January 2026 Research Update

This month added more real-world detail on how different complement-blocking medicines are being used in PNH, especially when people switch treatments or face special situations like pregnancy. Across these reports, longer-acting C5 blockers (such as ravulizumab) generally showed stable control of red blood cell breakdown, while a proximal inhibitor (iptacopan, a factor B blocker taken by mouth) was described as helpful in one person who had ongoing breakthrough hemolysis on a C5 blocker. Pegcetacoplan (a C3 blocker) was also reported in routine-care survey data with improvements in blood markers from the time it was started to the time of the survey. [1] [2] [3] [4]

In an Italian routine-care cohort of adults who switched from eculizumab to ravulizumab, hemolysis control was maintained over about 52 weeks and transfusion needs decreased, while breakthrough hemolysis was reported as rare. People also tended to prefer ravulizumab for convenience, and no meningococcal infections or thrombosis were reported during follow-up in this cohort. [1]

In pregnancy, an international retrospective series described 19 ravulizumab-treated pregnancies (in 16 women) that all ended in live births, and cord blood testing showed the drug could cross the placenta. Follow-up of the children (median 16.2 months) did not identify developmental concerns or severe infections in this report, while earlier pregnancies in the same patients treated with eculizumab included miscarriages and a preterm delivery. [2]

For pegcetacoplan, a cross-sectional real-world survey compared people who were new to complement inhibitors and those previously treated, and both groups showed improvement in hemoglobin and hemolysis-related lab markers from treatment start to the survey timepoint. In the same month, a small laboratory-focused case series described how pegcetacoplan changes complement lab measurements, including a large rise in circulating C3 and evidence that the alternative complement pathway was completely blocked while the classical pathway stayed largely intact. [4] [5]

A single case report described a person who switched from crovalimab (a C5 blocker) to iptacopan (a factor B blocker) because of breakthrough hemolysis, with a rapid rise in hemoglobin and no further breakthrough hemolysis reported over 12 months. Because this is one patient and there is no established standard for this specific switch, it mainly serves as an example of how switching may work for some individuals rather than a general result for everyone. [3]

For patients, this month mostly strengthens the picture that several complement-blocking options can maintain or improve key PNH outcomes in real-world settings, including after switching from one medicine to another and during pregnancy, but the certainty differs by the type of evidence. The pregnancy and routine-care ravulizumab reports may matter now because they describe outcomes in groups of patients, while the iptacopan switch story is early and based on a single person. Pegcetacoplan results add to the understanding that blood counts and hemolysis markers can improve in practice, and the detailed lab work helps explain why some complement tests change on this drug, which could matter for how results are interpreted. [2] [1] [4] [5] [3]

What remains uncertain is how well these experiences apply to every person with PNH, since some reports were retrospective, cross-sectional, or very small, and one was a single case. Even so, together they add practical context about stability of hemolysis control after switching to ravulizumab, early reassurance signals in ravulizumab-treated pregnancies as reported here, and the idea that proximal inhibition (such as iptacopan) may be considered when breakthrough hemolysis is a problem on a C5 blocker, pending broader confirmation. [1] [2] [3]

This month included studies about how PNH care and research measure outcomes and make comparisons, rather than new head-to-head clinical benefit results. Two papers focused on tools: one tested how well a fatigue questionnaire performs in adults with PNH, and another tested whether a model can predict eculizumab drug levels from blood samples. A separate economic analysis compared iptacopan with C5 blockers using a cost-per-responder approach over 24 weeks, aiming to frame how efficiently different options reach transfusion independence in modeled comparisons. [6] [7] [8]

Using data from two Phase 3 iptacopan trials, the FACIT-Fatigue questionnaire showed strong reliability and could detect meaningful within-person change, with an estimated meaningful change of 7.5 to 9.5 points on a 0 to 52 scale. In plain terms, this supports that fatigue scores collected in PNH studies can be consistent and sensitive enough to track changes over time. [6]

For eculizumab, a retrospective analysis reported that a published model could predict future trough levels with acceptable accuracy across several sampling scenarios, and it produced correct dose recommendations in over 80% of analyses. This does not show that outcomes improve, but it supports the idea that measuring drug levels and using a prediction model may be feasible for research or specialized monitoring. [7]

In a cost-per-responder analysis, iptacopan was reported to have a lower cost per responder than eculizumab or ravulizumab over 24 weeks, both for people who had used C5 inhibitors before and for those who were complement-inhibitor naive. The response definition centered on red blood cell transfusion independence, and the results reflect modeled economic comparisons rather than direct evidence that one option works better for every patient. [8]

For patients and caregivers, these studies mainly matter by improving how fatigue and treatment response can be measured and compared in PNH research. A stronger fatigue questionnaire means future trials and real-world studies can more confidently describe whether fatigue changed, not just hemoglobin or lab markers. The eculizumab drug-level modeling work suggests a pathway for more individualized monitoring in some settings, but it does not, by itself, prove better health outcomes. [6] [7]

The economic analysis may matter later for health-system decisions because it summarizes cost per transfusion-independence responder in a fixed timeframe, but it should not be read as a full picture of day-to-day benefits, side effects, or long-term results. Together, these papers add structure to how future PNH studies can talk about fatigue, drug exposure, and value, while leaving open the question of how best to apply them to individual situations. [8] [6]

This month also included early-stage studies aiming to explain PNH complications and to suggest future treatment directions, but these findings are not yet ready to predict what will happen for an individual patient. One translational study linked MUC4 gene mutations with a higher reported risk of thrombosis and explored a possible mechanism involving increased terminal complement deposition. Two laboratory-oriented projects proposed new drug directions: one described a newly developed factor B inhibitor with animal data and mention of preliminary clinical activity, and another used a cell model plus computer simulations to nominate existing medicines as repurposing candidates. [9] [10] [11]

In a small human cohort of classic PNH, MUC4 mutations were reported as an independent risk factor for thrombotic events, and blood and cell experiments suggested lower MUC4 expression may allow more C5b-9 (a terminal complement complex) to deposit on surfaces. In mouse clot models, loss of Muc4 was linked to longer clots, and preventive low-molecular-weight heparin reduced clot findings in those mice without major bleeding reported in that experiment. [9]

A drug discovery report described a small-molecule factor B inhibitor called (3R,4R)-15, showing strong blockade of the alternative complement pathway in laboratory testing and good oral availability in mice. The paper also noted preliminary clinical activity in PNH and stated that Phase 3 trials are ongoing, but it did not provide patient-level results in the summary provided. [10]

Using a PIGA-knockout cell model (meant to mimic a key genetic feature of PNH), another study built a network of gene regulators and then used computer docking to nominate leflunomide, dipyridamole, and pentoxifylline as possible candidates, with lab testing showing these drugs affected cell viability in the model. This is a starting point for hypothesis generation, not evidence that these medicines treat PNH in people. [11]

For patients, these studies mainly add understanding of why complications like blood clots may happen and how future treatments might be developed, but they are still early. The MUC4 study suggests a possible genetic contributor to thrombosis risk and connects it to complement activity, which could guide future research into risk markers or tailored prevention strategies if confirmed in larger groups. The factor B inhibitor and drug-repurposing work reflect ongoing efforts to expand oral and upstream complement-blocking options, but they should be viewed as research signals rather than proven choices. [9] [10] [11]

What remains uncertain is how well these results translate to everyday PNH care, because parts of the evidence come from small human samples, mice, or cell models. Even with those limits, the work helps clarify two themes that are becoming more central in PNH research: thrombosis may be influenced by more than one biological factor, and multiple points in the complement pathway (including factor B) are active targets for next-generation therapies. [9] [10]

Two case reports highlighted that PNH can show up in unexpected ways and that treatment changes are sometimes made when hemolysis is not fully controlled. One report emphasized kidney injury with iron deposition in the kidney as an early clue, even before obvious hemolysis was recognized. The other described a switch from crovalimab to iptacopan after breakthrough hemolysis, with symptom and hemoglobin improvement reported in that individual. [12] [3]

In the kidney case, a young woman had acute kidney injury and a biopsy showing acute tubular injury with hemosiderin (iron) deposition, and PNH was only confirmed years later with flow cytometry showing CD55 and CD59 deficiency. The report highlights that kidney iron deposition can be a clue to prior hidden hemolysis in unexplained kidney injury. [12]

In the treatment-switch case, a man with long-standing PNH had breakthrough hemolysis during crovalimab therapy and then switched to iptacopan, with hemoglobin rising quickly and staying higher during 12 months of follow-up. No breakthrough hemolysis or treatment-related adverse events were reported in that follow-up period. [3]

For patients and caregivers, these case reports mainly serve as real-world examples rather than general proof. The kidney case may matter now as awareness that PNH-related blood breakdown can sometimes be subtle and still affect organs like the kidneys, which could influence how unexplained kidney injury is investigated in future patients. The switching case adds a concrete example that changing from a C5 blocker to a proximal inhibitor can coincide with improved hemoglobin in one person, but it does not tell how often this happens or who will benefit. [12] [3]

The main uncertainty is that single-patient stories cannot separate drug effect from individual circumstances, and they cannot estimate how common the same pattern would be in others. Even so, these reports help clarify the range of PNH presentations and the kinds of clinical situations that lead doctors to consider additional testing or a change in complement-blocking strategy. [12] [3]