Paroxysmal Nocturnal Hemoglobinuria (PNH)
Conditions
Keywords
PNH, Paroxysmal, Hemoglobinuria
Brief summary
The purpose of this study was to determine the safety and efficacy of ACH-0144471 (also known as danicopan and ALXN2040) in currently untreated participants with PNH.
Detailed description
After 12 weeks of treatment, participants deriving clinical benefit were offered enrollment in a separate long-term extension study (ACH471-103, NCT03181633).
Interventions
DRUGDanicopan
Danicopan was administered as multiple oral doses over a period of at least 28 days.
Sponsors
Achillion, a wholly owned subsidiary of Alexion
Alexion Pharmaceuticals, Inc.
Study design
Allocation
NA
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* Currently untreated PNH participants with PNH Type III erythrocyte and/or granulocyte clone size ≥10% and anemia (hemoglobin \<12 grams/deciliter) with adequate reticulocytosis (as determined by the Investigator). * LDH ≥1.5 x the upper limit of normal. * Platelets ≥50,000/microliter without the need for platelet transfusions. * Documentation of vaccination for Neisseria meningitidis, Haemophilus influenza, and Streptococcus pneumoniae, or willingness to receive vaccinations during the screening period. * Negative pregnancy test for females prior to dosing and throughout the study.
Exclusion criteria
* History of a major organ transplant (for example, heart, lung, kidney, liver) or hematopoietic stem cell/marrow transplant. * Participants who had received another investigational agent within 30 days or 5 half-lives of the investigational agent prior to study entry, whichever is greater. * Participants who had received eculizumab at any dose or interval within the past 75 days before study entry. * Participants with known or suspected complement deficiency. * Participants with active bacterial infection or clinically significant active viral infection, a body temperature \>38°Celsius, or other evidence of infection on Day 1, or with a history of febrile illness within 14 days prior to first study drug administration. * History of meningococcal infection, or a first-degree relative or household contact with a history of meningococcal infection. * Females who were pregnant, nursing, or planning to become pregnant during the study or within 90 days of study drug administration or participants with a female partner who was pregnant, nursing, or planning to become pregnant during the study or within 90 days of study drug administration.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Change From Baseline In Serum LDH Levels At Day 28 | Baseline, Day 28 | Change from Baseline = Serum LDH levels on Day 28 - Baseline Serum LDH levels. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Change From Baseline In Serum LDH Levels At Day 84 | Baseline, Day 84 | Change from Baseline = Serum LDH levels on Day 84 - Baseline Serum LDH levels. |
| Paroxysmal Nocturnal Hemoglobinuria (PNH) Type III Red Blood Cell (RBC) Clone Size | Baseline, Day 28, and Day 84 | PNH RBC, summed type III, clone size levels were assessed from Baseline to Day 28 and Day 84. The PNH clone size refers to the percentage of PNH-affected cells versus normal cells within the total cell population. |
| Serious Adverse Events (SAEs), Grade 3 And Grade 4 Treatment-emergent Adverse Events (TEAEs), And Adverse Events (AEs) Leading To Discontinuation | After the first dose of study medication (Day 1) through 14 days after the last dose of study drug (up to Day 104) | An AE was as any untoward medical occurrence associated with the use of a drug in humans, whether or not considered drug related. An SAE was an AE that met at least 1 of the following criteria: resulted in death, was life-threatening, required inpatient hospitalization or prolongation of existing hospitalization for the AE, persistent or significant disability/incapacity or substantial disruption of the ability to conduct normal life functions, congenital anomaly/birth defect (in the child of a participant who was exposed to the study drug), important medical event or reaction. The intensity of an AE was graded according to the Common Terminology Criteria for Adverse Events (CTCAE) Adverse Event Severity Grading Table. A summary of SAEs and other non-serious AEs regardless of causality is located in the Reported Adverse Events module. |
| Grade 3 And Grade 4 Laboratory Abnormalities | After the first dose of study medication (Day 1) through 14 days after the last dose of study drug (up to Day 104). | Laboratory abnormalities were determined from laboratory measurements analyzed at the central or local laboratories, and were graded using CTCAE. |
| Change From Baseline In Hemoglobin (Hgb) At Days 28 And 84 | Baseline, Days 28 and 84 | Change from Baseline = Hgb levels on Days 28 or 84 - Baseline Hgb levels. |
| PK: Maximum Plasma Concentration (Cmax) | Days 6 and 20 | Serial blood samples were collected predose and up to 12 hours postdose. |
| PK: Time To Maximum Concentration (Tmax) | Days 6 and 20 | Serial blood samples were collected predose and up to 12 hours postdose. |
| Complement Alternative Pathway (AP) Functional Activity | Baseline and Day 28 | Serum AP functional activity was measured by the Wieslab functional immunoassay method. |
| Complement Bb | Baseline and Day 28 | Plasma Bb was measured by enzyme-linked immunosorbent assay (ELISA). |
| Pharmacokinetics (PK): Area Under The Plasma Concentration-time Curve From Time Of Administration To 8 Hours Post-dose (AUC0-8) | Days 6 and 20 | Serial blood samples were collected predose and up to 8 hours postdose. |
Countries
Italy, New Zealand, South Korea, United Kingdom
Participant flow
Pre-assignment details
The study was conducted in 2 parts. In Part 1, participants received danicopan for 28 days. Starting doses were 100 or 150 milligrams (mg) three times daily (TID). A further dose increase up to 175 mg TID (N=8 participants) and 200 mg TID (N=4 participants) was conducted. Participants with reductions in lactate dehydrogenase (LDH) meeting specified criteria were offered continued dosing beyond Day 28, for up to 8 additional weeks (Part 2).
Participants by arm
| Arm | Count |
|---|---|
| Danicopan Participants received danicopan 100 to 200 mg TID. | 10 |
| Total | 10 |
Withdrawals & dropouts
| Period | Reason | FG000 |
|---|---|---|
| Study Part 2: 84-Day Treatment | Adverse Event | 1 |
| Study Part 2: 84-Day Treatment | Withdrawal by Subject | 1 |
Baseline characteristics
| Characteristic | Danicopan |
|---|---|
| Age, Continuous | 35.94 years STANDARD_DEVIATION 13.575 |
| Ethnicity (NIH/OMB) Hispanic or Latino | 0 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 10 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants |
| Race/Ethnicity, Customized Asian | 1 Participants |
| Race/Ethnicity, Customized Native Hawaiian or Other Pacific Islander | 1 Participants |
| Race/Ethnicity, Customized Other | 1 Participants |
| Race/Ethnicity, Customized White | 7 Participants |
| Region of Enrollment Italy | 2 participants |
| Region of Enrollment New Zealand | 6 participants |
| Region of Enrollment South Korea | 1 participants |
| Region of Enrollment United Kingdom | 1 participants |
| Sex: Female, Male Female | 5 Participants |
| Sex: Female, Male Male | 5 Participants |
Adverse events
| Event type | EG000 affected / at risk |
|---|---|
| deaths Total, all-cause mortality | 0 / 10 |
| other Total, other adverse events | 9 / 10 |
| serious Total, serious adverse events | 1 / 10 |
Outcome results
Primary
Change From Baseline In Serum LDH Levels At Day 28
Change from Baseline = Serum LDH levels on Day 28 - Baseline Serum LDH levels.
Time frame: Baseline, Day 28
Population: All participants who received at least 1 dose of study drug and had analyzable data at the timepoints specified.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Danicopan | Change From Baseline In Serum LDH Levels At Day 28 | Change from Baseline | -971.7 international units per liter (IU/L) | Standard Deviation 549.76 |
| Danicopan | Change From Baseline In Serum LDH Levels At Day 28 | Baseline | 1416 international units per liter (IU/L) | Standard Deviation 540.25 |
| Danicopan | Change From Baseline In Serum LDH Levels At Day 28 | Day 28 (Part 1) | 444.3 international units per liter (IU/L) | Standard Deviation 255.78 |
Secondary
Change From Baseline In Hemoglobin (Hgb) At Days 28 And 84
Change from Baseline = Hgb levels on Days 28 or 84 - Baseline Hgb levels.
Time frame: Baseline, Days 28 and 84
Population: All participants who received at least 1 dose of study drug and had analyzable data at the timepoints specified.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Danicopan | Change From Baseline In Hemoglobin (Hgb) At Days 28 And 84 | Baseline | 9.76 grams/deciliter (g/dL) | Standard Deviation 1.758 |
| Danicopan | Change From Baseline In Hemoglobin (Hgb) At Days 28 And 84 | Part 1: Day 28 | 10.94 grams/deciliter (g/dL) | Standard Deviation 1.651 |
| Danicopan | Change From Baseline In Hemoglobin (Hgb) At Days 28 And 84 | Part 1: Change from Baseline at Day 28 | 1.18 grams/deciliter (g/dL) | Standard Deviation 0.877 |
| Danicopan | Change From Baseline In Hemoglobin (Hgb) At Days 28 And 84 | Part 2: Day 84 | 11.45 grams/deciliter (g/dL) | Standard Deviation 1.414 |
| Danicopan | Change From Baseline In Hemoglobin (Hgb) At Days 28 And 84 | Part 2: Change from Baseline at Day 84 | 1.80 grams/deciliter (g/dL) | Standard Deviation 1.166 |
Secondary
Change From Baseline In Serum LDH Levels At Day 84
Change from Baseline = Serum LDH levels on Day 84 - Baseline Serum LDH levels.
Time frame: Baseline, Day 84
Population: All participants who received at least 1 dose of study drug and had analyzable data at the timepoints specified.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Danicopan | Change From Baseline In Serum LDH Levels At Day 84 | Baseline | 1416 IU/L | Standard Deviation 540.25 |
| Danicopan | Change From Baseline In Serum LDH Levels At Day 84 | Day 84 (Part 2) | 537.3 IU/L | Standard Deviation 260.42 |
| Danicopan | Change From Baseline In Serum LDH Levels At Day 84 | Change from Baseline | -865.9 IU/L | Standard Deviation 447.86 |
Secondary
Complement Alternative Pathway (AP) Functional Activity
Serum AP functional activity was measured by the Wieslab functional immunoassay method.
Time frame: Baseline and Day 28
Population: All participants who received at least 1 dose of study drug and had analyzable data at the timepoints specified.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Danicopan | Complement Alternative Pathway (AP) Functional Activity | Baseline | 65.216 percentage of activity | Standard Deviation 13.7143 |
| Danicopan | Complement Alternative Pathway (AP) Functional Activity | Day 28 | 12.730 percentage of activity | Standard Deviation 14.3767 |
Secondary
Complement Bb
Plasma Bb was measured by enzyme-linked immunosorbent assay (ELISA).
Time frame: Baseline and Day 28
Population: All participants who received at least 1 dose of study drug and had analyzable data at the timepoints specified.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Danicopan | Complement Bb | Baseline | 2.24160 microgram (ug)/mL | Standard Deviation 0.773962 |
| Danicopan | Complement Bb | Day 28 | 0.83913 microgram (ug)/mL | Standard Deviation 0.838219 |
Secondary
Grade 3 And Grade 4 Laboratory Abnormalities
Laboratory abnormalities were determined from laboratory measurements analyzed at the central or local laboratories, and were graded using CTCAE.
Time frame: After the first dose of study medication (Day 1) through 14 days after the last dose of study drug (up to Day 104).
Population: All participants who received at least 1 dose of study drug.
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Danicopan | Grade 3 And Grade 4 Laboratory Abnormalities | Alanine aminotransferase increased | 1 Participants |
| Danicopan | Grade 3 And Grade 4 Laboratory Abnormalities | Aspartate aminotransferase increased | 1 Participants |
| Danicopan | Grade 3 And Grade 4 Laboratory Abnormalities | Low hemoglobin | 1 Participants |
| Danicopan | Grade 3 And Grade 4 Laboratory Abnormalities | Low neutrophil count | 4 Participants |
| Danicopan | Grade 3 And Grade 4 Laboratory Abnormalities | High triglycerides | 1 Participants |
Secondary
Paroxysmal Nocturnal Hemoglobinuria (PNH) Type III Red Blood Cell (RBC) Clone Size
PNH RBC, summed type III, clone size levels were assessed from Baseline to Day 28 and Day 84. The PNH clone size refers to the percentage of PNH-affected cells versus normal cells within the total cell population.
Time frame: Baseline, Day 28, and Day 84
Population: All participants who received at least 1 dose of study drug and had analyzable data at the timepoints specified.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Danicopan | Paroxysmal Nocturnal Hemoglobinuria (PNH) Type III Red Blood Cell (RBC) Clone Size | Baseline | 31.5363 percentage of the total cell population | Standard Deviation 24.62004 |
| Danicopan | Paroxysmal Nocturnal Hemoglobinuria (PNH) Type III Red Blood Cell (RBC) Clone Size | Day 28 | 43.6279 percentage of the total cell population | Standard Deviation 15.58021 |
| Danicopan | Paroxysmal Nocturnal Hemoglobinuria (PNH) Type III Red Blood Cell (RBC) Clone Size | Day 84 | 56.2953 percentage of the total cell population | Standard Deviation 19.85086 |
Secondary
Pharmacokinetics (PK): Area Under The Plasma Concentration-time Curve From Time Of Administration To 8 Hours Post-dose (AUC0-8)
Serial blood samples were collected predose and up to 8 hours postdose.
Time frame: Days 6 and 20
Population: All participants who received at least 1 dose of study drug and had analyzable data at the timepoints specified. PK analysis was not conducted on the 200 mg dose.
| Arm | Measure | Group | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|---|
| Danicopan | Pharmacokinetics (PK): Area Under The Plasma Concentration-time Curve From Time Of Administration To 8 Hours Post-dose (AUC0-8) | Day 6: 100 mg TID | 1432.611 hour (hr)*nanograms/milliliter (ng/mL) | Geometric Coefficient of Variation 19.41 |
| Danicopan | Pharmacokinetics (PK): Area Under The Plasma Concentration-time Curve From Time Of Administration To 8 Hours Post-dose (AUC0-8) | Day 20: 150 mg TID | 2370.421 hour (hr)*nanograms/milliliter (ng/mL) | Geometric Coefficient of Variation 14.92 |
| Danicopan | Pharmacokinetics (PK): Area Under The Plasma Concentration-time Curve From Time Of Administration To 8 Hours Post-dose (AUC0-8) | Day 20: 175 mg TID | 2278.038 hour (hr)*nanograms/milliliter (ng/mL) | Geometric Coefficient of Variation 37.3 |
Secondary
PK: Maximum Plasma Concentration (Cmax)
Serial blood samples were collected predose and up to 12 hours postdose.
Time frame: Days 6 and 20
Population: All participants who received at least 1 dose of study drug and had analyzable data at the timepoints specified. PK analysis was not conducted on the 200 mg dose.
| Arm | Measure | Group | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|---|
| Danicopan | PK: Maximum Plasma Concentration (Cmax) | Day 6: 100 mg TID | 347.707 ng/mL | Geometric Coefficient of Variation 9.57 |
| Danicopan | PK: Maximum Plasma Concentration (Cmax) | Day 20: 150 mg TID | 583.626 ng/mL | Geometric Coefficient of Variation 27.29 |
| Danicopan | PK: Maximum Plasma Concentration (Cmax) | Day 20: 175 mg TID | 516.8788 ng/mL | Geometric Coefficient of Variation 33.39 |
Secondary
PK: Time To Maximum Concentration (Tmax)
Serial blood samples were collected predose and up to 12 hours postdose.
Time frame: Days 6 and 20
Population: All participants who received at least 1 dose of study drug and had analyzable data at the timepoints specified. PK analysis was not conducted on the 200 mg dose.
| Arm | Measure | Group | Value (MEDIAN) |
|---|---|---|---|
| Danicopan | PK: Time To Maximum Concentration (Tmax) | Day 6: 100 mg TID | 4.17 hr |
| Danicopan | PK: Time To Maximum Concentration (Tmax) | Day 20: 150 mg TID | 3.67 hr |
| Danicopan | PK: Time To Maximum Concentration (Tmax) | Day 20: 175 mg TID | 4.11 hr |
Secondary
Serious Adverse Events (SAEs), Grade 3 And Grade 4 Treatment-emergent Adverse Events (TEAEs), And Adverse Events (AEs) Leading To Discontinuation
An AE was as any untoward medical occurrence associated with the use of a drug in humans, whether or not considered drug related. An SAE was an AE that met at least 1 of the following criteria: resulted in death, was life-threatening, required inpatient hospitalization or prolongation of existing hospitalization for the AE, persistent or significant disability/incapacity or substantial disruption of the ability to conduct normal life functions, congenital anomaly/birth defect (in the child of a participant who was exposed to the study drug), important medical event or reaction. The intensity of an AE was graded according to the Common Terminology Criteria for Adverse Events (CTCAE) Adverse Event Severity Grading Table. A summary of SAEs and other non-serious AEs regardless of causality is located in the Reported Adverse Events module.
Time frame: After the first dose of study medication (Day 1) through 14 days after the last dose of study drug (up to Day 104)
Population: All participants who received at least 1 dose of study drug.
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Danicopan | Serious Adverse Events (SAEs), Grade 3 And Grade 4 Treatment-emergent Adverse Events (TEAEs), And Adverse Events (AEs) Leading To Discontinuation | SAE | 1 Participants |
| Danicopan | Serious Adverse Events (SAEs), Grade 3 And Grade 4 Treatment-emergent Adverse Events (TEAEs), And Adverse Events (AEs) Leading To Discontinuation | TEAE Grade 3 | 1 Participants |
| Danicopan | Serious Adverse Events (SAEs), Grade 3 And Grade 4 Treatment-emergent Adverse Events (TEAEs), And Adverse Events (AEs) Leading To Discontinuation | TEAE Grade 4 | 1 Participants |
| Danicopan | Serious Adverse Events (SAEs), Grade 3 And Grade 4 Treatment-emergent Adverse Events (TEAEs), And Adverse Events (AEs) Leading To Discontinuation | AE leading to discontinuation | 1 Participants |