Controlled Trial Evaluating Avacopan in C3 Glomerulopathy

C3 glomerulopathy (C3G) is characterized by evidence of alternative complement activation
based on C3 deposition in the glomeruli. There are two forms of the disease: dense deposit
disease (DDD) and C3 glomerulonephritis (C3GN). There is no approved treatment for patients
with C3G.

This is a randomized, double blind, placebo controlled Phase 2 study to evaluate the safety
and efficacy of avacopan (CCX168) in patients with C3G. The primary objective is to evaluate
the efficacy of avacopan compared to placebo based on histologic changes in kidney biopsies
taken before and during treatment.

Inclusion Criteria:

1. Biopsy-proven C3G, either DDD or C3GN, with or without a renal transplant, and with
the following observations upon renal biopsy taken within 12 weeks prior to screening
or during screening:

1. ≥2-levels of magnitude greater staining of C3 than any combination of IgG, IgM,
IgA, kappa and lambda light chains, and C1q by immunohistochemistry, and

2. evidence of proliferative glomerulonephritis (mesangial hypercellularity of
greater than 3 mesangial cells per mesangial area and/or endocapillary
hypercellularity defined as an increased number of cells within glomerular
capillary lumina, causing luminal narrowing) based on light microscopy, and

3. confirmation of the presence of electron dense deposits in the glomeruli on
electron microscopy corresponding with the C3 immunofluorescence positivity;

2. Male or female subjects, aged at least 18 years; where approved, adolescents (12-17
year old) may be enrolled; female subjects of childbearing potential (i.e., those who
have experienced menarche and who is not permanently sterile or postmenopausal,
defined as at least 12 consecutive months with no menses without an alternative
medical cause) may participate if adequate contraception is used during, and for at
least the three months after study completion; Male subjects with partners of
childbearing potential may participate in the study if they had a vasectomy at least 6
months prior to randomization or if adequate contraception is used during, and for at
least the 3 months after study completion; Adequate contraception is defined as
resulting in a failure rate of less than 1% per year (combined estrogen and
progestogen [oral, intravaginal, or transdermal], or progestogen-only hormonal
contraception (oral, injectable, or implantable), intra-uterine device, intra-uterine
hormone releasing system, bilateral tubal occlusion, vasectomized partner, or true
sexual abstinence, i.e., in line with the preferred and usual lifestyle of the
subject);

3. Willing and able to give written Informed Consent and to comply with the requirements
of the study protocol; written Assent and Informed Consent must be obtained from the
legal guardian in accordance with regional laws or regulations for subjects 12 to 17
years of age; and

4. Judged to be otherwise fit for the study by the Investigator, based on medical
history, physical examination, and clinical laboratory assessments. Subjects with
clinical laboratory values that are outside of normal limits (other than those
specified in the Exclusion Criteria) and/or with other abnormal clinical findings that
are judged by the Investigator not to be of clinical significance, may be entered into
the study.

Exclusion Criteria:

1. Pregnant or nursing;

2. Tubulointerstitial fibrosis appears to be more than 50% based on standard assessment
using trichrome staining of the renal biopsy;

3. Use of eculizumab or another anti-C5 antibody within 26 weeks prior to dosing;

4. Secondary C3 disease, e.g., infection-associated disease, or associated with another
systemic or autoimmune disease; presence of a monoclonal spike on serum or urine
protein electrophoresis or immunofixation assay;

5. Currently on dialysis or likely will require dialysis within 7 days after screening;

6. History or presence of any form of cancer within the 5 years prior to screening, with
the exception of excised basal cell or squamous cell carcinoma of the skin, or
carcinoma in situ such as cervical or breast carcinoma in situ that has been excised
or resected completely and is without evidence of local recurrence or metastasis;

7. Positive hepatitis B virus (HBV), hepatitis C virus (HCV), or human immunodeficiency
virus (HIV) viral screening test indicative of acute or chronic infection;

8. Evidence of tuberculosis based on interferon γ release assay (IGRA), tuberculin
purified protein derivative (PPD) skin test, or chest radiography done at screening or
within 6 weeks prior to screening;

9. WBC count less than 3500/μL, or neutrophil count less than 1500/μL, or lymphocyte
count less than 500/μL before start of dosing;

10. Evidence of hepatic disease; AST, ALT, alkaline phosphatase, or bilirubin >3 x the
upper limit of normal before start of dosing;

11. Currently using a strong inducer of the CYP3A4 enzyme, such as carbamazepine,
phenobarbital, phenytoin, rifampin, or St. John's wort;

12. Known hypersensitivity to avacopan or inactive ingredients of the avacopan capsules
(including gelatin, polyethylene glycol, or Cremophor) or inability to swallow the
capsules;

13. Participated in any clinical study of an investigational product within 30 days prior
to screening or within 5 half-lives after taking the last dose; and

14. History or presence of any medical condition or disease which, in the opinion of the
Investigator, may place the subject at unacceptable risk for study participation.