Atacicept in Subjects with IgA Nephropathy (ORIGIN and ORIGIN 3)

Overview

Sponsor-declared trial summary

Key facts

Sponsor

Vera Therapeutics Inc.

Participant type

Patients

Age range

18-64 years, 65+ years

Gender

Male and Female

Therapeutic area

Diseases [C] - Pathological Conditions, Signs and Symptoms [C23]

Trial duration

15 Sep 2021 → ongoing

Decision date (initial)

2023-05-31

Transition trial

Yes

Low-intervention

No

Rare-disease indication

No

Vulnerable population

Yes

Funding sources

Vera Therapeutics, Inc.

External identifiers

EU CT number

2023-503772-24-00

EudraCT number

2020-004892-41

WHO UTN

U1111-1287-7816

ClinicalTrials.gov

NCT04716231

Trial design

CTIS Part I — objectives, methods, condition coding

Main objective

Scope: Pharmacodynamic, Dose response, Efficacy, Pharmacokinetic, Therapy, Safety

Phase 2b and Phase 3: Evaluate the effect of atacicept compared to placebo on change in proteinuria in adult subjects with IgAN

Secondary objectives 11

1. Phase 2b_01. Evaluate the effect of atacicept compared to placebo on change in proteinuria in adult subjects with IgAN
2. Phase 2b_02. Evaluate the effect of atacicept on change in proteinuria in adult subjects with IgAN
3. Phase 2b_03. Evaluate the effect of atacicept on rate of change in estimated glomerular filtration rate (eGFR)
4. Phase 2b_04. Evaluate the effect of atacicept on change in serum immunoglobulin levels, complement levels and on serum Gd-IgA1 levels
5. Phase 2b_05. Evaluate the safety and tolerability of atacicept
6. Phase 2b_06. Evaluate serum PK of atacicept
7. Phase 3_01. Evaluate the effect of atacicept compared to placebo on annualized rate of change in estimated glomerular filtration rate (eGFR)
8. Phase 3_02. Evaluate the effect of atacicept compared to placebo on change in Gd-IgA1
9. Phase 3_04. Evaluate the effect of atacicept compared to placebo on achieving hematuria resolution
10. Phase 3_05. Evaluate the effect of atacicept compared to placebo on time from randomization to first occurrence of composite kidney failure endpoint event
11. Phase 3_09. Evaluate the safety and tolerability of atacicept

Conditions and MedDRA coding

IgA Nephropathy

Regulatory references

Scientific advice from competent authorities

European Medicines Agency, Food And Drug Administration

Plan to share IPD

No

Eligibility criteria

Principal inclusion / exclusion criteria as submitted by sponsor

Inclusion criteria 16

1. Phase 2b_01. Must have the ability to understand and sign a written informed consent form, which must be obtained prior to initiation of study assessments
2. Phase 2b_02. Adult male or female of ≥18 years of age, or as per country specific legally or nationally recognized adult age, who provide written informed consent prior to performing any study assessments. For the Czech Republic an age limit of ≤70 also applies
3. Phase 2b_03. Diagnosis of IgAN as demonstrated by renal biopsy conducted within 10 years of the Screening Visit
4. Phase 2b_04. Total urine protein excretion > 0.75g per 24-hour or UPCR > 0.75 mg/mg based on a 24-hour urine sample during the Screening Period
5. Phase 2b_05. eGFR ≥ 30 mL/min/1.73 m2 at screening as per the Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) equation
6. Phase 2b_06. On a stable prescribed regimen of RAASi for at least 12 weeks that is at the maximum labeled or tolerated dose at screening. • The subject is eligible if they do not tolerate RAASi, provided their management of IgAN is SoC according to local guidelines. This must be documented by the Investigator.
7. Phase 2b_07. Systolic blood pressure ≤150 mmHg and diastolic blood pressure ≤90 mmHg at screening
8. Phase 2b_08. A female is eligible if she is not pregnant (i.e., after a confirmed menstrual period, a negative serum pregnancy test at screening and negative urine pregnancy test at Day 1), not breastfeeding (for at least 3 months prior to screening), and at least one of the following conditions applies: • Is not a woman of childbearing potential (WOCBP). OR • Is a WOCBP who agrees to use a highly effective contraceptive method (i.e., has a failure rate of less than 1% per year), as listed in Appendix 2, at least 7 days prior to randomization through 175 days after the last dose of study drug. See Appendix 2 for further details.
9. Phase 3_01. Must have the ability to understand and sign a written informed consent form, which must be obtained prior to initiation of study assessments
10. Phase 3_02. Adult male or female of ≥18 years of age, or as per country specific legally or nationally recognized adult age, who provide written informed consent prior to performing any study assessments
11. Phase 3_03. Diagnosis of IgAN as demonstrated by renal biopsy conducted within 10 years of the Screening Visit
12. Phase 3_04. Total urine protein excretion ≥1.0 g per 24-hour or urine protein to creatinine ratio (UPCR) ≥1.0 mg/mg based on a 24-hour urine sample during the Screening Period
13. Phase 3_05. eGFR ≥ 30 mL/min/1.73 m2 at screening as per the Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) equation
14. Phase 3_06. On a stable prescribed regimen of RASi (ACEi or ARB) for at least 12 weeks that is at the maximum labeled or tolerated dose at screening and from screening to study Day 1 • The subject is eligible if they do not tolerate RASi, provided their management of IgAN is standard of care (SoC) per local practice. This intolerance must be documented by the Investigator and discussed with the Medical Monitor.
15. Phase 3_07. Systolic blood pressure ≤150 mmHg and diastolic blood pressure ≤90 mmHg at screening
16. Phase 3_08. A female is eligible if she is not pregnant (i.e., after a confirmed menstrual period, a negative serum pregnancy test at screening and negative urine pregnancy test at Day 1), not breastfeeding (for at least 3 months prior to screening), and at least one of the following conditions applies: • Is not a woman of childbearing potential (WOCBP). OR • Is a WOCBP who agrees to use a highly effective contraceptive method (i.e., has a failure rate of less than 1% per year), as listed in Appendix 2, at least 7 days prior to randomization through 175 days after the last dose of study drug. See Appendix 2 for further details.

Exclusion criteria 48

1. Phase 2b_01. IgAN secondary to another condition (e.g., liver cirrhosis), or other causes of mesangial IgA deposition including IgA vasculitis (i.e., Henoch-Schonlein purpura), SLE, dermatitis herpetiformis, ankylosing spondylitis
2. Phase 2b_18. History of malignancy (hematologic or solid tumor) within 5 years prior to Screening Visit, except adequately treated basal cell or squamous cell carcinomas of the skin (no more than 3 lesions requiring treatment in lifetime) or carcinoma in situ/cervical intraepithelial neoplasia of the uterine cervix. *For Germany only the following criteria apply: History of malignancy within the past 5 years prior to Screening (except for adequately treated basal cell carcinoma or non-metastatic squamous cell carcinoma of the skin or cervical carcinoma in situ, with no evidence of recurrence).
3. Phase 2b_19. Known hypersensitivity to atacicept or any component of the formulated atacicept
4. Phase 2b_02. Evidence of rapidly progressive glomerulonephritis (loss of ≥ 50% of eGFR within 3 months of screening
5. Phase 2b_20. Major surgery within 6 weeks prior to the Screening Visit or planned/expected major surgery during the study period
6. Phase 2b_21. Clinically significant history of alcohol or drug abuse in the 1 year prior to the Screening Visit as per Investigator opinion
7. Phase 2b_22. Unwillingness or lack of capacity to follow all study procedures
8. Phase 2b_23. Treatment with other investigational agents within the last 4 weeks or 5 half-lives, whichever is longer, prior to the Screening Visit.
9. Phase 2b_03. Evidence of nephrotic syndrome within 6 months of screening (serum albumin < 30g/L in association with UPCR >3.5 mg/mg
10. Phase 2b_04. Total urine protein excretion ≥ 5g per 24-hour or urine protein to creatinine ratio (UPCR) ≥ 5 mg/mg based on a 24-hour urine sample during Screening
11. Phase 2b_05. Renal or other organ transplantation prior to, or expected during, the study with the exception of corneal transplants
12. Phase 2b_10. Clinically significant or predefined abnormalities per central laboratory tests, at the Screening Visit, meeting any of the criteria below: • serum IgG below 7 g/L • aspartate aminotransferase, alanine aminotransferase or alkaline phosphatase level > 2.5 × upper limit of normal (ULN) or total bilirubin >1.5 x ULN. i. If subject has a known history of Gilberts (history of isolated increase in total bilirubin without increase in liver transaminases), contact the Medical Monitor for further discussion. • For The Czech Republic only, the following criteria also apply: - hemoglobin <10 g/100 mL in men and hemoglobin <9 g/100 mL in women - platelets <100,000/mm3
13. Phase 2b_06. Concomitant chronic renal disease in addition to IgAN (e.g., diabetic nephropathy, primary focal segmental glomerulosclerosis (FSGS), membranous nephropathy, C3 glomerulopathy, lupus nephritis)
14. Phase 2b_07. Uncontrolled diabetes, defined as hemoglobin-A1c (HbA1c) >7.5% at screening
15. Phase 2b_08. History of tuberculosis (TB), untreated latent TB infection (LTBI), or evidence of active TB determined by a positive Quantiferon test at the Screening Visit.
16. Phase 2b_09. Prohibited medications: • Use of systemic corticosteroids or immunosuppressive medications (e.g., MMF, azathioprine, cyclophosphamide, hydroxychloroquine) for the treatment of IgAN within 3 months prior to screening or expected use during the study. • For non-IgAN indications (e.g., gout flare, exacerbation of asthma, severe rash, etc): • Within 3 months prior to randomization: Use of systemic corticosteroids or immunosuppressive medications for > 1 week or 0.5 mg/kg/day prednisolone or equivalent • Use of B-cell–directed biologic therapies including blisibimod, belimumab, rituximab, ocrelizumab for any period of time • Use of other biologics (e.g., anti-TNF, abatacept, anti-IL-6) and investigational biologics
17. Phase 3_01. Participation in the Phase 2b (Parts A and B) study or any previous treatment with atacicept.
18. Phase 3_02. IgAN secondary to another condition (e.g., liver cirrhosis), or other causes of mesangial IgA deposition including IgA vasculitis (i.e., Henoch-Schonlein purpura), systemic lupus erythematosus (SLE), dermatitis herpetiformis, ankylosing spondylitis
19. Phase 3_03. Evidence of rapidly progressive glomerulonephritis (loss of ≥ 50% of eGFR within 3 months of screening)
20. Phase 3_04. Total urine protein excretion ≥5g per 24-hour or urine protein to creatinine ratio (UPCR) ≥5 mg/mg based on a 24-hour urine sample during the Screening Period
21. Phase 3_05. Evidence of nephrotic syndrome within 6 months of screening (serum albumin <3.0 g/dL in association with UPCR >3.5 mg/mg)
22. Phase 3_06. Renal or other organ transplantation prior to, or expected during, the study, with the exception of corneal transplants
23. Phase 2b_11. Administration of live and live-attenuated vaccinations within 30 days prior to randomization
24. Phase 3_07. Concomitant chronic renal disease in addition to IgAN (e.g., diabetic nephropathy, primary focal segmental glomerulosclerosis (FSGS), membranous nephropathy, C3 glomerulopathy, lupus nephritis)
25. Phase 2b_12. History or current diagnosis of any demyelinating disease such as, but not restricted to, multiple sclerosis (MS) or optic neuritis (ON)
26. Phase 2b_13. Patients with history of unstable angina, Class III and IV congestive heart failure and/or clinically significant arrhythmia, as judged by the Investigator.
27. Phase 2b_14. Any condition, including any uncontrolled disease state other than IgAN, that in the opinion of the Investigator or the Sponsor/designee constitutes an inappropriate risk or a contraindication for participation in the study or that could interfere with the study objectives, conduct or evaluation
28. Phase 2b_15. Active clinically significant viral, bacterial or fungal infection, or any major episode of infection requiring hospitalization or treatment with parenteral anti-infectives within 4 weeks prior to, or during the Screening Visit, or completion of oral anti-infectives within 2 weeks prior to, or during the Screening Visit or a history of recurrent infections (i.e., 3 or more of the same type of infection in a 12-month rolling period). Vaginal candidiasis, onychomycosis and genital or oral herpes simplex virus considered by the Investigator to be sufficiently controlled are not exclusionary. *For Germany only, the following criteria also apply: Specifically for COVID-19: Evidence of positive test for SARS-CoV-2, by PCR, at the Screening Visit; Subjects with a previous COVID-19 infection may be included provided the PCR test is negative for SARS-CoV-2 and they do not have chronic symptoms as a result of COVID-19. COVID-19 testing may be performed at local lab, per site/local guidelines.
29. Phase 2b_16. History of acute or chronic infection with human immunodeficiency virus, hepatitis C virus, or hepatitis B virus. Positive hepatitis B surface antigen (HBsAg): Subjects who are HBsAg negative and hepatitis B core antibody (HBcAb) positive with no detectable hepatitis B virus (HBV) DNA are eligible but will require monthly HBV DNA monitoring through safety follow-up.
30. Phase 2b_17. History of splenectomy
31. Phase 3_08. Uncontrolled diabetes, defined as hemoglobin-A1c (HbA1c) >7.5% at screening
32. Phase 3_09. History of tuberculosis (TB), untreated latent TB infection (LTBI), or evidence of active TB determined by a positive Quantiferon test at the Screening Visit. If the subject is undergoing current treatment for LTBI, they must have received at least 4 continuous weeks of an appropriate LTBI treatment prior to the Screening Visit without evidence of re-exposure to be eligible for this study. If on LTBI treatment at the Screening Visit, the subject will be expected to complete an appropriate LTBI treatment regimen to remain in the trial. • Subjects with current household contacts with active TB will be excluded unless prophylaxis treatment has been completed, and evidence that household contacts have completed treatment is provided. • Indeterminate Quantiferon tests may be repeated once by the same test and will be considered positive if retest results are positive or indeterminate.
33. Phase 3_10. Prohibited medications: • Use of systemic corticosteroids (including oral budesonide) for the treatment of IgAN within 6 months prior to screening, from screening to Day 1 or expected use during the study. - For glucocorticosteroids (GCS), “Systemic” is defined as oral, rectal or injectable (intravenous or intramuscular) routes of administration. Other routes of administration are allowed, including intra-articular, inhaled, topical, ophthalmic, otic and intranasal. • For non-IgAN indications (e.g., gout flare, exacerbation of asthma, severe rash, etc.): - Within 12 weeks prior to randomization: Use of systemic corticosteroids or immunosuppressive medications for >1 week or average dose >0.5 mg/kg/day prednisolone or equivalent • Immunosuppressive medications (e.g., MMF, azathioprine, cyclophosphamide, hydroxychloroquine) for the treatment of IgAN within 12 weeks prior to screening, from screening to Day 1 or expected use during the study. • Use of traditional Chinese medications and/or Ayurvedic medications for IgAN within 12 weeks prior to screening, from screening to Day 1, or during the study period. - Including but not limited to: Lei Gong Teng, Tripterygium Wilfordii Hook F, Caulis sinomenii, and Sinomenium acutum. Any other medications used to treat IgAN that are not listed should be discussed with the Medical Monitor. • Use of B-cell–directed biologic therapies including but not limited to belimumab, rituximab, ocrelizumab for any period of time • Use of other biologics (e.g., anti-TNF, abatacept, anti-IL-6) and investigational biologics for any period of time • Use of endothelin receptor antagonists (ERAs) for any period of time • Use of complement inhibitors including but not limited to iptacopan for any period of time
34. Phase 3_11. Clinically significant or predefined abnormalities per central laboratory tests, at the Screening Visit, meeting any of the criteria below: • serum IgG below 7 g/L • aspartate aminotransferase, alanine aminotransferase or alkaline phosphatase level > 2.5 × upper limit of normal (ULN) or total bilirubin >1.5 x ULN. i. If subject has a known history of Gilberts (history of isolated increase in total bilirubin without increase in liver transaminases), contact the Medical Monitor for further discussion. • hemoglobin <10 g/100 mL in men and hemoglobin <9 g/100 mL in women • platelets <100 10^9/L
35. Phase 3_12. Administration of live and live-attenuated vaccinations within 30 days prior to randomization
36. Phase 3_13. History or current diagnosis of any demyelinating disease such as, but not restricted to, multiple sclerosis (MS) or optic neuritis (ON)
37. Phase 3_14. Patients with history of unstable angina, Class III and IV congestive heart failure and/or clinically significant arrhythmia, as judged by the Investigator.
38. Phase 3_15. Any condition, including any uncontrolled disease state other than IgAN, that in the opinion of the Investigator or the Sponsor/designee constitutes an inappropriate risk or a contraindication for participation in the study or that could interfere with the study objectives, conduct or evaluation
39. Phase 3_16. Active clinically significant viral, bacterial or fungal infection, or any major episode of infection requiring hospitalization or treatment with parenteral anti-infectives within 4 weeks prior to, or during the Screening Visit, or completion of oral anti-infectives within 2 weeks prior to, or during the Screening Visit or a history of recurrent infections (i.e., 3 or more of the same type of infection in a 12-month rolling period). Vaginal candidiasis, onychomycosis and genital or oral herpes simplex virus considered by the Investigator to be sufficiently controlled are not exclusionary. Specifically for COVID-19: Evidence of positive test for SARS-CoV-2, by PCR, at the Screening Visit; Subjects with a previous COVID-19 infection may be included provided the PCR test is negative for SARS-CoV-2 and they do not have chronic symptoms as a result of COVID-19. COVID-19 testing may be performed at local lab, per site/local guidelines.
40. Phase 3_17. History of acute or chronic infection with human immunodeficiency virus, or hepatitis B virus. • Positive hepatitis B surface antigen (HBsAg) are excluded • Subjects who are HBsAg negative, hepatitis B core antibody (HBcAb) positive, hepatitis B surface antibody (HBsAb) positive, and with no detectable hepatitis B virus (HBV) DNA are eligible but will require monthly HBV DNA monitoring through safety follow-up
41. Phase 3_18. Subjects with positive hepatitis C (HCV) RNA are excluded, however, subjects who are HCV antibody positive with no detectable HCV RNA at least 24 weeks after completion of antiviral therapy are eligible.
42. Phase 3_19. History of splenectomy
43. Phase 3_20. History of malignancy within the past 5 years prior to Screening (except for adequately treated basal cell carcinoma or non-metastatic squamous cell carcinoma of the skin or cervical carcinoma in situ, with no evidence of recurrence).
44. Phase 3_21. Known hypersensitivity to atacicept or any component of the formulated atacicept
45. Phase 3_22. Major surgery within 6 weeks prior to the Screening Visit or planned/expected major surgery during the study period (including the Safety FU Period) • Major surgery often involves opening one of the major body cavities (abdomen, chest, and skull) and/or use of general anesthesia. Types of surgery that have the highest risk include heart or lung, liver, abdomen, or major operations on the bones and joints (for example, hip replacement)
46. Phase 3_23. Clinically significant history of alcohol or drug abuse in the 1 year prior to the Screening Visit as per Investigator opinion
47. Phase 3_24. Unwillingness or lack of capacity to follow all study procedures
48. Phase 3_25. Treatment with other investigational agents within the last 4 weeks or 5 half-lives, whichever is longer, prior to the Screening Visit.

Endpoints

Primary and secondary outcome measures (English text)

Primary endpoints 2

1. Phase 2b_01. Urine protein to creatinine ratio (UPCR) week 24. Phase 3_01. Urine protein to creatinine ratio (UPCR) week 36
2. Phase 3_01. Urine protein to creatinine ratio (UPCR) week 36

Secondary endpoints 2

1. Phase 2b_01. Urine protein to creatinine ratio (UPCR) week 36. Phase 3_01. Annualized Rate of change in eGFR (ie., annualized eGFR total slope) week 104
2. Phase 3_01. Annualized Rate of change in eGFR (ie., annualized eGFR total slope) week 104

Investigational products

Investigational medicinal products (IMPs), comparators, placebo, auxiliary

Test 3

Placebo 1

Auxiliary 2

Sponsors and contacts

Sponsor organisations, regulatory contacts, third parties

Vera Therapeutics Inc.

Sponsor organisation

Vera Therapeutics Inc.

Address

2000 Sierra Point Parkway Suite 1200

City

Brisbane

Postcode

94005-1806

Country

United States

Scientific contact point

Organisation

Vera Therapeutics Inc.

Contact name

Regulatory

Public contact point

Organisation

Vera Therapeutics Inc.

Contact name

Regulatory

Third parties 6

Locations

13 EU/EEA countries · 35 investigational sites

By country

Investigational sites

Country notifications

Trial-start, recruitment-start, end and early-termination notifications submitted per Member State

Results and documents

Annex IV summary of results, Annex V layperson summary, and all documents registered in CTIS for this trial

Documents 247 files

Public protocol annexes, IB summaries, regulatory submissions and post-authorisation documents registered in CTIS.

Application history

23 submissions — initial application plus substantial / non-substantial modifications