FDA approves Fabhalta as first oral therapy for PNH

Novartis' treatment, previously known as iptacopan, should be taken twice daily

Lindsey Shapiro, PhD avatar

by Lindsey Shapiro, PhD |

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The U.S. Food and Drug Administration (FDA) has approved iptacopan for the treatment of adults with paroxysmal nocturnal hemoglobinuria (PNH). It will be sold under the brand name Fabhalta.

As the first oral monotherapy approved for the rare condition in the U.S., Fabhalta is expected to become available to eligible patients in December, according its developer, Novartis. It is indicated for both previously treated and treatment-naïve patients.

Additional regulatory filings are underway in other parts of the world.

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“The U.S. approval of Fabhalta is an extraordinary moment for people living with PNH, their loved ones and the healthcare providers who care for them,” Victor Bultó, president of Novartis in the U.S., said in a press release.

“This new, effective oral medicine may mean that patients can reset their expectations of living with PNH, a chronic and life-altering blood disease,” Bultó added.

As in clinical trials, the therapy will be taken as oral capsules (200 mg) twice daily with or without food. It should not be used by patients who have experienced serious allergic reactions to any of the ingredients in Fabhalta, or by people with unresolved infections caused by certain bacteria.

Fabhalta may lower the immune system’s ability to fight infections. Due to the risk for serious and potentially life-threatening bacterial infections while using the therapy, Fabhalta is available only through a restricted access program called Risk Evaluation and Mitigation Strategy (REMS). This requires that all patients who will take the medication first receive vaccinations against encapsulated bacteria.

In PNH, a part of the body’s immune system called the complement system, mistakenly attacks the body’s own red blood cells. Their destruction, called hemolysis, leads to symptoms of anemia, which occurs when there is lack of red blood cells available to carry oxygen to body tissues.

Soliris (eculizumab) and Ultomiris (ravulizumab), two of the main treatments currently available for PNH, both act to inhibit C5, a complement protein. In doing so, these treatments effectively inhibit intravascular hemolysis, or red blood cell destruction occurring inside blood vessels, thereby easing anemia.

Yet, some patients continue to experience anemia while on these therapies and still depend on blood transfusions to supply them with healthy red blood cells. This persistent anemia could be related to a failure to control extravascular hemolysis, when red blood cell destruction occurs outside blood vessels, in organs such as the liver and spleen.

How Fabhalta works

Fabhalta is designed to inhibit factor B, another complement protein that acts upstream of C5 in the complement cascade. By specifically targeting this earlier stage of complement activation, Fabhalta is thought to be able to prevent both intravascular and extravascular hemolysis. The first-in-class therapy now is the only FDA-approved treatment that targets factor B.

Fabhalta’s approval was based on data from two Phase 3 clinical trials: APPLY-PNH (NCT04558918), and APPOINT-PNH (NCT04820530).

APPLY-PNH enrolled 97 adults with PNH and residual anemia despite ongoing treatment with standard-of-care Soliris or Ultomiris. Participants were assigned randomly to receive twice-daily oral Fabhalta or to continue receiving intravenous (into-the-vein) standard care for about six months.

Fabhalta significantly outperformed standard care in its ability to boost the levels of hemoglobin — the protein in red blood cells that carries oxygen and is used as a standard measure of anemia.

Specifically, more participants on Fabhalta achieved clinically meaningful increases in hemoglobin levels — an increase of at least 2 grams per deciliter (g/dL) — without the need for blood transfusions (82.3%), than patients who continued on anti-C5 treatment (0%).

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Moreover, about two-thirds (67.7%) of patients in the Fabhalta group reached hemoglobin levels of at least 12 g/dL without transfusions, whereas none in the control group did. Nearly all Fabhalta-treated patients (95.2%) avoided transfusions altogether, compared with 45.7% in the standard care group.

In APPOINT-PNH, 40 adults with PNH who had never received any complement inhibitor therapy (treatment-naïve) were treated with Fabhalta for six months. Results here were similar, with 77.5% of participants achieving at least a 2 g/dL increase in hemoglobin after six months.

Side effects of Fabhalta

Common side effects associated with Fabhalta include headache, cold-like symptoms, diarrhea, abdominal pain, bacterial infections, nausea, viral infections, and rash.

“An efficacious oral treatment with a demonstrated safety profile could be practice-changing for physicians and help relieve burdens experienced by people with PNH,” said Vinod Pullarkat, MD, clinical professor at the City of Hope research center in California.

Novartis also is moving forward with developing Fabhalta for other complement-mediated diseases, including lupus nephritis, atypical hemolytic uremic syndrome, and others.

“As Novartis continues to focus on conditions with unmet patient need, we are exploring the potential of Fabhalta in other complement-mediated diseases — with an ultimate goal to drive meaningful change for patients,” Bultó said.