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PNH red blood cell hemolysis (picture source: standardofcare.
com)
com)
News on June 14, 2021 // - Novartis recently announced the data of a phase 2 clinical study (NCT03896152) of iptacopan (LNP023) for the treatment of paroxysmal nocturnal hemoglobinuria (PNH)
.
The results showed that in PNH patients who had not previously received a C5 inhibitor, iptacopan monotherapy for 12 weeks significantly reduced intravascular and extravascular hemolysis, and most patients achieved rapid and long-lasting improvement without blood transfusion
.
In this study, iptacopan was well tolerated and there were no unexpected safety findings
.
Novartis iptacopan monotherapy for 12 weeks significantly reduced intravascular and extravascular hemolysis, and most patients achieved rapid and long-lasting improvement without blood transfusion.
The results showed that in PNH patients who had not previously received a C5 inhibitor, iptacopan monotherapy for 12 weeks significantly reduced intravascular and extravascular hemolysis, and most patients achieved rapid and long-lasting improvement without blood transfusion
.
In this study, iptacopan was well tolerated and there were no unexpected safety findings
.
.
The new research results show the potential of iptacopan as a monotherapy for PNH
.
The results of another open-label phase II study (NCT03439839) previously published in the "Lancet Hematology" showed that PNH with active hemolysis after receiving standard care therapy (C5 inhibitor Soliris [eculizumab]) In patients, iptacopan as an add-on therapy significantly improved the hematological response and biomarkers of disease activity
.
This benefit continued to be maintained in patients who discontinued Soliris treatment
.
As an add-on therapy, iptacopan significantly improved the hematological response and biomarkers of disease activity.
The results of another open-label phase II study (NCT03439839) previously published in the "Lancet Hematology" showed that PNH with active hemolysis after receiving standard care therapy (C5 inhibitor Soliris [eculizumab]) In patients, iptacopan as an add-on therapy significantly improved the hematological response and biomarkers of disease activity
.
This benefit continued to be maintained in patients who discontinued Soliris treatment
.
.
This benefit continued to be maintained in patients who discontinued Soliris treatment
.
Biomarkers
PNH is a rare, life-threatening blood disease characterized by complement-driven hemolysis, thrombosis, and impaired bone marrow function, leading to anemia , fatigue, and other debilitating symptoms, which can severely affect the patient’s quality of life
.
Despite the use of current anti-C5 standard care therapies for treatment, a large proportion of PNH patients are still anemic and dependent on blood transfusions
.
anemia.
Despite the use of current anti-C5 standard care therapies for treatment, a large proportion of PNH patients are still anemic and dependent on blood transfusions
.
The chemical structure of iptacopan (picture source: medchemexpress.
com)
com)
iptacopan is a first-in-class, oral, potent, selective, small molecule, and reversible factor B inhibitor.
Factor B is a key serine protease in the alternative pathway of the complement system
.
At present, iptacopan is being developed for the treatment of some kidney diseases that are involved in the complement system and have significant unmet needs, including paroxysmal nocturnal hemoglobinuria (PNH), IgA nephropathy (IgAN), C3 glomerular disease (C3G), Atypical hemolytic uremic syndrome (aHUS), membranous nephropathy (MN)
.
UremiaFactor B is a key serine protease in the alternative pathway of the complement system
.
At present, iptacopan is being developed for the treatment of some kidney diseases that are involved in the complement system and have significant unmet needs, including paroxysmal nocturnal hemoglobinuria (PNH), IgA nephropathy (IgAN), C3 glomerular disease (C3G), Atypical hemolytic uremic syndrome (aHUS), membranous nephropathy (MN)
.
Recently published Phase II data showed that treatment of IgAN with iptacopan reduced proteinuria and stabilized renal function, treatment of C3G reduced the rate of decline of estimated glomerular filtration rate (eGFR) and stabilized renal function
.
Treatment of IgAN with iptacopan reduced proteinuria and stabilized renal function, treatment of C3G reduced the rate of decline of estimated glomerular filtration rate (eGFR) and stabilized renal function .
.
iptacopan is the most advanced asset in the Novartis kidney disease pipeline, and its target is the complement alternative pathway, which is a key driver of complement-driven kidney disease (CDRD)
.
Previously, iptacopan has been granted Orphan Drug Designation (ODD) for the treatment of PNH and C3G by the US FDA and EU EMA, ODD for the treatment of IgAN by EMA, Breakthrough Drug Designation (BTD) for the treatment of PNH by the FDA , and C3G by the EMA Priority Drug Eligibility (PRIME)
.
Novartis FDA.
Previously, iptacopan has been granted Orphan Drug Designation (ODD) for the treatment of PNH and C3G by the US FDA and EU EMA, ODD for the treatment of IgAN by EMA, Breakthrough Drug Designation (BTD) for the treatment of PNH by the FDA , and C3G by the EMA Priority Drug Eligibility (PRIME)
.
Complement activation cascade-PNH treatment modulation target (picture from literature: PMC6060635, click on the picture to see a larger picture)
NCT03896152 is a multi-country, multi-center, open-label, randomized, 2-cohort, dose-range phase 2 study.
It was carried out in 13 adult patients with PNH who had active hemolysis within the first 3 months and did not receive complement suppression therapy.
The efficacy, safety, pharmacokinetics/pharmacodynamics of iptacopan as a monotherapy
.
NCT03896152 is a multi-country, multi-center, open-label, randomized, 2-cohort, dose-range phase 2 study. It was carried out in 13 adult patients with PNH who had active hemolysis within the first 3 months and did not receive complement suppression therapy.
The efficacy, safety, pharmacokinetics/pharmacodynamics of iptacopan as a monotherapy
.
It was carried out in 13 adult patients with PNH who had active hemolysis within the first 3 months and did not receive complement suppression therapy.
The efficacy, safety, pharmacokinetics/pharmacodynamics of iptacopan as a monotherapy
.
The results showed that all patients who completed 12 weeks of treatment (n=11) reached the primary endpoint: lactate dehydrogenase (LDH) levels were reduced by at least 60%
.
LDH is a biomarker of intravascular hemolysis
.
Importantly, except for one patient who received a single red blood cell (RBC) transfusion, the rest of the patients did not have a blood transfusion during the 12-week treatment period
.
The patient’s other biomarkers of hemolysis also showed improvement, with a significant increase in the proportion of PNH RBC, indicating that both intravascular and extravascular hemolysis were fully controlled
.
All patients who completed 12 weeks of treatment (n=11) reached the primary endpoint: lactate dehydrogenase (LDH) levels were reduced by at least 60% .
LDH is a biomarker of intravascular hemolysis
.
Importantly, except for one patient who received a single red blood cell (RBC) transfusion, the rest of the patients did not have a blood transfusion during the 12-week treatment period
.
The patient’s other biomarkers of hemolysis also showed improvement, with a significant increase in the proportion of PNH RBC, indicating that both intravascular and extravascular hemolysis were fully controlled
.
.
LDH is a biomarker of intravascular hemolysis
.
Other biomarkers of hemolysis also showed improvement, with a significant increase in the proportion of PNH RBCs, indicating that both intravascular and extravascular hemolysis have been fully controlled
.
Biomarkers
During the 12-week treatment period, no serious adverse events or thromboembolic events were reported, and no unexpected safety results occurred
.
Two patients discontinued iptacopan treatment before completing 12 weeks of treatment: one patient was due to a non-severe headache, and the other patient was due to a doctor's decision due to a worsening of pre-existing neutropenia
.
The most common adverse reactions were headache (31%), abdominal discomfort (15%), elevated blood alkaline phosphatase (15%), cough (15%), oropharyngeal pain (15%), fever (increased body temperature) ; 15%), upper respiratory tract infection (15%)
.
Adverse reactions.
Two patients discontinued iptacopan treatment before completing 12 weeks of treatment: one patient was due to a non-severe headache, and the other patient was due to a doctor's decision due to a worsening of pre-existing neutropenia
.
The most common adverse reactions were headache (31%), abdominal discomfort (15%), elevated blood alkaline phosphatase (15%), cough (15%), oropharyngeal pain (15%), fever (increased body temperature) ; 15%), upper respiratory tract infection (15%)
.
John Tsai, Head of Global Drug Development and Chief Medical Officer of Novartis, said: "PNH is a rare, life-threatening blood disease that requires new treatment options
.
These positive results further strengthen iptacopan as a promising oral monotherapy.
Potential
.
We are very pleased to continue to explore the potential of iptacopan as a new standard for PNH treatment in the ongoing Phase 3 study
.
” ()
Novartis.
These positive results further strengthen iptacopan as a promising oral monotherapy.
Potential
.
We are very pleased to continue to explore the potential of iptacopan as a new standard for PNH treatment in the ongoing Phase 3 study
.
” ()
Original source: Novartis investigational oral therapy iptacopan (LNP023) shows benefit as monotherapy in treatment-naïve patients with rare and life-threatening blood disorder paroxysmal nocturnal hemoglobinuria
Novartis investigational oral therapy iptacopan (LNP023) shows benefit as monotherapy in treatment-naïve patients with rare and life-threatening blood disorder paroxysmal nocturnal hemoglobinuria 
