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

Phase 2

Terminated

Conditions: Paroxysmal Nocturnal Hemoglobinuria (PNH)

Interventions: Drug: ALXN2050

Registration Number: NCT04170023

Lead Sponsor: Alexion Pharmaceuticals, Inc.

Brief Summary: 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: 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.

Recruitment & Eligibility

Status: TERMINATED

Sex: All

Target Recruitment: 29

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:

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.

Study & Design

Study Type: INTERVENTIONAL

Study Design: SINGLE_GROUP

Arm && Interventions

Group	Intervention	Description
Open-label ALXN2050 Monotherapy	ALXN2050	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

Primary Outcome Measures

Name	Time	Method
Change From Baseline in Hgb at Week 12	Baseline, Week 12	Hgb baseline was defined as the lowest Hgb value observed between and including screening and first dose date. To address the impact of transfusion, Hgb values collected within 4 weeks after transfusion were not included in the primary efficacy analysis. Change from Baseline = Hgb at Week 12 - Baseline Hgb.

Secondary Outcome Measures

Name	Time	Method
Number of Participants Who Had Transfusion Avoidance During 12 Weeks of Treatment With ALXN2050	Baseline up to Week 12	Transfusion avoidance: participants remained transfusion-free and did not require a transfusion during the period of interest.
Number of Red Blood Cell (RBC) Units Transfused During 12 Weeks of Treatment	Baseline up to Week 12
Number of Transfusion Instances During 12 Weeks of Treatment	Baseline up to Week 12
Change From Baseline in Lactate Dehydrogenase (LDH) at Week 12	Baseline, Week 12	Change from Baseline = Serum LDH levels at Week 12 - Baseline Serum LDH levels.
Change From Baseline in Absolute Reticulocyte Count at Week 12	Baseline, Week 12	Change from Baseline = absolute reticulocyte count at Week 12 - Baseline reticulocyte count.
Change From Baseline in Direct and Total Bilirubin at Week 12	Baseline, Week 12
Change From Baseline in Paroxysmal Nocturnal Hemoglobinuria (PNH) Red Blood Cell (RBC) Clone Size at Week 12	Baseline, Week 12	The PNH RBC clone size refers to the percentage of PNH-affected cells versus normal cells within the total cell population. Change from Baseline = PNH clone size at Week 12 - Baseline PNH clone size.
Change From Baseline in Component 3 (C3) Fragment Deposition on PNH RBCs at Week 12	Baseline, Week 12	C3 fragment deposition on PNH RBC was used as a marker of intra and extravascular hemolysis. Data are presented for the change from baseline to Week 12 in percentage of PNH RBCs with C3 fragment deposition.
Number of Participants With Treatment-emergent Adverse Events (TEAEs), Serious Adverse Events (SAEs), and Events Leading to Discontinuation of Study Medication	From first dose of study drug up to Week 217	An adverse event (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, resulted in 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), or an important medical event or reaction. A TEAE was defined as an AE that emerged during treatment, had been absent prior to treatment, or worsened relative to the pretreatment state. A summary of all Serious Adverse Events and Other Adverse Events (nonserious) regardless of causality is located in the 'Reported Adverse Events' Section.
Change From Baseline in Hgb at the End of Treatment (EOT) During the LTE Period	Baseline, EOT visit (Maximum exposure: 213.4 weeks)	Hgb baseline was defined as the lowest Hgb value observed between and including screening and first dose date. Change from Baseline = Hgb at the EOT visit - Baseline Hgb.
Change From Baseline in LDH at the EOT During the LTE Period	Baseline, EOT visit (Maximum exposure: 213.4 weeks)	Change from Baseline = Serum LDH levels at the EOT visit - Baseline Serum LDH levels.
Change From Baseline in Functional Assessment of Chronic Illness Therapy (FACIT) Fatigue Scale (Version 4) Total Score at Week 12	Baseline, Week 12	The FACIT-Fatigue scale is a collection of quality-of-life questionnaires pertaining to the management of fatigue symptoms due to chronic illness. The FACIT-Fatigue is a 13-item questionnaire that assesses self-reported fatigue and its impact upon daily activities and function over the preceding 7 days. Participants scored each item on a 5-point scale: 0 (Not at all) to 4 (Very much). Total scores ranged from 0 to 52, with higher score indicating better quality of life.
Change From Baseline in FACIT-Fatigue Scale (Version 4) Total Score at the EOT During the LTE Period	Baseline, EOT visit (Maximum exposure: 213.4 weeks)	The FACIT-Fatigue scale is a collection of quality-of-life questionnaires pertaining to the management of fatigue symptoms due to chronic illness. The FACIT-Fatigue is a 13-item questionnaire that assesses self-reported fatigue and its impact upon daily activities and function over the preceding 7 days. Participants scored each item on a 5-point scale: 0 (Not at all) to 4 (Very much). Total scores ranged from 0 to 52, with higher score indicating better quality of life.