New Treatments & Payer Considerations for Paroxysmal Nocturnal Hemoglobinuria
By: Emily Crisano, PharmD, R.Ph., and Jason Peterson, R.Ph.
Paroxysmal nocturnal hemoglobinuria (PNH) is an ultra-rare, genetic blood disorder affecting the hematopoietic stem cells. The name itself reveals its nature: "paroxysmal" means sudden, "nocturnal" refers to night, and "hemoglobinuria" indicates the presence of hemoglobin in the urine. This condition affects both men and women equally, with approximately 13 out of every million people in the United States diagnosed—totaling around 5,000 cases, and about 400 to 500 new cases each year. Most patients are between 30 and 40 years old.
The hallmark symptom of PNH is dark-colored urine, typically noticed during late-night or early-morning trips to the bathroom. This occurs because the body mistakenly attacks its own red blood cells, breaking them down and excreting them in the urine—a process known as hemolysis. There are two types of hemolysis in PNH: intravascular (IVH), where red blood cells are destroyed within the blood vessels, and extravascular (EVH), where destruction occurs outside the blood vessels, such as in the spleen.
Patients with PNH often experience fatigue, shortness of breath, and abdominal pain. The condition is also linked to anemia-related issues, bone marrow suppression, and thrombosis (blood clots), the latter being the leading cause of death in PNH patients, accounting for 40% to 70% of known cases.
Before the advent of current pharmacological treatments, life expectancy for PNH patients was 10 to 20 years. However, with the introduction of complement inhibitors, life expectancy has significantly improved, now comparable to that of individuals without the condition.
Established Treatments
For patients without intense symptoms of hemolysis, management typically involves watchful waiting along with supportive care. For those with PNH who also suffer from severe bone marrow failure, the preferred approach is to evaluate them for allogeneic hematopoietic cell transplantation (HCT).
Complement Inhibitors
In cases of hemolytic PNH, where patients exhibit symptoms of hemolysis, the treatment of choice is a complement inhibitor such as Ultomiris, Soliris, and Empaveli. Complement inhibitors have shown greater efficacy in controlling hemolysis, preventing thrombosis, and managing pain compared to HCT and supportive care. However, these treatments must be continued indefinitely, are costly, and do not address PNH-associated aplastic anemia (AA) or myelodysplastic syndrome (MDS). All these therapies carry a Black Box Warning for serious and life-threatening infections and require Risk Evaluation and Mitigation Strategy (REMS) enrollment.
Ultomiris (ravulizumab) and Soliris (eculizumab) are known as complement C5 inhibitors. Clinical trials have shown they are well-tolerated and effective in managing symptomatic hemolytic PNH. These inhibitors reduce PNH-related symptoms, alleviate transfusion dependence, prevent thrombosis, and provide pain relief.
Ultomiris has a significantly longer half-life than Soliris, allowing for longer dosing intervals and reduced overall costs.
Soliris is administered intravenously every two weeks, whereas Ultomiris is given every eight weeks.
Soliris has a wholesale acquisition cost (WAC) of $508,794 annually and Ultomiris, has an annual cost of $447,886.
Ultomiris is often preferred over Soliris due to its convenience, lower cost, and fewer episodes of pharmacokinetic breakthrough hemolysis.
Empaveli (pegcetacoplan) is a peptide targeting complement C3, inhibiting both intravascular (IVH) and extravascular hemolysis (EVH). Unlike Soliris and Ultomiris, which only inhibit IVH, Empaveli can manage both types of hemolysis. This reduces the likelihood of patients needing transfusions to manage anemia. In clinical trials, 85% of patients on Empaveli avoided transfusion compared to only 15% on Soliris. Empaveli can be self-administered as a subcutaneous infusion every three days or via a single-use self-injector. It is priced at $488,251 (WAC) per year.
New Treatments
Fabhalta (iptacopan), introduced as the first oral complement inhibitor, was approved in December 2023 for adults with PNH. In trials, Fabhalta demonstrated superiority over Soliris and Ultomiris in sustaining hemoglobin levels without transfusions. In a head-to-head trial, Fabhalta achieved a 95.2% transfusion avoidance rate compared to 45.7% for Soliris and Ultomiris. This efficacy, combined with its convenience, has a premium price of $549,997 annually (WAC).
Voydeya (danicopan) was approved in March 2024 as an add-on therapy to Ultomiris or Soliris for treating EVH in adults with PNH. It is estimated that 10-20% of patients taking Ultomiris or Soliris will exhibit clinically significant EVH and require transfusion. Voydeya, a complement factor D inhibitor, is taken orally three times daily and would reduce the need for transfusions. Clinical trials showed that adding Voydeya to Ultomiris or Soliris significantly increased hemoglobin levels by Week 12, with almost 60% of patients achieving increased hemoglobin levels without transfusions and nearly 80% avoiding transfusions altogether. . Voydeya is priced at $50,261 annually (WAC), which is incremental to the costs of Ultomiris or Soliris.
Fabhalta and Voydeya also require REMS enrollment due to a Black Box Warning for serious and life-threatening infection. Future trials are needed to compare the clinical benefits of Voydeya combined with a C5 inhibitor versus Empaveli and versus Fabhalta. In addition, a cost-benefit analysis to determine which therapy regimen (Ultomiris/Soliris plus Voydeya vs. Empaveli vs. Fabhalta) provides greater value.
Future Treatments
The treatment pipeline for PNH is expanding, with manufacturers exploring alternative pathways to manage PNH while minimizing side effects.
RG6107 (crovalimab), expected to be approved in July 2024, is a novel C5 inhibitor that offers sustained complement inhibition through low-dose, subcutaneous administration every four weeks. The Phase III COMMODORE 2 study found crovalimab to be non-inferior to Soliris in controlling hemolysis and avoiding transfusions. It can be self-administered.
Veopoz (pozelimab) and LN-CC5 (cemdisiran) are being developed as a combination therapy for PNH. Veopoz, approved in August 2023 for Chaple disease, is a monoclonal antibody inhibitor of C5, while cemdisiran suppresses liver production of C5. A study showed that after switching from Soliris, none of the patients on this combination therapy experienced breakthrough hemolysis, and most did not require transfusions.
NM5072 (ruxoprubart) is an investigational anti-Bb humanized antibody that targets the alternative pathway, preventing extra- and intravascular hemolysis. Phase 1 trials confirmed its specificity to the alternative pathway without affecting the classical pathway.
KP104 is a first-in-class bifunctional biologic that inhibits both alternative and terminal complement pathways. Administered subcutaneously every two weeks, it showed promising results in a Phase 2 trial, with over 50% of patients achieving hemoglobin normalization without transfusions.
Biosimilar Market Entry
Biosimilars for PNH agents are beginning to make their way into the U.S. market, promising more affordable options for patients. As of May 2024, Bkemv became the first biosimilar to receive FDA approval as an alternative to Soliris. However, due to a settlement with Alexion Pharmaceuticals, Amgen will not release Bkemv in the U.S. until 2025. Meanwhile, Bkemv has been available in Europe since April 2023, providing an effective and lower-cost option for patients there.
Another promising biosimilar is SB12, marketed in Europe under the brand name Epysqli since May 2023. SB12 is currently under review by the FDA. If approved, it will offer another cost-effective treatment alternative for PNH patients in the U.S., further increasing accessibility and potentially reducing the financial burden associated with PNH treatments.
Payer Concerns
The choice between each treatment will be determined based on cost, efficacy, side effect profile, and patient tolerability. Fabhalta, Voydeya and Empaveli fall under the pharmacy benefit, while Ultomiris and Soliris are part of the medical benefit. Notably, Voydeya can only be used as an add-on agent for either Ultomiris or Soliris.
Given the complexity and high cost of PNH treatment, prior authorization will likely be required for all agents. Clinical criteria for prior authorization should consider factors such as patient age, diagnosis, specialty prescribing (oncologist/hematologist), enrollment in safety programs (such as REMS where applicable), and ensuring patients are up to date on vaccinations to avoid additional infections.
PNH is an expensive disease requiring meticulous clinical care to manage symptoms and progression effectively. Although the cost of medications may remain high as manufacturers develop alternative pathways for PNH treatment, there is hope that the entrance of biosimilars will make maintenance medications more affordable for patients. The future of PNH treatment will continue to evolve as new products are developed and introduced, offering promise for improved patient outcomes and reduced financial burden.
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