Paroxysmal Nocturnal Hemoglobinuria
Conditions
Keywords
Complement, alternative pathway, paroxysmal nocturnal hemoglobinuria, hemolysis, LNP023, PNH, LDH, hemoglobin, Iptacopan
Brief summary
This was a Phase II randomized, open-label, multicenter, efficacy, safety, pharmacokinetic and pharmacodynamic study assessing four iptacopan doses in adult Paroxysmal nocturnal hemoglobinuria (PNH) patients with active hemolysis who were not on eculizumab or any other complement inhibitor less than 3 months prior to first iptacopan dose. Active hemolysis was defined by a lactate dehydrogenase (LDH) value ≥ 1.5 × ULN.
Detailed description
LNP023 is a novel oral small molecular weight compound, that inhibits alternative complement pathway (AP). Blockade of the AP with oral LNP023 has the potential to prevent both intra - and extravascular hemolysis. The total study duration from Screening until end of study (EOS) was approximately 28 months. This three-period study included: * Screening phase: of up to 8 weeks * Period 1: a 4-week treatment period of iptacopan at the first dose in the assigned sequence * Period 2: an 8-week treatment period at the second dose in the assigned sequence * Period 3: an approximate 2-year treatment extension period for patients who responded to iptacopan treatment * Taper down period of 2 weeks was applicable only for patients discontinuing iptacopan treatment (Week 13 for non-responders or Week 109 for responders who did not enter the rollover extension program (REP) (Study CLNP023C12001B / NCT04747613)). During this taper down period, patients were to receive 25 mg qd (once a day) of iptacopan for 7 days, followed by 10 mg qd for 7 additional days. * An EOS visit that took place 1 week after the last iptacopan administration for patients not joining the REP. For patients joining the REP, the last treatment visit was the EOS visit. * A safety follow-up call 30 days after the last administration of iptacopan was performed for patients not joining the REP. Patients were randomized to Sequence 1 or Sequence 2 in a 1:1 ratio. Sequence 1: Four weeks of treatment with iptacopan 25 mg bid (Twice daily) in Period 1 followed by treatment with 100 mg bid in Period 2 and Period 3. If during Period 1, LDH was not reduced by ≥ 40% from the mean of pretreatment values by Week 2 (Day 15 study visit), the iptacopan dose was to be up-titrated to 100 mg bid (starting from Study Day 17). If LDH was not reduced by ≥ 40% from the mean of pretreatment values at Week 4 (Day 29), the iptacopan dose was to be up-titrated to 200 mg bid in Period 2 and Period 3 (starting from Study Day 30). In the approximate 2-year treatment extension (Period 3), patients maintained the same treatment regimen as used in Period 2. Sequence 2: Four weeks of treatment with iptacopan 50 mg bid in Period 1 followed by treatment with 200 mg bid in Period 2 and Period 3. If during Period 1, LDH was not reduced by ≥ 40% from the mean of pretreatment values by Week 2 (Day 15 study visit), the iptacopan dose was to be up-titrated to 200 mg bid (starting from Study Day 17). In the approximate 2-year treatment extension (Extension Period 3), patients remained on 200 mg bid. No further up-titration was possible
Interventions
DRUGLNP023
approximately 2 year of Treatment with LNP023
Sponsors
Novartis Pharmaceuticals
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
NONE
Intervention model description
Randomized, open label study
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
1. Written informed consent must be obtained before any assessment is performed. 2. Male and female patients at least 18 years old at baseline. 3. Diagnosis of active PNH based on documented clone size of ≥10% by RBCs and/or granulocytes, measured by GPI-deficiency on flow cytometry (screening or medical history data acceptable). 4. LDH values \> 1.5 x upper limit of the normal range (ULN) for at least 3 measurements over a maximum of 8 weeks prior to Day 1 (Screening, baseline or medical history data acceptable). 5. Hemoglobin level \< 10.5 g/dL at Baseline. 6. For Period 3 of the study, patients who as per judgment of Investigator benefit from LNP023 treatment based on reduced hemolytic parameters as compared to Screening and Baseline. 7. Vaccinations against N. meningitidis, S. pneumoniae and H. influenzae is required at least 4 weeks prior to first dosing with LNP023 (existing vaccinations should provide effective titers at time of LNP023 treatment start). If LNP023 treatment has to start earlier than 4 weeks post vaccination, prophylactic antibiotic treatment must be initiated. 8. Able to communicate well with the investigator, to understand and comply with the requirements of the study. -
Exclusion criteria
1. Participation in any other investigational drug trial or use of other investigational drugs at the time of enrollment, or within 5 elimination half-lives of enrollment, or within 30 days, whichever is longer; or longer if required by local regulations. 2. Patients treated with eculizumab or any other complement inhibitor less than 3 months prior to study Day 1 3. Known or suspected hereditary or acquired complement deficiency. 4. History of currently active primary or secondary immunodeficiency. 5. History of splenectomy. 6. History of bone marrow/ hematopoietic stem cell or solid organ transplants (e.g. heart, lung, kidney, liver). 7. Evidence of malignant disease, or malignancies diagnosed within the previous 5 years. 8. Patients with laboratory evidence of bone marrow failure (reticulocytes \< 60x10E9/L, or platelets \< 50x10E9/L or neutrophils \< 1x10E9/L) verified both at screening and baseline. 9. History of recurrent meningitis, history of meningococcal infections despite vaccination, as verified at both screening and baseline. 10. Presence or suspicion (based on judgment of the investigator) of active infection within 2 weeks prior to first dose of LNP023, or history of severe recurrent bacterial infections. 11. A positive HIV, Hepatitis B (HBV) or Hepatitis C (HCV) test result at screening. 12. Patients on immunosuppressive agents such, as but not limited to, cyclosporine, tacrolimus, mycophenolate or mycophenolic acid, cyclophosphamide, methotrexate or IV immunoglobulins, less than 8 weeks prior to first treatment with LNP023, unless on a stable regimen for at least 3 months prior to first LNP023 dose. 13. Systemic corticosteroids unless on a stable dose for at least 4 weeks before randomization. 14. Severe concurrent co-morbidities not amenable to active treatment; e.g., patients with severe kidney disease (CKD stage 4, dialysis), advanced cardiac disease (NYHA class IV), severe pulmonary arterial hypertension (WHO class IV), or unstable thrombotic event, as judged by the investigator, both at screening and baseline (unless baseline was skipped). 15. Any medical condition deemed likely to interfere with the patient's participation in the study, or likely to cause serious adverse events during the study. 16. History of hypersensitivity to the study treatment or its excipients or to drugs of similar chemical classes. 17. Female patients who are pregnant or breastfeeding, or intending to conceive during the course of the study. 18. Women of child-bearing potential, defined as all women physiologically capable of becoming pregnant, unless they are using highly effective methods of contraception during dosing and for 1 week after stopping of investigational drug
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Summary of Lactate Dehydrogenase (LDH) Responders | Week 2, week 4, week 8 and week 12 | A responder was defined as a patient with at least 60% reduction in LDH compared to Baseline or LDH below the upper limit of normal at any time up to and including Week 12 for that patient. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Change From Baseline in Hemoglobin | Baseline, Week 2, week 4, week 8 and week 12 | Hemoglobin was used as a hemolysis marker to determine the dose-response effect of iptacopan on the reduction of PNH-associated hemolysis. Whole blood was used to calculate the hemoglobin values. |
| Change From Baseline in Free Hemoglobin | Baseline, Week 2, week 4, week 8 and week 12 | Free hemoglobin was used as a hemolysis marker to determine the dose-response effect of iptacopan on the reduction of PNH-associated hemolysis. Whole blood was used to calculate the hemoglobin values. |
| Change From Baseline in Carboxyhemoglobin | Baseline, Week 2, week 4, week 8 and week 12 | Carboxyhemoglobin was used as a marker of intravascular and extravascular hemolysis to assess the effect of iptacopan. Whole blood was used to calculate the carboxyhemoglobin values. |
| Change From Baseline in Absolute Reticulocyte Count (ARC) | Baseline, week 2, week 4, week 8 and week 12 | Reticulocyte count was used as a marker of intravascular and extravascular hemolysis to assess the effect of iptacopan. Whole blood was used to calculate the absolute reticulocyte count. |
| Red Blood Cell Count: Change From Baseline in Erythrocytes | Baseline, week 2, week 4, week 8 and week 12 | Erythrocytes were used as a marker of intravascular and extravascular hemolysis to assess the effect of iptacopan. Whole blood was used to calculate erythrocytes values. |
| Change From Baseline in C3 Fragment Deposition on PNH RBC | Baseline, week 2, week 4, week 8 and week 12 | C3 fragment deposition on paroxysmal nocturnal hemoglobinuria red blood cell (PNH RBC) was used as a marker of intravascular and extravascular hemolysis to assess the effect of iptacopan. Accumulation of C3 fragments on red blood cells make them prone to phagocytosis causing extravascular hemolysis. Whole blood was used to calculate C3 fragment deposition on PNH RBC values. |
| Mean Haptoglobin Levels | Baseline, week 2, week 4, week 8 and week 12 | Haptoglobin levels were used as a hemolysis marker to determine the effect of iptacopan on the reduction of PNH-associated hemolysis. Serum was used to calculate haptoglobin levels. |
| Change From Baseline in Total Bilirubin | Baseline, week 2, week 4, week 8 and week 12 | Bilirubin levels were used as a hemolysis marker to determine the effect of iptacopan on the reduction of PNH-associated hemolysis. Serum was used to calculate bilirubin levels. |
| Mean Platelets Count | Baseline, week 2, week 4, week 8 and week 12 | Platelet counts were used as a marker of intravascular and extravascular hemolysis to assess the effect of iptacopan. Whole blood was used to calculate platelets count. |
| Mean Ferritin Levels | Baseline, Week 4, Week 8 and week 12 | Ferritin levels were used as a marker of intravascular and extravascular hemolysis to assess the effect of iptacopan. Serum was used to calculate ferritin levels. |
| Percent Change From Baseline in LDH Levels | Baseline, week 2, week 4, week 8 and week 12 | LDH was used as a hemolysis marker to determine the dose-response effect of iptacopan on the reduction of Paroxysmal nocturnal hemoglobinuria (PNH)-associated hemolysis. Active hemolysis is defined by an LDH value ≥ 1.5x upper limit of normal (ULN) Baseline LDH was calculated as the average of the last three screening values prior to randomization. Serum was used to calculate the LDH values |
| Pharmacokinetics Profile: Maximum Plasma Concentration (Cmax) | Day 29 and 57 | Cmax is the maximum (peak) observed plasma drug concentration after single dose administration (mass x volume-1). PK parameters were determined, using non-compartmental method(s) with Phoenix WinNonlin (Version 8.3), from the plasma concentration-time data. |
| Pharmacokinetics Profile: Area Under the Curve Tau (AUCtau) | Days 29 and 57 | The AUCtau is the area under the plasma concentration-time curve calculated to the end of a dosing interval (tau) at steady-state (amount x time x volume-1). AUCtau was estimated by imputing the 12-hour iptacopan plasma concentration as the PK profile's corresponding pre-dose (0-hour) value, that is, by assuming that at steady-state the iptacopan plasma concentration is the same as the beginning (pre-dose) and end (12 hours postdose) of the dosing interval. PK parameters were determined, using non-compartmental method(s) with Phoenix WinNonlin (Version 8.3), from the plasma concentration-time data. |
| Pharmacokinetics Profile: Minimum Plasma Concentration (Cmin) | Days 29 and 57 | Cmin is the lowest plasma concentration observed during a dosing interval at steady state \[mass / volume\]. PK parameters were determined, using non-compartmental method(s) with Phoenix WinNonlin (Version 8.3), from the plasma concentration-time data. |
| Pharmacokinetics Profile: Time to Reach Maximum Plasma Concentration (Tmax) | Days 29 and 57 | Tmax is the time to reach maximum (peak) plasma drug concentration after single dose administration (time). PK parameters were determined, using non-compartmental method(s) with Phoenix WinNonlin (Version 8.3), from the plasma concentration-time data. |
| Mean Fibrinogen Levels | Baseline, week 2, week 4, week 8 and week 12 | Fibrinogen level was used as a marker associated with risk of thrombosis. Plasma was used to calculate fibrinogen levels. |
| Mean Prothrombin Time (PT) | Baseline, week 2, week 4, week 8 and week 12 | Prothrombin time was used as a marker associated with risk of thrombosis. Plasma was used to calculate prothrombin time. |
| Mean Activated Partial Thromboplastin Time (aPTT) | Baseline, week 2, week 4, week 8 and week 12 | Activated partial thromboplastin time was used as a marker associated with risk of thrombosis. Plasma was used to calculate activated partial thromboplastin time. |
| Mean D-dimer Levels | Baseline, week 2, week 4, week 8 and week 12 | D-dimer levels were used as a marker associated with risk of thrombosis. Plasma was used to calculate D-dimer levels. |
| Mean Thrombin Clotting Time | Baseline, Week 4, Week 8 and Week 12 | thrombin clotting time was used as a marker associated with risk of thrombosis. Plasma was used to calculate thrombin clotting time. |
| Mean Clone Size | Baseline, week 2, week 4, week 8 and week 12 | PNH clone size was used as a marker of intravascular and extravascular hemolysis to assess the effect of iptacopan. Whole blood was used to calculate clone size values. |
Countries
Malaysia, Singapore, South Korea, Taiwan
Participant flow
Recruitment details
Participants took part in 5 investigative sites in 4 countries
Pre-assignment details
Participants underwent a screening period of up to 8 weeks
Participants by arm
| Arm | Count |
|---|---|
| LNP023 25 mg Bid/100 mg Bid Four weeks of treatment with iptacopan 25 mg bid in Period 1 followed by treatment with 100 mg bid in Period 2 and Period 3. | 7 |
| LNP023 50 mg Bid/200 mg Bid Four weeks of treatment with iptacopan 50 mg bid in Period 1 followed by treatment with 200 mg bid in Period 2 and Period 3. | 6 |
| Total | 13 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Adverse Event | 0 | 1 |
| Overall Study | Patient/guardian decision | 1 | 1 |
| Overall Study | Physician Decision | 1 | 0 |
| Overall Study | Technical problems | 1 | 0 |
Baseline characteristics
| Characteristic | LNP023 25 mg Bid/100 mg Bid | LNP023 50 mg Bid/200 mg Bid | Total |
|---|---|---|---|
| Age, Continuous | 34.4 years STANDARD_DEVIATION 15.27 | 42.5 years STANDARD_DEVIATION 11.98 | 38.2 years STANDARD_DEVIATION 13.93 |
| Race/Ethnicity, Customized Asian | 7 Participants | 6 Participants | 13 Participants |
| Sex: Female, Male Female | 2 Participants | 5 Participants | 7 Participants |
| Sex: Female, Male Male | 5 Participants | 1 Participants | 6 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk | EG003 affected / at risk | EG004 affected / at risk | EG005 affected / at risk |
|---|---|---|---|---|---|---|
| deaths Total, all-cause mortality | 0 / 7 | 0 / 6 | 0 / 7 | 0 / 5 | 0 / 7 | 0 / 5 |
| other Total, other adverse events | 2 / 7 | 4 / 6 | 3 / 7 | 1 / 5 | 4 / 7 | 4 / 5 |
| serious Total, serious adverse events | 0 / 7 | 0 / 6 | 0 / 7 | 0 / 5 | 0 / 7 | 0 / 5 |
Outcome results
Primary
Summary of Lactate Dehydrogenase (LDH) Responders
A responder was defined as a patient with at least 60% reduction in LDH compared to Baseline or LDH below the upper limit of normal at any time up to and including Week 12 for that patient.
Time frame: Week 2, week 4, week 8 and week 12
Population: The overall number of participants analyzed represents the participants in the PD analysis set who had at least one valid measurement of LDH.~The Pharmacodynamic (PD) analysis set is defined as patients with available PD data, who received any study drug and with no protocol deviations with relevant impact on PD data.~The number analyzed per row represents the participants with a valid LDH value for that particular visit.
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| LNP023 25 mg Bid/100 mg Bid | Summary of Lactate Dehydrogenase (LDH) Responders | Responders at week 2 | 6 Participants |
| LNP023 25 mg Bid/100 mg Bid | Summary of Lactate Dehydrogenase (LDH) Responders | Responders at week 4 | 7 Participants |
| LNP023 25 mg Bid/100 mg Bid | Summary of Lactate Dehydrogenase (LDH) Responders | Responders at week 8 | 7 Participants |
| LNP023 25 mg Bid/100 mg Bid | Summary of Lactate Dehydrogenase (LDH) Responders | Responders at week 12 | 7 Participants |
| LNP023 50 mg Bid/200 mg Bid | Summary of Lactate Dehydrogenase (LDH) Responders | Responders at week 12 | 5 Participants |
| LNP023 50 mg Bid/200 mg Bid | Summary of Lactate Dehydrogenase (LDH) Responders | Responders at week 2 | 5 Participants |
| LNP023 50 mg Bid/200 mg Bid | Summary of Lactate Dehydrogenase (LDH) Responders | Responders at week 8 | 5 Participants |
| LNP023 50 mg Bid/200 mg Bid | Summary of Lactate Dehydrogenase (LDH) Responders | Responders at week 4 | 5 Participants |
Secondary
Change From Baseline in Absolute Reticulocyte Count (ARC)
Reticulocyte count was used as a marker of intravascular and extravascular hemolysis to assess the effect of iptacopan. Whole blood was used to calculate the absolute reticulocyte count.
Time frame: Baseline, week 2, week 4, week 8 and week 12
Population: The overall number of participants analyzed represents the participants in the PD analysis set who had at least one valid measurement of reticulocyte count.~The number analyzed per row represents the participants with a valid reticulocyte count value both at baseline and that particular visit
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| LNP023 25 mg Bid/100 mg Bid | Change From Baseline in Absolute Reticulocyte Count (ARC) | Week 2 | -83.00 10^9 cells/L | Standard Deviation 78.75 |
| LNP023 25 mg Bid/100 mg Bid | Change From Baseline in Absolute Reticulocyte Count (ARC) | Week 4 | -118.44 10^9 cells/L | Standard Deviation 76.736 |
| LNP023 25 mg Bid/100 mg Bid | Change From Baseline in Absolute Reticulocyte Count (ARC) | Week 8 | -113.71 10^9 cells/L | Standard Deviation 72.3 |
| LNP023 25 mg Bid/100 mg Bid | Change From Baseline in Absolute Reticulocyte Count (ARC) | Week 12 | -93.00 10^9 cells/L | Standard Deviation 93.425 |
| LNP023 50 mg Bid/200 mg Bid | Change From Baseline in Absolute Reticulocyte Count (ARC) | Week 12 | -84.92 10^9 cells/L | Standard Deviation 123.408 |
| LNP023 50 mg Bid/200 mg Bid | Change From Baseline in Absolute Reticulocyte Count (ARC) | Week 2 | -94.23 10^9 cells/L | Standard Deviation 112.649 |
| LNP023 50 mg Bid/200 mg Bid | Change From Baseline in Absolute Reticulocyte Count (ARC) | Week 8 | -119.43 10^9 cells/L | Standard Deviation 117.048 |
| LNP023 50 mg Bid/200 mg Bid | Change From Baseline in Absolute Reticulocyte Count (ARC) | Week 4 | -132.63 10^9 cells/L | Standard Deviation 91.109 |
Secondary
Change From Baseline in C3 Fragment Deposition on PNH RBC
C3 fragment deposition on paroxysmal nocturnal hemoglobinuria red blood cell (PNH RBC) was used as a marker of intravascular and extravascular hemolysis to assess the effect of iptacopan. Accumulation of C3 fragments on red blood cells make them prone to phagocytosis causing extravascular hemolysis. Whole blood was used to calculate C3 fragment deposition on PNH RBC values.
Time frame: Baseline, week 2, week 4, week 8 and week 12
Population: The overall number of participants analyzed represents the participants in the PD analysis set who had at least one valid measurement of C3 fragment deposition.~The number analyzed per row represents the participants with a valid C3 fragment deposition value both at baseline and that particular visit.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| LNP023 25 mg Bid/100 mg Bid | Change From Baseline in C3 Fragment Deposition on PNH RBC | Week 2 | -1.31 % C3 fragment deposition on PNH RBC | Standard Deviation 0.932 |
| LNP023 25 mg Bid/100 mg Bid | Change From Baseline in C3 Fragment Deposition on PNH RBC | Week 4 | -1.43 % C3 fragment deposition on PNH RBC | Standard Deviation 1.217 |
| LNP023 25 mg Bid/100 mg Bid | Change From Baseline in C3 Fragment Deposition on PNH RBC | Week 8 | -1.85 % C3 fragment deposition on PNH RBC | Standard Deviation 1.293 |
| LNP023 25 mg Bid/100 mg Bid | Change From Baseline in C3 Fragment Deposition on PNH RBC | Week 12 | -1.65 % C3 fragment deposition on PNH RBC | Standard Deviation 1.221 |
| LNP023 50 mg Bid/200 mg Bid | Change From Baseline in C3 Fragment Deposition on PNH RBC | Week 12 | -2.75 % C3 fragment deposition on PNH RBC | Standard Deviation 3.002 |
| LNP023 50 mg Bid/200 mg Bid | Change From Baseline in C3 Fragment Deposition on PNH RBC | Week 2 | -1.88 % C3 fragment deposition on PNH RBC | Standard Deviation 1.457 |
| LNP023 50 mg Bid/200 mg Bid | Change From Baseline in C3 Fragment Deposition on PNH RBC | Week 8 | -2.90 % C3 fragment deposition on PNH RBC | Standard Deviation 2.654 |
| LNP023 50 mg Bid/200 mg Bid | Change From Baseline in C3 Fragment Deposition on PNH RBC | Week 4 | -2.74 % C3 fragment deposition on PNH RBC | Standard Deviation 2.584 |
Secondary
Change From Baseline in Carboxyhemoglobin
Carboxyhemoglobin was used as a marker of intravascular and extravascular hemolysis to assess the effect of iptacopan. Whole blood was used to calculate the carboxyhemoglobin values.
Time frame: Baseline, Week 2, week 4, week 8 and week 12
Population: The overall number of participants analyzed represents the participants in the PD analysis set who had at least one valid measurement of carboxyhemoglobin.~The number analyzed per row represents the participants with a valid carboxyhemoglobin value both at baseline and that particular visit
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| LNP023 25 mg Bid/100 mg Bid | Change From Baseline in Carboxyhemoglobin | Week 2 | -0.01 Percentage of carboxyhemoglobin | Standard Deviation 0.516 |
| LNP023 25 mg Bid/100 mg Bid | Change From Baseline in Carboxyhemoglobin | Week 4 | -0.36 Percentage of carboxyhemoglobin | Standard Deviation 0.472 |
| LNP023 25 mg Bid/100 mg Bid | Change From Baseline in Carboxyhemoglobin | Week 8 | -0.50 Percentage of carboxyhemoglobin | Standard Deviation 0.664 |
| LNP023 25 mg Bid/100 mg Bid | Change From Baseline in Carboxyhemoglobin | Week 12 | -0.95 Percentage of carboxyhemoglobin | Standard Deviation 0.316 |
| LNP023 50 mg Bid/200 mg Bid | Change From Baseline in Carboxyhemoglobin | Week 12 | -0.78 Percentage of carboxyhemoglobin | Standard Deviation 1.704 |
| LNP023 50 mg Bid/200 mg Bid | Change From Baseline in Carboxyhemoglobin | Week 2 | -0.72 Percentage of carboxyhemoglobin | Standard Deviation 0.697 |
| LNP023 50 mg Bid/200 mg Bid | Change From Baseline in Carboxyhemoglobin | Week 8 | -1.12 Percentage of carboxyhemoglobin | Standard Deviation 0.916 |
| LNP023 50 mg Bid/200 mg Bid | Change From Baseline in Carboxyhemoglobin | Week 4 | -0.98 Percentage of carboxyhemoglobin | Standard Deviation 0.582 |
Secondary
Change From Baseline in Free Hemoglobin
Free hemoglobin was used as a hemolysis marker to determine the dose-response effect of iptacopan on the reduction of PNH-associated hemolysis. Whole blood was used to calculate the hemoglobin values.
Time frame: Baseline, Week 2, week 4, week 8 and week 12
Population: The overall number of participants analyzed represents the participants in the PD analysis set who had at least one valid measurement of free hemoglobin.~The number analyzed per row represents the participants with a valid free hemoglobin value both at baseline and that particular visit.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| LNP023 25 mg Bid/100 mg Bid | Change From Baseline in Free Hemoglobin | Week 2 | -39.84 mg/dL | Standard Deviation 26.521 |
| LNP023 25 mg Bid/100 mg Bid | Change From Baseline in Free Hemoglobin | Week 4 | -31.88 mg/dL | Standard Deviation 35.314 |
| LNP023 25 mg Bid/100 mg Bid | Change From Baseline in Free Hemoglobin | Week 8 | -31.85 mg/dL | Standard Deviation 27.517 |
| LNP023 25 mg Bid/100 mg Bid | Change From Baseline in Free Hemoglobin | Week 12 | -39.58 mg/dL | Standard Deviation 31.612 |
| LNP023 50 mg Bid/200 mg Bid | Change From Baseline in Free Hemoglobin | Week 12 | -14.75 mg/dL | Standard Deviation 6.293 |
| LNP023 50 mg Bid/200 mg Bid | Change From Baseline in Free Hemoglobin | Week 2 | -13.53 mg/dL | Standard Deviation 5.093 |
| LNP023 50 mg Bid/200 mg Bid | Change From Baseline in Free Hemoglobin | Week 8 | -16.31 mg/dL | Standard Deviation 48.877 |
| LNP023 50 mg Bid/200 mg Bid | Change From Baseline in Free Hemoglobin | Week 4 | -29.26 mg/dL | Standard Deviation 24.218 |
Secondary
Change From Baseline in Hemoglobin
Hemoglobin was used as a hemolysis marker to determine the dose-response effect of iptacopan on the reduction of PNH-associated hemolysis. Whole blood was used to calculate the hemoglobin values.
Time frame: Baseline, Week 2, week 4, week 8 and week 12
Population: The overall number of participants analyzed represents the participants in the PD analysis set who had at least one valid measurement of hemoglobin.~The number analyzed per row represents the participants with a valid hemoglobin value both baseline and that particular visit.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| LNP023 25 mg Bid/100 mg Bid | Change From Baseline in Hemoglobin | Week 2 | 6.88 g/L | Standard Deviation 5.812 |
| LNP023 25 mg Bid/100 mg Bid | Change From Baseline in Hemoglobin | Week 4 | 9.61 g/L | Standard Deviation 11.857 |
| LNP023 25 mg Bid/100 mg Bid | Change From Baseline in Hemoglobin | Week 8 | 15.02 g/L | Standard Deviation 9.154 |
| LNP023 25 mg Bid/100 mg Bid | Change From Baseline in Hemoglobin | Week 12 | 23.36 g/L | Standard Deviation 14.378 |
| LNP023 50 mg Bid/200 mg Bid | Change From Baseline in Hemoglobin | Week 12 | 37.11 g/L | Standard Deviation 26.171 |
| LNP023 50 mg Bid/200 mg Bid | Change From Baseline in Hemoglobin | Week 2 | 31.83 g/L | Standard Deviation 10.362 |
| LNP023 50 mg Bid/200 mg Bid | Change From Baseline in Hemoglobin | Week 8 | 38.08 g/L | Standard Deviation 25.956 |
| LNP023 50 mg Bid/200 mg Bid | Change From Baseline in Hemoglobin | Week 4 | 36.58 g/L | Standard Deviation 17.875 |
Secondary
Change From Baseline in Total Bilirubin
Bilirubin levels were used as a hemolysis marker to determine the effect of iptacopan on the reduction of PNH-associated hemolysis. Serum was used to calculate bilirubin levels.
Time frame: Baseline, week 2, week 4, week 8 and week 12
Population: The overall number of participants analyzed represents the participants in the PD analysis set who had at least one valid measurement of bilirubin.~The number analyzed per row represents the participants with a valid bilirubin value both at baseline and that particular visit.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| LNP023 25 mg Bid/100 mg Bid | Change From Baseline in Total Bilirubin | Week 2 | -19.81 umol/L | Standard Deviation 7.855 |
| LNP023 25 mg Bid/100 mg Bid | Change From Baseline in Total Bilirubin | Week 4 | -19.95 umol/L | Standard Deviation 10.62 |
| LNP023 25 mg Bid/100 mg Bid | Change From Baseline in Total Bilirubin | Week 8 | -20.24 umol/L | Standard Deviation 12.612 |
| LNP023 25 mg Bid/100 mg Bid | Change From Baseline in Total Bilirubin | Week 12 | -21.61 umol/L | Standard Deviation 5.998 |
| LNP023 50 mg Bid/200 mg Bid | Change From Baseline in Total Bilirubin | Week 12 | -23.17 umol/L | Standard Deviation 18.195 |
| LNP023 50 mg Bid/200 mg Bid | Change From Baseline in Total Bilirubin | Week 2 | -23.93 umol/L | Standard Deviation 16.735 |
| LNP023 50 mg Bid/200 mg Bid | Change From Baseline in Total Bilirubin | Week 8 | -25.53 umol/L | Standard Deviation 16.471 |
| LNP023 50 mg Bid/200 mg Bid | Change From Baseline in Total Bilirubin | Week 4 | -25.93 umol/L | Standard Deviation 15.992 |
Secondary
Mean Activated Partial Thromboplastin Time (aPTT)
Activated partial thromboplastin time was used as a marker associated with risk of thrombosis. Plasma was used to calculate activated partial thromboplastin time.
Time frame: Baseline, week 2, week 4, week 8 and week 12
Population: The overall number of participants analyzed represents the participants in the PD analysis set who had at least one valid measurement of aPTT.~The number analyzed per row represents the participants with a valid aPTT value for that particular visit.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| LNP023 25 mg Bid/100 mg Bid | Mean Activated Partial Thromboplastin Time (aPTT) | Week 2 | 25.83 seconds | Standard Deviation 2.039 |
| LNP023 25 mg Bid/100 mg Bid | Mean Activated Partial Thromboplastin Time (aPTT) | Week 8 | 27.04 seconds | Standard Deviation 2.914 |
| LNP023 25 mg Bid/100 mg Bid | Mean Activated Partial Thromboplastin Time (aPTT) | Week 4 | 26.10 seconds | Standard Deviation 2.156 |
| LNP023 25 mg Bid/100 mg Bid | Mean Activated Partial Thromboplastin Time (aPTT) | Week 12 | 26.48 seconds | Standard Deviation 3.396 |
| LNP023 25 mg Bid/100 mg Bid | Mean Activated Partial Thromboplastin Time (aPTT) | Baseline | 23.63 seconds | Standard Deviation 2.28 |
| LNP023 50 mg Bid/200 mg Bid | Mean Activated Partial Thromboplastin Time (aPTT) | Week 12 | 24.95 seconds | Standard Deviation 1.279 |
| LNP023 50 mg Bid/200 mg Bid | Mean Activated Partial Thromboplastin Time (aPTT) | Baseline | 23.32 seconds | Standard Deviation 2.47 |
| LNP023 50 mg Bid/200 mg Bid | Mean Activated Partial Thromboplastin Time (aPTT) | Week 2 | 25.66 seconds | Standard Deviation 1.454 |
| LNP023 50 mg Bid/200 mg Bid | Mean Activated Partial Thromboplastin Time (aPTT) | Week 4 | 26.46 seconds | Standard Deviation 1.802 |
| LNP023 50 mg Bid/200 mg Bid | Mean Activated Partial Thromboplastin Time (aPTT) | Week 8 | 26.84 seconds | Standard Deviation 3.389 |
Secondary
Mean Clone Size
PNH clone size was used as a marker of intravascular and extravascular hemolysis to assess the effect of iptacopan. Whole blood was used to calculate clone size values.
Time frame: Baseline, week 2, week 4, week 8 and week 12
Population: The overall number of participants analyzed represents the participants in the PD analysis set who had at least one valid measurement of clone size.~The number analyzed per row represents the participants with a valid clone size value for that particular visit.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| LNP023 25 mg Bid/100 mg Bid | Mean Clone Size | Week 2 | 54.95 Percentage of PNH Red Blood Cells | Standard Deviation 12.943 |
| LNP023 25 mg Bid/100 mg Bid | Mean Clone Size | Week 8 | 79.62 Percentage of PNH Red Blood Cells | Standard Deviation 14.308 |
| LNP023 25 mg Bid/100 mg Bid | Mean Clone Size | Baseline | 33.63 Percentage of PNH Red Blood Cells | Standard Deviation 18.149 |
| LNP023 25 mg Bid/100 mg Bid | Mean Clone Size | Week 12 | 82.87 Percentage of PNH Red Blood Cells | Standard Deviation 11.903 |
| LNP023 25 mg Bid/100 mg Bid | Mean Clone Size | Week 4 | 65.88 Percentage of PNH Red Blood Cells | Standard Deviation 12.907 |
| LNP023 50 mg Bid/200 mg Bid | Mean Clone Size | Week 12 | 91.08 Percentage of PNH Red Blood Cells | Standard Deviation 7.842 |
| LNP023 50 mg Bid/200 mg Bid | Mean Clone Size | Week 4 | 73.74 Percentage of PNH Red Blood Cells | Standard Deviation 24.616 |
| LNP023 50 mg Bid/200 mg Bid | Mean Clone Size | Baseline | 49.13 Percentage of PNH Red Blood Cells | Standard Deviation 29.701 |
| LNP023 50 mg Bid/200 mg Bid | Mean Clone Size | Week 8 | 85.06 Percentage of PNH Red Blood Cells | Standard Deviation 16.381 |
| LNP023 50 mg Bid/200 mg Bid | Mean Clone Size | Week 2 | 65.65 Percentage of PNH Red Blood Cells | Standard Deviation 29.279 |
Secondary
Mean D-dimer Levels
D-dimer levels were used as a marker associated with risk of thrombosis. Plasma was used to calculate D-dimer levels.
Time frame: Baseline, week 2, week 4, week 8 and week 12
Population: The overall number of participants analyzed represents the participants in the PD analysis set who had at least one valid measurement of D-dimer.~The number analyzed per row represents the participants with a valid D-dimer value for that particular visit.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| LNP023 25 mg Bid/100 mg Bid | Mean D-dimer Levels | Week 2 | 0.32 mg fibrinogen-equivalent unit (FEU)/L | Standard Deviation 0.23 |
| LNP023 25 mg Bid/100 mg Bid | Mean D-dimer Levels | Week 8 | 0.24 mg fibrinogen-equivalent unit (FEU)/L | Standard Deviation 0.225 |
| LNP023 25 mg Bid/100 mg Bid | Mean D-dimer Levels | Week 4 | 0.29 mg fibrinogen-equivalent unit (FEU)/L | Standard Deviation 0.199 |
| LNP023 25 mg Bid/100 mg Bid | Mean D-dimer Levels | Week 12 | 0.25 mg fibrinogen-equivalent unit (FEU)/L | Standard Deviation 0.184 |
| LNP023 25 mg Bid/100 mg Bid | Mean D-dimer Levels | Baseline | 0.39 mg fibrinogen-equivalent unit (FEU)/L | Standard Deviation 0.236 |
| LNP023 50 mg Bid/200 mg Bid | Mean D-dimer Levels | Week 12 | 0.31 mg fibrinogen-equivalent unit (FEU)/L | Standard Deviation 0.147 |
| LNP023 50 mg Bid/200 mg Bid | Mean D-dimer Levels | Baseline | 0.84 mg fibrinogen-equivalent unit (FEU)/L | Standard Deviation 0.345 |
| LNP023 50 mg Bid/200 mg Bid | Mean D-dimer Levels | Week 2 | 0.49 mg fibrinogen-equivalent unit (FEU)/L | Standard Deviation 0.189 |
| LNP023 50 mg Bid/200 mg Bid | Mean D-dimer Levels | Week 4 | 0.43 mg fibrinogen-equivalent unit (FEU)/L | Standard Deviation 0.172 |
| LNP023 50 mg Bid/200 mg Bid | Mean D-dimer Levels | Week 8 | 0.36 mg fibrinogen-equivalent unit (FEU)/L | Standard Deviation 0.215 |
Secondary
Mean Ferritin Levels
Ferritin levels were used as a marker of intravascular and extravascular hemolysis to assess the effect of iptacopan. Serum was used to calculate ferritin levels.
Time frame: Baseline, Week 4, Week 8 and week 12
Population: The overall number of participants analyzed represents the participants in the PD analysis set who had at least one valid measurement of ferritin.~The number analyzed per row represents the participants with a valid ferritin value for that particular visit.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| LNP023 25 mg Bid/100 mg Bid | Mean Ferritin Levels | Baseline | 176.97 ug/L | Standard Deviation 404.254 |
| LNP023 25 mg Bid/100 mg Bid | Mean Ferritin Levels | Week 4 | 174.21 ug/L | Standard Deviation 431.042 |
| LNP023 25 mg Bid/100 mg Bid | Mean Ferritin Levels | Week 8 | 178.31 ug/L | Standard Deviation 443.346 |
| LNP023 25 mg Bid/100 mg Bid | Mean Ferritin Levels | Week 12 | 203.22 ug/L | Standard Deviation 454.296 |
| LNP023 50 mg Bid/200 mg Bid | Mean Ferritin Levels | Week 12 | 320.40 ug/L | Standard Deviation 526.783 |
| LNP023 50 mg Bid/200 mg Bid | Mean Ferritin Levels | Baseline | 258.90 ug/L | Standard Deviation 418.114 |
| LNP023 50 mg Bid/200 mg Bid | Mean Ferritin Levels | Week 8 | 304.74 ug/L | Standard Deviation 521.535 |
| LNP023 50 mg Bid/200 mg Bid | Mean Ferritin Levels | Week 4 | 287.88 ug/L | Standard Deviation 517.901 |
Secondary
Mean Fibrinogen Levels
Fibrinogen level was used as a marker associated with risk of thrombosis. Plasma was used to calculate fibrinogen levels.
Time frame: Baseline, week 2, week 4, week 8 and week 12
Population: The overall number of participants analyzed represents the participants in the PD analysis set who had at least one valid measurement of fibrinogen.~The number analyzed per row represents the participants with a valid fibrinogen value for that particular visit.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| LNP023 25 mg Bid/100 mg Bid | Mean Fibrinogen Levels | Week 2 | 3.27 g/L | Standard Deviation 0.935 |
| LNP023 25 mg Bid/100 mg Bid | Mean Fibrinogen Levels | Week 8 | 2.77 g/L | Standard Deviation 0.399 |
| LNP023 25 mg Bid/100 mg Bid | Mean Fibrinogen Levels | Baseline | 3.44 g/L | Standard Deviation 0.851 |
| LNP023 25 mg Bid/100 mg Bid | Mean Fibrinogen Levels | Week 12 | 2.94 g/L | Standard Deviation 0.802 |
| LNP023 25 mg Bid/100 mg Bid | Mean Fibrinogen Levels | Week 4 | 2.80 g/L | Standard Deviation 0.338 |
| LNP023 50 mg Bid/200 mg Bid | Mean Fibrinogen Levels | Week 12 | 3.09 g/L | Standard Deviation 0.699 |
| LNP023 50 mg Bid/200 mg Bid | Mean Fibrinogen Levels | Week 2 | 2.93 g/L | Standard Deviation 0.445 |
| LNP023 50 mg Bid/200 mg Bid | Mean Fibrinogen Levels | Week 4 | 2.78 g/L | Standard Deviation 0.566 |
| LNP023 50 mg Bid/200 mg Bid | Mean Fibrinogen Levels | Week 8 | 3.19 g/L | Standard Deviation 0.531 |
| LNP023 50 mg Bid/200 mg Bid | Mean Fibrinogen Levels | Baseline | 3.50 g/L | Standard Deviation 1.178 |
Secondary
Mean Haptoglobin Levels
Haptoglobin levels were used as a hemolysis marker to determine the effect of iptacopan on the reduction of PNH-associated hemolysis. Serum was used to calculate haptoglobin levels.
Time frame: Baseline, week 2, week 4, week 8 and week 12
Population: The overall number of participants analyzed represents the participants in the PD analysis set who had at least one valid measurement of haptoglobin.~The number analyzed per row represents the participants with a valid haptoglobin value for that particular visit.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| LNP023 25 mg Bid/100 mg Bid | Mean Haptoglobin Levels | Week 2 | 0.27 g/L | Standard Deviation 0.251 |
| LNP023 25 mg Bid/100 mg Bid | Mean Haptoglobin Levels | Week 8 | 0.38 g/L | Standard Deviation 0.456 |
| LNP023 25 mg Bid/100 mg Bid | Mean Haptoglobin Levels | Week 4 | 0.24 g/L | Standard Deviation 0.255 |
| LNP023 25 mg Bid/100 mg Bid | Mean Haptoglobin Levels | Week 12 | 0.25 g/L | Standard Deviation 0.356 |
| LNP023 25 mg Bid/100 mg Bid | Mean Haptoglobin Levels | Baseline | 0.05 g/L | Standard Deviation 0 |
| LNP023 50 mg Bid/200 mg Bid | Mean Haptoglobin Levels | Week 12 | 0.18 g/L | Standard Deviation 0.225 |
| LNP023 50 mg Bid/200 mg Bid | Mean Haptoglobin Levels | Baseline | 0.05 g/L | Standard Deviation 0 |
| LNP023 50 mg Bid/200 mg Bid | Mean Haptoglobin Levels | Week 2 | 0.41 g/L | Standard Deviation 0.499 |
| LNP023 50 mg Bid/200 mg Bid | Mean Haptoglobin Levels | Week 4 | 0.49 g/L | Standard Deviation 0.49 |
| LNP023 50 mg Bid/200 mg Bid | Mean Haptoglobin Levels | Week 8 | 0.41 g/L | Standard Deviation 0.374 |
Secondary
Mean Platelets Count
Platelet counts were used as a marker of intravascular and extravascular hemolysis to assess the effect of iptacopan. Whole blood was used to calculate platelets count.
Time frame: Baseline, week 2, week 4, week 8 and week 12
Population: The overall number of participants analyzed represents the participants in the PD analysis set who had at least one valid measurement of platelets count.~The number analyzed per row represents the participants with a valid platelets count value for that particular visit.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| LNP023 25 mg Bid/100 mg Bid | Mean Platelets Count | Week 2 | 223.71 10^9 cells/L | Standard Deviation 76.707 |
| LNP023 25 mg Bid/100 mg Bid | Mean Platelets Count | Week 8 | 184.43 10^9 cells/L | Standard Deviation 50.856 |
| LNP023 25 mg Bid/100 mg Bid | Mean Platelets Count | Week 4 | 203.17 10^9 cells/L | Standard Deviation 68.52 |
| LNP023 25 mg Bid/100 mg Bid | Mean Platelets Count | Week 12 | 189.33 10^9 cells/L | Standard Deviation 54.617 |
| LNP023 25 mg Bid/100 mg Bid | Mean Platelets Count | Baseline | 190.45 10^9 cells/L | Standard Deviation 59.938 |
| LNP023 50 mg Bid/200 mg Bid | Mean Platelets Count | Week 12 | 140.75 10^9 cells/L | Standard Deviation 59.618 |
| LNP023 50 mg Bid/200 mg Bid | Mean Platelets Count | Baseline | 156.42 10^9 cells/L | Standard Deviation 52.321 |
| LNP023 50 mg Bid/200 mg Bid | Mean Platelets Count | Week 2 | 158.20 10^9 cells/L | Standard Deviation 62.683 |
| LNP023 50 mg Bid/200 mg Bid | Mean Platelets Count | Week 4 | 138.20 10^9 cells/L | Standard Deviation 57.085 |
| LNP023 50 mg Bid/200 mg Bid | Mean Platelets Count | Week 8 | 141.20 10^9 cells/L | Standard Deviation 46.569 |
Secondary
Mean Prothrombin Time (PT)
Prothrombin time was used as a marker associated with risk of thrombosis. Plasma was used to calculate prothrombin time.
Time frame: Baseline, week 2, week 4, week 8 and week 12
Population: The overall number of participants analyzed represents the participants in the PD analysis set who had at least one valid measurement of prothrombin time.~The number analyzed per row represents the participants with a valid prothrombin time value for that particular visit.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| LNP023 25 mg Bid/100 mg Bid | Mean Prothrombin Time (PT) | Week 12 | 10.33 seconds | Standard Deviation 0.501 |
| LNP023 25 mg Bid/100 mg Bid | Mean Prothrombin Time (PT) | Baseline | 10.04 seconds | Standard Deviation 0.474 |
| LNP023 25 mg Bid/100 mg Bid | Mean Prothrombin Time (PT) | Week 2 | 10.51 seconds | Standard Deviation 0.426 |
| LNP023 25 mg Bid/100 mg Bid | Mean Prothrombin Time (PT) | Week 4 | 10.29 seconds | Standard Deviation 0.593 |
| LNP023 25 mg Bid/100 mg Bid | Mean Prothrombin Time (PT) | Week 8 | 10.66 seconds | Standard Deviation 0.665 |
| LNP023 50 mg Bid/200 mg Bid | Mean Prothrombin Time (PT) | Week 8 | 10.98 seconds | Standard Deviation 1.678 |
| LNP023 50 mg Bid/200 mg Bid | Mean Prothrombin Time (PT) | Week 4 | 10.22 seconds | Standard Deviation 0.311 |
| LNP023 50 mg Bid/200 mg Bid | Mean Prothrombin Time (PT) | Baseline | 9.84 seconds | Standard Deviation 0.21 |
| LNP023 50 mg Bid/200 mg Bid | Mean Prothrombin Time (PT) | Week 12 | 10.13 seconds | Standard Deviation 0.359 |
| LNP023 50 mg Bid/200 mg Bid | Mean Prothrombin Time (PT) | Week 2 | 10.18 seconds | Standard Deviation 0.179 |
Secondary
Mean Thrombin Clotting Time
thrombin clotting time was used as a marker associated with risk of thrombosis. Plasma was used to calculate thrombin clotting time.
Time frame: Baseline, Week 4, Week 8 and Week 12
Population: The overall number of participants analyzed represents the participants in the PD analysis set who had at least one valid measurement of thrombin clotting time.~The number analyzed per row represents the participants with a valid thrombin clotting time value for that particular visit.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| LNP023 25 mg Bid/100 mg Bid | Mean Thrombin Clotting Time | Baseline | 14.77 seconds | Standard Deviation 1.994 |
| LNP023 25 mg Bid/100 mg Bid | Mean Thrombin Clotting Time | Week 4 | 14.93 seconds | Standard Deviation 0.642 |
| LNP023 25 mg Bid/100 mg Bid | Mean Thrombin Clotting Time | Week 8 | 14.90 seconds | Standard Deviation 0.624 |
| LNP023 25 mg Bid/100 mg Bid | Mean Thrombin Clotting Time | Week 12 | 16.08 seconds | Standard Deviation 1.53 |
| LNP023 50 mg Bid/200 mg Bid | Mean Thrombin Clotting Time | Week 12 | 15.35 seconds | Standard Deviation 0.526 |
| LNP023 50 mg Bid/200 mg Bid | Mean Thrombin Clotting Time | Baseline | 14.83 seconds | Standard Deviation 0.916 |
| LNP023 50 mg Bid/200 mg Bid | Mean Thrombin Clotting Time | Week 8 | 15.48 seconds | Standard Deviation 0.923 |
| LNP023 50 mg Bid/200 mg Bid | Mean Thrombin Clotting Time | Week 4 | 15.58 seconds | Standard Deviation 1.293 |
Secondary
Percent Change From Baseline in LDH Levels
LDH was used as a hemolysis marker to determine the dose-response effect of iptacopan on the reduction of Paroxysmal nocturnal hemoglobinuria (PNH)-associated hemolysis. Active hemolysis is defined by an LDH value ≥ 1.5x upper limit of normal (ULN) Baseline LDH was calculated as the average of the last three screening values prior to randomization. Serum was used to calculate the LDH values
Time frame: Baseline, week 2, week 4, week 8 and week 12
Population: The overall number of participants analyzed represents the participants in the PD analysis set who had at least one valid measurement of LDH.~The number analyzed per row represents the participants with a valid LDH value at both baseline and that particular visit.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| LNP023 25 mg Bid/100 mg Bid | Percent Change From Baseline in LDH Levels | Week 2 | -76.52 Percent change in LDH levels | Standard Deviation 18.478 |
| LNP023 25 mg Bid/100 mg Bid | Percent Change From Baseline in LDH Levels | Week 4 | -79.75 Percent change in LDH levels | Standard Deviation 16.025 |
| LNP023 25 mg Bid/100 mg Bid | Percent Change From Baseline in LDH Levels | Week 8 | -81.73 Percent change in LDH levels | Standard Deviation 22.832 |
| LNP023 25 mg Bid/100 mg Bid | Percent Change From Baseline in LDH Levels | Week 12 | -86.17 Percent change in LDH levels | Standard Deviation 8.896 |
| LNP023 50 mg Bid/200 mg Bid | Percent Change From Baseline in LDH Levels | Week 12 | -85.92 Percent change in LDH levels | Standard Deviation 9.013 |
| LNP023 50 mg Bid/200 mg Bid | Percent Change From Baseline in LDH Levels | Week 2 | -84.98 Percent change in LDH levels | Standard Deviation 8.186 |
| LNP023 50 mg Bid/200 mg Bid | Percent Change From Baseline in LDH Levels | Week 8 | -88.30 Percent change in LDH levels | Standard Deviation 8.744 |
| LNP023 50 mg Bid/200 mg Bid | Percent Change From Baseline in LDH Levels | Week 4 | -89.72 Percent change in LDH levels | Standard Deviation 5.43 |
Secondary
Pharmacokinetics Profile: Area Under the Curve Tau (AUCtau)
The AUCtau is the area under the plasma concentration-time curve calculated to the end of a dosing interval (tau) at steady-state (amount x time x volume-1). AUCtau was estimated by imputing the 12-hour iptacopan plasma concentration as the PK profile's corresponding pre-dose (0-hour) value, that is, by assuming that at steady-state the iptacopan plasma concentration is the same as the beginning (pre-dose) and end (12 hours postdose) of the dosing interval. PK parameters were determined, using non-compartmental method(s) with Phoenix WinNonlin (Version 8.3), from the plasma concentration-time data.
Time frame: Days 29 and 57
Population: The overall number of participants analyzed represents the participants in the PK analysis set who had at least one valid measurement of AUCtau.~The number analyzed per row represents the participants with a valid AUCtau value for that particular visit.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| LNP023 25 mg Bid/100 mg Bid | Pharmacokinetics Profile: Area Under the Curve Tau (AUCtau) | Day 29 | 9630 h*ng/mL | Standard Deviation 3870 |
| LNP023 50 mg Bid/200 mg Bid | Pharmacokinetics Profile: Area Under the Curve Tau (AUCtau) | Day 29 | 15200 h*ng/mL | Standard Deviation 2390 |
| LNP023 100 mg Bid | Pharmacokinetics Profile: Area Under the Curve Tau (AUCtau) | Day 57 | 19800 h*ng/mL | Standard Deviation 4900 |
| LNP023 200 mg Bid | Pharmacokinetics Profile: Area Under the Curve Tau (AUCtau) | Day 57 | 33300 h*ng/mL | Standard Deviation 8830 |
Secondary
Pharmacokinetics Profile: Maximum Plasma Concentration (Cmax)
Cmax is the maximum (peak) observed plasma drug concentration after single dose administration (mass x volume-1). PK parameters were determined, using non-compartmental method(s) with Phoenix WinNonlin (Version 8.3), from the plasma concentration-time data.
Time frame: Day 29 and 57
Population: The overall number of participants analyzed represents the participants in the PK analysis set who had at least one valid measurement of Cmax.~The Pharmacokinetic (PK) analysis set is defined as patients with at least one available valid PK concentration measurement, who received any study drug and with no protocol deviations that impact on PK data.~The number analyzed per row represents the participants with a valid Cmax value for that particular visit.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| LNP023 25 mg Bid/100 mg Bid | Pharmacokinetics Profile: Maximum Plasma Concentration (Cmax) | Day 29 | 1240 ng/mL | Standard Deviation 372 |
| LNP023 50 mg Bid/200 mg Bid | Pharmacokinetics Profile: Maximum Plasma Concentration (Cmax) | Day 29 | 1800 ng/mL | Standard Deviation 368 |
| LNP023 100 mg Bid | Pharmacokinetics Profile: Maximum Plasma Concentration (Cmax) | Day 57 | 2640 ng/mL | Standard Deviation 590 |
| LNP023 200 mg Bid | Pharmacokinetics Profile: Maximum Plasma Concentration (Cmax) | Day 57 | 4520 ng/mL | Standard Deviation 1520 |
Secondary
Pharmacokinetics Profile: Minimum Plasma Concentration (Cmin)
Cmin is the lowest plasma concentration observed during a dosing interval at steady state \[mass / volume\]. PK parameters were determined, using non-compartmental method(s) with Phoenix WinNonlin (Version 8.3), from the plasma concentration-time data.
Time frame: Days 29 and 57
Population: The overall number of participants analyzed represents the participants in the PK analysis set who had at least one valid measurement of Cmin.~The number analyzed per row represents the participants with a valid Cmin value for that particular visit.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| LNP023 25 mg Bid/100 mg Bid | Pharmacokinetics Profile: Minimum Plasma Concentration (Cmin) | Day 29 | 520 ng/mL | Standard Deviation 299 |
| LNP023 50 mg Bid/200 mg Bid | Pharmacokinetics Profile: Minimum Plasma Concentration (Cmin) | Day 29 | 809 ng/mL | Standard Deviation 239 |
| LNP023 100 mg Bid | Pharmacokinetics Profile: Minimum Plasma Concentration (Cmin) | Day 57 | 931 ng/mL | Standard Deviation 460 |
| LNP023 200 mg Bid | Pharmacokinetics Profile: Minimum Plasma Concentration (Cmin) | Day 57 | 1510 ng/mL | Standard Deviation 416 |
Secondary
Pharmacokinetics Profile: Time to Reach Maximum Plasma Concentration (Tmax)
Tmax is the time to reach maximum (peak) plasma drug concentration after single dose administration (time). PK parameters were determined, using non-compartmental method(s) with Phoenix WinNonlin (Version 8.3), from the plasma concentration-time data.
Time frame: Days 29 and 57
Population: The overall number of participants analyzed represents the participants in the PK analysis set who had at least one valid measurement of Tmax.~The number analyzed per row represents the participants with a valid Tmax value for that particular visit.
| Arm | Measure | Group | Value (MEDIAN) |
|---|---|---|---|
| LNP023 25 mg Bid/100 mg Bid | Pharmacokinetics Profile: Time to Reach Maximum Plasma Concentration (Tmax) | Day 29 | 1.50 hours |
| LNP023 50 mg Bid/200 mg Bid | Pharmacokinetics Profile: Time to Reach Maximum Plasma Concentration (Tmax) | Day 29 | 2.00 hours |
| LNP023 100 mg Bid | Pharmacokinetics Profile: Time to Reach Maximum Plasma Concentration (Tmax) | Day 57 | 1.53 hours |
| LNP023 200 mg Bid | Pharmacokinetics Profile: Time to Reach Maximum Plasma Concentration (Tmax) | Day 57 | 2.00 hours |
Secondary
Red Blood Cell Count: Change From Baseline in Erythrocytes
Erythrocytes were used as a marker of intravascular and extravascular hemolysis to assess the effect of iptacopan. Whole blood was used to calculate erythrocytes values.
Time frame: Baseline, week 2, week 4, week 8 and week 12
Population: The overall number of participants analyzed represents the participants in the PD analysis set who had at least one valid measurement of erythrocytes.~The number analyzed per row represents the participants with a valid erythrocytes value both at baseline and that particular visit.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| LNP023 25 mg Bid/100 mg Bid | Red Blood Cell Count: Change From Baseline in Erythrocytes | Week 2 | 0.49 10^12 cells/L | Standard Deviation 0.194 |
| LNP023 25 mg Bid/100 mg Bid | Red Blood Cell Count: Change From Baseline in Erythrocytes | Week 4 | 0.74 10^12 cells/L | Standard Deviation 0.401 |
| LNP023 25 mg Bid/100 mg Bid | Red Blood Cell Count: Change From Baseline in Erythrocytes | Week 8 | 1.16 10^12 cells/L | Standard Deviation 0.396 |
| LNP023 25 mg Bid/100 mg Bid | Red Blood Cell Count: Change From Baseline in Erythrocytes | Week 12 | 1.38 10^12 cells/L | Standard Deviation 0.531 |
| LNP023 50 mg Bid/200 mg Bid | Red Blood Cell Count: Change From Baseline in Erythrocytes | Week 12 | 1.38 10^12 cells/L | Standard Deviation 0.77 |
| LNP023 50 mg Bid/200 mg Bid | Red Blood Cell Count: Change From Baseline in Erythrocytes | Week 2 | 1.02 10^12 cells/L | Standard Deviation 0.407 |
| LNP023 50 mg Bid/200 mg Bid | Red Blood Cell Count: Change From Baseline in Erythrocytes | Week 8 | 1.38 10^12 cells/L | Standard Deviation 0.796 |
| LNP023 50 mg Bid/200 mg Bid | Red Blood Cell Count: Change From Baseline in Erythrocytes | Week 4 | 1.26 10^12 cells/L | Standard Deviation 0.619 |