• Approval based on APPLY-PNH trial in adults with PNH and anemia despite prior anti-C5 treatment, and supported by the APPOINT-PNH study in complement inhibitor-naïve patients1-5

• In APPLY-PNH, patients who switched to Fabhalta experienced superior increases of hemoglobin levels ≥ 2 g/dL (82.3% vs. 0%) and hemoglobin level ≥ 12 g/dL (67.7% vs. 0%), both in the absence of red blood cell transfusions, vs. patients who continued on anti-C5 treatment1,2

• Fabhalta, now available for both previously treated and treatment-naïve patients, is the only FDA-approved Factor B inhibitor of the immune system's complement pathway, which drives complement-mediated hemolysis in PNH1,6

• Significant unmet need remains in PNH, a chronic and rare blood disorder; despite anti-C5 therapy, a large proportion of patients can remain anemic and dependent on blood transfusions7,8

• Late-stage Fabhalta development program ongoing in multiple complement-mediated conditions

EAST HANOVER, N.J., Dec. 5, 2023 /PRNewswire/ -- Novartis 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 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.

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.

Important Safety Information
FABHALTA is a medicine that affects part of the immune system and may lower one's ability to fight infections. FABHALTA increases the chance of getting serious infections caused by encapsulated bacteria, including Streptococcus pneumoniae, Neisseria meningitidis, and Haemophilus influenzae type B. These serious infections may quickly become life-threatening or fatal if not recognized and treated early. Patients must complete or update vaccinations against these bacteria at least 2 weeks before starting FABHALTA. If patients have not completed these vaccinations and FABHALTA therapy must be started right away, they should receive the required vaccinations as soon as possible. If patients have not been vaccinated and FABHALTA must be started right away, they should also receive antibiotics to take for as long as their doctor tells them. If patients have been vaccinated against these bacteria in the past, they might need additional vaccinations before starting FABHALTA. Their doctor will decide if they need additional vaccinations. Vaccines do not prevent all infections caused by encapsulated bacteria. Patients should call their doctor or get emergency medical care right away if they have any of these signs and symptoms of a serious infection: fever with or without shivers or chills; fever with chest pain and cough; fever with high heart rate; headache and fever; confusion; clammy skin; fever and a rash; fever with breathlessness/fast breathing; headache with nausea or vomiting; headache with stiff neck or stiff back; body aches with flu-like symptoms; or eyes sensitive to light. Doctors will give their patients a Patient Safety Card about the risk of serious infections. Patients must carry it with them at all times during treatment and for 2 weeks after their last dose of FABHALTA. The risk of serious infections may continue for a few weeks after their last dose of FABHALTA. It is important for patients to show this card to any doctor who treats them. This will help doctors diagnose and treat patients quickly.

FABHALTA is only available through a program called the FABHALTA Risk Evaluation and Mitigation Strategy (REMS). Before patients can take FABHALTA, their doctor must enroll in the FABHALTA REMS program, counsel patients about the risk of serious infections caused by certain bacteria, give patients information about the symptoms of serious infections, make sure that patients are vaccinated against serious infections caused by encapsulated bacteria and that they receive antibiotics if they need to start FABHALTA right away and are not up to date on vaccinations, as well as give patients a Patient Safety Card about the risk of serious infections.

Since FABHALTA may increase patients' cholesterol and triglycerides, their doctor will do blood tests to check their levels periodically.

Patients should not take FABHALTA if they are allergic to FABHALTA or any of the ingredients in FABHALTA. Patients should not take FABHALTA if they have a serious infection caused by encapsulated bacteria, including Streptococcus pneumoniae, Neisseria meningitidis, or Haemophilus influenzae type B when starting FABHALTA.

Before taking FABHALTA, patients should tell their doctor about all  their medical conditions, including if they have an infection or fever, have kidney or liver problems, are pregnant or plan to become pregnant (it is not known if FABHALTA will harm an unborn baby), or are breastfeeding or plan to breastfeed as it is not known if FABHALTA passes into breast milk. Patients should not breastfeed during treatment and for 5 days after the last dose of FABHALTA.

Patients should tell their doctor about all the medicines they take, including prescription and over-the-counter medicines, vitamins, and herbal supplements. Taking FABHALTA with certain other medicines may affect the way FABHALTA works and may cause side effects. Patients should know the medicines they take and the vaccines they receive. Patients should keep a list of them to show their doctor and pharmacist when they get a new medicine.

If patients have PNH and stop taking FABHALTA, their doctor will need to monitor them closely for at least 2 weeks after stopping FABHALTA. Stopping treatment with FABHALTA may cause a breakdown of red blood cells due to PNH. Symptoms or problems that can happen due to breakdown of red blood cells include decreased hemoglobin level in the blood; blood in the urine; shortness of breath; trouble swallowing; tiredness; pain in the stomach (abdomen); blood clots, stroke, and heart attack; and erectile dysfunction (ED). It is important that patients take FABHALTA exactly as their doctor tells them to lower the possibility of breakdown of red blood cells due to PNH.

The most common side effects of FABHALTA include headache; nasal congestion, runny nose, cough, sneezing, and sore throat (nasopharyngitis); diarrhea; pain in the stomach (abdomen); infections (viral and bacterial); nausea; and rash.