Study of Danicopan in Participants With Paroxysmal Nocturnal Hemoglobinuria With Inadequate Response to Eculizumab

Study Overview
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Brief Summary
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To determine the effectiveness of ACH-0144471 (also known as danicopan and ALXN2040) in improving anemia when given with eculizumab for 24 weeks in participants with PNH. Danicopan dose may be increased within each participant, to a maximum of 200 milligrams (mg) three times daily (TID) based on safety and efficacy at protocol-specified time points.

Detailed Description
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The purpose of this study is to determine the effectiveness of danicopan in improving anemia, as measured by increased blood hemoglobin, when given with eculizumab (a drug commonly used for treatment of PNH) for 24 weeks in participants with PNH. The 24-week treatment period was followed by a long-term extension phase. In the extension phase, participants received the same danicopan dose plus eculizumab as they were receiving at the end of 24-week treatment phase. Results are reported for the 24-week treatment period.

Official Title
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A Phase 2 Open-label Study of ACH-0144471 in Patients With Paroxysmal Nocturnal Hemoglobinuria (PNH) Who Have an Inadequate Response to Eculizumab Monotherapy

Conditions
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Paroxysmal Nocturnal Hemoglobinuria (PNH)

Intervention / Treatment
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* Drug: Danicopan
* Drug: Eculizumab


Participation Criteria
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Eligibility Criteria
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Key Inclusion Criteria: Diagnosed with PNH Have received at least one red blood cell transfusion within last 12 weeks Anemia with adequate reticulocytosis Must be on a stable regimen of eculizumab Platelet count ≥ 40,000/microliter without the need for platelet transfusions Documentation of vaccination for Neisseria meningitidis, Haemophilus influenza, and Streptococcus pneumoniae or willingness to receive vaccinations based on local guidelines Willingness to receive antibiotic prophylaxis Female participants must use highly effective birth control to prevent pregnancy during the clinical trial and for 30 days after their last dose of study drug Male participants must use a highly effective birth control with a female partner to prevent pregnancy during the clinical trial and for 90 days after the last dose of study drug Key Exclusion Criteria: Current evidence of bone marrow failure or aplastic anemia requiring treatment History of a major organ transplant or hematopoietic stem cell/marrow transplant Received another investigational agent within 30 days or 5 half-lives of the investigational agent prior to study entry, whichever is greater Documented C5 complement protein mutations Known or suspected complement deficiency Contraindication to any of the required vaccinations Active bacterial infection or clinically significant active viral infection, a body temperature >38°C, or other evidence of infection History of meningococcal infection, or a first-degree relative or household contact with a history of meningococcal infection History of hypersensitivity reactions to commonly used antibacterial agents Note: Additional inclusion/exclusion criteria may apply, per protocol.

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 65 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
Allocation: Non-Randomized
Intervention Model: Sequential Assignment
Interventional Model Description: Four groups will be studied and enrolled sequentially.
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Group 1: 100 mg Danicopan TID + Eculizumab<br>Starting dose of 100 mg danicopan TID in combination with eculizumab. | Drug: Danicopan<br>* Participants received a daily oral dose of danicopan TID during the treatment period.<br>Drug: Eculizumab<br>* Participants received intravenous eculizumab administered at the participant's usual dose and schedule.<br>* Other names: Soliris;|
| Experimental: Group 2: Initial dose 100 or 150 mg Danicopan TID + Eculizumab<br>Starting dose of 100 or 150 mg danicopan TID in combination with eculizumab. | Drug: Danicopan<br>* Participants received a daily oral dose of danicopan TID during the treatment period.<br>Drug: Eculizumab<br>* Participants received intravenous eculizumab administered at the participant's usual dose and schedule.<br>* Other names: Soliris;|
| Experimental: Group 3: Initial dose of 100, 150, or 200 mg Danicopan TID + Eculizumab<br>Starting dose of 100, 150, or 200 mg danicopan TID in combination with eculizumab. | Drug: Danicopan<br>* Participants received a daily oral dose of danicopan TID during the treatment period.<br>Drug: Eculizumab<br>* Participants received intravenous eculizumab administered at the participant's usual dose and schedule.<br>* Other names: Soliris;|
| Experimental: Group 4: Optimal Dose of Danicopan TID + Eculizumab<br>Optimal dose (starting dose of either 100, 150, or 200 mg, as determined from Groups 1-3) of danicopan TID in combination with eculizumab. | Drug: Danicopan<br>* Participants received a daily oral dose of danicopan TID during the treatment period.<br>Drug: Eculizumab<br>* Participants received intravenous eculizumab administered at the participant's usual dose and schedule.<br>* Other names: Soliris;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change From Baseline In Hemoglobin At Week 24 |  | Baseline, Week 24 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number Of Units Of Red Blood Cells (RBCs) Transfused During 24 Weeks Of Treatment |  | Within 24 weeks prior to first dose and during 24-week treatment period | 
| Number Of Participants Without RBC Transfusions During 24 Weeks Of Treatment |  | Within 24 weeks prior to first dose and during 24-week treatment period | 
| Change From Baseline In Lactate Dehydrogenase At Week 24 |  | Baseline, Week 24 | 
| Number Of Participants With Serious Adverse Events (SAEs), Grade 3 And Grade 4 Adverse Events (AEs), And Events Leading To Discontinuation Of Study Drug | An AE was defined 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. | Day 1 (after dosing) through end of study (maximum exposure: 1631 days) | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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PNH, Paroxysmal Nocturnal Hemoglobinuria, ACH-0144471, Danicopan, Eculizumab, ALXN2040