Garden Experts Insights | Current and Ongoing Innovative Treatments in PNH – Prof. E. Solomou

Current and Ongoing Innovative Treatments in Paroxysmal Nocturnal Hemoglobinuria

Elena Solomou
MD, PhD
Professor Internal Medicine-Hematology
University of Patras Medical School, Greece

This article is part of the GARDEN Experts Insights series, featuring key perspectives from leading international experts who contribute to GARDEN educational initiatives and webinars.
In this edition, Professor Elena Solomou explores the rapidly evolving therapeutic landscape of paroxysmal nocturnal hemoglobinuria (PNH), reviewing current standards of care and the next generation of complement-targeted therapies. Drawing on the latest clinical evidence, she discusses how innovative treatment strategies are expanding beyond C5 inhibition toward more personalized approaches aimed at improving disease control, reducing treatment burden, and enhancing long-term patient outcomes.

Introduction

Paroxysmal nocturnal hemoglobinuria (PNH) has become one of the most compelling examples of how advances in translational medicine can fundamentally change the management of a rare hematologic disease. Characterized by chronic complement-mediated hemolysis, bone marrow failure, and a markedly increased risk of thrombosis, PNH was historically associated with substantial morbidity and premature mortality. The discovery that somatic mutations in the PIGA gene lead to the loss of the complement regulatory proteins CD55 and CD59 established uncontrolled activation of the alternative complement pathway as the central driver of disease pathophysiology. This mechanistic understanding paved the way for the development of targeted complement inhibitors that have transformed clinical outcomes over the past two decades. (Shah & Bhatt, 2021)

The introduction of terminal complement inhibition represented a landmark achievement in PNH management. Eculizumab, the first monoclonal antibody directed against complement component C5, demonstrated that selective inhibition of terminal complement activation could effectively prevent intravascular hemolysis, reduce thrombotic complications, decrease transfusion requirements, and substantially improve survival. Its long-acting successor, Ravulizumab, further reduced treatment burden by extending dosing intervals while maintaining comparable efficacy.

Collectively, these agents redefined the standard of care and established complement inhibition as the cornerstone of modern PNH therapy.
Although these impressive developments have occurred, there are significant shortcomings in the first-generation C5 inhibitors that have been identified through clinical trials and experience in clinical practice. A significant percentage of patients remain clinically significant anaemic with persistent fatigability, breakthrough haemolysis and transfusion dependence despite good terminal complement control. These are chronic presentations, mostly attributable to ongoing extravascular hemolysis caused by the upstream activation of complement, and in many patients, to the underlying bone marrow failure. As a result, there is still a significant proportion of people that do not achieve optimal disease control when treated with conventional C5 blockade (Bektas et al., 2020).

This has prompted the emergence of a new generation of complement-targeted therapies, which go beyond terminal C5 inhibition. Novel agents against C3, factor B, and factor D seek to offer wider control of complement activation, and to target intravascular and extravascular hemolysis. Meanwhile, advances in drug delivery, such as subcutaneous formulations, oral complement inhibitors and longer-acting biologics, are enhancing convenience of treatment and expanding treatment options to address the needs of individual patients. As mentioned all along the webinar by E. Solomou, the management of PNH is no longer dependent upon a single therapeutic approach, but rather a more complex treatment landscape in which there is a greater need to consider disease phenotype, residual disease burden, patient preference, and long-term treatment goals for therapeutic selection. The current and emerging innovative therapies that are defining this rapidly evolving era of PNH management are reviewed.

From C5 Blockade to Next Generation Therapy

The treatment of paroxysmal nocturnal hemoglobinuria has evolved remarkably over the past three decades, transforming the disease from a condition managed primarily through supportive care to one in which highly targeted therapies can achieve sustained disease control. This evolution reflects a deeper understanding of complement biology and illustrates how advances in molecular medicine have translated into increasingly effective and patient-centered therapeutic strategies. Rather than representing isolated innovations, each successive generation of therapy has been developed to overcome the limitations of its predecessor, progressively improving efficacy, convenience, and quality of life.

Plasma Therapy and Supportive Care

The treatment of PNH was almost exclusively directed at controlling the effects of the disease rather than preventing them, before the introduction of complement-targeted therapy. Repeatedly patients had to be transfused with red blood cells to control chronic hemolytic anemia, and folic acid and iron were given regularly to make up for increased erythropoiesis and iron loss during hemoglobinuria. During attacks of severe hemolysis, corticosteroids were sometimes used, but it was unclear whether they were beneficial over the long-term and they were often associated with toxicity related to the treatment.

Thrombosis was the most significant cause of death in PNH and even more difficult to treat. In high-risk patients, long-term anti-coagulation was sometimes being considered, but still the thrombotic events were occurring despite the use of the pro-phylactic treatment. Allogeneic Hematopoietic Stem Cell Transplantation was the only potentially curative therapy available for subjects with severe bone marrow failure or refractory disease. Its use was limited, however, to carefully selected patients because of transplant-related mortality, graft-versus-host disease, donor availability and procedure-associated complications. As a result, supportive care was effective in reducing some of the symptoms of PNH, but it did not prevent the complement-mediated destruction of erythrocytes and most patients continued to suffer from progressive organ damage and a decrease in life expectancy (Röth & Dührsen, 2011).

Eculizumab and the Era of Targeted Complement Inhibition

One of the most significant developments was the emergence of the first monoclonal antibody targeting complement component C5, eculizumab. The ability of eculizumab to inhibit the formation of the membrane attack complex (C5b) prevented intravascular hemolysis caused by complement. This was the first therapy to directly target the molecular mechanism of the disease, instead of just treating the consequences of it (Jiao et al., 2021).

A dramatic decrease in intravascular hemolysis and in the need for transfusion was observed, along with a normalization of lactate dehydrogenase levels and marked improvements in fatigue and health-related quality of life, in clinical trials. Perhaps most importantly, long term observational studies have demonstrated a dramatic decrease in thromboembolic events, such that those patients who were treated could approach the survival of the general population. These results paved the way for the use of terminal complement inhibition as the basis for the treatment of PNH in the modern era and fundamentally changed the prognosis for patients with PNH.

However, as experience with the use of C5 inhibitors in clinical practice grew, it became clear that inhibition of C5 was not sufficient to fully prevent disease activity (Horiuchi & Tsukamoto, 2016). The presence of C3-mediated extravascular hemolysis in the spleen and liver led to anemic patients despite good biochemical control of intravascular hemolysis. Others had breakthrough hemolysis, which was due to insufficient complement inhibition at the end of the dosing intervals or when complement activation was stimulated, for example, by infections or surgery. In addition, the IV every two weeks was a significant treatment burden for many patients.

Ravulizumab and Extended C5 Inhibition

The next big step in terminal complement inhibition was the development of ravulizumab. Ravulizumab was engineered to have a much longer half-life, but still act on C5 as eculizumab does, via neonatal Fc receptor recycling. In Phase III trials, sustained complement inhibition, control of intravascular hemolysis, avoidance of transfusion and prevention of breakthrough hemolysis were shown to be not inferior, and the dosing interval was increased from every 2 wks to every 8 wks. This significantly simplified treatment and convenience for patients who need long-term treatment (Rondeau et al., 2020).

The drawback of terminal complement inhibition was not overcome, however, by ravulizumab. Upstream of C5, activation of complement was still present, causing C3 fragments to deposit on erythrocytes, which led to extravascular hemolysis and some patients continued to have residual anemia. As a result, while extended C5 inhibition enhanced treatment convenience it did not meet all the unmet clinical needs that remained to spur the development of next-generation complement therapies.

Proximal Complement Inhibition

Persistent extravascular hemolysis led to the study of earlier components of the complement cascade. Investigators started to look at proximal regulators of complement activation, such as C3, factor B and factor D, to stop complement activation prior to C3 deposition. This approach was a significant paradigm change in the treatment of PNH. In addition to blocking intravascular hemolysis, proximal complement inhibition could lead to more effective disease control than terminal C5 blockade alone. The clinical trials of agents like pegcetacoplan, iptacopan and danicopan have consistently shown that they improve hemoglobin concentration, reduce transfusion dependency and lead to a better correction of residual anemia in patients with inadequate response to C5 inhibitors. The results indicate that there are limitations that have been present since the first generation of biologics, which could be addressed by broader complement regulation.

The Emergence of Oral Therapies

The introduction of oral complement inhibitors has been another important step forward in the development of PNH therapies. All complement-directed therapies were given intravenously or subcutaneously, which meant that the patient had to visit the hospital or be given infusions at home for life. Oral agents that target factor B or factor D (Factor D is used in combination with C5 inhibitors) have ushered in a whole new class of therapeutic options that offer effective complement inhibition and ease of daily oral administration.
In addition to enhancing patient preference and adherence, oral treatments could also help to streamline long-term disease management and provide greater access to treatment in health care environments where infusion therapy is difficult. These agents will gain long-term efficacy and safety data as they continue to be used, and will be an increasingly important part of the personalized care of PNH patients.

Combination Strategies

There has also been increasing awareness of the clinical diversity of PNH and the emergence of combination therapeutic strategies. Researchers are testing combinations of inhibitors that attack multiple parts of the complement pathway, or pairing existing C5 inhibitors with inhibitors that target early steps in the complement pathway.
This approach is especially appealing to those who remain anemic or suffer from breakthrough hemolysis despite optimal treatment. Early clinical trials have shown the potential of add-on proximal inhibition to further enhance Hb levels, even in the presence of control of intravascular hemolysis, which suggests a more personalized strategy for complement modulation by disease characteristics.

C5 Inhibitors

The addition of C5 inhibitors represented a turning point in the care of PNH, moving from a condition treated with supportive measures to one that might be targeted with complement inhibition. Perhaps more significantly, these treatments proved that blocking terminal complement activation could modify the natural history of PNH, significantly decreasing intravascular hemolysis, thrombotic events, and PNH-related mortality. In the long-term experience, however, C5 inhibition proved to transform patient care, but it also revealed significant biological constraints that led to the creation of the next generation of complement-directed therapies (Imre Bodó et al., 2023).

Eculizumab as the First Therapeutic Breakthrough

Eculizumab is the first complement component C5 inhibitor developed to block the formation of the membrane attack complex that is the cause of intravascular hemolysis in PNH. The mechanism of hemolysis was targeted directly with eculizumab, which was a shift in treatment paradigm from previous supportive therapies that only addressed the effects of hemolysis (Hillmen et al., 2006).

The TRIUMPH trial showed that eculizumab immediately and consistently reduced intravascular hemolysis, with virtually normalization of lactate dehydrogenase (LDH) levels, 49% of patients stabilizing their hemoglobin levels versus none receiving a placebo, and nearly half becoming transfusion independent. Significant improvements in fatigue and health-related quality of life were also observed. This was corroborated in the SHEPHERD study, which found similar LDH levels, fewer transfusions and continued clinical improvement in a larger PNH population. Long-term follow-up also revealed a significant decrease in thromboembolic events, the most common cause of death in PNH, and observational studies revealed a survival rate close to that of the general population.

Ravulizumab and Extended Complement Control

Although it has proven to be a game-changer, eculizumab must be infused intravenously every two weeks and maintaining optimal drug levels is critical to avoid intravascular hemolysis. This is a very frequent dosing regimen, which makes treatment more cumbersome and demands frequent visits to the hospital, making treatment more difficult for many patients.
To overcome these limitations, ravulizumab was modified to improve the neonatal Fc receptor recycling, thereby prolonging its half-life without changing its mechanism of action, which is the inhibition of C5.

In the phase III ALXN1210-301 and ALXN1210-302 trials, ravulizumab was non-inferior to eculizumab on all key efficacy endpoints: normalization of LDH, transfusion avoidance, stabilization of hemoglobin, and prevention of breakthrough hemolysis. Most importantly, the dosing interval was increased from every two weeks to every eight weeks, which means that the number of infusions has been reduced from about 26 per year to 6-7 per year without a decrease in disease control. This reduced treatment burden, increased convenience and increased patient satisfaction. Unlike eculizumab, however, ravulizumab does not prevent C3-mediated extravascular hemolysis, which means that some patients suffer from residual anemia, and underscores the need for new complement therapeutics.

Why Innovation Continued

While eculizumab and ravulizumab revolutionized the care of PNH, neither drug was able to completely control disease activity. These therapies act by blocking complement at the C5 level, thus preventing the formation of the membrane attack complex and the control of intravascular hemolysis. Upstream of C5, however, the complement system is still activated and C3 continues to be deposited onto erythrocytes. These C3-opsonised red blood cells are then removed by the macrophages in the spleen and liver, despite proper terminal complement inhibition, leading to ongoing extravascular hemolysis.

In long-term clinical practice this biological constraint became more and more apparent. Most of the patients had complete suppression of intravascular hemolysis, but many had persistent anemia, fatigue, reticulocytosis, high bilirubin, and continued transfusion needs. Moreover, breakthrough hemolysis was still a significant issue. Pharmacokinetic breakthrough can happen when levels of the drug drop at the end of the dosing interval, while pharmacodynamic breakthrough can happen during an infection, surgery, pregnancy, or other inflammatory diseases that cause high levels of the complement system.

Ravulizumab has a longer half-life than eculizumab, which has less pharmacokinetic breakthrough, but it does not eliminate it.
The unmet clinical needs led to the development of therapeutic innovations focusing on proximal complement inhibition. New approaches to C5 blockade go upstream to the complement components C3, factor B, and factor D, which prevent intravascular and extravascular hemolysis, rather than just C5 blockade. These treatments work to achieve more complete disease control through hemoglobin recovery, decreasing the need for transfusion, and minimizing residual disease activity. Therefore, the efficacy of eculizumab and ravulizumab set the groundwork for the current treatment of PNH and paved the way for the next generation of complement inhibitors.

Proximal Complement Inhibition

Although the use of terminal C5 inhibitors revolutionized the treatment of PNH, the continued anemia and extravascular hemolysis indicated an important biological limitation of complement blockade at the terminal level. This knowledge contributed to the shift in therapeutic strategies to proximal complement inhibition, a strategy which will prevent the formation of the membrane attack complex and the deposition of C3 by blocking the complement cascade upstream of C5.

Proximal inhibitors block the activation of complement at an earlier stage, and can therefore inhibit intravascular and extravascular hemolysis, providing the potential for more complete disease control.
Three key therapeutic targets have arisen. C3 inhibition blocks activation of all downstream complement pathways, factor B inhibition prevents formation of the alternative pathway C3 convertase and factor D inhibition blocks amplification of the alternative complement pathway. These strategies have changed the goals of treatment from control of hemolysis to correction of anemia, less dependence on transfusion, and better patient care.

Pegcetacoplan

The targeted C3 inhibitor pegcetacoplan was the first treatment to show that C3 inhibition could overcome many of the limitations of C5 blockade. Unlike terminal complement inhibition, pegcetacoplan prevents C3 activation, which prevents both intravascular and extravascular hemolysis, resulting in a more comprehensive improvement of red blood cell survival (Chan et al., 2024). The clinical utility has been proven in the phase III PEGASUS study, which included patients with chronic anemia despite stable eculizumab treatment.

Pegcetacoplan also resulted in a mean increase in hemoglobin of 3.84 g/dL at 16 weeks versus eculizumab, and 85% of patients were transfusion-free compared with 15% of those in the eculizumab group. Lactate dehydrogenase levels were kept under effective control, so there was continued suppression of intravascular hemolysis as well as the C3 mediated extravascular destruction of erythrocytes was addressed. These hematologic improvements were associated with clinically relevant decreases in fatigue and substantial improvements in health-related QOL (Hillmen et al., 2021).

Iptacopan

Iptacopan is the first oral factor B inhibitor approved for PNH, and it works by targeting the alternative pathway of the complement system, which stops intra- and extravascular hemolysis, and eliminates the need for intravenous therapy. Among the 82% of patients who did not need transfusion, 82% had sustained hemoglobin levels ≥2 g/dL, while 2% continued to receive C5 inhibition. Over 95% were not blood transfusion dependent, and LDH normalized quickly. This was also found to be the case in complement inhibitor-naïve patients in the APPOINT-PNH trial, and the extension study showed long-term efficacy, sustained hematologic improvement and good long-term safety (Xu et al., 2024).

Danicopan

Danicopan is an oral factor D inhibitor that has been developed as an add-on treatment for patients who are still having clinically significant extravascular hemolysis despite being on C5 inhibitors. Danicopan selectively inhibits the alternative pathway amplification loop and does not block terminal C5, which provides a complementary mechanism to enhance incomplete responses.
The phase III ALPHA trial showed that the addition of danicopan to continued eculizumab or ravulizumab treatment resulted in a mean increase in hemoglobin of ~2.4 g/dL, a significant decrease in transfusion need, and an improvement in extravascular hemolysis markers without impacting intravascular hemolysis markers. Patients also experienced clinically significant decreases in fatigue and in overall quality of life, further highlighting the need to optimize treatment for anemia, despite good disease control (Gul et al., 2025).

Oral Therapies

One of the biggest breakthroughs in the treatment of PNH in recent years has been the development of complement inhibitors that can be taken by mouth, which means that people with PNH don’t need to take them intravenously or under their skin for their entire lives. In addition to its convenience, oral agents provide greater treatment flexibility, reduce the number of hospital visits and can potentially enhance long-term adherence, which is crucial in a chronic disease that requires constant complement inhibition.

In phase III trials, Iptacopan has shown to be highly effective as first-line treatment and an alternative to C5 inhibitors, with sustained hemoglobin improvement, normalization of lactate dehydrogenase, and high transfusion independence rates. An oral factor D inhibitor, Danicopan, has proven to be especially useful as add-on therapy for patients with persistent extravascular hemolysis despite blocking C5, improving hemoglobin levels without compromising control of intravascular hemolysis. Oral complement inhibitors could play a significant role in the future of personalized PNH care, providing a balance between effectiveness, ease of use, and adherence to treatment.

Combination Therapy

Even in the presence of effective terminal complement inhibition, however, there is a significant subset of patients with PNH who continue to have anemia from ongoing C3-mediated extravascular hemolysis, and underlying bone marrow failure may also restrict hematologic recovery. These unmet needs have led to the use of combination therapeutic approaches to inhibit the complement cascade at several different sites.
The most promising strategy is to combine danicopan, an oral factor D inhibitor, with continued eculizumab or ravulizumab treatment.

During the phase III ALPHA trial, danicopan add-on therapy significantly elevated hemoglobin by ~ 2.4 g/dL, reduced transfusion requirements and effectively controlled extravascular hemolysis without affecting terminal complement inhibition (Kulasekararaj et al., 2024). Another approach is to replace C5 inhibitors with pegcetacoplan in patients with chronic anemia; in the PEGASUS trial, pegcetacoplan was shown to be more effective at improving hemoglobin levels and reducing the need for transfusion (Peffault de Latour et al., 2024). Some of these strategies represent the trend toward individual therapy – treatment is customized based on the level of residual disease activity and not just complete C5 blockade.

Emerging Treatments

The therapeutic pipeline for PNH remains growing, with several new therapies on the horizon that would provide more durable complement inhibition, increased convenience and better disease control. Crovalimab is a long-acting anti-C5 monoclonal antibody administered subcutaneously, and has been shown to be as effective as existing C5 inhibitors, but with a lower treatment burden. Pozelimab is able to produce durable suppression of terminal complement activity, which means that it could be dosed less frequently, through dual inhibition of C5 production and activation.

Other investigational agents such as KP104 aim to add anticoagulant effects to complement regulation to further decrease the thrombotic risk. At the same time, new siRNA-targeted drugs, new long-acting antibodies and next generation of subcutaneous inhibitors of proximal complement components are progressing through clinical development, with an increasing focus on personalized and convenient complement modulation, and potentially more complete (Waheed et al., 2025).

Remaining Challenges

Although tremendous therapeutic advances have been made, there are still several challenges that affect the management of PNH. In some patients, residual anemia and occasional breakthrough hemolysis remain a concern, especially in patients with persistent extravascular hemolysis and/or underlying bone marrow failure. With the growing variety of complement inhibitors, patient selection is becoming increasingly crucial, with individualized treatment depending on disease characteristics and clinical responses. Chronic complement inhibition requires constant monitoring for encapsulated bacterial infections and needs to be complemented by appropriate vaccination and preventive measures. Lastly, novel therapies are costly and are not equally available worldwide, and finding effective, reliable biomarkers for therapy selection and for monitoring response is an active research area.

Conclusion & Future Outlook

The treatment of PNH is moving into a new paradigm with a better understanding of the biology of complement and an increasing number of targeted therapies. The emphasis has now moved from just suppressing intravascular hemolysis to providing complete disease control through correction of residual anemia, prevention of extravascular hemolysis, reduction of treatment burden and enhancement of long-term quality of life.

Oral agents, proximal inhibitors, combination therapies, and new drugs are maturing, and the concept of individualized complement inhibition is the new therapeutic paradigm that is moving towards routine clinical practice.
Precision medicine is the future of PNH management, where treatment is personalized based on the biology of the disease, treatment response, and patient preference and is not a one-size-fits-all approach. Optimization of long-term outcomes is expected with personalized complement inhibition, which includes the use of proximal inhibitors and combination therapy.

The earlier the treatment is started, the less organ damage and thrombotic complications that will be irreversible. Meanwhile, long acting subcutaneous agents and oral drugs will further decrease the burden of treatment and increase adherence. In the future, gene-editing therapies and other potentially single treatment approaches could provide long-term disease containment; and biomarker-based treatment decisions and digital monitoring tools will further personalize patient care (Tamdin & Rodgers, 2025).

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