Novartis announced FDA approval for Fabhalta

Novartis (NYSE: NVS) today announced that the U.S. Food and Drug Administration (FDA) approved Fabhalta^® (iptacopan) as the first oral monotherapy for the treatment of adults with paroxysmal nocturnal hemoglobinuria (PNH)¹. Fabhalta is a Factor B inhibitor that acts proximally in the alternative complement pathway of the immune system, providing comprehensive control of red blood cell (RBC) destruction within and outside the blood vessels (intra- and extravascular hemolysis [IVH and EVH]). In clinical trials, treatment with Fabhalta increased hemoglobin levels (≥ 2 g/dL from baseline in the absence of RBC transfusions) in the majority of patients and in APPLY-PNH nearly all patients treated with Fabhalta did not receive blood transfusions^1-5.

"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, MRCP, Clinical Professor, Department of Hematology and Hematopoietic Cell Transplantation, City of Hope. "In clinical studies, iptacopan was superior to anti-C5s in hemoglobin improvement in the absence of RBC transfusion and transfusion avoidance rate, and also effective in complement inhibitor-naïve individuals, by providing clinically meaningful hemoglobin-level increases without the need for blood transfusions."

The FDA approval is based on the Phase III APPLY-PNH trial in patients with residual anemia (hemoglobin < 10 g/dL) despite prior anti-C5 treatment who switched to Fabhalta, which demonstrated superiority in hemoglobin improvement in the absence of RBC transfusions and in transfusion avoidance rate over patients who stayed on anti-C5 treatments^1,2. Approval was also supported by the Phase III APPOINT-PNH study in complement inhibitor-naïve patients^1,3. The 24-week core treatment periods in APPLY-PNH and APPOINT-PNH trials respectively showed^1-3:

• Patients with sustained increase of hemoglobin levels ≥ 2 g/dL^a from baseline in the absence of transfusions: 82.3% of anti-C5-experienced Fabhalta patients responded vs. 0% for anti-C5 (difference of 81.5%^b, P<0.0001); 77.5% of complement inhibitor-naïve patients using Fabhalta achieved this outcome (sensitivity analysis showed 87.5%^c)^1-3.
• Patients with sustained hemoglobin level ≥ 12 g/dL^a in the absence of transfusions: 67.7% of anti-C5-experienced Fabhalta patients responded vs. 0% for anti-C5 (difference of 66.6%^b, P<0.0001)^1-2.
• Patients avoiding transfusion^d,e: Transfusion avoidance rate 95.2% for anti-C5-experienced Fabhalta patients vs. 45.7% for anti-C5 (difference of 49.5%^b, P<0.0001)^1-2.

In the APPLY-PNH trial, the most commonly reported (≥10%) adverse reactions (ARs) with Fabhalta vs. anti-C5s were: headache^f (19% vs. 3%), nasopharyngitis^g (16% vs. 17%), diarrhea (15% vs. 6%), abdominal pain^f (15% vs. 3%), bacterial infection^h (11% vs. 11%), nausea (10% vs. 3%), and viral infectionⁱ (10% vs. 31%)^1,2. In the APPOINT-PNH trial, the most commonly reported ARs (≥10%) were headache^f (28%), viral infectionⁱ (18%), nasopharyngitis^g (15%), and rash^j (10%)^1,3. In APPLY-PNH, serious ARs were reported in two (3%) patients with PNH receiving Fabhalta, which included pyelonephritis, urinary tract infection and COVID-19^1,2. In APPOINT-PNH, serious ARs were reported in two (5%) patients with PNH receiving Fabhalta, which included COVID-19 and bacterial pneumonia^1,3. Fabhalta may cause serious infections caused by encapsulated bacteria and is available only through a Risk Evaluation and Mitigation Strategy (REMS) that requires vaccinations for encapsulated bacteria¹.

People with PNH have an acquired mutation making red blood cells susceptible to premature destruction by the complement system^6,8. PNH is characterized by hemolysis, bone marrow failure, and thrombosis in varying combinations and levels of severity^6-8. Existing C5 inhibitor treatments, administered as infusions, may leave PNH symptoms uncontrolled^7,8. Up to 88% of patients on anti-C5 treatment may have persistent anemia with over one-third of those patients requiring blood transfusions at least once per year^7,8.

"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," said Victor Bultó, President US, Novartis. "This new, effective oral medicine may mean that patients can reset their expectations of living with PNH, a chronic and life-altering blood disease. 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."

Discovered and developed by Novartis, Fabhalta is expected to be available in the United States in December. Additional regulatory filings and reviews for Fabhalta in PNH are currently underway around the world.

^aAssessed between Day 126 and Day 168. ^bAdjusted difference in proportion. ^cSensitivity analysis incorporates data from local labs when central labs were not available. ^dAssessed between Day 14 and Day 168. ^eTransfusion avoidance is defined as absence of administration of packed-red blood cell transfusions between Day 14 and Day 168. ^fIncludes similar terms. ^gNasopharyngitis contains: rhinitis allergic, upper respiratory tract infection, pharyngitis, rhinitis. ^hBacterial infection contains: pyelonephritis, urinary tract infection, bronchitis bacterial, bronchitis haemophilus, cholecystitis, folliculitis, cellulitis, arthritis bacterial, sepsis, klebsiella infection, staphylococcal infection, Pseudomonas infection, hordeolum, pneumonia bacterial. ⁱViral infection contains: COVID-19, herpes zoster, oral herpes, nasal herpes, influenza A virus test positive, influenza. ^jRash: dermatitis allergic, acne, erythema multiforme, rash maculo-papular, rash erythematous.

Indication
FABHALTA is a prescription medicine used to treat adults with paroxysmal nocturnal hemoglobinuria (PNH).

It is not known if FABHALTA is safe and effective in children.

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