Trial Outcomes & Findings for Study of Efficacy and Safety of Twice Daily Oral Iptacopan (LNP023) in Adult PNH Patients Who Are Naive to Complement Inhibitor Therapy (NCT NCT04820530)

Results Overview

Sustained increase in hemoglobin levels (responder) is defined as an increase from baseline in hemoglobin levels of ≥ 2 g/dL on three out of four measurements between Day 126 and 168 of the core treatment period, without requiring red blood cell (RBC) transfusions between Day 14 and Day 168. Requiring RBC transfusions refers to any patient receiving transfusions or meeting protocol defined criteria (Hemoglobin level of ≤9 g/dL (≤8 g/dL for Chinese population) with signs and or symptoms of sufficient severity to warrant a transfusion or Hemoglobin of ≤7 g/dL (≤6 g/dL for Chinese population), regardless of presence of clinical signs and/or symptoms). The term 'marginal proportion' can be interpreted as the population average probability of being a responder. Results incorporated a method to handle missing data using multiple imputation. Hence, all 40 patients enrolled contributed to the primary analysis.

Recruitment status

COMPLETED

Study phase

PHASE3

Target enrollment

40 participants

Primary outcome timeframe

Baseline, hemoglobin between Day 126 and Day 168 and absence of transfusions between Day 14 and Day 168

Results posted on

2024-10-09

Participant Flow

Participants took part in 12 investigative sites in 8 countries: France(1), United Kingdom(1), Italy(1), Korea, Republic of(1), Singapore(1), China(3), Malaysia(2), Germany(2)

All patients provided written informed consent prior to the start of any study-related activities. Vaccination against Neisseria meningitidis, Streptococcus pneumoniae and Haemophilus influenzae infections was required prior to the start of treatment.

Participant milestones

Participant milestones
Measure	LNP023 Participants receive LNP023 at a dose of 200 mg b.i.d. orally
Core Treatment Period STARTED	40
Core Treatment Period COMPLETED	40
Core Treatment Period NOT COMPLETED	0
Extension Treatment Period STARTED	40
Extension Treatment Period COMPLETED	40
Extension Treatment Period NOT COMPLETED	0

Reasons for withdrawal

Withdrawal data not reported

Baseline Characteristics

Study of Efficacy and Safety of Twice Daily Oral Iptacopan (LNP023) in Adult PNH Patients Who Are Naive to Complement Inhibitor Therapy

Baseline characteristics by cohort

Baseline characteristics by cohort
Measure	LNP023 n=40 Participants Participants receive LNP023 at a dose of 200 mg b.i.d. orally
Age, Continuous	42.1 years STANDARD_DEVIATION 15.85 • n=5 Participants
Sex: Female, Male Female	17 Participants n=5 Participants
Sex: Female, Male Male	23 Participants n=5 Participants
Race/Ethnicity, Customized White	12 Participants n=5 Participants
Race/Ethnicity, Customized Black or African American	1 Participants n=5 Participants
Race/Ethnicity, Customized Asian	27 Participants n=5 Participants

PRIMARY outcome

Timeframe: Baseline, hemoglobin between Day 126 and Day 168 and absence of transfusions between Day 14 and Day 168

Population: Full Analysis Set (FAS): All patients with confirmed eligibility to whom study treatment was assigned.

Sustained increase in hemoglobin levels (responder) is defined as an increase from baseline in hemoglobin levels of ≥ 2 g/dL on three out of four measurements between Day 126 and 168 of the core treatment period, without requiring red blood cell (RBC) transfusions between Day 14 and Day 168. Requiring RBC transfusions refers to any patient receiving transfusions or meeting protocol defined criteria (Hemoglobin level of ≤9 g/dL (≤8 g/dL for Chinese population) with signs and or symptoms of sufficient severity to warrant a transfusion or Hemoglobin of ≤7 g/dL (≤6 g/dL for Chinese population), regardless of presence of clinical signs and/or symptoms). The term 'marginal proportion' can be interpreted as the population average probability of being a responder. Results incorporated a method to handle missing data using multiple imputation. Hence, all 40 patients enrolled contributed to the primary analysis.

Outcome measures

Outcome measures
Measure	LNP023 n=40 Participants Participants receive LNP023 at a dose of 200 mg b.i.d. orally
Marginal Proportion (Expressed as Percentage) of Participants With Sustained Increase in Hemoglobin Levels From Baseline of ≥ 2 g/dL in the Absence of Red Blood Cell Transfusions	92.2 Percentage of responders Interval 82.5 to 100.0

SECONDARY outcome

Timeframe: Hemoglobin between Day 126 and Day 168 and absence of transfusions between Day 14 and Day 168

Population: Full Analysis Set (FAS): All patients with confirmed eligibility to whom study treatment was assigned.

Sustained hemoglobin levels (responder) is defined as hemoglobin levels ≥ 12 g/dL on three out of four measurements between Day 126 and 168 of the core treatment period, without requiring red blood cell (RBC) transfusions between Day 14 and Day 168. Requiring RBC transfusions refers to any patient receiving transfusions or meeting protocol defined criteria (Hemoglobin level of ≤9 g/dL (≤8 g/dL for Chinese population) with signs and or symptoms of sufficient severity to warrant a transfusion or Hemoglobin of ≤7 g/dL (≤6 g/dL for Chinese population), regardless of presence of clinical signs and/or symptoms). The term 'marginal proportion' can be interpreted as the population average probability of being a responder. Results incorporated a method to handle missing data using multiple imputation. Hence, all 40 patients enrolled contributed to the analysis.

Outcome measures

Outcome measures
Measure	LNP023 n=40 Participants Participants receive LNP023 at a dose of 200 mg b.i.d. orally
Marginal Proportion (Expressed as Percentage) With Sustained Hemoglobin Levels of ≥ 12 g/dL in the Absence of Red Blood Cell Transfusions	62.8 Percentage of responders Interval 47.5 to 77.5

SECONDARY outcome

Timeframe: Between Day 14 and Day 168

Population: Full Analysis Set (FAS): All patients with confirmed eligibility to whom study treatment was assigned.

Marginal proportion (expressed as percentage) of participants who did not require transfusions between Day 14 and Day 168. Requiring RBC transfusions refers to any patient receiving transfusions or meeting protocol defined criteria (Hemoglobin level of ≤9 g/dL (≤8 g/dL for Chinese population) with signs and or symptoms of sufficient severity to warrant a transfusion or Hemoglobin of ≤7 g/dL (≤6 g/dL for Chinese population), regardless of presence of clinical signs and/or symptoms). The term 'marginal proportion' can be interpreted as the population average probability of being a responder. The 95% CI was obtained using the bootstrap method

Outcome measures

Outcome measures
Measure	LNP023 n=40 Participants Participants receive LNP023 at a dose of 200 mg b.i.d. orally
Marginal Proportion (Expressed as Percentage) of Participants Who Remain Free From Transfusions	97.6 Percentage of participants Interval 92.5 to 100.0

SECONDARY outcome

Timeframe: Baseline, Day 126 to 168

Population: Full Analysis Set (FAS): All patients with confirmed eligibility to whom study treatment was assigned.

Change from baseline in hemoglobin levels as mean of visits between Day 126 and Day 168. In order to factor out the effect of transfusions in this analysis, if a patient had a transfusion during the core treatment period, the hemoglobin (Hb) values during 30 days following the transfusion were excluded and Hb data were imputed. Change from baseline was analyzed using a mixed model of repeated measures which included age (indicator variable of age ≥ 45 years), sex, history of transfusion (yes/no) prior to study treatment, visit, and baseline hemoglobin as fixed effects and the interaction between visit and baseline hemoglobin levels.

Outcome measures

Outcome measures
Measure	LNP023 n=40 Participants Participants receive LNP023 at a dose of 200 mg b.i.d. orally
Change From Baseline in Hemoglobin Levels in the Core Treatment Period	4.28 g/dL Interval 3.87 to 4.7

SECONDARY outcome

Timeframe: Baseline, Day 126 to 168

Population: Full Analysis Set (FAS): All patients with confirmed eligibility to whom study treatment was assigned.

Percent change from baseline in lactate dehydrogenase (LDH) levels as mean of visits between Day 126 and Day 168. Percentage change from baseline was analyzed using a mixed model for repeated measures (MMRM) which includes age (indicator variable of age ≥ 45 years), sex, history of transfusion (yes/no) prior to study treatment, visit, baseline LDH as fixed effects and visit\*baseline LDH as interaction. Results incorporated a method to handle missing data using multiple imputation. Hence, all 40 patients enrolled contributed to the analysis.

Outcome measures

Outcome measures
Measure	LNP023 n=40 Participants Participants receive LNP023 at a dose of 200 mg b.i.d. orally
Percent Change From Baseline in LDH	-83.55 Percent change from baseline in LDH Interval -84.9 to -82.08

SECONDARY outcome

Timeframe: Between Day 1 and Day 168

Population: Full Analysis Set (FAS): All patients with confirmed eligibility to whom study treatment was assigned.

Adjusted annualized rate of clinical breakthrough hemolysis (BTH) events is carried out using the Wilson method. The breakthrough is defined clinical if either there is a decrease in hemoglobin levels equal to or more than 2 g/dL (compared to the latest assessment, or within 15 days) or if patients present signs or symptoms of gross hemoglobinuria, painful crisis, dysphagia or any other significant clinical PNH-related signs \& symptoms, in presence of laboratory evidence of intravascular hemolysis.

Outcome measures

Outcome measures
Measure	LNP023 n=40 Participants Participants receive LNP023 at a dose of 200 mg b.i.d. orally
Adjusted Annualized Clinical BTH Rate in the Core Treatment Period	0.00 BTH events/year Interval 0.0 to 0.17

SECONDARY outcome

Timeframe: Baseline and mean of visits between Day 126 and 168

Population: Full Analysis Set (FAS): All patients with confirmed eligibility to whom study treatment was assigned.

Change from baseline in absolute reticulocyte counts as mean of visits between Day 126 and Day 168. Change from baseline was analyzed using a MMRM which includes age (indicator variable of age ≥ 45 years), sex, history of transfusion (yes/no) prior to study treatment, visit, baseline reticulocyte counts as fixed effects and visit\*baseline reticulocyte counts as interaction.

Outcome measures

Outcome measures
Measure	LNP023 n=40 Participants Participants receive LNP023 at a dose of 200 mg b.i.d. orally
Change From Baseline in Absolute Reticulocyte Count	-82.48 x10^9 cells/L Interval -89.33 to -75.62

SECONDARY outcome

Timeframe: Baseline and mean of visits between Day 126 and Day 168

Population: Full Analysis Set (FAS): All patients with confirmed eligibility to whom study treatment was assigned.

Change from baseline in FACIT-Fatigue scores as mean of visits between Day 126 and Day 168. The FACIT-Fatigue is a 13-item questionnaire with support for its validity and reliability in PNH that assesses patient self-reported fatigue and its impact on daily activities and function. All FACIT scales are scored so that a high score is better. As each of the 13 items of the FACIT-F Scale ranges from 0-4, the range of possible scores is 0-52, with 0 being the worst possible score and 52 the best. Change from baseline was analyzed using a Mixed Model of Repeated Measures (MMRM) which includes age (indicator variable of age ≥ 45 years), sex, history of transfusion (yes/no) prior to study treatment, visit, baseline FACIT-Fatigue score as fixed effects and visit\*baseline FACIT-Fatigue score as interaction.

Outcome measures

Outcome measures
Measure	LNP023 n=40 Participants Participants receive LNP023 at a dose of 200 mg b.i.d. orally
Change From Baseline in FACIT-Fatigue Score	10.75 score on a scale Interval 8.66 to 12.84

SECONDARY outcome

Timeframe: Between Day 1 and Day 168

Population: Full Analysis Set (FAS): All patients with confirmed eligibility to whom study treatment was assigned.

Adjusted annual rate is carried out using the Wilson method. A MAVE is defined as: acute peripheral vascular occlusion, amputation (non-traumatic; nondiabetic), cerebral arterial occlusion/cerebrovascular accident, cerebral venous occlusion, dermal thrombosis, gangrene (non-traumatic; nondiabetic), hepatic/portal vein thrombosis (Budd-Chiari syndrome), mesenteric/visceral arterial, thrombosis or infarction, mesenteric/visceral vein thrombosis or infarction, myocardial infarction, pulmonary embolus, renal arterial thrombosis, renal vein thrombosis, thrombophlebitis / deep vein thrombosis, transient ischemic attack, unstable angina or other.

Outcome measures

Outcome measures
Measure	LNP023 n=40 Participants Participants receive LNP023 at a dose of 200 mg b.i.d. orally
Adjusted Annualized Major Adverse Vascular Events Rate in the Core Treatment Period	0.00 MAVE events/year Interval 0.0 to 0.17

OTHER_PRE_SPECIFIED outcome

Timeframe: Baseline, Day 336

Population: Full analysis set: All patients with confirmed eligibility to whom study treatment was assigned. Only participants with valid Hb measurements at Day 336 were analyzed.

Patients with hematological response are those with an increase in Hb from baseline ≥ 2g/dL irrespective of red blood cell (RBC) transfusions and patients achieving Hb ≥ 12g/dL irrespective of RBC transfusions.

Outcome measures

Outcome measures
Measure	LNP023 n=39 Participants Participants receive LNP023 at a dose of 200 mg b.i.d. orally
Percentage of Patients Meeting Hematological Response Criteria Irrespective of RBC Transfusions ≥2 g/dL increase in Hb from baseline irrespective of RBC transfusions	97.4 Percentage of participants
Percentage of Patients Meeting Hematological Response Criteria Irrespective of RBC Transfusions Hb ≥ 12g/dL irrespective of transfusions	79.5 Percentage of participants

OTHER_PRE_SPECIFIED outcome

Timeframe: Between Day 14 and Day 336

Population: Full analysis set: All patients with confirmed eligibility to whom study treatment was assigned.

Requiring Red Blood Cells (RBC) transfusions refers to any patient receiving transfusions or meeting protocol defined criteria (Hemoglobin level of ≤9 g/dL (≤8 g/dL for Chinese population) with signs and or symptoms of sufficient severity to warrant a transfusion or Hemoglobin of ≤7 g/dL (≤6 g/dL for Chinese population), regardless of presence of clinical signs and/or symptoms).

Outcome measures

Outcome measures
Measure	LNP023 n=40 Participants Participants receive LNP023 at a dose of 200 mg b.i.d. orally
Marginal Proportion (Expressed as Percentage) of Patients Not Receiving and Not Requiring RBC Transfusions	97.5 Percentage of participants Interval 92.5 to 100.0

OTHER_PRE_SPECIFIED outcome

Timeframe: Baseline, Day 336

Population: Full analysis set: All patients with confirmed eligibility to whom study treatment was assigned. Only participants with valid Hb measurements at Day 336 were analyzed.

Change from baseline in Hemoglobin at Visit Day 336

Outcome measures

Outcome measures
Measure	LNP023 n=39 Participants Participants receive LNP023 at a dose of 200 mg b.i.d. orally
Change From Baseline in Hemoglobin Levels	5.09 g/dL Standard Deviation 2.010

OTHER_PRE_SPECIFIED outcome

Timeframe: Baseline, Day 336

Population: Full Analysis Set (FAS): All patients with confirmed eligibility to whom study treatment was assigned.

Change from baseline in Lactate dehydrogenase (LDH) at Visit Day 336

Outcome measures

Outcome measures
Measure	LNP023 n=40 Participants Participants receive LNP023 at a dose of 200 mg b.i.d. orally
Change From Baseline in LDH at Visit Day 336	-1393.3 U/L Standard Deviation 652.15

OTHER_PRE_SPECIFIED outcome

Timeframe: Between Day 1 and Day 336

Population: Full Analysis Set (FAS): All patients with confirmed eligibility to whom study treatment was assigned.

Adjusted annualized rate of clinical breakthrough hemolysis (BTH) events is carried out using the Wilson method. The breakthrough is defined clinical if either there is a decrease in hemoglobin levels equal to or more than 2 g/dL (compared to the latest assessment, or within 15 days) or if patients present signs or symptoms of gross hemoglobinuria, painful crisis, dysphagia or any other significant clinical PNH-related signs \& symptoms, in presence of laboratory evidence of intravascular hemolysis.

Outcome measures

Outcome measures
Measure	LNP023 n=40 Participants Participants receive LNP023 at a dose of 200 mg b.i.d. orally
Adjusted Annualized Clinical BTH Rate After the Start of LNP023 Treatment	0.05 BTH events/year Interval 0.01 to 0.17

OTHER_PRE_SPECIFIED outcome

Timeframe: Baseline, Day 336

Population: Full Analysis Set (FAS): All patients with confirmed eligibility to whom study treatment was assigned. Only participants with valid absolute reticulocyte count measurements at baseline and Day 336 were analyzed.

Change from baseline in absolute reticulocyte count at visit Day 336.

Outcome measures

Outcome measures
Measure	LNP023 n=39 Participants Participants receive LNP023 at a dose of 200 mg b.i.d. orally
Change From Baseline in Absolute Reticulocyte Count at Day 336	-76.55 x10^9 cells/L Standard Deviation 50.149

OTHER_PRE_SPECIFIED outcome

Timeframe: Baseline, Day 336

Population: Full Analysis Set (FAS): All patients with confirmed eligibility to whom study treatment was assigned. Only participants with valid FACIT-Fatigue scores at baseline and Day 336 were analyzed.

The FACIT-Fatigue is a 13-item questionnaire with support for its validity and reliability in PNH that assesses patient self-reported fatigue and its impact on daily activities and function. All FACIT scales are scored so that a high score is better. As each of the 13 items of the FACIT-F Scale ranges from 0-4, the range of possible scores is 0-52, with 0 being the worst possible score and 52 the best.

Outcome measures

Outcome measures
Measure	LNP023 n=39 Participants Participants receive LNP023 at a dose of 200 mg b.i.d. orally
Change From Baseline in FACIT-Fatigue Score	10.4 score on a scale Standard Deviation 10.14

OTHER_PRE_SPECIFIED outcome

Timeframe: Between Day 1 and Day 336

Population: Full Analysis Set (FAS): All patients with confirmed eligibility to whom study treatment was assigned.

Adjusted annual rate is carried out using the Wilson method. A Major Adverse Vascular Events (MAVE) is defined as: acute peripheral vascular occlusion, amputation (non-traumatic; nondiabetic), cerebral arterial occlusion/cerebrovascular accident, cerebral venous occlusion, dermal thrombosis, gangrene (non-traumatic; nondiabetic), hepatic/portal vein thrombosis (Budd-Chiari syndrome), mesenteric/visceral arterial, thrombosis or infarction, mesenteric/visceral vein thrombosis or infarction, myocardial infarction, pulmonary embolus, renal arterial thrombosis, renal vein thrombosis, thrombophlebitis / deep vein thrombosis, transient ischemic attack, unstable angina or other

Outcome measures

Outcome measures
Measure	LNP023 n=40 Participants Participants receive LNP023 at a dose of 200 mg b.i.d. orally
Adjusted Annualized Major Adverse Vascular Events Rate After the Start of LNP023 Treatment	0.00 MAVE events/year Interval 0.0 to 0.09

Adverse Events

LNP023 200mg b.i.d.

Serious events: 8 serious events

Other events: 24 other events

Deaths: 0 deaths

Serious adverse events

Serious adverse events
Measure	LNP023 200mg b.i.d. n=40 participants at risk LNP023 200mg b.i.d.
Blood and lymphatic system disorders Breakthrough haemolysis	2.5% 1/40 • Adverse events of LNP023 group were reported from first dose of study treatment until the end of study treatment plus up to 30 days, up to a maximum duration of 48 weeks
Eye disorders Cataract	2.5% 1/40 • Adverse events of LNP023 group were reported from first dose of study treatment until the end of study treatment plus up to 30 days, up to a maximum duration of 48 weeks
Infections and infestations COVID-19	5.0% 2/40 • Adverse events of LNP023 group were reported from first dose of study treatment until the end of study treatment plus up to 30 days, up to a maximum duration of 48 weeks
Infections and infestations Infection	2.5% 1/40 • Adverse events of LNP023 group were reported from first dose of study treatment until the end of study treatment plus up to 30 days, up to a maximum duration of 48 weeks
Infections and infestations Pneumonia	2.5% 1/40 • Adverse events of LNP023 group were reported from first dose of study treatment until the end of study treatment plus up to 30 days, up to a maximum duration of 48 weeks
Infections and infestations Pneumonia bacterial	2.5% 1/40 • Adverse events of LNP023 group were reported from first dose of study treatment until the end of study treatment plus up to 30 days, up to a maximum duration of 48 weeks
Metabolism and nutrition disorders Type 2 diabetes mellitus	2.5% 1/40 • Adverse events of LNP023 group were reported from first dose of study treatment until the end of study treatment plus up to 30 days, up to a maximum duration of 48 weeks
Neoplasms benign, malignant and unspecified (incl cysts and polyps) Malignant melanoma	2.5% 1/40 • Adverse events of LNP023 group were reported from first dose of study treatment until the end of study treatment plus up to 30 days, up to a maximum duration of 48 weeks

Other adverse events

Other adverse events
Measure	LNP023 200mg b.i.d. n=40 participants at risk LNP023 200mg b.i.d.
Gastrointestinal disorders Abdominal pain	7.5% 3/40 • Adverse events of LNP023 group were reported from first dose of study treatment until the end of study treatment plus up to 30 days, up to a maximum duration of 48 weeks
Gastrointestinal disorders Constipation	7.5% 3/40 • Adverse events of LNP023 group were reported from first dose of study treatment until the end of study treatment plus up to 30 days, up to a maximum duration of 48 weeks
Gastrointestinal disorders Diarrhoea	15.0% 6/40 • Adverse events of LNP023 group were reported from first dose of study treatment until the end of study treatment plus up to 30 days, up to a maximum duration of 48 weeks
Gastrointestinal disorders Vomiting	7.5% 3/40 • Adverse events of LNP023 group were reported from first dose of study treatment until the end of study treatment plus up to 30 days, up to a maximum duration of 48 weeks
General disorders Pyrexia	7.5% 3/40 • Adverse events of LNP023 group were reported from first dose of study treatment until the end of study treatment plus up to 30 days, up to a maximum duration of 48 weeks
Infections and infestations COVID-19	17.5% 7/40 • Adverse events of LNP023 group were reported from first dose of study treatment until the end of study treatment plus up to 30 days, up to a maximum duration of 48 weeks
Infections and infestations Upper respiratory tract infection	17.5% 7/40 • Adverse events of LNP023 group were reported from first dose of study treatment until the end of study treatment plus up to 30 days, up to a maximum duration of 48 weeks
Metabolism and nutrition disorders Iron deficiency	7.5% 3/40 • Adverse events of LNP023 group were reported from first dose of study treatment until the end of study treatment plus up to 30 days, up to a maximum duration of 48 weeks
Nervous system disorders Headache	30.0% 12/40 • Adverse events of LNP023 group were reported from first dose of study treatment until the end of study treatment plus up to 30 days, up to a maximum duration of 48 weeks

Additional Information

Study Director

Novartis Pharmaceuticals

Phone: + 1 862 778 8300

Email: [email protected]

Results disclosure agreements

Principal investigator is a sponsor employee The terms and conditions of Novartis' agreements with its investigators may vary. However, Novartis does not prohibit any investigator from publishing. Any publications from a single-site are postponed until the publication of the pooled data (i.e., data from all sites) in the clinical trial.
Publication restrictions are in place

Restriction type: OTHER