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

NCT03124368 | Completed Phase 2 Results FDA Drug

• 2 other identifiers: ACH471-2012016-003525-42
• Study Type: interventional
• Target: 6
• Locations: 3 countries
• Sites: 3

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.

Conditions

C3 Glomerulonephritis; Dense Deposit Disease; C3 Glomerulopathy; Immune Complex Mediated Membranoproliferative Glomerulonephritis; Membranoproliferative Glomerulonephritis Types I, II, and III

Keywords

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

Outcome Measures

Primary Outcomes (2)

• Change From Baseline In Serum C3 Complement Protein (C3) Levels On 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

  Baseline, Day 15

• Change From Baseline In Plasma Intact C3 Level On 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

  Baseline, Day 15

Secondary Outcomes (9)

• Change From Baseline In Total Complement Classical Pathway (CP) Activity On Day 14

  Baseline, Day 14

• Change From Baseline In Total Complement Alternative Pathway (AP) Functional Activity (AP Wieslab) On Day 15

  Baseline, Day 15

• Time To Achieving Peak Serum C3 Levels

  From The First Day Of Dosing through Day 14

• 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

  Up to Day 49

• Pharmacokinetics (PK): Area Under The Plasma Concentration-time Curve From Time Of Administration To 8 Hours Postdose (AUC0-8)

  Days 1 and 7

Study Arms (2)

Group 1: Danicopan 100 mg TID (Sentinel)

EXPERIMENTAL

All participants received 100 milligrams (mg) of danicopan three times per day (TID) during the Treatment Period.

Drug: Danicopan

Group 2: Danicopan up to 200 mg TID

EXPERIMENTAL

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

Interventions

Danicopan DRUG

Participants received study drug for 14 days (Treatment Period), followed by a taper over the next 7 days (Taper Period).

Also known as: ACH-4471, ACH4471, 4471, ACH-0144471, ALXN2040

Group 1: Danicopan 100 mg TID (Sentinel); Group 2: Danicopan up to 200 mg TID

Eligibility Criteria

• Age: 16 Years - 65 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Child (0-17), Adult (18-64), Older Adult (65+)

You may qualify if:

• 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

You may not qualify if:

• 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

Sponsors & Collaborators

• Alexion Pharmaceuticals, Inc.: lead
• Achillion, a wholly owned subsidiary of Alexion: collaborator

Study Sites (3)

Clinical Trial Site

Melbourne, Australia

Location

Clinical Trial Site

Antwerp, Belgium

Location

Clinical Trial Site

Leiden, Netherlands

Location

MeSH Terms

Conditions

Glomerulonephritis, Membranoproliferative

Interventions

danicopan

Condition Hierarchy (Ancestors)

Glomerulonephritis; Nephritis; Kidney Diseases; Urologic Diseases; Female Urogenital Diseases; Female Urogenital Diseases and Pregnancy Complications; Urogenital Diseases; Male Urogenital Diseases; Immune System Diseases

Limitations and Caveats

The sample size of the study was based on very limited clinical cases of C3G and IC-MPGN and the exploratory nature of this study to evaluate the effectiveness of danicopan. Plasma intact C3 values should be regarded with caution. Plasma intact C3 values were generated using a new multiplex assay method with limited historical experience, and internal studies have suggested this new assay is subject to unexplained experimental variation arising during sample preparation and handling.

Results Point of Contact

• Title: Alexion Pharmaceuticals Inc.
• Organization: Alexion Pharmaceuticals Inc.

clinicaltrials@alexion.com

855-752-2356

Publication Agreements

• PI is Sponsor Employee: No
• Restrictive Agreement: Yes

Study Design

• Study Type: interventional
• Phase: phase 2
• Allocation: NON RANDOMIZED
• Masking: NONE
• Purpose: BASIC SCIENCE
• Intervention Model: SEQUENTIAL
• Sponsor Type: INDUSTRY
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: April 12, 2017
• First Posted: April 21, 2017
• Study Start: August 9, 2017
• Primary Completion: December 21, 2018
• Study Completion: January 9, 2019
• Last Updated: November 4, 2021
• Results First Posted: July 13, 2021

Record last verified: 2021-10

Locations

BE (1); NL (1); AU (1)