Research on next-generation complement inhibitors aims to improve upon the standard-of-care therapies, which are parenteral agents that block complement protein C5. The inhibition of C5 occurs at a very distal point in the complement pathway, and this may create leakage via the alternative pathway. This results in a certain proportion of patients not having a full response to treatment despite the best inhibition of C5. The leakage is characterized by the development of extravascular hemolysis via opsonization owing to the deposition of C3b on red blood cells.

The rationale behind a more proximal inhibition of complement is that it not only might prevent extravascular hemolysis but also may be more effective at saturating targets at a point upstream in the cascade, so that you do not get to the point of having large numbers of free targets in circulation. At the ASH conference, Marano and colleagues shared their work investigating potential biomarkers of terminal, alternative, and classical complement pathways in PNH. Their findings showed that proximal complement inhibitors disable the terminal complement as well, and this eventually leads to the prevention of both intravascular and extravascular hemolysis (abstract 2568).

Another limitation of the currently available agents is the requirement for intravenous (IV) administration, as this is often inconvenient for patients. We tried to mitigate this by increasing the dosing interval and developing subcutaneous (SQ) regimens. This included converting ravulizumab from an IV formulation to an SQ formulation and the development of the new-generation C5 inhibitor crovalimab, which is being examined in patients using an IV loading dose with subsequent SQ doses. However, since some patients do not like injections, many are attracted to the advantages of an oral pill. It is analogous to individuals preferring oral therapies for diabetes treatment over injecting insulin. While some patients who are current responders to eculizumab or ravulizumab may opt to continue injectable therapy, others—particularly new patients—will prefer oral therapy.

An additional scenario to consider is the treatment of breakthrough hemolysis in view of the emerging proximal complement inhibitors. In the current paradigm, this means making another clinic visit for an injection. If you think about a patient who just received, say, $80,000 worth of ravulizumab 1 week ago, they would then need to come in for another $80,000 treatment just to block the breakthrough hemolysis. If oral therapy becomes available, it is possible that we might learn that breakthrough events can be managed initially by advising the patient to take an extra pill.

The new and emerging proximal complement inhibitors include those that inhibit C3 and some that are in development that inhibit factors B and D. The C3 inhibitor pegcetacoplan is available by SQ injection, while the factor B inhibitor iptacopan and the factor D inhibitors that are in development are oral. If the new therapies pan out as hoped, they will eventually replace the IV agents.

Now, certainly, there are some potential disadvantages of oral therapies. For example, what if the patient is not compliant? Additionally, with any newer therapy, the longer a drug is administered, the more likely it is that additional safety characteristics will be revealed. However, there have already been many patients who have been treated with iptacopan, which was the focus of the late-breaking LBA-2 abstract at ASH 2022, and it appears to be very well tolerated. A good measure of tolerability is how many patients continue on treatment, and there was a very low rate of iptacopan discontinuation in this study.

Another potential concern with proximal complement inhibitors is infection risk. We know that with C5 inhibition, with appropriate vaccinations and precautions, patients tolerate these agents quite well. It is interesting to note that when pegcetacoplan was first being considered, there were many concerns related to the potential for infection owing to the novelty of proximal inhibition, but there have now been numerous patients who have been treated with pegcetacoplan, and the safety profile has been favorable. As seen at the ASH conference, no thrombotic events or meningitis infections were reported in an open-label, multicenter, extension study among previous participants of pegcetacoplan phase 1, 2, and 3 trials (abstract 1248).