A Proof-of-Mechanism Study to Determine the Effect of Danicopan on C3 Levels in Participants With C3G or IC-MPGN

• ClinicalTrials.gov Identifier: NCT03124368
• Recruitment Status: Completed
• First Posted: April 21, 2017
• Results First Posted: July 13, 2021
• Last Update Posted: November 4, 2021
• Sponsor: Alexion Pharmaceuticals
• Collaborator: Achillion, a wholly owned subsidiary of Alexion
• Information provided by (Responsible Party): Alexion Pharmaceuticals

Study Description

Brief Summary:

The primary objective of this study was to determine whether ACH-0144471 (also known as danicopan and ALXN2040) increases blood C3 complement protein (C3) levels in participants with low C3 levels due to either C3G or IC-MPGN.

Condition or disease	Intervention/treatment	Phase
C3 Glomerulonephritis; Dense Deposit Disease; C3 Glomerulopathy; Immune Complex Mediated Membranoproliferative Glomerulonephritis; Membranoproliferative Glomerulonephritis Types I, II, and III	Drug: Danicopan	Phase 2

Study Design

• Study Type: Interventional (Clinical Trial)
• Actual Enrollment: 6 participants
• Allocation: Non-Randomized
• Intervention Model: Sequential Assignment
• Masking: None (Open Label)
• Primary Purpose: Basic Science
• Official Title: A Phase 2a Proof-of-Mechanism, Open-Label Study to Determine the Effect of ACH-0144471 on C3 Levels in Participants With Low C3 Levels Due to Either C3 Glomerulopathy (C3G) or Immune-Complex Membranoproliferative Glomerulonephritis (IC-MPGN)
• Actual Study Start Date: August 9, 2017
• Actual Primary Completion Date: December 21, 2018
• Actual Study Completion Date: January 9, 2019

Arms and Interventions

Arm	Intervention/treatment
Experimental: Group 1: Danicopan 100 mg TID (Sentinel); All participants received 100 milligrams (mg) of danicopan three times per day (TID) during the Treatment Period.	Drug: Danicopan; Participants received study drug for 14 days (Treatment Period), followed by a taper over the next 7 days (Taper Period).; Other Names: ACH-4471; ACH4471; 4471; ACH-0144471; ALXN2040
Experimental: Group 2: Danicopan up to 200 mg TID; All participants received not more than 200 mg of danicopan TID depending on the available safety, pharmacokinetic, and pharmacodynamic data from Group 1 (Sentinel) during the Treatment Period.	Drug: Danicopan; Participants received study drug for 14 days (Treatment Period), followed by a taper over the next 7 days (Taper Period).; Other Names: ACH-4471; ACH4471; 4471; ACH-0144471; ALXN2040

Outcome Measures

Primary Outcome Measures :

1. Change From Baseline In Serum C3 Complement Protein (C3) Levels On Day 15 [ Time Frame: Baseline, Day 15 ]

   Serum C3 levels were measured by conventional Roche immunoturbidimetric assay method.

   Change from Baseline = Serum C3 levels on Day 15 - Baseline Serum C3 levels

2. Change From Baseline In Plasma Intact C3 Level On Day 15 [ Time Frame: Baseline, Day 15 ]
   Plasma Intact C3 level were measured by a novel multiplex assay method. Change from Baseline = Plasma Intact C3 levels on Day 15 - Baseline Plasma Intact C3 levels

Secondary Outcome Measures :

1. Change From Baseline In Total Complement Classical Pathway (CP) Activity On Day 14 [ Time Frame: Baseline, Day 14 ]

   CP activity was measured in serum by the DiaSorin Complement Activation Enzyme (CAE) functional immunoassay method, which measures terminal complement complex formation following activation. Results are expressed in CAE units which are calculated relative to previously established CAE activity of a positive control serum.

   Change from Baseline = Total Complement CP Activity on Day 14 - Baseline Total Complement CP Activity

2. Change From Baseline In Total Complement Alternative Pathway (AP) Functional Activity (AP Wieslab) On Day 15 [ Time Frame: Baseline, Day 15 ]

   AP functional activity was measured in serum by the Wieslab functional immunoassay method, which measures terminal complement complex (TCC) formation following AP-specific activation. Results are expressed as percent TCC production relative to a positive control serum.

   Change from Baseline = Total Complement AP Functional Activity on Day 15 - Baseline Total Complement AP Functional Activity

3. Time To Achieving Peak Serum C3 Levels [ Time Frame: From The First Day Of Dosing through Day 14 ]
   Serial serum samples were collected on Days 1, 7, and 14.
4. Number Of Participants With Serious Adverse Events (SAEs), Grade 3 And Grade 4 Treatment-emergent Adverse Events (TEAEs), And Adverse Events (AEs) Leading To Discontinuation [ Time Frame: Up to Day 49 ]
   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.
5. Pharmacokinetics (PK): Area Under The Plasma Concentration-time Curve From Time Of Administration To 8 Hours Postdose (AUC0-8) [ Time Frame: Days 1 and 7 ]
   Serial blood samples were collected at 0, 1, 1.5, 2, 2.5, 3, 4, 6, and 8 hours post-dose on Days 1 and 7.
6. PK: Maximum Plasma Concentration (Cmax) [ Time Frame: Days 1 and 7 ]
   Serial blood samples were collected at 0, 1, 1.5, 2, 2.5, 3, 4, 6, and 8 hours post-dose on Days 1 and 7.
7. PK: Time To Maximum Concentration (Tmax) [ Time Frame: Days 1 and 7 ]
   Serial blood samples were collected at 0, 1, 1.5, 2, 2.5, 3, 4, 6, and 8 hours post-dose on Days 1 and 7.
8. Change From Baseline In Bb Fragment Of Complement Factor B (Bb) At Day 15 [ Time Frame: Baseline, Day 15 ]

   Plasma Bb was measured by enzyme-linked immunosorbent assay (ELISA).

   Change from Baseline = Complement Bb on Day 15 - Baseline

9. Change From Baseline In Soluble Terminal Complement Complex (sC5b-9) At Day 15 [ Time Frame: Baseline, Day 15 ]

   Plasma sC5b-9 was measured by ELISA.

   Change from Baseline = sC5b-9 on Day 15 - Baseline sC5b-9

Eligibility Criteria

• Ages Eligible for Study: 16 Years to 65 Years (Child, Adult, Older Adult)
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Criteria

Key Inclusion Criteria:

• Must have had clinical diagnosis of C3G (C3 glomerulonephritis or dense deposit disease, the 2 types of C3G) or idiopathic IC-MPGN by renal biopsy for at least 3 months prior to dosing, with the pathologic diagnosis verified by a review of the renal biopsy by the study central pathologist
• C3 must have been <50% of the lower limit of normal
• C4 complement protein (C4) must have been >90% of the lower limit of normal
• Must have been willing to comply with study-specific vaccination requirements for Haemophilus influenzae, Streptococcus pneumoniae, and Neisseria meningitidis strains A, C, W, and Y
• Negative pregnancy test for females prior to dosing and throughout the study

Key Exclusion Criteria:

• History of a major organ transplant (for example, heart, lung, kidney, liver) or hematopoietic stem cell/marrow transplant. Individuals receiving renal replacement therapy were also excluded
• Evidence of monoclonal gammopathy of unclear significance, infections, malignancy, autoimmune diseases, or other conditions to which C3G or IC-MPGN may have been secondary
• Estimated glomerular filtration rate (using Modification of Diet in Renal Disease equation) <45 milliliters/minute/1.73 square meters at the time of Screening or at any time over the preceding 4 weeks
• Receipt of eculizumab at any dose or interval within the past 75 days prior to dosing
• Use of tacrolimus or cyclosporine within 2 weeks of the first dose of danicopan
• History of febrile illness, a body temperature >38°Celsius, or other evidence of a clinically significant active infection, within 14 days prior to 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

Contacts and Locations

Locations

Australia

Clinical Trial Site

Melbourne, Australia

Belgium

Clinical Trial Site

Antwerpen, Belgium

Netherlands

Clinical Trial Site

Leiden, Netherlands

Sponsors and Collaborators

Alexion Pharmaceuticals

Achillion, a wholly owned subsidiary of Alexion

  Study Documents (Full-Text)

Documents provided by Alexion Pharmaceuticals:

Study Protocol  [PDF] June 9, 2017

Statistical Analysis Plan  [PDF] January 2, 2019

More Information

• Responsible Party: Alexion Pharmaceuticals
• ClinicalTrials.gov Identifier: NCT03124368
• Other Study ID Numbers: ACH471-201; 2016-003525-42 ( EudraCT Number )
• First Posted: April 21, 2017
• Results First Posted: July 13, 2021
• Last Update Posted: November 4, 2021
• Last Verified: October 2021

• Studies a U.S. FDA-regulated Drug Product: Yes
• Studies a U.S. FDA-regulated Device Product: No
• Product Manufactured in and Exported from the U.S.: Yes

Keywords provided by Alexion Pharmaceuticals:

factor D; FD; alternative pathway; complement mediated disease; idiopathic MPGN; MPGN Type I; MPGN Type II; MPGN Type III; Primary MPGN; MCGN; Mesangiocapillary Glomerulonephritis; C3 Glomerulopathy; C3G; Membranoproliferative Glomerulonephritis; C3GN; Dense Deposit Disease; DDD

Additional relevant MeSH terms:

Glomerulonephritis; Glomerulonephritis, Membranoproliferative; Nephritis; Kidney Diseases; Urologic Diseases; Immune System Diseases