A Real-Life Experience of Iptacopan in Paroxysmal Nocturnal Hemoglobinuria
Authors: Ahmed Arooj , Orland Mark , Thiagarajan Praveena , Basch Megan , Unlu Serhan , Bravo-Perez Carlos , Awada Hussein , Durmaz Arda , Gurnari Carmelo , Lytvynova Olga , Brady Zachary , D'Addona Matteo , Visconte Valeria , Maciejewski Jaroslaw 
Published: December 2024

The availability of complement inhibitors has dramatically changed the management of PNH. The longest experience exists with C5 inhibitors. Introduction of C3 blockade allowed also to overcome extravascular hemolysis in patients with break through hemolysis. Parenteral treatment options like complement protein C5 and C3 inhibitors, thus, became the mainstay therapeutic options in PNH. Recently, the PNH therapeutic armamentarium has been expanded by the FDA approval of an oral factor B blocker, iptacopan administered as single agent to effectively control hemolysis in PNH. Obviously, there are many advantages and disadvantages of parenteral administration but oral agents may provide convenience. Established drugs have a track record of safety, but new proximal inhibitors may improve response rates in those who do not attain CR. Here, we provide a real-world experience with ipacopan to allow projections as to how expanded treatment options may affect the standard of care in this disease.
We analyzed PNH patients who in course of their care inquired on the spectrum of therapies for PNH during routine outpatient follow up visits. Among 36 patients with a classical hemolytic PNH, a total of 30 patients were either started (N=4) or switched to iptacopan (N=26) from prior anti-complement treatment modalities. Of the currently treated patients, 16 were considered robust responders, while less than optimal hematologic improvement was present in 10 patients. Following consideration of the specific clinical situation and patient education as to the pros and cons of the newly available treatments, 30 patients elected to start iptacopan (26 treated and 4 treatment-naïve) of whom 10 are currently in the approval process. Of 17 responders on current complement blockers, 6 elected to remain on their current medication by personal preference of administration, impact on their wellbeing and blood counts, extensive track record of their current medication and concerns about difficulty with long-term coverage.
The 4 complement-inhibitor “naïve” patients were offered 3 treatment options (pegcetacoplan, ravulizumab, iptacopan) and all selected iptacopan mainly due the convenience of oral medication. 2 of the 4 are currently in the approval process. The other 2 who received the drug showed improvement in Hgb from 10.5 and 11.9 to 11.3 and 12.1 respectively. Retic count and LDH also showed marked improvement indicating response within 3 months of starting iptacopan therapy.
The previously treated patients who switched (n=26) had a median of 2 previous anti-complement inhibitors. Their therapy prior to switch included eculizumab (N=4), ravulizumab (N=13), pegcetacoplan (n=9). A prior diagnosis of aplastic anemia was present in 50% of our cohort. The median duration of the last regimen was 137 weeks.
Out of 26 patients with prior treatment, 16 had satisfactory/excellent response and their switch was predicated on the convenience of oral administration or coverage issues. Their average Hgb was 12.8 g/dL at the start of treatment vs 13.9 g/dL in 3-months, retic 3.2 vs 2.4% after 3 months, LDH 278 vs 222 IU/dL prior to and at 3 months of therapy.
In 10 patients prior therapy was not perceived as satisfactory as a main factor to initiate iptacopan. Average Hgb in these patients increased from 8.7 g/dL at the start of the treatment vs 9.8 g/dL in 3-months. There was also a significant decrease in LDH from 3-months after starting treatment 247 vs 196 IU/dL. Retic count significantly decreased from baseline 3-months after starting treatment (2.4±0.6 vs. 4.3±3.1%; p=0.042) at the start of the treatment.
Overall, in all patients the PNH granulocyte clone size increased from before treatment (44±40) compared to 3 months after treatment (59±35; p=.03). The PNH erythrocytes increased from before treatment (31±5) compared to 3 months after treatment (45±34; p=0.22).
Except for 2 instances of mildly increased lipids, no events like AE/thrombosis were reported. One patient developed community acquired pneumonia. Commonly reported side effect was intermittent mild headaches treatable with acetaminophen. No breakthrough hemolysis was observed, there were 2 instances of missing a dose without any complications.
In conclusion, iptacopan provides a viable treatment option in those with suboptimal responses to current therapy and allows to achieve comparable results in patients otherwise well controlled by other complement inhibitors.