Cold Agglutinin Disease (CAD), Immune Thrombocytopenia (ITP)
Conditions
Keywords
LNP023, Iptacopan, Immune thrombocytopenia, Cold agglutinin disease, Autoimmune benign hematological disorders
Brief summary
The main purpose of this study was to evaluate the efficacy and safety of iptacopan in participants with autoimmune benign hematological disorders such as primary immune thrombocytopenia and primary cold agglutinin disease.
Detailed description
This was an open-label, single-arm (within each cohort), multi-center, non-confirmatory basket study to assess the efficacy, safety and pharmacokinetics of iptacopan in participants with autoimmune benign hematological disorders. The study was set up as a basket study to allow inclusion of new cohorts (indications). The study included 2 cohorts: primary immune thrombocytopenia (ITP) and primary cold agglutinin disease (CAD). Participants in Cohort 1 (ITP) were stratified in two groups according to high/low complement activation (i.e., based on sC5b-9 level at screening). No additional cohorts were added during the study. The study consisted of a screening period, a 12-week treatment period (Part A), a washout (for responders)/follow-up (for non-responders) period after Part A, and, for responders only, an additional treatment extension period for up to 24 months (Part B). Non-responders who had signs of clinical benefit according to the Investigator's assessment could also continue treatment with iptacopan in Part B. The washout period prior to the start of part B lasted up to 4 weeks.
Interventions
DRUGIptacopan
Iptacopan 200 mg BID given orally (capsule)
Sponsors
Novartis Pharmaceuticals
Study design
Allocation
NA
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Intervention model description
This is a basket study with different Cohorts.
Eligibility
Sex/Gender
ALL
Age
18 Years to 120 Years
Healthy volunteers
No
Inclusion criteria
All Cohorts: * Written informed consent * Vaccination against Neisseria meningitidis and Streptococcus pneumoniae infections was required and vaccination against Haemophilus influenzae infection is recommended prior to the start of treatment. * Weight of at least 35 kg Cohort 1 specific inclusion criteria: * Participants with a diagnosis of persistent or chronic primary ITP * Participants must have received at least 1 unique prior therapy administered with the intention to treat ITP * Sustained thrombocytopenia Cohort 2 specific inclusion criteria: * Participants with a diagnosis of primary CAD * Participants must have received at least 1 unique prior therapy administered with the intention to treat CAD * Laboratory evidence of ongoing hemolysis * Sustained anemia
Exclusion criteria
All cohorts: * Use of other investigational drugs at the time of enrollment, or within 5 half-lives of enrollment, or within 30 days, whichever is longer; or longer if required by local regulations * Past or concomitant use of medications prohibited by the protocol * Known or suspected hereditary or acquired complement deficiency * History of primary or secondary immunodeficiency, including a positive HIV test result * Chronic infection with Hepatitis B or C virus * History of recurrent invasive infections caused by encapsulated organisms, including Neisseria meningitidis, Streptococcus pneumoniae, or Haemophilus influenzae * Presence or suspicion of any active infection within 14 days prior to first study drug administration. * Any medical condition deemed likely to interfere with the participant's participation in the study * Any malignant disease diagnosed within the past 5 years, with the exception of localized non-melanoma skin cancer, in situ cervical cancer, or, for CAD, a low-grade lymphoproliferative disorder. * History of bone marrow/hematopoietic stem cell or solid organ transplantation. * Women of child-bearing potential, defined as all women physiologically capable of becoming pregnant, unless they are using effective methods of contraception during dosing of investigational drug and for 1 week after last iptacopan dose * Active severe bleeding or history of intracranial hemorrhage. * Liver disease, or liver injury as indicated by abnormal liver function tests. * Severe concurrent comorbidities of unstable medical conditions. Cohort 1 specific
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Cohort 1 (ITP): Number of Participants With a Clinically Meaningful Response | Up to 12 weeks (Part A) | A study participant with ITP was considered a responder if all the below criteria were met: 1. Platelet count of ≥50 k/μL sustained for at least 2 consecutive weeks during the main, 12-week treatment part 2. Absence of rescue therapy or prohibited medications to treat ITP 3. Lack of treatment discontinuation |
| Cohort 2 (CAD): Number of Participants With a Clinically Meaningful Response | Baseline, up to 12 weeks (Part A) | A study participant with CAD was considered a responder if all the below criteria were met: 1. Hemoglobin level increase of ≥1.5 g/dL above baseline sustained for at least 2 consecutive weeks during the main, 12-week treatment part 2. Absence of rescue therapy or prohibited medications to treat CAD 3. Lack of treatment discontinuation |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Cohort 1 (ITP): Duration of Time During Which Platelet Count Remains ≥50 k/μL Without the Use of Rescue Therapy | Up to 12 weeks (Part A) | The duration of response corresponds to the duration of time during which a participant's platelet count remains ≥50 k/μL without the use of rescue therapy. The duration of response was considered as cumulative if there were non-continuous periods of response. Duration of response was analyzed for responders only. |
| Cohort 2 (CAD): Duration of Time During Which Hemoglobin Level Remains ≥1.5 g/dL Above Baseline Without the Use of Rescue Therapy | Baseline, up to 12 weeks (Part A) | The duration of response corresponds to the duration of time during which a participant's hemoglobin level remained ≥1.5 g/dL above baseline without the use of rescue therapy. The duration of response was considered as cumulative if there were non-continuous periods of response. Duration of response was analyzed for responders only. |
| Cohort 1 (ITP): Magnitude of Platelet Count Increase From Baseline | Baseline, up to 12 weeks (Part A) | The magnitude of increase in platelet count compared to baseline was derived for each participant at each visit and time point. Best response across all visits is presented (highest value). The following categories were used: absolute platelet counts increase \<50, ≥50 and \<100, ≥100 and \<150, and ≥150 k/uL. This endpoint is only applicable to participants without rescue therapy in the treatment period. |
| Cohort 2 (CAD): Magnitude of Hemoglobin Increase From Baseline | Baseline, up to 12 weeks (Part A) | The magnitude of increase in hemoglobin level compared to baseline was derived for each participant at each visit and time point. Best response across all visits is presented (highest value). The following categories were used: Hb increase from baseline by \<1, ≥1 and \<1.5, ≥1.5 and \<2, and ≥2 g/dL. This endpoint is only applicable to participants without rescue therapy in the treatment period. |
| Cohort 1 (ITP): Need for Rescue Therapy During Part A | Up to 12 weeks (Part A) | Rescue therapy was defined as any therapy with ITP indication that started on or after Day 1. Rescue therapy, if indicated, could be initiated at the Investigator's discretion. From Day 1 onwards, if rescue therapy was needed before response criteria were met, the participant was treated as a non-responder. Conversely, use of rescue therapy after the primary endpoint was met, would not impact the response status with respect to that endpoint. For ITP, rescue therapy generally consisted of corticosteroids, intravenous immunoglobulins or anti-Rho(D) immunoglobulin and may had been indicated in case of worsening thrombocytopenia and/or signs or symptoms of bleeding. |
| Cohort 2 (CAD): Need for Rescue Therapy During Part A | Up to 12 weeks (Part A) | Rescue therapy was defined as any therapy with CAD indication that started on or after Day 1. Rescue therapy, if indicated, could be initiated at the Investigator's discretion. From Day 1 onwards, if rescue therapy was needed before response criteria were met, the participant was treated as a non-responder. Conversely, use of rescue therapy after the primary endpoint was met, would not impact the response status with respect to that endpoint. For CAD, rescue therapy generally consisted of plasmapheresis, intravenous immunoglobulins (IVIG) and/or red blood cell transfusions and may had been indicated in case of worsening anemia and/or critical hemolysis. |
| Cohort 2 (CAD): Change From Baseline in Lactate Dehydrogenase (LDH) | Baseline, up to 12 weeks (Part A) | LDH was measured in serum samples to assess the effect of treatment with iptacopan on relevant disease biomarkers. |
| Cohort 1 (ITP): Time to First Platelet Count ≥50 k/μL | Up to 12 weeks (Part A) | The first time that a participant had a platelet count ≥50 k/μL after first dose of study treatment. Time to the first response was assessed for responders only. |
| Cohort 2 (CAD): Change From Baseline in Reticulocyte Count | Baseline, up to 12 weeks (Part A) | Reticulocyte count was measured in blood samples to assess the effect of treatment with iptacopan on relevant disease biomarkers. |
| Cohort 2 (CAD): Change From Baseline in Haptoglobin | Baseline, up to 12 weeks (Part A) | Haptoglobin was measured in serum or plasma samples to assess the effect of treatment with iptacopan on relevant disease biomarkers. |
| Cohort 1 and 2: Number of Participants With AEs and SAEs During the On-treatment Period in Part A and B | From first dose of study treatment to 7 days after last dose, up to approximately 43 weeks (Cohort 1) and 103 weeks (Cohort 2) | Number of participants with AEs (any adverse events regardless of seriousness) and serious adverse events (SAEs), including changes from baseline in vital signs, electrocardiograms and laboratory results qualifying and reported as AEs. AE grades to characterize the severity of the AEs were based on the Common Terminology Criteria for Adverse Events (CTCAE) version 5.0. For CTCAE v5.0, Grade 1 = mild; Grade 2 = moderate; Grade 3 = severe; Grade 4 = life-threatening; Grade 5 = death related to AE. The on-treatment period is defined from the day of first administration of study drug up to 7 days after the last administration of study drug. |
| Cohort 1 and 2: Maximum Observed Plasma Concentration (Cmax) of Iptacopan | Pre-dose, 0.5, 2, 4 and 6 hours after iptacopan administration on Day 15 and Day 57 of Part A | Pharmacokinetic (PK) parameters were calculated based on iptacopan plasma concentrations by using non-compartmental methods. Cmax is defined as the maximum (peak) observed concentration following a dose. |
| Cohort 1 and 2: Time to Maximum Observed Plasma Concentration (Tmax) of Iptacopan | Pre-dose, 0.5, 2, 4 and 6 hours after iptacopan administration on Day 15 and Day 57 of Part A | PK parameters were calculated based on iptacopan plasma concentrations by using non-compartmental methods. Tmax is defined as the time to reach maximum (peak) observed concentration following a dose. Actual sampling times were considered for the calculation of PK parameters. |
| Cohort 1 and 2: Area Under the Plasma Concentration-time Curve From Time Zero to the Time of the Last Quantifiable Concentration (AUClast) of Iptacopan | Pre-dose, 0.5, 2, 4 and 6 hours after iptacopan administration on Day 15 and Day 57 of Part A | PK parameters were calculated based on iptacopan plasma concentrations by using non-compartmental methods. The linear trapezoidal method was used for area under the curve (AUC) calculation. |
| Cohort 1 and 2: Trough Plasma Concentration (Ctrough) of Iptacopan | Pre-dose on Day 15, 29 and 57 of Part A | Ctrough is defined as the concentration reached immediately before the next dose is administered. All drug concentrations below the lower limit of quantification were treated as zero for the calculation of PK parameters. |
| Cohort 2 (CAD): Change From Baseline in Total Bilirubin | Baseline, up to 12 weeks (Part A) | Total bilirubin was measured in serum samples to assess the effect of treatment with iptacopan on relevant disease biomarkers. |
| Cohort 2 (CAD): Time to First Hemoglobin Level ≥1.5 g/dL Above Baseline | Baseline, up to 12 weeks (Part A) | The first time that a participant had a hemoglobin level ≥1.5 g/dL above baseline after first dose of study treatment. Time to the first response was assessed for responders only. |
Countries
Germany, Italy, South Korea, Spain, United Kingdom, United States
Participant flow
Recruitment details
Participants took part in 8 investigative sites in 6 countries.
Pre-assignment details
The screening period began once patients had signed the study informed consent. Screening evaluations had to be completed within 8 weeks prior to the first dose of study treatment. The treatment period started on Day 1 of Part A.
Participants by arm
| Arm | Count |
|---|---|
| Cohort 1 (ITP) Iptacopan 200 mg twice daily (b.i.d.) in participants with primary immune thrombocytopenia (ITP) | 9 |
| Cohort 2 (CAD) Iptacopan 200 mg twice daily (b.i.d.) in participants with primary cold agglutinin disease (CAD) | 10 |
| Total | 19 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Part A | Adverse Event | 0 | 1 |
| Part A | Lack of Efficacy | 3 | 0 |
| Part A | Protocol deviation | 1 | 0 |
| Part A | Subject decision | 1 | 0 |
| Part B | Adverse Event | 0 | 1 |
| Part B | Lack of Efficacy | 0 | 1 |
| Part B | Study terminated by sponsor | 1 | 6 |
Baseline characteristics
| Characteristic | Cohort 1 (ITP) | Cohort 2 (CAD) | Total |
|---|---|---|---|
| Age, Continuous | 44.2 years STANDARD_DEVIATION 20.77 | 66.7 years STANDARD_DEVIATION 10.01 | 56.1 years STANDARD_DEVIATION 19.36 |
| Age, Customized 18 - <65 years | 7 Participants | 5 Participants | 12 Participants |
| Age, Customized 65 - <85 years | 2 Participants | 5 Participants | 7 Participants |
| Hemoglobin | — | 86.7 gram/liter STANDARD_DEVIATION 9.06 | 86.7 gram/liter STANDARD_DEVIATION 9.06 |
| Platelets | 14.6 platelets*10^9/liter STANDARD_DEVIATION 10.53 | — | 14.6 platelets*10^9/liter STANDARD_DEVIATION 10.53 |
| Race/Ethnicity, Customized Asian | 3 Participants | 0 Participants | 3 Participants |
| Race/Ethnicity, Customized White | 6 Participants | 10 Participants | 16 Participants |
| Sex: Female, Male Female | 5 Participants | 10 Participants | 15 Participants |
| Sex: Female, Male Male | 4 Participants | 0 Participants | 4 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk |
|---|---|---|---|
| deaths Total, all-cause mortality | 0 / 9 | 0 / 10 | 0 / 19 |
| other Total, other adverse events | 7 / 9 | 9 / 10 | 16 / 19 |
| serious Total, serious adverse events | 1 / 9 | 1 / 10 | 2 / 19 |
Outcome results
Primary
Cohort 1 (ITP): Number of Participants With a Clinically Meaningful Response
A study participant with ITP was considered a responder if all the below criteria were met: 1. Platelet count of ≥50 k/μL sustained for at least 2 consecutive weeks during the main, 12-week treatment part 2. Absence of rescue therapy or prohibited medications to treat ITP 3. Lack of treatment discontinuation
Time frame: Up to 12 weeks (Part A)
Population: Participants from Cohort 1 in the Pharmacodynamic (PD) analysis set. Results are presented by sC5b-9 stratification group (sC5b-9 high and sC5b-9 low) and overall.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Cohort 1 (ITP) - sC5b-9 High | Cohort 1 (ITP): Number of Participants With a Clinically Meaningful Response | 0 Participants |
| Cohort 1 (ITP) - sC5b-9 Low | Cohort 1 (ITP): Number of Participants With a Clinically Meaningful Response | 0 Participants |
| Cohort 1 (ITP) | Cohort 1 (ITP): Number of Participants With a Clinically Meaningful Response | 0 Participants |
Primary
Cohort 2 (CAD): Number of Participants With a Clinically Meaningful Response
A study participant with CAD was considered a responder if all the below criteria were met: 1. Hemoglobin level increase of ≥1.5 g/dL above baseline sustained for at least 2 consecutive weeks during the main, 12-week treatment part 2. Absence of rescue therapy or prohibited medications to treat CAD 3. Lack of treatment discontinuation
Time frame: Baseline, up to 12 weeks (Part A)
Population: Participants from Cohort 2 in the PD analysis set.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Cohort 1 (ITP) - sC5b-9 High | Cohort 2 (CAD): Number of Participants With a Clinically Meaningful Response | 5 Participants |
Secondary
Cohort 1 and 2: Area Under the Plasma Concentration-time Curve From Time Zero to the Time of the Last Quantifiable Concentration (AUClast) of Iptacopan
PK parameters were calculated based on iptacopan plasma concentrations by using non-compartmental methods. The linear trapezoidal method was used for area under the curve (AUC) calculation.
Time frame: Pre-dose, 0.5, 2, 4 and 6 hours after iptacopan administration on Day 15 and Day 57 of Part A
Population: Participants in the PK analysis set (PAS) who had an available value for the outcome measure on the assessed study day. PAS consisted of all participants with at least one available valid PK concentration measurement, who received any study drug and with no protocol deviations or AEs which may have impacted iptacopan's PK.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Cohort 1 (ITP) - sC5b-9 High | Cohort 1 and 2: Area Under the Plasma Concentration-time Curve From Time Zero to the Time of the Last Quantifiable Concentration (AUClast) of Iptacopan | Day 15 | 24200.0 hr*ng/mL | Standard Deviation 6110 |
| Cohort 1 (ITP) - sC5b-9 High | Cohort 1 and 2: Area Under the Plasma Concentration-time Curve From Time Zero to the Time of the Last Quantifiable Concentration (AUClast) of Iptacopan | Day 57 | 21300.0 hr*ng/mL | Standard Deviation 5280 |
| Cohort 1 (ITP) - sC5b-9 Low | Cohort 1 and 2: Area Under the Plasma Concentration-time Curve From Time Zero to the Time of the Last Quantifiable Concentration (AUClast) of Iptacopan | Day 15 | 31100.0 hr*ng/mL | Standard Deviation 5830 |
| Cohort 1 (ITP) - sC5b-9 Low | Cohort 1 and 2: Area Under the Plasma Concentration-time Curve From Time Zero to the Time of the Last Quantifiable Concentration (AUClast) of Iptacopan | Day 57 | 28200.0 hr*ng/mL | Standard Deviation 6880 |
Secondary
Cohort 1 and 2: Maximum Observed Plasma Concentration (Cmax) of Iptacopan
Pharmacokinetic (PK) parameters were calculated based on iptacopan plasma concentrations by using non-compartmental methods. Cmax is defined as the maximum (peak) observed concentration following a dose.
Time frame: Pre-dose, 0.5, 2, 4 and 6 hours after iptacopan administration on Day 15 and Day 57 of Part A
Population: Participants in the PK analysis set (PAS) who had an available value for the outcome measure on the assessed study day. PAS consisted of all participants with at least one available valid PK concentration measurement, who received any study drug and with no protocol deviations or AEs which may have impacted iptacopan's PK.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Cohort 1 (ITP) - sC5b-9 High | Cohort 1 and 2: Maximum Observed Plasma Concentration (Cmax) of Iptacopan | Day 15 | 3190.0 ng/mL | Standard Deviation 465 |
| Cohort 1 (ITP) - sC5b-9 High | Cohort 1 and 2: Maximum Observed Plasma Concentration (Cmax) of Iptacopan | Day 57 | 2940.0 ng/mL | Standard Deviation 1020 |
| Cohort 1 (ITP) - sC5b-9 Low | Cohort 1 and 2: Maximum Observed Plasma Concentration (Cmax) of Iptacopan | Day 15 | 4800.0 ng/mL | Standard Deviation 838 |
| Cohort 1 (ITP) - sC5b-9 Low | Cohort 1 and 2: Maximum Observed Plasma Concentration (Cmax) of Iptacopan | Day 57 | 4420.0 ng/mL | Standard Deviation 1300 |
Secondary
Cohort 1 and 2: Number of Participants With AEs and SAEs During the On-treatment Period in Part A and B
Number of participants with AEs (any adverse events regardless of seriousness) and serious adverse events (SAEs), including changes from baseline in vital signs, electrocardiograms and laboratory results qualifying and reported as AEs. AE grades to characterize the severity of the AEs were based on the Common Terminology Criteria for Adverse Events (CTCAE) version 5.0. For CTCAE v5.0, Grade 1 = mild; Grade 2 = moderate; Grade 3 = severe; Grade 4 = life-threatening; Grade 5 = death related to AE. The on-treatment period is defined from the day of first administration of study drug up to 7 days after the last administration of study drug.
Time frame: From first dose of study treatment to 7 days after last dose, up to approximately 43 weeks (Cohort 1) and 103 weeks (Cohort 2)
Population: All participants who received at least one dose of study treatment.
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Cohort 1 (ITP) - sC5b-9 High | Cohort 1 and 2: Number of Participants With AEs and SAEs During the On-treatment Period in Part A and B | Severe AEs | 1 Participants |
| Cohort 1 (ITP) - sC5b-9 High | Cohort 1 and 2: Number of Participants With AEs and SAEs During the On-treatment Period in Part A and B | AEs | 7 Participants |
| Cohort 1 (ITP) - sC5b-9 High | Cohort 1 and 2: Number of Participants With AEs and SAEs During the On-treatment Period in Part A and B | Treatment-related AEs | 2 Participants |
| Cohort 1 (ITP) - sC5b-9 High | Cohort 1 and 2: Number of Participants With AEs and SAEs During the On-treatment Period in Part A and B | Treatment-related severe AEs | 1 Participants |
| Cohort 1 (ITP) - sC5b-9 High | Cohort 1 and 2: Number of Participants With AEs and SAEs During the On-treatment Period in Part A and B | SAEs | 0 Participants |
| Cohort 1 (ITP) - sC5b-9 High | Cohort 1 and 2: Number of Participants With AEs and SAEs During the On-treatment Period in Part A and B | Treatment-related SAEs | 0 Participants |
| Cohort 1 (ITP) - sC5b-9 High | Cohort 1 and 2: Number of Participants With AEs and SAEs During the On-treatment Period in Part A and B | Fatal SAEs | 0 Participants |
| Cohort 1 (ITP) - sC5b-9 High | Cohort 1 and 2: Number of Participants With AEs and SAEs During the On-treatment Period in Part A and B | Treatment-related fatal SAEs | 0 Participants |
| Cohort 1 (ITP) - sC5b-9 Low | Cohort 1 and 2: Number of Participants With AEs and SAEs During the On-treatment Period in Part A and B | Treatment-related fatal SAEs | 0 Participants |
| Cohort 1 (ITP) - sC5b-9 Low | Cohort 1 and 2: Number of Participants With AEs and SAEs During the On-treatment Period in Part A and B | SAEs | 1 Participants |
| Cohort 1 (ITP) - sC5b-9 Low | Cohort 1 and 2: Number of Participants With AEs and SAEs During the On-treatment Period in Part A and B | AEs | 9 Participants |
| Cohort 1 (ITP) - sC5b-9 Low | Cohort 1 and 2: Number of Participants With AEs and SAEs During the On-treatment Period in Part A and B | Fatal SAEs | 0 Participants |
| Cohort 1 (ITP) - sC5b-9 Low | Cohort 1 and 2: Number of Participants With AEs and SAEs During the On-treatment Period in Part A and B | Treatment-related AEs | 3 Participants |
| Cohort 1 (ITP) - sC5b-9 Low | Cohort 1 and 2: Number of Participants With AEs and SAEs During the On-treatment Period in Part A and B | Severe AEs | 0 Participants |
| Cohort 1 (ITP) - sC5b-9 Low | Cohort 1 and 2: Number of Participants With AEs and SAEs During the On-treatment Period in Part A and B | Treatment-related SAEs | 0 Participants |
| Cohort 1 (ITP) - sC5b-9 Low | Cohort 1 and 2: Number of Participants With AEs and SAEs During the On-treatment Period in Part A and B | Treatment-related severe AEs | 0 Participants |
Secondary
Cohort 1 and 2: Time to Maximum Observed Plasma Concentration (Tmax) of Iptacopan
PK parameters were calculated based on iptacopan plasma concentrations by using non-compartmental methods. Tmax is defined as the time to reach maximum (peak) observed concentration following a dose. Actual sampling times were considered for the calculation of PK parameters.
Time frame: Pre-dose, 0.5, 2, 4 and 6 hours after iptacopan administration on Day 15 and Day 57 of Part A
Population: Participants in the PK analysis set (PAS) who had an available value for the outcome measure on the assessed study day. PAS consisted of all participants with at least one available valid PK concentration measurement, who received any study drug and with no protocol deviations or AEs which may have impacted iptacopan's PK.
| Arm | Measure | Group | Value (MEDIAN) |
|---|---|---|---|
| Cohort 1 (ITP) - sC5b-9 High | Cohort 1 and 2: Time to Maximum Observed Plasma Concentration (Tmax) of Iptacopan | Day 15 | 2 hours |
| Cohort 1 (ITP) - sC5b-9 High | Cohort 1 and 2: Time to Maximum Observed Plasma Concentration (Tmax) of Iptacopan | Day 57 | 2 hours |
| Cohort 1 (ITP) - sC5b-9 Low | Cohort 1 and 2: Time to Maximum Observed Plasma Concentration (Tmax) of Iptacopan | Day 15 | 1 hours |
| Cohort 1 (ITP) - sC5b-9 Low | Cohort 1 and 2: Time to Maximum Observed Plasma Concentration (Tmax) of Iptacopan | Day 57 | 1.97 hours |
Secondary
Cohort 1 and 2: Trough Plasma Concentration (Ctrough) of Iptacopan
Ctrough is defined as the concentration reached immediately before the next dose is administered. All drug concentrations below the lower limit of quantification were treated as zero for the calculation of PK parameters.
Time frame: Pre-dose on Day 15, 29 and 57 of Part A
Population: Participants in the PK analysis set (PAS) who had an available value for the outcome measure on the assessed study day. PAS consisted of all participants with at least one available valid PK concentration measurement, who received any study drug and with no protocol deviations or AEs which may have impacted iptacopan's PK.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Cohort 1 (ITP) - sC5b-9 High | Cohort 1 and 2: Trough Plasma Concentration (Ctrough) of Iptacopan | Day 15 | 1670.0 ng/mL | Standard Deviation 1320 |
| Cohort 1 (ITP) - sC5b-9 High | Cohort 1 and 2: Trough Plasma Concentration (Ctrough) of Iptacopan | Day 29 | 1670.0 ng/mL | Standard Deviation 927 |
| Cohort 1 (ITP) - sC5b-9 High | Cohort 1 and 2: Trough Plasma Concentration (Ctrough) of Iptacopan | Day 57 | 1680.0 ng/mL | Standard Deviation 758 |
| Cohort 1 (ITP) - sC5b-9 Low | Cohort 1 and 2: Trough Plasma Concentration (Ctrough) of Iptacopan | Day 15 | 1980.0 ng/mL | Standard Deviation 1720 |
| Cohort 1 (ITP) - sC5b-9 Low | Cohort 1 and 2: Trough Plasma Concentration (Ctrough) of Iptacopan | Day 29 | 1330.0 ng/mL | Standard Deviation 337 |
| Cohort 1 (ITP) - sC5b-9 Low | Cohort 1 and 2: Trough Plasma Concentration (Ctrough) of Iptacopan | Day 57 | 1410.0 ng/mL | Standard Deviation 320 |
Secondary
Cohort 1 (ITP): Duration of Time During Which Platelet Count Remains ≥50 k/μL Without the Use of Rescue Therapy
The duration of response corresponds to the duration of time during which a participant's platelet count remains ≥50 k/μL without the use of rescue therapy. The duration of response was considered as cumulative if there were non-continuous periods of response. Duration of response was analyzed for responders only.
Time frame: Up to 12 weeks (Part A)
Population: Participants from Cohort 1 in the Pharmacodynamic (PD) analysis set who were responders. Results are presented by sC5b-9 stratification group (sC5b-9 high and sC5b-9 low) and overall.
Secondary
Cohort 1 (ITP): Magnitude of Platelet Count Increase From Baseline
The magnitude of increase in platelet count compared to baseline was derived for each participant at each visit and time point. Best response across all visits is presented (highest value). The following categories were used: absolute platelet counts increase \<50, ≥50 and \<100, ≥100 and \<150, and ≥150 k/uL. This endpoint is only applicable to participants without rescue therapy in the treatment period.
Time frame: Baseline, up to 12 weeks (Part A)
Population: Participants from Cohort 1 in the Pharmacodynamic (PD) analysis set who did not use rescue therapy in the treatment period of Part A. Results are presented by sC5b-9 stratification group (sC5b-9 high and sC5b-9 low) and overall.
| Arm | Measure | Category | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Cohort 1 (ITP) - sC5b-9 High | Cohort 1 (ITP): Magnitude of Platelet Count Increase From Baseline | Absolute platelet counts increase >=100 k/uL and <150 k/uL | 0 Participants |
| Cohort 1 (ITP) - sC5b-9 High | Cohort 1 (ITP): Magnitude of Platelet Count Increase From Baseline | Absolute platelet counts increase <50 k/uL | 1 Participants |
| Cohort 1 (ITP) - sC5b-9 High | Cohort 1 (ITP): Magnitude of Platelet Count Increase From Baseline | Absolute platelet counts increase >=150 k/uL | 0 Participants |
| Cohort 1 (ITP) - sC5b-9 High | Cohort 1 (ITP): Magnitude of Platelet Count Increase From Baseline | Absolute platelet counts increase >=50 k/uL and <100 k/uL | 0 Participants |
| Cohort 1 (ITP) - sC5b-9 Low | Cohort 1 (ITP): Magnitude of Platelet Count Increase From Baseline | Absolute platelet counts increase >=100 k/uL and <150 k/uL | 0 Participants |
| Cohort 1 (ITP) - sC5b-9 Low | Cohort 1 (ITP): Magnitude of Platelet Count Increase From Baseline | Absolute platelet counts increase >=50 k/uL and <100 k/uL | 0 Participants |
| Cohort 1 (ITP) - sC5b-9 Low | Cohort 1 (ITP): Magnitude of Platelet Count Increase From Baseline | Absolute platelet counts increase <50 k/uL | 2 Participants |
| Cohort 1 (ITP) - sC5b-9 Low | Cohort 1 (ITP): Magnitude of Platelet Count Increase From Baseline | Absolute platelet counts increase >=150 k/uL | 0 Participants |
| Cohort 1 (ITP) | Cohort 1 (ITP): Magnitude of Platelet Count Increase From Baseline | Absolute platelet counts increase >=150 k/uL | 0 Participants |
| Cohort 1 (ITP) | Cohort 1 (ITP): Magnitude of Platelet Count Increase From Baseline | Absolute platelet counts increase <50 k/uL | 3 Participants |
| Cohort 1 (ITP) | Cohort 1 (ITP): Magnitude of Platelet Count Increase From Baseline | Absolute platelet counts increase >=50 k/uL and <100 k/uL | 0 Participants |
| Cohort 1 (ITP) | Cohort 1 (ITP): Magnitude of Platelet Count Increase From Baseline | Absolute platelet counts increase >=100 k/uL and <150 k/uL | 0 Participants |
Secondary
Cohort 1 (ITP): Need for Rescue Therapy During Part A
Rescue therapy was defined as any therapy with ITP indication that started on or after Day 1. Rescue therapy, if indicated, could be initiated at the Investigator's discretion. From Day 1 onwards, if rescue therapy was needed before response criteria were met, the participant was treated as a non-responder. Conversely, use of rescue therapy after the primary endpoint was met, would not impact the response status with respect to that endpoint. For ITP, rescue therapy generally consisted of corticosteroids, intravenous immunoglobulins or anti-Rho(D) immunoglobulin and may had been indicated in case of worsening thrombocytopenia and/or signs or symptoms of bleeding.
Time frame: Up to 12 weeks (Part A)
Population: Participants from Cohort 1 in the Pharmacodynamic (PD) analysis set. Results are presented by sC5b-9 stratification group (sC5b-9 high and sC5b-9 low) and overall.
| Arm | Measure | Category | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Cohort 1 (ITP) - sC5b-9 High | Cohort 1 (ITP): Need for Rescue Therapy During Part A | No | 1 Participants |
| Cohort 1 (ITP) - sC5b-9 High | Cohort 1 (ITP): Need for Rescue Therapy During Part A | Yes | 2 Participants |
| Cohort 1 (ITP) - sC5b-9 Low | Cohort 1 (ITP): Need for Rescue Therapy During Part A | No | 2 Participants |
| Cohort 1 (ITP) - sC5b-9 Low | Cohort 1 (ITP): Need for Rescue Therapy During Part A | Yes | 3 Participants |
| Cohort 1 (ITP) | Cohort 1 (ITP): Need for Rescue Therapy During Part A | No | 3 Participants |
| Cohort 1 (ITP) | Cohort 1 (ITP): Need for Rescue Therapy During Part A | Yes | 5 Participants |
Secondary
Cohort 1 (ITP): Time to First Platelet Count ≥50 k/μL
The first time that a participant had a platelet count ≥50 k/μL after first dose of study treatment. Time to the first response was assessed for responders only.
Time frame: Up to 12 weeks (Part A)
Population: Participants from Cohort 1 in the Pharmacodynamic (PD) analysis set who were responders. Results are presented by sC5b-9 stratification group (sC5b-9 high and sC5b-9 low) and overall.
Secondary
Cohort 2 (CAD): Change From Baseline in Haptoglobin
Haptoglobin was measured in serum or plasma samples to assess the effect of treatment with iptacopan on relevant disease biomarkers.
Time frame: Baseline, up to 12 weeks (Part A)
Population: Participants from Cohort 2 in the PD analysis set with an available value for the outcome measure at both baseline and end of treatment in Part A.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Cohort 1 (ITP) - sC5b-9 High | Cohort 2 (CAD): Change From Baseline in Haptoglobin | 0.12 gram/liter (g/L) | Standard Deviation 0.236 |
Secondary
Cohort 2 (CAD): Change From Baseline in Lactate Dehydrogenase (LDH)
LDH was measured in serum samples to assess the effect of treatment with iptacopan on relevant disease biomarkers.
Time frame: Baseline, up to 12 weeks (Part A)
Population: Participants from Cohort 2 in the PD analysis set with an available value for the outcome measure at both baseline and end of treatment in Part A.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Cohort 1 (ITP) - sC5b-9 High | Cohort 2 (CAD): Change From Baseline in Lactate Dehydrogenase (LDH) | -277.83 Units/liter (U/L) | Standard Deviation 88.966 |
Secondary
Cohort 2 (CAD): Change From Baseline in Reticulocyte Count
Reticulocyte count was measured in blood samples to assess the effect of treatment with iptacopan on relevant disease biomarkers.
Time frame: Baseline, up to 12 weeks (Part A)
Population: Participants from Cohort 2 in the PD analysis set with an available value for the outcome measure at both baseline and end of treatment in Part A.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Cohort 1 (ITP) - sC5b-9 High | Cohort 2 (CAD): Change From Baseline in Reticulocyte Count | -37.45 reticulocytes * 10^9/liter | Standard Deviation 17.205 |
Secondary
Cohort 2 (CAD): Change From Baseline in Total Bilirubin
Total bilirubin was measured in serum samples to assess the effect of treatment with iptacopan on relevant disease biomarkers.
Time frame: Baseline, up to 12 weeks (Part A)
Population: Participants from Cohort 2 in the PD analysis set with an available value for the outcome measure at both baseline and end of treatment in Part A.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Cohort 1 (ITP) - sC5b-9 High | Cohort 2 (CAD): Change From Baseline in Total Bilirubin | -15.63 micromole/liter (μmol/L) | Standard Deviation 12.979 |
Secondary
Cohort 2 (CAD): Duration of Time During Which Hemoglobin Level Remains ≥1.5 g/dL Above Baseline Without the Use of Rescue Therapy
The duration of response corresponds to the duration of time during which a participant's hemoglobin level remained ≥1.5 g/dL above baseline without the use of rescue therapy. The duration of response was considered as cumulative if there were non-continuous periods of response. Duration of response was analyzed for responders only.
Time frame: Baseline, up to 12 weeks (Part A)
Population: Participants from Cohort 2 in the PD analysis set who were responders.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Cohort 1 (ITP) - sC5b-9 High | Cohort 2 (CAD): Duration of Time During Which Hemoglobin Level Remains ≥1.5 g/dL Above Baseline Without the Use of Rescue Therapy | 56.0 days |
Secondary
Cohort 2 (CAD): Magnitude of Hemoglobin Increase From Baseline
The magnitude of increase in hemoglobin level compared to baseline was derived for each participant at each visit and time point. Best response across all visits is presented (highest value). The following categories were used: Hb increase from baseline by \<1, ≥1 and \<1.5, ≥1.5 and \<2, and ≥2 g/dL. This endpoint is only applicable to participants without rescue therapy in the treatment period.
Time frame: Baseline, up to 12 weeks (Part A)
Population: Participants from Cohort 2 in the PD analysis set who did not use rescue therapy in the treatment period of Part A.
| Arm | Measure | Category | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Cohort 1 (ITP) - sC5b-9 High | Cohort 2 (CAD): Magnitude of Hemoglobin Increase From Baseline | Hb increase by <1.0 g/dL | 2 Participants |
| Cohort 1 (ITP) - sC5b-9 High | Cohort 2 (CAD): Magnitude of Hemoglobin Increase From Baseline | Hb increase by >=1.0 g/dL and <1.5 g/dL | 1 Participants |
| Cohort 1 (ITP) - sC5b-9 High | Cohort 2 (CAD): Magnitude of Hemoglobin Increase From Baseline | Hb increase by =>1.5 g/dL and <2 g/dL | 2 Participants |
| Cohort 1 (ITP) - sC5b-9 High | Cohort 2 (CAD): Magnitude of Hemoglobin Increase From Baseline | Hb increase by =>2 g/dL | 4 Participants |
Secondary
Cohort 2 (CAD): Need for Rescue Therapy During Part A
Rescue therapy was defined as any therapy with CAD indication that started on or after Day 1. Rescue therapy, if indicated, could be initiated at the Investigator's discretion. From Day 1 onwards, if rescue therapy was needed before response criteria were met, the participant was treated as a non-responder. Conversely, use of rescue therapy after the primary endpoint was met, would not impact the response status with respect to that endpoint. For CAD, rescue therapy generally consisted of plasmapheresis, intravenous immunoglobulins (IVIG) and/or red blood cell transfusions and may had been indicated in case of worsening anemia and/or critical hemolysis.
Time frame: Up to 12 weeks (Part A)
Population: Participants from Cohort 2 in the PD analysis set.
| Arm | Measure | Category | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Cohort 1 (ITP) - sC5b-9 High | Cohort 2 (CAD): Need for Rescue Therapy During Part A | No | 9 Participants |
| Cohort 1 (ITP) - sC5b-9 High | Cohort 2 (CAD): Need for Rescue Therapy During Part A | Yes | 1 Participants |
Secondary
Cohort 2 (CAD): Time to First Hemoglobin Level ≥1.5 g/dL Above Baseline
The first time that a participant had a hemoglobin level ≥1.5 g/dL above baseline after first dose of study treatment. Time to the first response was assessed for responders only.
Time frame: Baseline, up to 12 weeks (Part A)
Population: Participants from Cohort 2 in the PD analysis set who were responders.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Cohort 1 (ITP) - sC5b-9 High | Cohort 2 (CAD): Time to First Hemoglobin Level ≥1.5 g/dL Above Baseline | 29.0 days |