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Paroxysmal nocturnal hemoglobinuria | ICER Report | US Payer | 2024 | iPharmaCenter

Paroxysmal nocturnal hemoglobinuria (PNH) presents as a rare blood disorder marked by the persistent destruction of red blood cells (hemolytic anemia) and the formation of blood clots (thrombosis). Hemolytic anemia chiefly occurs through fatigue and can necessitate ongoing reliance on blood transfusions in severe cases. Thrombosis stands as the leading cause of mortality.


PNH has a prevalence ranging from 10 to 20 cases per million individuals and predominantly affects adults, with no discernible bias towards sex, race, ethnicity, or geography. The condition arises from the uncontrolled activation of the immune system's complement pathway, leading to hemolysis. C5 inhibitor therapy has revolutionized PNH management by significantly mitigating intravascular hemolysis, thrombosis, and mortality rates, aligning life expectancies with age-matched controls.


Clinical experts advocate for the use of FDA-approved intravenous C5 inhibitors, such as eculizumab or ravulizumab, administered every 2 or 8 weeks, respectively, for symptomatic PNH cases, constituting the majority of patients.

Ravulizumab is preferred over eculizumab due to its extended half-life, resulting in fewer incidences of breakthrough hemolysis and lower treatment costs.

However, approximately 20% of patients remain dependent on transfusions due to extravascular hemolysis resulting from C5 inhibitor therapy.


Pegcetacoplan, another FDA-approved treatment option for PNH, administered subcutaneously twice weekly, effectively prevents both intra and extravascular hemolysis. Yet, its use is predominantly reserved for patients on stable C5 inhibitor regimens with clinically significant extravascular hemolysis due to concerns regarding increased risk of breakthrough intravascular hemolysis and potential thrombosis.

Iptacopan and danicopan represent two novel proximal complement inhibitors.

Iptacopan, an oral Factor B inhibitor administered twice daily, received FDA approval on December 6, 2023, for the treatment of all PNH patients. Conversely, danicopan, an oral Factor D inhibitor taken thrice daily, is under consideration by the FDA as an adjunct therapy to C5 inhibitors, specifically for treatment-experienced patients on stable C5 inhibitor regimens with clinically significant extravascular hemolysis.

Clinical evaluation of iptacopan in two small 24-week trials, namely APPOINT-PNH and APPLY-PNH, demonstrated significant hematologic response in both treatment-naïve and treatment-experienced patients, respectively.

Iptacopan achieved primary endpoints of increased hemoglobin levels without transfusions and exhibited few serious adverse events, reinforcing its potential as a promising therapeutic option for PNH management.


The ALPHA trial, a 12-week placebo-controlled randomized controlled trial (RCT) involving 86 treatment-experienced patients with clinically significant extravascular hemolysis (EVH), served as the primary source of evidence for the efficacy of adding danicopan. At the time of this report's publication, data was available for only approximately the initial 75% of the randomized population (n=63). The addition of danicopan notably enhanced hematologic response compared to placebo, demonstrating a significant increase in hemoglobin levels from baseline between the groups (+2.4 g/dL, p<0.001), along with secondary outcomes indicating a higher percentage of patients achieving increased hemoglobin levels ≥2 g/dL from baseline without requiring transfusions (60% versus 0%) and experiencing reduced fatigue. Danicopan exhibited minimal serious adverse effects.


Due to variations in treatment options and trial methodologies, we evaluated the clinical evidence separately for treatment-naive and treatment-experienced populations with paroxysmal nocturnal hemoglobinuria (PNH). For iptacopan, the findings from two small-scale studies of short duration failed to alleviate experts' concerns regarding the risk of breakthrough intravascular hemolysis and thrombosis. In treatment-naive PNH patients, the evidence for iptacopan was deemed insufficient ("I") due to the absence of comparative efficacy data against C5 inhibitors, which are considered the standard of care.


In contrast, for treatment-experienced PNH patients on a stable C5 inhibitor regimen with clinically significant EVH, the evidence for Iptacopan versus continuation of a C5 inhibitor was categorized as promising for moderate to substantial overall benefit but remained inconclusive ("P/I") due to uncertainties regarding long-term efficacy and safety, particularly concerning breakthrough hemolysis and thrombosis, which are less common but more severe complications. Additionally, despite acknowledging its oral formulation's convenience, the lack of comparative efficacy data against pegcetacoplan led us to rate the evidence for iptacopan versus pegcetacoplan as insufficient ("I").


The addition of danicopan to a C5 inhibitor was generally well-received by patients and clinicians, as it provided dual protection against both intra and extravascular hemolysis and offered greater assurance against thrombosis. However, concerns regarding costs were raised. Despite the small scale and short duration of the trial, danicopan combined with C5 inhibition was considered comparable or superior to the continuation of a C5 inhibitor alone for treatment-experienced PNH patients with clinically significant EVH (rated as C++). Nonetheless, due to the lack of comparative efficacy data, the evidence for adding danicopan to a C5 inhibitor versus pegcetacoplan was deemed insufficient ("I").


We constructed a novel decision analytic model to assess the cost-effectiveness of iptacopan compared to ravulizumab and the addition of danicopan to ravulizumab alone in treatment-experienced PNH patients with clinically significant extravascular hemolysis, from a healthcare perspective. Treatment with iptacopan, when compared to ravulizumab, resulted in marginal gains in Quality-Adjusted Life Years (QALYs) and equivalent Life Years (LYs). However, at the yearly placeholder cost of $550,377, iptacopan treatment incurred higher expenses than ravulizumab, yielding an estimated incremental cost-effectiveness ratio of $1,368,000 per QALY or LY gained. ICER analysis concluded that in instances where a significant portion of the traditional Health Benefit Price Benchmark (HBPB) stems from cost offsets of therapies whose prices do not align with patient benefits, shared savings calculations are deemed more appropriate as HBPBs. Approximately 94% of iptacopan's traditional HBPB originates from offsetting the costs of C5 inhibitor therapies, which are believed to have prices misaligned with patient benefits. Under the shared saving scenario with a $150,000 annual cap on cost offsets, the HBPB for iptacopan ranges from $156,000 to $157,000 annually.


In the comparison between adding danicopan to ravulizumab versus ravulizumab alone, the former resulted in slight improvements in QALYs and LYs with the same number of LYs. However, at the assumed placeholder cost of $150,000 per year, adding Danicopan incurred significantly higher expenses. At this assumed cost, the incremental cost-effectiveness ratio for adding danicopan was $9,457,000 per QALY or LY gained. The HBPB for danicopan as an add-on therapy to a C5 inhibitor ranged from an annual price of $12,300 to $13,100.

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