Evidence report on PNH treatments Fabhalta, danicopan released

ICER: Concerns remain about both therapies' long-term efficacy, safety

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by Steve Bryson PhD |

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Fabhalta (iptacopan) and danicopan are two first-in-class treatments for paroxysmal nocturnal hemoglobinuria (PNH) that provide important health benefits in clinical trials, but uncertainties remain regarding their long-term efficacy and safety.

That’s according to an evidence report from the Institute for Clinical and Economic Review (ICER), an independent nonprofit research institute that reports on the effectiveness and value of medicines and other medical services. It evaluated the comparative effectiveness of the two therapies.

PNH is caused by the abnormal activation of a group of immune proteins that make up the complement cascade, leading to the destruction of red blood cells (hemolysis).

Ultomiris (ravulizumab) and Soliris (eculizumab) are two therapies approved for PNH to help prevent blood cell destruction. They target a complement protein called C5 to stop complement activation.

Despite their effectiveness, about 20% of patients still require blood transfusions due to extravascular hemolysis (EVH), which refers to instances where red blood cells are destroyed outside blood vessels. The medicines also come at a high cost.

“PNH is a rare, acquired blood disorder that primarily manifests in fatigue, and if severe, requires lifelong dependence on blood transfusions,” Foluso Agboola, ICER’s vice president of research, said in a press release. “Complement C5 inhibitors, the current standard of care, have transformed this condition. However, C5 inhibitors are extremely costly, and patients, patient advocates, and clinical experts uniformly expressed concern about the access and affordability of these lifelong PNH treatments.”

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What is Fabhalta?

Approved in the U.S. in December 2023 for all PNH patients, Fabhalta is an oral therapy that suppresses factor B, another complement protein that acts upstream of C5 in the complement cascade. Unlike C5 inhibitors, Fabhalta should help prevent blood cell destruction inside and outside blood vessels.

Fabhalta’s approval was supported by data from two Phase 3 clinical trials: APPOINT-PNH (NCT04820530) and APPLY-PNH (NCT04558918). APPOINT-PNH enrolled 40 previously untreated PHN patients and most achieved a substantial response. Data from APPLY-PNH, which enrolled 97 treatment-experienced patients with clinically significant EVH, showed Fabhalta was associated with improved responses compared with continuing treatment with a C5 inhibitor.

The two small studies didn’t ease concerns about the risk of breakthrough hemolysis and thrombosis (blood clotting events). For previously untreated patients, ICER rated the evidence for Fabhalta as insufficient, due to the lack of comparative efficacy data versus a C5 inhibitor.

For patients on a stable C5 regimen with clinically significant EVH, ICER rated the evidence for Fabhalta versus continuing treatment with a C5 inhibitor as promising for moderate to substantial net benefit. They also rated it as inconclusive, due to the uncertainty about its long-term benefit and safety, especially regarding hemolysis and thrombosis.

Fabhalta carries a list price of $550,377 per year. ICER’s cost modeling suggests it needs to be priced 70% lower — between $156,000 and $157,000 annually — to meet commonly accepted thresholds for cost-effectiveness, a measure that includes both the costs and associated health outcomes.

How does danicopan work in PNH?

Danicopan is an oral therapy under review by regulatory authorities in the U.S. and the European Union. It was recently approved in Japan, where it’s marketed as Voydeya, as an add-on therapy for patients who don’t adequately respond to C5 inhibitors.

Danicopan blocks a different complement protein, called factor D, and is designed to control EVH while not interfering with C5 inhibitors that control red blood cell destruction within blood vessels.

Evidence for danicopan’s efficacy was supported by the Phase 3 ALPHA trial (NCT04469465). Among the treatment-experienced patients with clinically significant EVH who participated in it, danicopan substantially improved responses as an add-on over a placebo.

Although the trial was small, because the therapy was well tolerated when combined with C5 inhibitors, ICER rated danicopan comparable to or better than continuing treatment with a C5 inhibitor. Because it hasn’t been approved in the U.S., its manufacturer hasn’t announced its list price. ICER’s model suggests the price would need to be anywhere between $12,300 and $13,100 annually to be cost-effectiveness.

On Feb. 16, the report will be reviewed at a virtual public meeting of the California Technology Assessment Forum (CTAF), one of ICER’s three independent committees made up of medical science experts, practicing clinicians, and patient engagement and advocacy leaders.

“[Fabhalta] (as an alternative to C5 inhibitor therapy) and danicopan (as an add-on to a C5 inhibitor) are promising new oral options for PNH patients. We look forward to our public meeting at which all stakeholders can discuss the evidence for these new treatments, the tensions created by the cost of the current standard of care, and the extent to which the high costs of C5 inhibitors should drive considerations of fair pricing for new PNH treatments,” Agboola said.