ICER committee in favor of add-on danicopan for PNH, pending pricing

No evidence shown for net health benefit of Fabhalta over C5 inhibitor

Margarida Maia, PhD avatar

by Margarida Maia, PhD |

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An independent appraisal committee voted that there was adequate evidence to show that adding danicopan to a C5 inhibitor may benefit certain people with paroxysmal nocturnal hemoglobinuria (PNH), pending price listing.

Committee members also decided the evidence isn’t adequate to show a net health benefit for Fabhalta (iptacopan) over a C5 inhibitor. At its current pricing, Fabhalta may represent “low” long-term value for money, the committee found in a final evidence report released by the Institute for Clinical and Economic Review (ICER), a nonprofit that reviews treatments to determine their value, helping patients, doctors, and policymakers make informed healthcare decisions.

PNH occurs when the complement system, a part of the immune system, wrongly attacks and breaks down blood cells, particularly red blood cells. This results in anemia, or too few red blood cells carrying oxygen to tissues.

Medications approved for PNH include Soliris (eculizumab) and Ultomiris (ravulizumab), which block complement activation by targeting C5, a complement protein. Not everyone responds adequately to these medications, however. Some patients continue to have symptoms like fatigue, which, “if severe, requires lifelong dependence on blood transfusions,” Foluso Agboola, ICER’s vice president of research, said in a press release. “[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. … However, there are still uncertainties around the long-term benefits of both therapies.”

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Fabhalta study results

Approved in the U.S. in late 2023, Novartis’ Fabhalta is an oral medicine that inhibits another complement protein called factor B, which acts upstream of C5 in the complement cascade.

Unlike C5 inhibitors, Fabhalta should prevent red blood cell breakdown inside blood vessels (intravascular hemolysis) and outside blood vessels (extravascular hemolysis). Extravascular hemolysis, or EVH, is considered clinically significant when it calls for regular blood transfusions.

Fabhalta’s approval was based on results of two six-month Phase 3 clinical trials. In the single-arm APPOINT-PNH (NCT04820530) study, the majority of 40 previously untreated PNH patients had sustained increases in hemoglobin, the protein that carries oxygen in red blood cells.

In APPLY-PNH (NCT04558918), which included 97 treated PNH patients who were on a C5 inhibitor for at least six months, Fabhalta was better than standard of care with the C5 inhibitor at increasing hemoglobin without a need for blood transfusions.

But the committee voted 12-1 that the evidence isn’t adequate to show a net health benefit for Fabhalta over a C5 inhibitor in untreated patients, mainly over concerns that APPOINT-PNH lacked a comparison arm. The committee also vote 7-6 that the evidence doesn’t show a net health benefit for switching to Fabhalta over continuing on a C5 inhibitor in treated patients with clinically significant EVH.

The committee found that at a list price of $550,377 per year, Fabhalta represents “low” long-term value for money. An economic analysis suggested it should be priced between $178,000 and $180,000 annually for its cost to be considered fair based on how well it works.

Decision about danicopan

Voydeya (danicopan) was approved in Japan earlier this year as an add-on treatment for PNH patients who fail to respond well to C5 inhibitors. In the European Union, marketing authorization has been recommended for patients with residual anemia despite C5 inhibitors.

An oral medication from Alexion, AstraZeneca Rare Disease, danicopan blocks factor D, a complement protein. It’s designed to control EVH while not interfering with how well Soliris or Ultomiris work to control intravascular hemolysis.

Based on results of a Phase 3 clinical trial, the panel voted 10-3 that a net health benefit was demonstrated for adding danicopan to a C5 inhibitor compared with a C5 inhibitor alone.

In that trial, called ALPHA (NCT04469465), adding danicopan to a C5 inhibitor led to better control of anemia than an add-on placebo in PNH patients with clinically significant EVH who’d been treated.

“As indicated by the votes from the independent appraisal committee, the current evidence was judged more favorably for add-on danicopan in treatment-experienced PNH patients with anemia,” Agboola said.

Because danicopan is under regulatory review in the U.S., its price is not known. An economic analysis suggested a fair price as an add-on to a C5 inhibitor would be between $12,300 and $13,100 annually.

When compared with Empaveli (pegcetacoplan), which was approved for PNH in the U.S. in 2021, neither Fabhalta nor danicopan have adequate backing evidence to show an extra health benefit, according to the committee.

A draft version of this report was reviewed in February at a public meeting of the California Technology Assessment Forum (CTAF), one of ICER’s three independent evidence appraisal committees.

“The discussion during the public meeting highlighted the impact of high costs associated with C5 inhibitors — the current standard of care for PNH — on accessibility and affordability, and its effect on the pricing of new PNH therapies,” Agboola said.