FIRST-LINE TREATMENT OF PNH PATIENTS WITH IPTACOPAN LEADS TO RAPID AND DURABLE HEMOGLOBIN INCREASE BY CONTROLLING BOTH INTRA- AND EXTRAVASCULAR HEMOLYSIS
Author(s): ,
Jun Ho Jang
Affiliations:
Sungkyunkwan University School of Medicine,Samsung Medical Center,Seoul,Korea, Republic Of
,
Lily Wong
Affiliations:
Hematology Unit,Queen Elizabeth Hospital,Kota Kinabalu,Malaysia
,
Bor-Sheng Ko
Affiliations:
Department of Internal Medicine,National Taiwan University Hospital,Taipei,Taiwan, Province of China
,
Sung-Soo Yoon
Affiliations:
Department of Internal Medicine,Seoul National University Hospital,Seoul,Korea, Republic Of
,
Katie Li
Affiliations:
Clinical Sciences and Innovation,Novartis Institutes for BioMedical Research,Shanghai,China
,
Izabela Rozenberg
Affiliations:
Clinical Sciences and Innovation,Novartis Institutes for BioMedical Research,Basel,Switzerland
,
Prasanna K. Nidamarthy
Affiliations:
Biostatistics & Pharmacometrics,Novartis Healthcare Private Limited,Hyderabad,India
,
Raghav Chawla
Affiliations:
Translational Medicine,Novartis Institutes for BioMedical Research,Basel,Switzerland
,
Guido Junge
Affiliations:
Translational Medicine,Novartis Institutes for BioMedical Research,Basel,Switzerland
Eng Soo Yap
Affiliations:
Investigational Medicine Unit,National University Hospital Singapore,Singapore,Singapore
EHA Library. Ho Jang J. 06/09/21; 324581; S173
Jun Ho Jang
Jun Ho Jang
Contributions
Abstract
Presentation during EHA2021: All Oral presentations will be made available as of Friday, June 11, 2021 (09:00 CEST) and will be accessible for on-demand viewing until August 15, 2021 on the Virtual Congress platform.

Abstract: S173

Type: Oral Presentation

Session title: New directions in aplastic anemia and PNH

Background
Paroxysmal nocturnal hemoglobinuria (PNH) is a severe hematological disease caused by an acquired PIGA mutation in hematopoietic stem cells, leading to loss of regulatory proteins affecting the complement alternative pathway, of which factor B is an essential component. The only regulatory approved treatment for hemolytic PNH is based on antibodies targeting complement component 5 (C5), controlling intravascular hemolysis, reducing thromboembolic events, and eventually improving long-term survival. However, 20-50% of patients remain transfusion-dependent due to persistent extravascular hemolysis, and an additional 20-40% exhibit varying degrees of residual anemia. Iptacopan (LNP023) is a new, oral, selective and potent first-in-class factor B inhibitor, designed to block both intra- and extravascular hemolysis. 

Aims
The trial presented here investigates the effect of first-line iptacopan monotherapy on intra- and extravascular hemolysis, the extent of red blood cell (RBC) C3 opsonization, and changes in hemoglobin levels in anti-C5 naive PNH patients with active hemolysis.

Methods
CLNP023X2204 (NCT03896152) is a multi-national, randomized Phase 2 efficacy, safety, pharmacokinetics/-dynamics study assessing four iptacopan doses in two separate cohorts with two treatment periods each in treatment-naive adult PNH patients with active hemolysis. The primary objective is to assess the effect of iptacopan on the reduction of PNH-associated hemolysis. Additional objectives include assessing the effect on hemoglobin levels, the dose-response effect, and the effect on markers associated with a risk of thrombosis.

Results
A total of N=13 patients (ages 20-62; n=7 female) were randomized to either Cohort 1 (iptacopan 25-to-100 mg dose increase at Week 4; N=7) or Cohort 2 (50-to-200 mg; N=6). Median (range) lab values at baseline were: Hb 86.5 (68-107) g/L, reticulocytes 209 (30-352) x10E9/L, LDH 1686 (1008-3761) U/L, bilirubin 27.0 (20.0-51.0) umol/L; haptoglobin was below lower limit of detection for all patients. The primary endpoint of lowering LDH by at least 60% was reached for all patients. Mean LDH levels declined by 79.7 and 86.2% in Cohort 1 and by 89.7 and 85.9% in Cohort 2 at weeks 4 and 12, respectively [Figure 1]. Importantly, all patients remained transfusion-free up until week 12, with the exception of one patient who received a single RBC transfusion on study day 3; Hb levels spontaneously increased by a mean of 23.4 and 37.1 g/L at week 12 in Cohorts 1 and 2, respectively [Figure 1]; and no thromboembolic events were reported. In addition, reticulocyte counts decreased by a mean of 93.0 and 84.9 x10E9/L, and bilirubin decreased by a mean of 21.6 and 23.2 umol/L in Cohorts 1 and 2, respectively. Iptacopan was well tolerated (n=1 discontinued from the trial at Day 2 due to headache); no fatal events and no serious adverse events were reported during the 12-week treatment period.

Conclusion
Iptacopan is a new, well-tolerated oral factor B inhibitor that blocks both intra- and extravascular hemolysis in patients with hemolytic PNH. 12-week study results demonstrate that, in anti-C5 naive patients with active hemolysis, iptacopan therapy ≥50 mg BID results in normalization of various hemolytic markers and resolution of anemia. Maximal effects on various efficacy parameters were obtained at 200 mg BID. These results demonstrate that proximal inhibition of the complement cascade parallel and further improve the hematological benefit seen with anti-C5 therapies, with iptacopan eventually offering an alternative first-line therapy for patients with PNH.

Keyword(s): Complement, Paroxysmal nocturnal hemoglobinuria (PNH)

Presentation during EHA2021: All Oral presentations will be made available as of Friday, June 11, 2021 (09:00 CEST) and will be accessible for on-demand viewing until August 15, 2021 on the Virtual Congress platform.

Abstract: S173

Type: Oral Presentation

Session title: New directions in aplastic anemia and PNH

Background
Paroxysmal nocturnal hemoglobinuria (PNH) is a severe hematological disease caused by an acquired PIGA mutation in hematopoietic stem cells, leading to loss of regulatory proteins affecting the complement alternative pathway, of which factor B is an essential component. The only regulatory approved treatment for hemolytic PNH is based on antibodies targeting complement component 5 (C5), controlling intravascular hemolysis, reducing thromboembolic events, and eventually improving long-term survival. However, 20-50% of patients remain transfusion-dependent due to persistent extravascular hemolysis, and an additional 20-40% exhibit varying degrees of residual anemia. Iptacopan (LNP023) is a new, oral, selective and potent first-in-class factor B inhibitor, designed to block both intra- and extravascular hemolysis. 

Aims
The trial presented here investigates the effect of first-line iptacopan monotherapy on intra- and extravascular hemolysis, the extent of red blood cell (RBC) C3 opsonization, and changes in hemoglobin levels in anti-C5 naive PNH patients with active hemolysis.

Methods
CLNP023X2204 (NCT03896152) is a multi-national, randomized Phase 2 efficacy, safety, pharmacokinetics/-dynamics study assessing four iptacopan doses in two separate cohorts with two treatment periods each in treatment-naive adult PNH patients with active hemolysis. The primary objective is to assess the effect of iptacopan on the reduction of PNH-associated hemolysis. Additional objectives include assessing the effect on hemoglobin levels, the dose-response effect, and the effect on markers associated with a risk of thrombosis.

Results
A total of N=13 patients (ages 20-62; n=7 female) were randomized to either Cohort 1 (iptacopan 25-to-100 mg dose increase at Week 4; N=7) or Cohort 2 (50-to-200 mg; N=6). Median (range) lab values at baseline were: Hb 86.5 (68-107) g/L, reticulocytes 209 (30-352) x10E9/L, LDH 1686 (1008-3761) U/L, bilirubin 27.0 (20.0-51.0) umol/L; haptoglobin was below lower limit of detection for all patients. The primary endpoint of lowering LDH by at least 60% was reached for all patients. Mean LDH levels declined by 79.7 and 86.2% in Cohort 1 and by 89.7 and 85.9% in Cohort 2 at weeks 4 and 12, respectively [Figure 1]. Importantly, all patients remained transfusion-free up until week 12, with the exception of one patient who received a single RBC transfusion on study day 3; Hb levels spontaneously increased by a mean of 23.4 and 37.1 g/L at week 12 in Cohorts 1 and 2, respectively [Figure 1]; and no thromboembolic events were reported. In addition, reticulocyte counts decreased by a mean of 93.0 and 84.9 x10E9/L, and bilirubin decreased by a mean of 21.6 and 23.2 umol/L in Cohorts 1 and 2, respectively. Iptacopan was well tolerated (n=1 discontinued from the trial at Day 2 due to headache); no fatal events and no serious adverse events were reported during the 12-week treatment period.

Conclusion
Iptacopan is a new, well-tolerated oral factor B inhibitor that blocks both intra- and extravascular hemolysis in patients with hemolytic PNH. 12-week study results demonstrate that, in anti-C5 naive patients with active hemolysis, iptacopan therapy ≥50 mg BID results in normalization of various hemolytic markers and resolution of anemia. Maximal effects on various efficacy parameters were obtained at 200 mg BID. These results demonstrate that proximal inhibition of the complement cascade parallel and further improve the hematological benefit seen with anti-C5 therapies, with iptacopan eventually offering an alternative first-line therapy for patients with PNH.

Keyword(s): Complement, Paroxysmal nocturnal hemoglobinuria (PNH)

By clicking “Accept Terms & all Cookies” or by continuing to browse, you agree to the storing of third-party cookies on your device to enhance your user experience and agree to the user terms and conditions of this learning management system (LMS).

Cookie Settings
Accept Terms & all Cookies