Study of the Oral Factor D (FD) Inhibitor ALXN2050 in PNH Patients as Monotherapy

Study Overview
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Brief Summary
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The study will evaluate the efficacy and safety of the oral Factor D (FD) inhibitor ALXN2050 (ACH-0145228) monotherapy in patients with PNH that are treatment naïve, or patients currently treated with eculizumab who still experience anemia and reticulocytosis, or patients currently treated with ALXN2040 (danicopan) as monotherapy. After signing consent, participants will have periodic visits through Week 12, at which time the primary endpoint and key secondary assessments will be analyzed. Participants will continue on treatment past 12 weeks into a long-term extension portion of the trial.

Detailed Description
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Experimental: Open-label ALXN2050 Monotherapy orally Group 1: Patients with PNH who are treatment naïve Group 2: Patients with PNH who have received complement component 5 (C5) inhibition with eculizumab for at least 6 months, who continue to experience anemia and reticulocytes above the upper limit of normal (ULN) who will switch to ALXN2050 monotherapy Group 3: Patients with PNH receiving danicopan monotherapy in study ACH471-103 will switch to ALXN2050 monotherapy After signing the informed consent form, participants will enter the screening period. During the Screening Period, eligibility and screening assessments will be performed. Screening assessments may be spread over more than one visit if necessary. At the baseline visit, screened participants who continue to meet eligibility criteria will enter the Treatment Period. The treatment phase will be followed by a long-term extension phase, where ALXN2050 will continue to be administered. Blood will be collected to assess the efficacy endpoints, such as, change in hemoglobin (Hgb), lactate dehydrogenase (LDH), and other measures of hemolysis. Safety and transfusion requirements will also be assessed. Participants will continue on treatment past 12 weeks in a long-term extension portion of the trial.

Official Title
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A Phase 2 Open-Label Proof of Concept Study to Assess the Efficacy, Safety, and Pharmacokinetics of the Oral Factor D (FD) Inhibitor ALXN2050 (ACH-0145228) in Paroxysmal Nocturnal Hemoglobinuria (PNH) Patients as Monotherapy

Conditions
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Paroxysmal Nocturnal Hemoglobinuria (PNH)

Intervention / Treatment
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* Drug: ALXN2050


Participation Criteria
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Eligibility Criteria
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Key Inclusion Criteria: Diagnosis of PNH. Male or female, ≥ 18 years of age Eligibility Criteria: Eligibility Criteria Specific for Group 1: PNH Patients who have no history of treatment with any complement inhibitor at any dose. PNH Type III erythrocyte or granulocyte clone size ≥10% Absolute reticulocyte count ≥100×10^9/liter [L]. Anemia (Hgb <10.5 grams/deciliter [g/dL]). LDH ≥1.5× upper limit of normal. Platelet count ≥30,000/microliter (µL) Absolute neutrophil count (ANC) ≥750/ µL. Eligibility Criteria Specific for Group 2: Stable background regimen of at least 24 weeks for eculizumab without change in dose or interval for at least the past 8 weeks Anemia (Hgb <10 g/dL) Absolute reticulocyte count ≥100×10^9/L Platelet count ≥30,000/µL Absolute neurophil count (ANC) ≥750/ µL Eligibility Criteria Specific for Group 3: 1. Patient received danicopan during Study ACH471-103 Key Exclusion Criteria: History of a major organ transplant or hematopoietic stem cell/marrow transplant . Known aplastic anemia or other bone marrow failure that requires HSCT, or if these patients are on immunosuppressive agents for less than 24 weeks. Known underlying bleeding disorders or any other conditions leading to anemia not primarily associated with PNH. Estimated glomerular filtration rate <30 milliliters/minute/1.73 meters squared and/or are on dialysis.

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: Open-label ALXN2050 Monotherapy<br>Experimental: Open-label ALXN2050 Monotherapy ALXN2050 orally administered Group 1: Patients with PNH who are treatment naïve Group 2: Patient with PNH who have received complement component 5 (C5) inhibition with eculizumab for at least 6 months, who continue to experience anemia and reticulocytes above the upper limit of normal (ULN) Group 3: Patients with PNH who have received danicopan monotherapy during study ACH471-103 | Drug: ALXN2050<br>* Oral FD inhibitor<br>* Other names: ACH-0145228;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change In HgB Relative To Baseline |  | Week 12 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number Of Patients Who Have Transfusion Avoidance |  | Up to Week 12 | 
| Number Of RBC Units Transfused and Transfusion Instances |  | Up to Week 12 | 
| Change In LDH Relative To Baseline |  | Week 12 | 
| Change From Baseline In Absolute Reticulocyte Count |  | Week 12 | 
| Change From Baseline In Direct Bilirubin |  | Week 12 | 
| Change From Baseline In Total Bilirubin |  | Week 12 | 
| Change From Baseline In PNH RBC Clone Size |  | Week 12 | 
| Change From Baseline In C3 Complement Protein Fragment Deposition On PNH RBCs |  | Week 12 | 
| Incidence of TEAEs, SAEs, and Events Leading To Discontinuation Of Study Medication |  | Through Study Completion | 
| Change in HgB Relative To Baseline |  | Long-term Extension Period | 
| Change in LDH Relative To Baseline |  | Long-term Extension Period | 
| Change in FACIT Fatigue Scale (Version 4) Scores Relative To Baseline |  | Week 12, Week 160 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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paroxysmal nocturnal hemoglobinuria, PNH, extravascular hemolysis, EVH, factor D inhibitor, complement, C5 inhibitor, danicopan