Complement-Mediated Kidney Disease

To evaluate the safety and tolerability of ADX-038

Injection

An siRNA duplex oligonucleotide conjugated to GalNAc

220

300 mg /1.5 mL

Incidence and severity of treatment-emergent adverse
event (TEAEs)

To be eligible to participate in this study, participants must meet all the inclusion criteria below.
1. Age ≥18 years at the time of signing informed consent.
2. Has provided written informed consent and any authorizations required by local law and
be willing to comply with all study requirements for the duration of the study.
3. Has a mean eGFR ≥30 mL/min/1.73m2 (using the creatinine-based the Chronic Kidney
Disease Epidemiology Collaboration [CKD-EPI] formula 2021 for adults) from both
Screening Visits (Inker 2021).
4. Has clinical evidence of active kidney disease based on mean UPCR ≥0.8 g/g from
two 24-hour urine collections within the Screening Period closest to Day 1 attributed to the
kidney disease of the cohort in which they are enrolling, per the Investigator’s opinion.
5. Has been on supportive care including a stable dosing regimen of ACEi or ARB at the
maximally tolerated dose (per Investigator’s judgment and local practice and not
exceeding the locally approved maximal daily dose) for at least 90 days before Day 1 and
the dosing regimen is expected to remain stable for the duration of the study. Participants
with allergies or intolerance to ACEi/ARB are eligible, but the Investigator must
document the reason for not taking these medications.
6. If taking diuretics, other antihypertensive therapy, and/or renoprotective medications
(including mineralocorticoid antagonists, SGLT2 inhibitors, sparsentan and endothelin
receptor antagonists), the doses should be stable for at least 90 days prior to Day 1 and
the dosing regimen is expected to remain stable for the duration of the study.
7. The following vaccine requirements need to be completed at least 2 weeks prior to Day 1:
a. Completed vaccination schedule for Streptococcus pneumoniae, Haemophilus
influenzae, and Neisseria meningitidis serotypes ACWY with appropriate boosters
per local guidance.
b. Completed at least 2 doses of a 3-dose vaccine series for Neisseria meningitidis
serotype B (MenB). The third dose may be administered during the study.
8. Participants agree to receive vaccine boosters for MenACWY, MenB, Streptococcus
pneumoniae, and Haemophilus influenzae as appropriate per local guidance during the
study.
9. Women of childbearing potential must have 2 negative serum pregnancy tests during
Screening and a negative urine pregnancy test on Day 1 before study drug administration
and must agree to use highly effective contraceptive methods if engaged in sexual
activity of childbearing potential (refer to Section 13.2) from the time of signing the
informed consent form (ICF) until the EOS Visit or 28 days after the last dose of study
drug, whichever is longer.
10. Women must not be breastfeeding.
11. Fertile men must agree to use acceptable contraceptive methods if engaged in sexual
activity with a partner of childbearing potential (refer to Section 13.2) from the time of
signing the ICF until the EOS Visit or 28 days after the last dose of study drug,
whichever is longer.
12. Fertile men must agree not to donate sperm after study drug administration on Day 1 until
the EOS Visit or 28 days after the last dose of study drug, whichever is longer.

Participants who meet any of the following criteria will be excluded from the study.
1. Has a known or suspected hereditary or acquired complement deficiency.
2. Received a kidney transplant or has received renal replacement therapy for >72 hours
consecutively at any time.
3. Has a history of a major solid organ transplant (eg, heart, lung, liver) or has received a
hematopoetic stem cell/bone marrow transplant.
4. Has other significant kidney diseases (outside of cohort in which they are enrolling) that
would interfere with interpretation of the study.
5. Has presence of rapidly progressive glomerular nephritis or acute kidney injury.
6. Has a history of recurrent invasive infections caused by encapsulated bacteria
(eg, meningococcus or pneumococcus).
7. Has a major concurrent comorbidity, including but not limited to advanced cardiac
disease (eg, New York Heart Association class IV) or severe pulmonary disease
(eg, severe pulmonary hypertension [World Health Organization class IV]). Any major
cardiovascular event in the past year, including a myocardial infarction or a
cerebrovascular event requiring hospitalization.
8. Has an active malignancy and/or a history of malignancy in the past 5 years, with the
exception of completely excised non-melanoma skin cancer or low-grade cervical
intraepithelial neoplasia and with no evidence of recurrence for ≥3 years prior to Day 1.
9. Has a history of splenectomy.
10. Has evidence of monoclonal gammopathy of unclear significance (MGUS), infections,
malignancy, autoimmune diseases, or other conditions to which C3G, IC-MPGN, or IgAN
is secondary. This includes a diagnosis of Henoch-Schonlein Purpura (IgA vasculitis).
11. For IgAN, has taken chronic systemic corticosteroids at any dose (including budesonide)
within 3 months prior to Screening, with the exception of corticosteroids used for <7 days
for an acute reason >2 weeks prior to Day 1. For C3G or IC-MPGN, has taken systemic
corticosteroids >15 mg/day prednisone or equivalent for >7 days within 2 weeks prior to
Day 1.
12. Received complement inhibitor treatments (including eculizumab or ravulizumab) within
6 months prior to Day 1 or are considered to be nonresponders to complement inhibitor
treatments.
13. Is currently using any systemic immunosuppressant biologics or broad
immunosuppressants such as cyclophosphamide, JAK inhibitors, or CNI within 3 months
prior to Day 1 with the exception of those permitted (eg, MMF for C3GN or IC-MPGN).
Use of longer-acting biologics such as rituximab or obinutuzumab within 6 months prior
to Day 1 is also exclusionary.
14. Has a history of active tuberculosis (TB [treated or untreated]), untreated latent TB
infection (LTBI), or evidence of active TB during Screening (preferred testing is by
Quantiferon when available and per local regulations). Note: Participants with history of
treated latent TB are permitted to enroll if they have evidence of completion of treatment
and they meet all other eligibility criteria.
15. Has an active systemic viral (including COVID-19), bacterial, or fungal infection within
14 days prior to Day 1.
16. Has known HIV infection (per participant history and/or medical records) or a positive
HIV test during Screening.
17. Has a positive serology test for hepatitis B surface antigen (HBsAg) or positive serology
test for hepatitis C virus (HCV) with a detectable RNA concentration during Screening.
18. Has liver dysfunction as indicated by any of the following abnormal LFTs during Screening:
a. Alanine aminotransferase (ALT) or aspartate aminotransferase (AST) >1.5 × upper
limit of normal (ULN).
b. Total bilirubin >1.5 × ULN (unless due to Gilbert’s syndrome).
19. Has a systolic blood pressure >160 mmHg or a diastolic blood pressure >90 mmHg on
Day 1.
20. Has any of the following laboratory parameters during Screening:
a. White blood cell count >1.2 × ULN or <0.8 × lower limit of normal (LLN).
b. Hemoglobin <9 mg/dL.
c. Platelet count <100,000/μL.
21. Participated in an interventional drug study within the last 90 days or 5 half-lives,
whichever is longer, prior to Screening.
22. Donated any blood products (>200 mL) within 30 days prior to Screening.
23. Received a blood transfusion within 90 days prior to Screening.
24. Received prior treatment with another CFB RNA/DNA-based therapy.
25. Has any other significant medical conditions that, in the opinion of the Investigator,
would make the participant unsuitable for inclusion in the study, or could interfere with
study assessments or put the participant at risk for experiencing significant adverse
effects during the study.