Managing Paroxysmal Nocturnal Hemoglobinuria in an Evolving Treatment Landscape

Paroxysmal nocturnal hemoglobinuria (PNH) is a rare, severe, and potentially life-threatening condition. Treatments targeting the complement pathway have revolutionized its management but have introduced iatrogenic conditions, prompting the development of novel therapies now emerging in the treatment landscape. In a recent AJMC® Stakeholder Summit, moderated by Ryan Haumschild, PharmD, MS, MBA, vice president of ambulatory pharmacy services at Emory Healthcare and Winship Cancer Institute in Atlanta, Georgia, a panel of experts explored the pathophysiology of PNH in the context of these therapies. The panel discussed challenges in managing patients with PNH, determining when to switch therapies, supporting adherence, and addressing economic challenges within this disease space.

Pathophysiology and Disease Burden

PNH is an acquired hematopoietic stem cell disorder marked by hemolytic anemia, thrombosis, smooth muscle dystonia, and potential bone marrow failure.^1,2 Due to its rarity, epidemiological data on PNH are limited, but its estimated prevalence is approximately 38 per 1 million individuals, with incidence ranging from 0.08 to 0.57 per 100,000 person-years.³ PNH is caused by a random and sporadic somatic mutation in the PIGA gene. Clonal expansion of the affected hematopoietic stem cell leads to progenitor cells that are deficient in glycosylphosphatidylinositol (GPI), a molecule that anchors protective proteins to the cell surface.^1,2,4 The absence of GPI prevents attachment of complement inhibitors CD55 and CD59, leaving these otherwise healthy blood cells susceptible to chronic complement-mediated destruction.^1,2,4 PNH can occur in individuals of any age, but the median age of diagnosis is approximately 35 years, and the condition affects men and women equally.^4,5 Patients receiving supportive care alone have a median survival of approximately 10 to 22 years, with thrombosis being the leading cause of death.⁶

Symptoms and Clinical Manifestations

Symptoms, progression, and severity of PNH vary among individuals, depending on the percentage of blood cells lacking protective proteins, with chronic hemolysis being central to the disorder’s clinical manifestations.^3-5 The degree of hemolysis, which may worsen during periods of infection, trauma, or stress, impacts the severity of PNH symptoms.⁴ Fatigue is the most widespread symptom and is often debilitating, affecting 80.9% of patients in the International PNH Registry.^4,5 Other common PNH symptoms include hemoglobinuria (45.0%), dyspnea (45.3%), abdominal pain (35.2%), dysphagia (16.5%), and erectile dysfunction (24.2% of male patients).⁵ Many of these symptoms arise from smooth muscle dystonia due to free hemoglobin irreversibly binding to nitric oxide, making it unavailable to regulate smooth muscle cells.⁴ Nitric oxide depletion can also trigger thrombosis by activating platelets and promoting their aggregation.⁴ If untreated, PNH can lead to substantial health complications, such as major adverse vascular events (18.8%), thrombotic events (13.3%), and impaired renal function (42.8%), with many patients (61.3%) requiring red blood cell transfusions.^4,5 Common sites of thrombosis include liver veins (Budd-Chiari syndrome); abdominal veins such as the portal, mesenteric, and splenic veins; and brain regions such as the sagittal and cavernous sinuses.⁴ Overall, PNH symptoms have a major impact on daily life, contributing to a loss of independence, reduced physical activity, and functional decline.⁴

In PNH, hemolysis occurs both within the blood vessels (intravascular) and outside in organs such as the spleen or liver (extravascular).⁴ Intravascular hemolysis occurs when affected red blood cells are destroyed during complement activation, characterized by significantly elevated lactate dehydrogenase (LDH) levels, low haptoglobin, high unconjugated bilirubin, and an increase in reticulocytes (immature red blood cells) as a compensatory bone marrow response.^1,7 Conversely, extravascular hemolysis occurs when PNH cells with accumulated C3 fragments are consumed by macrophages.¹ In untreated PNH, intravascular hemolysis is non-antibody mediated (Coombs negative); however, after treatment with a C5 inhibitor, Coombs tests may become positive for C3, indicating a shift from intravascular to extravascular hemolysis.^1,8,9

The rarity of PNH, along with its complex pathophysiology leading to multisystemic, nonspecific symptoms, often leads to delayed diagnosis.⁴ Data indicate that time from onset of symptoms to diagnosis of PNH varies widely among patients and typically involves consultations with multiple health care providers.¹⁰ Nearly one-fourth of patients wait more than 5 years to receive a diagnosis, and more than a third consult with at least 5 specialists from various fields before receiving the PNH diagnosis.^4,10

Stakeholder Insights

Understanding the complex pathophysiology, diagnostic challenges, and clinical implications of PNH is essential for the effective management and treatment of this severe blood disorder. David Dingli, MD, PhD, a hematologist at Mayo Clinic in Rochester, Minnesota, provided a thorough description of PNH pathophysiology, noting that it is important to consider complement and how it is regulated, stem cells, and red blood cells, “because it is the combination of these phenomena that actually result in the disease.” Dingli further explained that the lack of complement regulatory proteins CD55 and CD59 on cell surfaces leads to unchecked complement activation, resulting in continuous production of C3 and C5, formation of the membrane attack complex, and subsequent destruction of red blood cells through intravascular hemolysis. This hemolysis causes symptoms such as hemoglobinuria, jaundice, and anemia, while also increasing the risk of smooth muscle spasms and thrombotic events. Dingli described the mechanisms of intravascular and extravascular hemolysis in PNH. In untreated PNH, C3 accumulates on the cell surface, leading to the formation of the C5 membrane attack complex and subsequent intravascular destruction of red blood cells. Treatment with a C5 inhibitor effectively blocks this intravascular hemolysis by mimicking the role of CD59, although it does not replicate the function of CD55. Consequently, the complement cascade up to CD5 remains active, and C3 continues to coat the red blood cells. These cells, now surviving longer in the circulation, accumulate more C3 and become susceptible to phagocytosis, primarily in the liver, leading to extravascular hemolysis—a phenomenon that was identified soon after the introduction of C5 inhibition therapy. Dingli added that “clinically, this can be distinguished because the patient with intravascular hemolysis will classically have a very high LDH [level]…. The untreated patient will have a negative Coombs test. But once we treat [them] with a C5 inhibitor, the LDH will come down, but the red cells can become coated with C3, so the Coombs test can become positive and that could be a hint for extravascular hemolysis.”

Brian P. Mulherin, MD, a hematologist-oncologist from the American Oncology Network in Indianapolis, Indiana, emphasized the rarity of PNH, noting that it often goes unrecognized and may not be familiar to all payers. Mulherin said, “It is not uncommon for patients to have symptoms, sometimes for years, before PNH is diagnosed. In fact, we know that delayed diagnosis is probably the norm, not the exception.” He added that patients are typically diagnosed during their prime working years, often while raising young families, and they frequently dismiss their symptoms, which is concerning as the disease progresses and anemia worsens with time.

Mulherin identified diagnostic “red flags” for PNH, including thrombosis at unusual sites, such as dural venous sinus thrombosis, portal vein thrombosis, and those associated with Budd-Chiari syndrome, especially in younger individuals. He also highlighted Coombs-negative hemolysis, aplastic anemia, and symptoms of smooth muscle dystonia, such as abdominal pains, dysphagia, and erectile dysfunction. Mulherin emphasized the severe risks associated with unchecked hemolysis, which can lead to pulmonary hypertension, chronic kidney disease, and liver dysfunction.

Jamie Koprivnikar, MD, a hematologist-oncologist from the John Theurer Cancer Center at Hackensack University Medical Center in Hackensack, New Jersey, noted that patients with PNH often consult multiple providers and specialists on their path to diagnosis because of its nonspecific symptoms. “These patients may be experiencing a symptom like abdominal pain. And so, who do they see? They see their primary care doctor. Their primary care doctor sends them to a gastroenterologist. A patient is having erectile dysfunction. Who do they see? The urologist. These are really subspecialists who are not trained to think about or look for a complicated and rare hematologic disorder like PNH.” Koprivnikar explained that “the rarity of the disease and the wide spectrum of manifestations, which can affect almost every organ system in the body, [are] what lead to the difficulty…and delays in diagnosis.”

Koprivnikar explained the clinical impact and progression of PNH, noting typical symptoms that prompt diagnosis. Patients with PNH often experience debilitating fatigue that greatly impairs their daily activities and ability to work. This fatigue stems from both the anemia and a systemic inflammatory response. Koprivnikar added that “PNH has been called the most vicious prothrombotic state that we know of today in medicine. So the No. 1 killer of [patients with] PNH is thrombosis. It’s responsible for up to two-thirds of PNH-attributable deaths.” Additionally, there is a high incidence of chronic kidney disease and pulmonary hypertension among patients with the disorder.

Overview of the Treatment Landscape

Complement blockade with first-line intravenous C5 inhibitors, such as eculizumab and ravulizumab, has been the cornerstone of PNH treatment.^11,12 These monoclonal antibodies target the terminal complement protein C5, preventing its cleavage and participation in membrane attack complex formation, significantly reducing intravascular hemolysis, and preventing major complications.¹¹ Eculizumab, first approved in 2007 as a biweekly intravascular infusion, has demonstrated reductions in hemolysis, transfusions, and thrombotic events, while improving renal function and overall quality of life.^13-16 Ravulizumab was later developed for a longer dosing interval of every 8 weeks. Data from phase 3 clinical trials demonstrated noninferior efficacy compared with eculizumab, both in complement inhibitor–naive patients and those previously treated with eculizumab, leading to the agent’s approval in 2018.^17,18

Despite the efficacy of C5 inhibitors, some treated patients are affected by persistent anemia and transfusion dependence.¹¹ Persistent anemia despite C5 inhibition is typically due to incomplete complement blockade, leading to breakthrough hemolysis or to extravascular hemolysis of circulating GPI-negative erythrocytes.¹¹ Breakthrough hemolysis, which can be chronic or recurrent, is defined by an acute, recurrent elevation in LDH levels, plus at least 1 new or worsening symptom of intravascular hemolysis.¹¹ In contrast, C5 inhibitor treatment can lead to extravascular hemolysis due to the accumulation of C3b on GPI-negative erythrocytes.¹¹ Diagnosis of extravascular hemolysis is indicated by normal or slightly elevated LDH levels, reticulocytosis, and a C3d-positive Coombs test, which is present in more than 50% of patients with PNH treated with eculizumab.¹¹

To address iatrogenic C3-mediated extravascular hemolysis caused by C5 inhibitors, proximal complement inhibitors targeting C3, factor D, and factor B have been developed.¹¹

Pegcetacoplan is a pegylated C3 inhibitor approved for treatment of PNH, providing an option that targets a different component of the complement system. Administered subcutaneously, twice weekly, pegcetacoplan showed superiority over eculizumab in stabilizing hemoglobin and controlling hemolysis in both complement inhibitor–experienced and complement inhibitor–naive patients.^19,20 However, acute hemolysis episodes in some patients prompted additional dosing strategies to manage breakthrough hemolysis.¹⁹

Iptacopan, a first-in-class oral factor B inhibitor, acts upstream of C5, inhibiting both terminal complement–mediated intravascular hemolysis and complement 3–mediated extravascular hemolysis.¹² Twice-daily iptacopan monotherapy notably increased hemoglobin levels, improved fatigue scores, reduced reticulocyte counts, and lowered breakthrough hemolysis rates among both treatment-naive patients and patients with anemia previously treated with C5 inhibitors, representing a potentially practice-changing therapy for patients with an inadequate response to anti-C5 antibodies.^21,22

Dual-target complement inhibition in PNH aims to block C5 directly while also providing proximal inhibition to protect against or treat extravascular hemolysis.¹¹ Adding the oral factor D inhibitor danicopan to ravulizumab or eculizumab for patients with PNH with clinically significant extravascular hemolysis greatly improved hemoglobin concentration compared with placebo.²³ Danicopan also increased the likelihood of transfusion avoidance and hemoglobin normalization, indicating meaningful quality-of-life improvements.²³ This dual-target approach addresses clinically significant extravascular hemolysis while protecting against severe breakthrough hemolysis.²³

Patients with ongoing anemia due to clinically significant extravascular hemolysis, particularly those who are symptomatic or transfusion dependent, are optimal candidates for switching to proximal inhibition.¹¹ Considerations when choosing therapy include patient preference, adherence to oral therapies, and challenges with self-administered delivery mechanisms.¹¹

Stakeholder Insights

The goal of treating patients with PNH is to improve hemoglobin levels, enhance quality of life, prevent thrombosis, and mitigate organ damage. Mulherin clarified that “not everybody with a PNH clone has clinical PNH and requires treatment,” elaborating how treatment is the level 1 recommendation for those who experience major symptoms associated with the primary or secondary effects of hemolysis. He categorized the treatments into 2 main types, including C5 inhibitors that affect the terminal complement and proximal complement blockers that target signaling higher in the complement cascade. Among proximal complement blockers, pegcetacoplan affects C3, “the central nexus around which much of disease management revolves,” whereas iptacopan is a factor B inhibitor, “which helps prevent C3 from being active and forming the C3 convertase,” Mulherin explained. The newest treatment, danicopan, is uniquely designed to be taken in conjunction with a C5 inhibitor for patients who remain anemic despite treatment. Mulherin noted that the differences in routes of administration and frequency, along with economic and logistical considerations, may influence treatment choice.

There are various efficacy end points that are significant in the clinical trials for PNH treatments. Dingli noted that these end points include measures such as LDH levels, hemoglobin concentrations, and transfusion avoidance. LDH is a key indicator of intravascular hemolysis control, with levels less than 1.5 times the upper limit of normal suggesting effective therapy. Hemoglobin improvement is crucial for patient well-being, as higher hemoglobin levels greatly enhance quality of life. Additionally, decreased bilirubin levels and reticulocyte counts indicate controlled hemolysis and reduced fatigue. Dingli emphasized that “reduction in the risk of thrombosis is a very important metric,” as thrombosis was a primary cause of early mortality in patients with PNH before complement inhibition therapies.

PNH therapies have evolved to target specific components of the complement cascade, reflecting our deepening understanding of the disease, Dingli explained. By blocking C5, eculizumab significantly reduces symptoms such as hemoglobinuria and anemia, lowers LDH levels, improves hemoglobin and reticulocyte counts, and increases red blood cell survival. Most importantly, it substantially reduces the risk of thrombotic events, the primary cause of death in patients with PNH. Dingli emphasized that “the patient with classic hemolytic PNH, who is adequately treated with a C5 inhibitor, can have a life expectancy that approaches, ifnot equal[s]…, that of age-matched controls, which is truly a remarkable achievement for the field.” Mulherin added that the approval of eculizumab in 2007 “revolutionized the treatment of this disease.” However, due to the extravascular hemolysis associated with C5 inhibition, pegcetacoplan was developed to block both intravascular and extravascular hemolysis by targeting C3. Recent advances have further explored the proximal pathway, leading to the introduction of iptacopan and danicopan. Dingli summarized that the drugs that are now available “target specific components of the complement cascade to block the formation of the membrane attack complex.”

Ravulizumab, which Koprivnikar described as the longer-acting version of eculizumab, has demonstrated noninferiority to eculizumab in studies 301 (NCT02946463) and 302 (NCT03056040). Koprivnikar explained that “ravulizumab may inhibit free C5 even a bit more potently than eculizumab does,” which could reduce episodes of breakthrough hemolysis.

Dingli discussed the approval of pegcetacoplan following the results of the PEGASUS (NCT03500549) and PRINCE (NCT04085601) trials. In the PEGASUS trial, pegcetacoplan was added to stable doses of eculizumab in patients with anemia, resulting in improved hemoglobin levels. Patients maintained their hemoglobin improvement when continuing pegcetacoplan, while those reverting to eculizumab saw their hemoglobin levels drop. Dingli noted that “clearly, the drug was able to control this phenomenon of extravascular hemolysis that presumably was present in these patients.” The PRINCE trial enrolled complement inhibitor–naive patients with PNH, and data showed that pegcetacoplan effectively controlled both intravascular and extravascular hemolysis, as well as improving hemoglobin levels. Dingli explained that “the risk associated with pegcetacoplan is breakthrough hemolysis,” especially in complement-amplifying conditions such as infections, trauma, or pregnancy, or after undergoing surgery or receiving vaccines. An episode of breakthrough hemolysis can lead to notable drops in hemoglobin levels, hemoglobinuria, anemia symptoms, and increased thrombotic risk.

Iptacopan was approved in December 2023 following the results of 2 phase 3 trials, APPLY-PNH (NCT04558918) and APPOINT-PNH (NCT04820530), representing the first oral drug for PNH, Mulherin explained. The APPOINT-PNH trial data showed that more than 90% of complement inhibitor–naive patients achieved the primary end point, increasing their hemoglobin level by at least 2 g/dL. Similarly, findings from the APPLY-PNH trial demonstrated that more than 70% of patients pretreated with ravulizumab or eculizumab reached this end point when they switched to iptacopan. Despite investigators’ theoretical concerns about breakthrough hemolysis, trial data indicated that such events were generally mild to moderate and well controlled. Mulherin added that, unexpectedly, iptacopan can affect lipid levels, causing increases in total cholesterol, low-density lipoprotein cholesterol, and triglycerides. Regular monitoring of lipid profiles is recommended for patients receiving iptacopan, but it is generally very well tolerated.

Among the recent “exciting FDA approvals for this ultrarare disease,” Koprivnikar noted that the agency approved danicopan in April 2024 as an add-on therapy based on the results of the phase 3 ALPHA trial (NCT04469465). She highlighted that danicopan improved hemoglobin levels and addressed clinically significant extravascular hemolysis when added to stable anti-C5 treatment in patients with PNH, while also reducing the risk of thrombosis.

Haumschild commented that the treatment options have “good efficacy and an overall manageable safety profile,” but noted the importance of considering patient adherence and the route of administration when selecting therapies for PNH. Koprivnikar emphasized the need for personalized treatment plans. She assesses a patient’s ability to adhere to different administration routes—oral, subcutaneous, or intravenous—before deciding on a plan. “It’s not a one-size-fits-all treatment, and it really comes down to pretty subtle and nuanced patient-based decisions and a lot of back-and-forth in conversation with…patients,” Koprivnikar explained. For newly diagnosed patients, she uses shared decision-making to discuss the various treatment options, routes of administration, and the long-term safety and efficacy data. For symptomatic patients already receiving complement inhibitor therapy, she confirms extravascular hemolysis and discusses the options, including add-on therapy with danicopan or monotherapy with iptacopan or pegcetacoplan.

Mulherin explained that several factors prompt discussions about switching therapies for patients already receiving treatment. Key considerations include the patient’s response and tolerance to the current therapy and socioeconomic factors. Mulherin agreed that confirming anemia is due to extravascular hemolysis is critical. If patients experience adverse effects, such as headaches from iptacopan or injection site reactions from pegcetacoplan, switching therapies might be beneficial. Mulherin indicated how crucial adherence issues are, as well as insurance and socioeconomic factors. “Ideally, you want to pick the best drug for the patient, the best fit for them from day 1…so you don’t have to go through this switching exercise for multiple therapies,” he emphasized.

Dingli highlighted major advancements in the treatment landscape of PNH and other complement inhibitor–related rare diseases, noting the growing recognition and manipulation of complement systems. He emphasized that treatments have evolved from targeting C5 to C3 to other proximal inhibitors, with investigational oral agents showing promise. Dingli noted, “The idea of a proximal inhibitor with an oral agent seems quite attractive,” especially for patients who may benefit from the convenience of oral therapy. “I do not see a big issue with [adherence to] proximal inhibitors because…patients generally do not feel very well,” he added. Dingli also mentioned ongoing developments in gene therapy, which could allow for biannual treatments by enabling the liver to produce monoclonal antibodies targeting C3.

Financial Factors and the Future of PNH Treatment

Patients treated with eculizumab face a substantial disease burden, resulting in substantial health care costs from the payer perspective.²⁴ Findings from a real-world claims data study of 151 US patients receiving eculizumab from 2014 to 2019 revealed that more than one-third remained dependent on transfusions despite treatment.²⁴ Transfusion-dependent patients incurred greater clinical and economic burdens, with annual hospitalization costs nearly $250,000 higher than those of transfusion-free patients.²⁴ Results from a second retrospective claims data analysis from 2016 to 2020 of 271 patients with PNH demonstrated that only 25% of newly diagnosed patients received a PNH-specific pharmacologic treatment, with an average time from diagnosis to treatment of 4.7 months.²⁵ Adherence to treatment was high, yet more than half of patients discontinued therapy. Average costs per patient per month were $18,978, primarily driven by pharmacy and infusion, outpatient, and inpatient costs.²⁵ Despite treatment availability, 40% of patients had an inpatient stay, and 51% had an emergency department visit.²⁵

These data underscore the need for better care management and new treatment options to address delays in treatment, frequent transfusions, high hospitalization, and emergency department use.^24,25 They also reflect treatment patterns, health care resource utilization, and costs before the introduction of proximal complement inhibitors, which hold promise for reducing disease burden and associated expenses upon their integration into clinical practice.^24,25 To further reduce costs in treating PNH, biosimilars have been developed.¹¹ The recent approval of eculizumab-aeeb, the first biosimilar for PNH, enhances patient access to more affordable treatments.²⁶ As newer therapies and biosimilars become more widely available, the overall cost for treating patients with PNH is expected to decrease.

Stakeholder Insights

A typical patient journey does not exist for individuals with PNH, as each case presents a unique set of diverse symptoms, Koprivnikar explained. “Delays in diagnosis tend to be the rule rather than the exception...owing to the fact that PNH is such a rare disease and the fact that patients really present with a diverse range of symptoms.” Once diagnosed, patients have several up-front options available, including eculizumab, ravulizumab, pegcetacoplan, and iptacopan. Koprivnikar emphasized the importance of educating patients, indicating that “understanding [the disease] will reinforce the need for [adherence] in this potentially deadly and fatal disease.” After discussing each therapy with patients, she begins the required vaccinations and insurance authorizations before starting treatment. “All…the companies that have had FDA-approved agents are committed to treating this rare group of patients and trying to pave the way forward in terms of insurance authorization and drug access and reimbursement,” Koprivnikar added. Once therapy is initiated, Koprivnikar follows patients closely to monitor their response. “What’s really amazing is that if the therapy isn’t working for a particular individual, we can troubleshoot, we can switch therapies, we can add therapies,” she remarked.

For patients receiving treatment, Mulherin explained that “[the need for transfusions] should be a red flag to the person treating the PNH. If a person is still requiring transfusions outside of the context of a significant complement-amplifying condition, there’s a problem. And you really need to look at changing therapy.” Transfusion avoidance or reduction has been a key end point in clinical trials. Haumschild agreed, noting how vital it is to be aware of external transfusions, which are often recorded in the electronic medical record.

To monitor patients with PNH, assess treatment effectiveness, and manage potential complications, Dingli performs a comprehensive monitoring protocol. This includes regular complete blood count tests for hemoglobin, white blood cells, and platelets to assess anemia and bone marrow failure; reticulocyte counts to distinguish between bone marrow failure and ongoing hemolysis; and LDH and bilirubin levels to differentiate hemolysis types. He also monitors kidney and liver function, serum ferritin for iron deficiency, D-dimer for thrombotic risk, and flow cytometry for clone size. Baseline and periodic abdominal ultrasounds help detect silent thrombotic events. Tests are conducted at baseline and intervals of 3 to 6 months, with additional lipid profiles for treatments like iptacopan.

Koprivnikar emphasized that although having multiple treatment options for PNH is beneficial, each drug carries potential risks. She noted, “These drugs are available only through REMS, a risk evaluation and mitigation strategy program, because of this risk of infection with encapsulated organisms [due to complement inhibition], and it is required that all patients receive a certain number of vaccinations.” Koprivnikar stressed the importance of initial vaccinations and continuous revaccination and boosters over time, following Advisory Committee on Immunization Practices guidelines. She ensures patients carry a wallet card indicating their risk for infections, which they can present in emergencies. Koprivnikar remains “vigilant about reviewing that a patient’s vaccinations are up to date and also reviewing the signs and symptoms for which a patient should be seeking immediate medical attention.”

Mulherin echoed Koprivnikar’s sentiment that manufacturers are helpful, assisting with prior authorization and quick start programs and accommodating patients’ schedules. He added that his group partners with dispensing pharmacies, which allows for better monitoring and easier access to medications. He emphasized the benefits of medically integrated dispensing, where pharmacists oversee the patient’s medication regimen, stating that it “assures a much more seamless experience and is much easier for the patients to obtain the medication.” Haumschild agreed, citing a study whose data showed that patients with access to internal dispensing had 25% better adherence and faster treatment initiation than with external dispensing.

Ensuring patient adherence is challenging to monitor, highlighting the importance of involving caregivers to support patients in their treatment journey. Koprivnikar pointed out that pharmaceutical companies provide various resources to help with adherence, such as setting up anti-C5 infusions in different locations, providing nurses to assist with anti-C3 infusions at home, and offering programs for patients taking oral therapies. “We really want to take advantage of the resources that the pharmaceutical manufacturers have provided us [with], which I think are substantial,” she remarked. Additionally, practical strategies such as using pill boxes, phone timers, and reminders can help patients stay adherent to their medications.

Financial considerations have a major influence on treatment decisions for PNH. Mulherin noted that “these drugs are not inexpensive. Eculizumab had the dubious distinction of being the most expensive drug on the planet for several years running.” Unlike in Europe and Australia, in the United States, patients rarely face access issues due to manufacturer co-pay assistance programs. However, high out-of-pocket costs can still be a barrier, particularly as patients age and transition to Medicare. The Inflation Reduction Act may help reduce these costs as may the development of biosimilars for more affordable pricing. Mulherin emphasized the importance of choosing the right drug from the start, considering the long-term financial and therapeutic implications for the patient.

PNH is often diagnosed in young patients, affecting them during their prime working years and resulting in a major loss of life quality and economic productivity. Mulherin explained that “[PNH] is something that’s going to require ongoing, indefinite therapy. And yes, there is a hefty price tag with it, but in order to provide these patients [with] optimal care to keep them alive, to prevent them from having thrombosis, that is what’s required.” Mulherin also highlighted the substantial research and development efforts in this field, suggesting hope for the future. He noted that insights from PNH research can benefit other medical areas, including cardiovascular disease.

Dingli emphasized that “when we have therapies that can essentially turn a life-threatening disease into a disease with a normal life span, then we cannot afford to miss it,” even if it is a rare disease. He added that diagnosing PNH is not difficult if one considers the disorder, recommending flow cytometry for any patient with Coombs-negative hemolytic anemia. Dingli acknowledged the high cost of the drugs but stressed their pivotal impact on altering the natural history of disease, improving patients’ quality of life, and enabling them to remain productive, which should be considered in the overall economic evaluation.

Koprivnikar acknowledged that although there are many effective treatments for PNH, several questions remain. She emphasized the need to determine optimal hemoglobin levels and evidence-based breakthrough hemolysis management strategies. Koprivnikar stressed the importance of ongoing research and data collection, supported by pharmaceutical sponsors, to address these unanswered questions for this rare but sizable group of patients. •

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26. FDA approves first interchangeable biosimilar for two rare diseases. News release. FDA. May 28, 2024. Accessed June 7, 2024. https://www.fda.gov/news-events/press-announcements/fda-approves-first-interchangeable-biosimilar-two-rare-diseases