from Canadian experts about the implications for clinical practice.

Chief Medical Editor: Dr. Léna Coïc, Montréal, Quebec

Insights into management of aHUS with eculizumab and ravulizumab

In aHUS, dysregulation of complement leads to thrombotic microangiopathy (TMA), which can block blood vessels and lead to organ damage in sites including the heart and kidney. Kidney failure is common, and many patients will require dialysis or a transplant. Eculizumab is an inhibitor of the terminal complement component C5; it is administered intravenously every two weeks and was until recently the standard of care for managing aHUS. In Canada and many other jurisdictions, this standard is now evolving toward ravulizumab, a next-generation C5 inhibitor with an eight-week dosing interval.¹ Several studies at Kidney Week provided clinical and real-world data to reinforce the profile of ravulizumab both as a switch from eculizumab and as a first-line option.

Dr Bradley Dixon, University of Colorado School of Medicine, Aurora, presented the final analysis of two phase 3 clinical trials of ravulizumab in patients with aHUS who were either naïve to complement inhibitors (adults and children) or who switched from eculizumab (children only). Both trials met their primary endpoint of complete TMA response after the initial 26-week evaluation period, defined by both normalization of hematologic parameters (platelet count and lactate dehydrogenase [LDH]), and at least a 25% improvement in serum creatinine from baseline; among the inhibitor-naïve patients, complete TMA response at Week 26 was 54% for adults and 75% for children. “There was a robust signal of complete TMA response after the initial 26-week evaluation period, but even into the long-term extension, additional patients met the criteria of complete TMA response in both the C5-naïve adult and pediatric patients,” said Dr Dixon. “This final analysis over a median duration of more than two years successfully demonstrated that continuation of ravulizumab treatment is associated with sustained control of the disease in both adult and pediatric patients with aHUS.”¹

A chart review in treatment-naïve aHUS patients provided further support for ravulizumab in this patient population. Dr Ramy Magdy Hanna, University of California, Irvine, and colleagues assessed the real-world effectiveness of ravulizumab on TMA response, laboratory tests and need for dialysis in 79 adults. Improvements in clinical endpoints were observed as early as Day 4 and sustained out to the final study visit at Month 12 (Figure 1); median time to a complete TMA response was 3.0 months (range 1.0 to 13.0 months). “The study provides real-world evidence to support the immediate and sustained benefits of initiating ravulizumab in patients with aHUS as seen by the early response and continued improvement,” concluded the authors.²

Figure 1. Platelet count, LDH, and serum creatinine from baseline to Month 12 of ravulizumab treatment.

Adapted from Hanna RM et al., Poster SA-PO804 at Kidney Week 2024, October 24–27, 2024.²

Complete TMA response was defined as normalization of platelet count (≥150 x 10⁹/L), normalization of LDH (≤246 U/L) and ≥25% improvement in serum creatinine.

IQR, interquartile range; LDH, lactate dehydrogenase; SCr, serum creatinine; TMA, thrombotic microangiopathy.

Data from the Global aHUS Registry provided additional evidence for switching from eculizumab to ravulizumab in the subset of patients with aHUS who previously received a kidney transplant. Dr Anja Gaeckler, University Hospital Essen, Germany, and colleagues investigated safety, efficacy, and patient characteristics in 32 individuals who received at least one kidney transplant before switching to ravulizumab. Following the switch, no rejections, graft failures, or new events of dialysis, transplantation, or TMA were reported, and kidney function (estimated glomerular filtration rate, eGFR), LDH, and platelet count remained stable. The overall safety profile was consistent with known adverse events with ravulizumab and there were no meningococcal events or deaths. “This analysis from the Global aHUS Registry provides real-world evidence of the successful transition from eculizumab to ravulizumab in kidney transplant patients with aHUS,” they concluded.³

Expert perspective and key takeaways for Canadian clinicians

Dr. Lakshman Gunaratnam is an Associate Professor of Medicine and clinician-scientist at Western University, with research and clinical interests in kidney transplantation. Asked about the importance of complement in kidney disease, he said, “I think there's a lot of renewed interest in complement, especially in transplant, and potentially even in future for improving antibody-mediated rejection and delayed graft function.”

On the topic of moving from eculizumab to ravulizumab in transplanted patients to maintain control of aHUS, Dr Gunaratnam said he’s “not concerned about switching. I'm convinced that the efficacy of complement inhibition is maintained – as good or better – with ravulizumab, and I think it also improves adherence with the reduced frequency of administration. I think it'll be a much better drug, and I'm also looking forward to using [ravulizumab] for inducing patients up-front.”

An emerging role for complement inhibition in IgA nephropathy

IgA nephropathy (IgAN) is the most common glomerular disease worldwide and a leading cause of kidney failure. It arises from chronic deposition of a modified form of immunoglobulin A in the kidneys, which can trigger complement-mediated tissue damage. Until recently there has been no disease-specific treatment option; management has focused on blood pressure reduction and anti-inflammatory medications such as steroids. Now that the role of complement in IgAN pathophysiology is becoming more established, existing complement inhibitor medications are being trialed as potential disease-modifying therapies.⁴

Iptacopan, an inhibitor of the proximal complement component factor B, was recently approved by the US FDA as the first complement inhibitor for the reduction of proteinuria in primary IgAN, based on the interim results of the phase III APPLAUSE-IgAN trial.⁵ (Iptacopan is not yet approved in this indication in Canada.) At Kidney Week a subset analysis examined outcomes in patients (n=27) with advanced IgAN and eGFR <30 mL/min/1.73m², a population in which treatment is generally limited to palliative/supportive care. The analysis showed that iptacopan was well tolerated with a favourable safety and efficacy profile, making it a potential option in this difficult-to-manage population.⁶

The terminal complement inhibitor ravulizumab is also being investigated in IgAN, although it is not yet approved for this indication in Canada or elsewhere. The phase II SANCTUARY trial presented at Kidney Week by Dr James Tumlin, Emory University, Atlanta, Georgia, showed a clinically meaningful reduction in proteinuria for ravulizumab versus placebo. “On top of standard therapy, ravulizumab dropped urinary protein levels [urinary protein/creatinine] by just over 40%, compared to just under 11% in the placebo group, getting down to a nadir level of around 1.06 g/g,” said Dr Tumlin. “In the ravulizumab group in the extension to Week 50, there was also a very similar drop in proteinuria at 41%. And what we think is very encouraging is that when patients in the placebo group switched over to ravulizumab, they got a near-identical drop in proteinuria of 43% at 26 weeks.”⁷

Expert perspective and key takeaways for Canadian clinicians

Dr Susan Huang is an Assistant Professor at Western University and was an investigator on the SANCTUARY trial. She said, “[IgAN is] a heterogeneous population where everyone presents slightly differently and the progression is different, but overall, the amount of proteinuria does indicate prognosis. So if we can show reduction in proteinuria, that may translate into better renal outcomes.” She hopes that the upcoming phase 3 trial of ravulizumab in IgAN – for which her centre is currently recruiting – and other studies will show how decreases in proteinuria may provide long-term clinical benefits such as protecting the kidney and preventing the need for dialysis or transplant.

“We’re starting to understand the involvement of complement in IgA nephropathy,” said Dr Huang. “And with the availability of complement blockers and other drugs, it opens up another door to be able to help these patients.” She hopes that in future, additional studies may show how combination treatment with multiple therapies directed against different targets could further enhance outcomes in IgAN. “People want to avoid steroids because of side effects, but they can have a role to play in IgAN,” she said.  “Similarly, complement may have its role. So a combination approach might turn out to be valuable, but we need more data.”

Dr Gunaratnam also commented on the potential value of complement inhibition in the post-transplant setting in IgAN. “IgAN recurs quite a bit after transplant, and recurrence of the primary disease is a major cause of graft failure,” he said. “So it will be exciting if in future we can see any data about the application of C5 inhibitors post-transplant for the specific purpose of diminishing the recurrence of IgAN.”

References

1. Dixon B et al. Oral presentation SA-OR64 at Kidney Week 2024, October 24–27, 2024.

2. Hanna RM et al. Poster SA-PO804 at Kidney Week 2024, October 24–27, 2024.

3. Gaeckler A et al. Poster SA-PO805 at Kidney Week 2024, October 24–27, 2024.

4. Jhaveri KD and Reich H. Otsuka exhibitor spotlight at Kidney Week 2024, October 24–27, 2024.

5. Novartis press release. Novartis receives FDA accelerated approval for Fabhalta® (iptacopan), the first and only complement inhibitor for the reduction of proteinuria in primary IgA nephropathy (IgAN). Available at: https://www.novartis.com/news/media-releases/novartis-receives-fda-accelerated-approval-fabhalta-iptacopan-first-and-only-complement-inhibitor-reduction-proteinuria-primary-iga-nephropathy-igan

6. Rizk D et al. Poster FR-PO853 at Kidney Week 2024, October 24–27, 2024.

7. Tumlin J et al. Oral presentation FR-OR60 at Kidney Week 2024, October 24–27, 2024.