Study of Danicopan in Participants With Paroxysmal Nocturnal Hemoglobinuria (PNH)

Study Overview
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Brief Summary
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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
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After 12 weeks of treatment, participants deriving clinical benefit were offered enrollment in a separate long-term extension study (ACH471-103, NCT03181633).

Official Title
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A Phase 2 Open-Label Proof of Concept Study to Assess the Efficacy, Safety, and Pharmacokinetics of ACH-0144471 in Untreated Patients With Paroxysmal Nocturnal Hemoglobinuria

Conditions
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Paroxysmal Nocturnal Hemoglobinuria (PNH)

Intervention / Treatment
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* Drug: Danicopan


Participation Criteria
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Eligibility Criteria
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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.

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Danicopan<br>Starting doses of danicopan ranged from 100 to 150 milligrams (mg) three times daily (TID), with subsequent dose escalation up to 200 mg TID based on response (clinical and biochemical) for 28 days (Part 1). 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). | Drug: Danicopan<br>* Danicopan was administered as multiple oral doses over a period of at least 28 days.<br>* Other names: ALXN2040;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change From Baseline In Serum LDH Levels At Day 28 | Change from Baseline = Serum LDH levels on Day 28 - Baseline Serum LDH levels. | Baseline, Day 28 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change From Baseline In Hemoglobin (Hgb) At Days 28 And 84 | Change from Baseline = Hgb levels on Days 28 or 84 - Baseline Hgb levels. | Baseline, Days 28 and 84 | 
| Change From Baseline In Serum LDH Levels At Day 84 | Change from Baseline = Serum LDH levels on Day 84 - Baseline Serum LDH levels. | Baseline, Day 84 | 
| 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. | Baseline, Day 28, and Day 84 | 
| 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. | After the first dose of study medication (Day 1) through 14 days after the last dose of study drug (up to Day 104) | 
| 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. | After the first dose of study medication (Day 1) through 14 days after the last dose of study drug (up to Day 104). | 
| 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. | Days 6 and 20 | 
| PK: Maximum Plasma Concentration (Cmax) | Serial blood samples were collected predose and up to 12 hours postdose. | Days 6 and 20 | 
| PK: Time To Maximum Concentration (Tmax) | Serial blood samples were collected predose and up to 12 hours postdose. | Days 6 and 20 | 
| Complement Alternative Pathway (AP) Functional Activity | Serum AP functional activity was measured by the Wieslab functional immunoassay method. | Baseline and Day 28 | 
| Complement Bb | Plasma Bb was measured by enzyme-linked immunosorbent assay (ELISA). | Baseline and Day 28 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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PNH, Paroxysmal, Hemoglobinuria