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  • Writer's pictureThe Rare360 Editorial Team

New Horizon in PNH Treatment: FDA Approves First Oral Drug

Updated: Jan 16

Rubber stamp with FDA and pills on craft paper. 3d illustration

Iptacopan (Fabhalta): A Novel Breakthrough in PNH Treatment

The US Food and Drug Administration (FDA) has approved iptacopan (Fabhalta) for the treatment of paroxysmal nocturnal hemoglobinuria (PNH) in adults, marking a significant milestone as the first and only FDA-approved factor B inhibitor targeting the immune system’s complement pathway. On December 05, 2023, the FDA's approval of iptacopan represents a crucial advancement in addressing the underlying causes of PNH, a rare blood disorder affecting 10 to 20 individuals per one million worldwide. This disorder is characterized by a mutation that renders red blood cells susceptible to premature destruction, leading to complications such as anemia, bone marrow failure, thrombosis, and other symptoms.


Iptacopan, an oral factor B inhibitor impacting the alternative complement pathway, demonstrates comprehensive control over the destruction of red blood cells both within and outside the blood vessels. Beyond its current indication, iptacopan is undergoing development for various complement-mediated diseases, including immunoglobulin A nephropathy, C3 glomerulopathy, immune complex membranoproliferative glomerulonephritis, and atypical hemolytic uremic syndrome. The approval of iptacopan opens new avenues in the treatment landscape, offering hope for patients with PNH and other complement-related conditions.


Clinical Trials and Efficacy of Iptacopan

The FDA's approval of iptacopan (Fabhalta) for the treatment of PNH was based on two significant phase 3 clinical trials that enrolled people who had either previously received other PNH treatments known as C5 inhibitors (APPLY-PNH trail, NCT04558918) or who hadn’t (APPOINT-PNH trial, NCT04820530).


Supported by data from the APPLY-PNH trial and the APPOINT-PNH study, the approval highlighted iptacopan's therapeutic capabilities in increasing hemoglobin levels without the need for red blood cell transfusion. The APPLY-PNH trial (involving 97 patients), a phase 3, multinational, multicenter study, evaluated the efficacy and safety of twice-daily oral iptacopan monotherapy (200 mg). It aimed to demonstrate the drug's therapeutic capabilities over anti-C5 antibody treatments in adult patients experiencing residual anemia despite prior anti-C5 treatment.


The APPOINT-PNH study, which enrolled 40 complement inhibitor-naïve patients, assessed the efficacy and safety of twice-daily oral iptacopan monotherapy (200 mg) in adults new to complement inhibitor therapy.


During the 24-week core treatment periods in both trials, iptacopan showed clinically significant results. In anti-C5-experienced patients with a sustained increase in hemoglobin levels of ≥2 g/dL from baseline without transfusions, 82.3% responded to iptacopan compared to 0% for anti-C5 (P < .0001). Similarly, among complement inhibitor-naïve patients treated with iptacopan, 77.5% achieved this outcome.


For patients with sustained hemoglobin levels of ≥12 g/dL without transfusions, 67.7% of anti-C5-experienced iptacopan patients responded compared to 0% for anti-C5 (P < .0001). The transfusion avoidance rate was 95.2% for anti-C5-experienced iptacopan patients compared to 45.7% for anti-C5 (P < .0001). These results underscore iptacopan's effectiveness in both anti-C5-experienced and complement inhibitor-naïve individuals, further supporting its role as a promising treatment option for PNH.


Safety Profile: Adverse Reactions

In the APPLY-PNH trial, the most commonly reported adverse reactions were headache, nasopharyngitis, diarrhea, abdominal pain, bacterial infection, nausea, and viral infection. Among the participants, 3% of those receiving iptacopan reported serious adverse reactions, encompassing pyelonephritis, urinary tract infection, and COVID-19.


In the APPOINT-PNH trial, the commonly reported adverse reactions were headache, viral infection, nasopharyngitis, and rash. Of those receiving iptacopan, 5% reported serious adverse reactions, including instances of COVID-19 and bacterial pneumonia.

Adverse Reactions

APPLY-PNH

APPLY-PNH

APPOINT-PNH


FABHLTA (N=62) n (%)

Anti-C5 (N=35) n (%)

FABHLTA (N=40) n (%)

Headache

12 (19)

1 (3)

11 (28)

Nasopharyngitis

10 (16)

6 (17)

6 (15)

Diarrhea

9 (15)

2 (6)

3 (8)

Abdominal Pain

9 (15)

1 (3)

3 (8)

Bacterial Infection

7 (11)

4 (11)

2 (5)

Nausea

6 (10)

1 (3)

2 (5)

Viral Infection

6 (10)

11 (31)

7 (18)

Arthralgia

5 (8)

1 (3)

0

Thrombocytopenia

4 (6)

0

0

Dizziness

4 (6)

0

1 (3)

Systemic Hypertension

4 (6)

0

0

Lipid Disorder

4 (6)

0

3 (8)

Rash

2 (3)

0

4 (10)

Table 1: Adverse Reactions Reported in Patients Treated with FABHALTA in APPLY-PNH or APPOINT-PNH Studies (24-Week Treatment Period)


Market Access and Risk Evaluation for Iptacopan

The pharmaceutical company has announced that iptacopan (Fabhalta) will be accessible in the United States later this month; however, the pricing details have not yet been disclosed. The treatment comes with a boxed warning highlighting an elevated risk of "life-threatening infections caused by encapsulated bacteria”. To ensure safe use, iptacopan will be distributed through a Risk Evaluation and Mitigation Strategy (REMS) program, which mandates vaccinations for encapsulated bacteria.


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