IgA Nephropathy

• To assess the efficacy of fostamatinib administered orally for 24 weeks to subjects with IgA nephropathy, as measured by change in renal function and histology. • To investigate the safety and tolerability of fostamatinib administered orally for 24 weeks to subjects with IgA nephropathy.

Fostamatinib (R788)

100, 150mg(b.i.d.)

Primary Efficacy Endpoint:
• Mean change from Baseline (Visit 2) of proteinuria as measured by sPCR at 24 weeks (Visit 9)
Secondary Efficacy Endpoints:
• Mean change from pre-treatment to post-treatment in mesangial hypercellularity on renal biopsies.
• Percentage of subjects with ≥ 30% reduction in proteinuria from Baseline (Visit 2) at 24 weeks (Visit 9)
• Mean change from pre-treatment to post-treatment in endocapillary hypercellularity on renal biopsies.
• Mean change from pre-treatment to post-treatment in segmental or global glomerulosclerosis on renal biopsies.
• Mean change from pre-treatment to post-treatment in tubulointerstitial scarring on renal biopsies.
• Mean change from Baseline (Visit 2) of eGFR at 12 weeks (Visit 7).
• Mean change from Baseline (Visit 2) of eGFR at 24 weeks (Visit 9).
• Mean change from Baseline (Visit 2) of proteinuria at 12 weeks (Visit 7).
• Percentage of subjects with sPCR < 50 mg/mmol at 12 weeks (Visit 7).
• Mean change of haematuria (dipstick test) from Baseline (Visit 2) at 12 weeks (Visit 7).
• Mean change of haematuria (dipstick test) from Baseline (Visit 2) at 24 weeks (Visit 9).

Inclusion Criteria:
1. Signed informed consent prior to any study specific screening procedures.
2. Male or female between 18 to 70 years of age.
3. Females must be either post-menopausal for at least 1 year, surgically sterile, or, if of child-bearing potential, must not be pregnant or lactating. If sexually active, must agree to use an acceptable method of birth control throughout the duration of the trial and for 30 days following the last dose.
4. A pre-study renal biopsy obtained within 180 days prior to Baseline (Visit 2) will be reviewed by the central panel of renal pathologists to ensure subjects meet the following histologic entry criteria:
• Consistent with IgA nephropathy
• Mesangial hypercellularity score of ≥ 0.5 (M1) and/or presence of endocapillary hypercellularity (E1) on renal biopsy (using the Oxford Classification)
• < 50% of cortical area involved by tubular atrophy or interstitial fibrosis (T0 or T1)
• < 50% glomerular crescents
5. Treatment with an ACEi and/or an ARB for at least 90 days at the maximum approved (or tolerated) dose prior to Screening (Visit 1b). Subjects should remain on the same dose of ACEi or ARB during the treatment period (Visits 2-9).
6. Proteinuria > 1 gm/day or sPCR > 100 mg/mmol at diagnosis of IgA nephropathy or prior to initiation of angiotensin blockade.
7 Proteinuria > 0.50 gm/day (sPCR > 50 mg/mmol) at Screening (Visit 1b).
8. Blood pressure controlled to ≤ 130/80 with angiotensin blockade with or without other anti-hypertensive agents. Subjects should be taking the maximum approved (or tolerated) dose of an ACEi or ARB before an additional anti-hypertensive agent is added. If additional anti-hypertensive therapy is required, other agents (beta-blockers, calcium channel blockers, or diuretics) may be added. Patients may be reassessed if BP < 140/90, but > 130/80.
9. Otherwise in stable health as determined by the Investigator based on medical history and laboratory tests during the screening period. See Exclusion Criteria for specific exclusions.
10. In the Investigator’s opinion, has the ability to understand the nature of the study and any hazards of participation and to communicate satisfactorily with the Investigator.

1. History of or active, clinically significant, respiratory, gastrointestinal (including pancreatitis), hepatic, neurological, psychiatric, musculoskeletal, genitourinary, dermatological, or other disorder that, in the Investigator’s opinion, could affect the conduct of the study or the absorption, metabolism or excretion of the study drug.
2. Have had any major cardiovascular event within the 180 days prior to randomisation, including but not limited to: myocardial infarction, unstable angina, cerebrovascular accident, pulmonary embolism, or New York Heart Association Class III or IV heart failure.
3. Diagnosis or history suggestive of Henoch-Schonlein purpura.
4. Estimated glomerular filtration rate (eGFR) < 30 mL/min/1.73 m2 (using the MDRDequation) at the time of Screening (Visit 1b) and Baseline (Visit 2).
5. A 50% decrease in eGFR from most recent pre-study clinic visit to Visit 1b.
6. Greater than 3.5g proteinuria/ 24h (sPCR > 350 mg/mmol) at Baseline (Visit 2).
7 An absolute neutrophil count of < 1,500/μL, Hgb < 9 g/L, ALT or AST of > 1.5x ULN, total bilirubin > 2.0 mg/dL. The Investigator may reassess these laboratory abnormalities within 30 days after Screening (Visit 1b) and/or Baseline (Visit 2).
8. Acute gastrointestinal symptoms (eg, nausea, vomiting, diarrhoea) at Baseline (Visit 2). The subject may be reassessed after full recovery from the acute gastrointestinal illness.
9. Active bacterial or parasitic infections, including tuberculosis.
10. Positive serologic test for hepatitis B or hepatitis C (subjects may be included if confirmed hepatitis C recombinant immunoblot assay negative or hepatitis C virus RNA negative [qualitative]), or subjects with suspected human immunodeficiency virus (HIV).
11. Prior or current use of corticosteroids (unless for non-renal indications).
12. Prior or current use of immunosuppressive agents including cyclosporine, cyclophosphamide, azathioprine, mycophenylate mofetil, Rituximab (or other anti-B cell therapies).
13. Have a significant infection, an acute infection such as influenza, or who are known to have an active inflammatory process at the time of Screening (Visit 1b) or Baseline (Visit 2). The subject may be reassessed after recovery from an acute infection.
14. Currently enrolled in an investigational drug or device study or have used an investigational drug or device within 30 days or 5 half-lives (whichever is longer) of Screening (Visit 1a).
15. Are unable or unwilling to follow instructions, including participation in all study assessments and visits.
16. Have a history of alcohol or substance abuse that, in the judgment of the Investigator, may impair or risk the subject’s full participation in the study.
17. Have a condition or be in a situation that the Investigator feels may put the subject at significant risk, may confound the study results, or may interfere significantly with the subject’s participation in the study.
18. Have a known allergy and/or sensitivity to the study drug or its excipients.