Danicopan as Add-on Therapy to a C5 Inhibitor in Paroxysmal Nocturnal Hemoglobinuria (PNH) Participants Who Have Clinically Evident Extravascular Hemolysis (EVH)(ALPHA)

A Phase 3 Study of Danicopan (ALXN2040) as Add-on Therapy to a C5 Inhibitor (Eculizumab or Ravulizumab) in Patients With Paroxysmal Nocturnal Hemoglobinuria Who Have Clinically Evident Extravascular Hemolysis (EVH)

The main objective of this study is to evaluate the efficacy of danicopan as add-on therapy to a complement component 5 (C5) inhibitor (eculizumab or ravulizumab) in participants with PNH who have clinically evident EVH.

Study Overview

• Status: Completed
• Conditions: Paroxysmal Nocturnal Hemoglobinuria
• Intervention / Treatment: Drug: Placebo; Drug: Danicopan; Drug: C5 Inhibitor

Detailed Description

This is a multiple-region, randomized, double-blind, placebo controlled, multiple-dose, study in participants with PNH who have clinically evident EVH on a C5 inhibitor (eculizumab or ravulizumab).

Participants will be randomized to receive danicopan or placebo, in a 2:1 ratio for 12 weeks (Treatment Period 1) in addition to their C5 inhibitor (eculizumab or ravulizumab) therapy. At Week 12, participants randomized to receive placebo will be switched to danicopan in addition to their C5 inhibitor for an additional 12 weeks (Treatment Period 2) and participants randomized to danicopan will continue on danicopan for an additional 12 weeks, while remaining on their ongoing C5 inhibitor therapy.

At the end of the 2 treatment periods (Week 24), participants may enter a Long-Term Extension (LTE) Period and continue to receive danicopan in addition to their C5 inhibitor therapy. The Long-Term Extension period will consist of a first year of LTE(Year1) and a second year of optional LTE(Year2).All patients will complete 72 weeks of LTE(Year 1) assessments. After Week 72 (at the end of the first year of LTE), patients have the choice to complete participation in this study or continue to the optional second year (Year2) of LTE.

• Study Type: Interventional
• Enrollment (Actual): 86
• Phase: Phase 3

Contacts and Locations

Study Locations

• Brazil
  • Belem, Brazil, 66053-000
    • Research Site
  • Curitiba, Brazil, 80810-050
    • Research Site
  • Goiania, Brazil, 74605-020
    • Research Site
  • Porto Alegre, Brazil, 90110-270
    • Research Site
  • Rio De De Janeiro, Brazil, 20211030
    • Research Site
• Canada
  • Ontario
    • Toronto, Ontario, Canada, M5G 2C4
      • Research Site
• Czechia
  • Brno, Czechia, 625 00
    • Research Site
• France
  • Lille, France, 59037
    • Research Site
  • Paris, France, 75010
    • Research Site
  • Pessac, France, 33604
    • Research Site
  • Pierre Benite Cedex, France, 69495
    • Research Site
• Germany
  • Ulm, Germany, 89081
    • Research Site
• Greece
  • Athens, Greece, 11527
    • Research Site
  • Thessaloniki, Greece, 57010
    • Research Site
• Israel
  • Haifa, Israel, 31048
    • Research Site
  • Jerusalem, Israel, 91120
    • Research Site
• Italy
  • Avellino, Italy, 83100
    • Research Site
  • Bassano del Grappa, Italy, 36061
    • Research Site
  • Firenze, Italy, 50134
    • Research Site
  • Milano, Italy, 20122
    • Research Site
  • Reggio Calabria, Italy, 89131
    • Research Site
  • Roma, Italy, 00161
    • Research Site
• Japan
  • Bunkyo-Ku, Japan, 113 8603
    • Research Site
  • Fukuoka, Japan, 812-8582
    • Research Site
  • Kashiwa-shi, Japan, 277-8567
    • Research Site
  • Kyoto-shi, Japan, 605-0981
    • Research Site
  • Nagakute-shi, Japan, 480-1195
    • Research Site
  • Ogaki-shi, Japan, 503-8502
    • Research Site
  • Osaka-shi, Japan, 530-8480
    • Research Site
  • Osakasayama, Japan, 589-8511
    • Research Site
  • Shibuya-ku, Japan, 150-8935
    • Research Site
  • Tanabe-shi, Japan, 646-8588
    • Research Site
  • Toyoake-shi, Japan, 470-1192
    • Research Site
  • Tsukuba-shi, Japan, 305-8576
    • Research Site
• Korea, Republic of
  • Daejeon, Korea, Republic of, 35015
    • Research Site
  • Seoul, Korea, Republic of, 03722
    • Research Site
  • Seoul, Korea, Republic of, 06351
    • Research Site
  • Seoul, Korea, Republic of, 06591
    • Research Site
  • Suwon, Korea, Republic of, 16247
    • Research Site
• Malaysia
  • Kota Kinabalu, Malaysia, 88586
    • Research Site
  • Kuching, Malaysia, 93586
    • Research Site
  • Miri, Malaysia, 98000
    • Research Site
• Netherlands
  • Maastricht, Netherlands, 6229 HX
    • Research Site
• Poland
  • Gdansk, Poland, 80-214
    • Research Site
• Spain
  • Barcelona, Spain, 08036
    • Research Site
  • Barcelona, Spain, 08916
    • Research Site
  • Las Palmas de Gran Canaria, Spain, 35020
    • Research Site
  • Madrid, Spain, 28040
    • Research Site
  • Majadahonda, Spain, 28222
    • Research Site
  • Sevilla, Spain, 41013
    • Research Site
• Taiwan
  • Taipei, Taiwan, 100
    • Research Site
• Thailand
  • Bangkok, Thailand, 10330
    • Research Site
• United Kingdom
  • Airdrie, United Kingdom, ML6 0JS
    • Research Site
  • Leeds, United Kingdom, BD7 1DP
    • Research Site
  • London, United Kingdom, SE5 9NU
    • Research Site
• United States
  • California
    • Los Angeles, California, United States, 90089
      • Research Site
  • Florida
    • Weston, Florida, United States, 33331
      • Research Site
  • Illinois
    • Chicago, Illinois, United States, 60612
      • Research Site
  • Michigan
    • Kalamazoo, Michigan, United States, 49007
      • Research Site
  • New York
    • New York, New York, United States, 10065
      • Research Site
  • Texas
    • Dallas, Texas, United States, 75390
      • Research Site
  • Wisconsin
    • Milwaukee, Wisconsin, United States, 53212
      • Research Site

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

• Diagnosis of PNH

• Clinically Evident EVH defined by:

  • Anemia (Hgb ≤9.5 gram/deciliter) with absolute reticulocyte count ≥120 x 10^9/liter
• Receiving an approved C5 inhibitor for at least 6 months prior to Day 1
• Platelet count ≥30,000/microliters (µL)
• Absolute neutrophil counts ≥500/μL
• Documentation of/or willingness to receive vaccinations for N. meningiditis and prophylactic antibiotics as required

Exclusion Criteria:

• History of a major organ transplant or hematopoietic stem cell transplantation (HSCT)
• Participants with known aplastic anemia or other bone marrow failure that requires HSCT or other therapies including anti-thymocyte globulin and/or immunosuppressants
• Known or suspected complement deficiency

• Laboratory abnormalities at screening, including:

  • Alanine aminotransferase >2 x ULN (>3 x ULN in case of patients with documented liver iron overload defined by serum ferratin values

    • 500 ng/ML)
  • Direct bilirubin >2 x ULN (unless due to EVH or documented Gilbert's Syndrome)
• Current evidence of biliary cholestasis
• Estimated glomerular filtration rate of <30 milliliters/minute/1.73 meter squared and/or are on dialysis
• Evidence of human immunodeficiency virus, hepatitis B, or active hepatitis C infection at screening

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Double

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Danicopan + C5 Inhibitor; Participants will receive danicopan, in addition to their C5 inhibitor therapy, for 24 weeks (12 weeks in Treatment Period 1, followed by 12 weeks in Treatment Period 2).	Drug: Danicopan; Oral tablet; Other Names: ALXN2040; Drug: C5 Inhibitor; Participants will continue to receive their ongoing C5 inhibitor (eculizumab or ravulizumab) therapy according to their usual dose and schedule.
Placebo Comparator: Placebo + C5 Inhibitor; Participants will receive placebo, in addition to their C5 inhibitor therapy, for 12 weeks during Treatment Period 1. At Week 12, participants randomized to receive placebo will be switched to danicopan for an additional 12 weeks (Treatment Period 2).	Drug: Placebo; Oral tablet; Drug: C5 Inhibitor; Participants will continue to receive their ongoing C5 inhibitor (eculizumab or ravulizumab) therapy according to their usual dose and schedule.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Change From Baseline in Hgb at Week 12	Baseline was defined as the lowest Hgb value observed between and including Screening and Day 1. The least square (LS) mean and standard error (SE) were produced using mixed-effect model for repeated measures (MMRM). Hgb values collected within 4 weeks after transfusion were not included in the MMRM.	Baseline, Week 12

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Percentage of Participants With Hgb Increase of ≥2 g/dL (≥20 g/L) From Baseline in the Absence of Transfusion at Week 12	The criterion was defined as ≥20 g/L increase in Hgb from Baseline to Week 12 and remaining transfusion free during the 12-Week TP1. Participants who withdrew from the study early during the 12-Week TP1 or had missing Hgb value at Week 12 were considered as not achieving the criterion.	Week 12
Percentage of Participants With Transfusion Avoidance Through Week 12	Participants achieved transfusion avoidance if they remained transfusion free and did not require a transfusion as per protocol-specified guidelines from Week 1 through Week 12. Participants who discontinued study treatment early before Week 12 were considered as not achieving transfusion avoidance.	Week 12
Change From Baseline in Functional Assessment of Chronic Illness Therapy (FACIT) Fatigue Score at Week 12	The FACIT-Fatigue was 13-item questionnaire scored on a 5-point Likert scale (0 = not at all, 4 = very much) that assesses self-reported fatigue and its impact on daily activities and function. Total scores range from 0 to 52 with higher score indicating less fatigue better health-related quality of life. LS mean and SE were produced using MMRM.	Baseline, Week 12
Change From Baseline in Absolute Reticulocyte Count at Week 12	LS mean and SE were produced using MMRM.	Baseline, Week 12
Change in the Number of Red Blood Cell (RBC) Units Transfused From 24 Weeks Prior to Initiation of Treatment to Post 24 Weeks of Treatment		24 weeks prior to initiation of treatment to post 24 weeks of treatment
Change in Number of Transfusion Instances From 24 Weeks Prior to Initiation of Treatment to Post 24 Weeks of Treatment		24 weeks prior to initiation of treatment to post 24 weeks of treatment
Percentage of Participants With Transfusion Avoidance Through Week 24		Week 24
Change in the Number of RBC Units Transfused From 12 Weeks Prior to Initiation of Treatment to Post 12 Weeks of Treatment	LS mean and SE were produced using analysis of covariance (ANCOVA).	12 weeks prior to initiation of treatment to post 12 weeks of treatment
Change in Number of Transfusion Instances From 12 Weeks Prior to Initiation of Treatment to Post 12 Weeks of Treatment	LS mean and SE were produced using ANCOVA.	12 weeks prior to initiation of treatment to post 12 weeks of treatment
Change From Baseline FACIT Fatigue Scores at Week 24		Baseline, Week 24
Percentage of Participants With Hgb Stabilization During Last 12 Weeks of Treatment in Participants Receiving 24 Weeks of Danicopan		Week 12 to Week 24
Percentage of Participants With Hgb Increase of ≥2 g/dL (≥ 20 g/L) From Baseline in the Absence of Transfusion at Week 24		Week 24
Change From Baseline in Total and Direct Bilirubin at Week 12	Baseline was defined as the last nonmissing value prior to first dose of study intervention. LS mean and SE were produced using MMRM.	Baseline, Week 12
Change From Baseline in Paroxysmal Nocturnal Hemoglobinuria (PNH) RBC Clone Size at Week 12	The PNH clone size refers to the percentage of PNH-affected cells versus normal cells within the total cell population. Baseline was defined as the last nonmissing value prior to first dose of study intervention. LS mean and SE were produced using MMRM.	Baseline, Week 12
Change From Baseline in C3 Fragment Deposition (C3d PNH Type 3 Cells) on PNH RBCs at Week 12	Baseline was defined as the last nonmissing value prior to first dose of study intervention. LS mean and SE were produced using MMRM.	Baseline, Week 12
Change From Baseline in Lactate Dehydrogenase at Week 12	Baseline was defined as the average of all available assessments prior to the first dose of study intervention. LS mean and SE were produced using MMRM.	Baseline, Week 12
Percentage of Participants With Hgb Normalization at Week 12	Hgb normalization was defined as Hgb value above lower limit of normal (LLN) reference range. For male, the LLN was 125 grams (g)/liter (L), for female, the LLN was 110 g/L. Participants with transfusions within 4 weeks prior to Week 12 were considered as not meeting Hgb normalization regardless of actual value observed at Week 12.	Week 12
Percentage of Participants With Hgb Normalization at Week 24		Week 24

Collaborators and Investigators

• Sponsor: Alexion Pharmaceuticals, Inc.

Publications and helpful links

Helpful Links

• Mechanistic Evaluation of Efficacy Using Biomarkers of the Oral, Small Molecule Factor D Inhibitor, Danicopan (ACH-4471), in Untreated Patients with Paroxysmal Nocturnal Hemoglobinuria (PNH)
• A Phase 2 Open-Label Study of Danicopan (ACH-0144471) in Patients with Paroxysmal Nocturnal Hemoglobinuria (PNH) Who Have an Inadequate Response to Eculizumab Monotherapy
• Danicopan (ACH-4471) in Untreated Patients with Paroxysmal Nocturnal Hemoglobinuria (PNH) Phase 2, Open-label, Proof of Concept Study of the Oral, Small Molecule Factor D Inhibitor

Study record dates

Study Major Dates

• Study Start (Actual): December 16, 2020
• Primary Completion (Actual): June 29, 2022
• Study Completion (Actual): January 16, 2024

Study Registration Dates

• First Submitted: July 9, 2020
• First Submitted That Met QC Criteria: July 9, 2020
• First Posted (Actual): July 14, 2020

Study Record Updates

• Last Update Posted (Estimated): February 6, 2024
• Last Update Submitted That Met QC Criteria: February 1, 2024
• Last Verified: February 1, 2024

More Information

Terms related to this study

• Keywords: Complement; Danicopan; Paroxysmal Nocturnal Hemoglobinuria (PNH); Extravascular Hemolysis (EVH); Factor D inhibitor; C5 inhibitor
• Additional Relevant MeSH Terms: Pathologic Processes; Urologic Diseases; Urological Manifestations; Bone Marrow Diseases; Hematologic Diseases; Urination Disorders; Anemia; Proteinuria; Anemia, Hemolytic; Myelodysplastic Syndromes; Female Urogenital Diseases; Female Urogenital Diseases and Pregnancy Complications; Urogenital Diseases; Male Urogenital Diseases; Hemoglobinuria; Hemoglobinuria, Paroxysmal; Hemolysis
• Other Study ID Numbers: ALXN2040-PNH-301; 2019-003829-18 (EudraCT Number)

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No