On December 6, 2023 Novartis reported 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) (Press release, Novartis, DEC 6, 2023, https://www.novartis.com/news/media-releases/novartis-receives-fda-approval-fabhalta-iptacopan-offering-superior-hemoglobin-improvement-absence-transfusions-first-oral-monotherapy-adults-pnh [SID1234638158]). 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 transfusions1-5.

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"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 treatments1,2. Approval was also supported by the Phase III APPOINT-PNH study in complement inhibitor-naïve patients1,3. The 24-week core treatment periods in APPLY-PNH and APPOINT-PNH trials respectively showed1-3:

Patients with sustained increase of hemoglobin levels ≥ 2 g/dLa 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/dLa 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 transfusiond,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: headachef (19% vs. 3%), nasopharyngitisg (16% vs. 17%), diarrhea (15% vs. 6%), abdominal painf (15% vs. 3%), bacterial infectionh (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 headachef (28%), viral infectioni (18%), nasopharyngitisg (15%), and rashj (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-191,2. In APPOINT-PNH, serious ARs were reported in two (5%) patients with PNH receiving Fabhalta, which included COVID-19 and bacterial pneumonia1,3.
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 system6,8. PNH is characterized by hemolysis, bone marrow failure, and thrombosis in varying combinations and levels of severity6-8. Existing C5 inhibitor treatments, administered as infusions, may leave PNH symptoms uncontrolled7,8. 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 year7,8.

"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.

About APPLY-PNH
APPLY-PNH (NCT04558918) was a Phase III, randomized, multinational, multicenter, active-comparator controlled, open-label trial to evaluate the efficacy and safety of twice-daily, oral Fabhalta monotherapy (200 mg) for the treatment of PNH by assessing if switching to Fabhalta was superior to continuing on anti-C5 therapies (US-approved and non-US-approved eculizumab and ravulizumab) in adult patients presenting with residual anemia (Hb <10 g/dL) despite a stable regimen of anti-C5 treatment in the last six months prior to randomization2,9. The trial enrolled 97 patients who were randomized in an 8:5 ratio to either twice-daily, oral Fabhalta monotherapy, or intravenous anti-C5 therapies (continuing with the same regimen as they were on prior to randomization)2,9.

About APPOINT-PNH
APPOINT-PNH (NCT04820530) was a Phase III, multinational, multicenter, open-label, uncontrolled single-arm study to evaluate the efficacy and safety of twice-daily, oral Fabhalta monotherapy (200 mg) in adult PNH patients who are naïve to complement inhibitor therapy, including anti-C5 therapies (eculizumab or ravulizumab)3,10. The trial enrolled 40 patients who received twice-daily, oral Fabhalta monotherapy3,10.

About paroxysmal nocturnal hemoglobinuria (PNH)
PNH is a rare, chronic and serious complement-mediated blood disorder6. People with PNH have an acquired mutation in some of their hematopoietic stem cells (which are located in the bone marrow and can grow and develop into RBCs, white blood cells and platelets) that causes them to produce RBCs that are susceptible to premature destruction by the complement system6,8. This leads to intravascular hemolysis (destruction of RBCs within blood vessels) and extravascular hemolysis (destruction of RBCs mostly in the spleen and liver), which cause anemia (low levels of circulating RBCs), thrombosis (formation of blood clots) and other debilitating symptoms6,8.
 
It is estimated that approximately 10-20 people per million worldwide live with PNH6. Although PNH can develop at any age, it is often diagnosed in people between 30-40 years old11,12.
 
PNH has a significant unmet need not fully addressed by anti-C5 therapies (eculizumab or ravulizumab): despite treatment with anti-C5s, a large proportion of people with PNH may remain anemic, and dependent on blood transfusions6-8,13,14.

About Fabhalta (iptacopan)
Fabhalta (iptacopan) is an oral, Factor B inhibitor of the alternative complement pathway15-17. Fabhalta is indicated for the treatment of adults with paroxysmal nocturnal hemoglobinuria (PNH).
 
Discovered at Novartis, Fabhalta is currently in development for a range of complement-mediated diseases including immunoglobulin A nephropathy (IgA nephropathy), C3 glomerulopathy (C3G), immune complex membranoproliferative glomerulonephritis (IC-MPGN) and atypical hemolytic uremic syndrome (aHUS).
 
Based on disease prevalence, unmet needs and data from Phase II studies, Fabhalta has received FDA Breakthrough Therapy Designation in PNH, FDA Breakthrough Therapy Designation in C3G, orphan drug designations from the FDA and EMA in PNH and C3G, EMA PRIME designation for C3G, and EMA orphan drug designation in IgAN18-21.