ADVOCATE Trial

ADVOCATE Trial Design:

The phase 3 ADVOCATE trial compared a TAVNEOS® arm to an Active Control arm:^1,3
- 330 newly diagnosed or relapsing patients with GPA or MPA
- 52 weeks in a randomized, double-blind, double-dummy, active-controlled fashion
TAVNEOS® arm = TAVNEOS + rituximab, or cyclophosphamide (followed by azathioprine or mycophenolate mofetil^*)¹
Active Control arm = Prednisone taper + rituximab, or cyclophosphamide (followed by azathioprine or mycophenolate mofetil^*)¹

^*If azathioprine not tolerated.¹

Primary endpoints:

The trial sought to evaluate whether patients could achieve remission^† at Week 26 and sustained remission^‡ at Week 52.¹

^†Remission was defined as achieving a BVAS of 0 and not taking glucocorticoids for treatment of GPA or MPA within 4 weeks prior to Week 26.

^‡Sustained remission was defined as remission at Week 26 and Week 52 and not taking glucocorticoids for treatment of GPA or MPA for 4 weeks before Week 52, without relapse^¶between Week 26 and Week 52.

^¶Relapse was defined as the occurrence of at least 1 major item, at least 3 non-major items, or 1 or 2 non-major items for at least 2 consecutive visits based on Birmingham Vasculitis Activity Score (BVAS) after a BVAS of 0 had been achieved.

Study Design Overview

Differences in glucocorticoid exposure were evaluated throughout the duration of the ADVOCATE trial⁴

^#Also received prednisone-matched placebo for 20 weeks.¹

^§Also received TAVNEOS®-matched placebo twice daily for 52 weeks.¹

Glucocorticoids were allowed as pre-medication for rituximab to reduce hypersensitivity reactions, taper after glucocorticoids given during the Screening period, treatment of persistent vasculitis, worsening of vasculitis, or relapses, as well as for non-vasculitis reasons such as adrenal insufficiency.¹

PR3 = proteinase 3; MPO = myeloperoxidase.

Baseline Characteristics

Patients in ADVOCATE presented with a wide spectrum of clinical manifestations^1,3

The treatment arms were well balanced regarding baseline demographics and disease characteristics of patients:^1,3

Patients had active disease: At least one major item (62.4%), or at least three minor items (87.3%), or at least two renal items of proteinuria and hematuria (35.5%) in the BVAS^2,3,||

Baseline Characteristics² (N = 330)	n (%)
Newly diagnosed	229 (69.4%)
Relapsed	101 (30.6%)
GPA	181 (54.8%)
MPA	149 (45.2%)
Anti-PR3	142 (43.0%)
Anti-MPO	188 (57.0%)
Renal and Other (RBC Casts and/or Glomerulonephritis) involvement	268 (81.2%)
General organ involvement	225 (68.2%)
Ear/nose/throat involvement	144 (43.6%)
Chest involvement	142 (43%)
Rituximab Standard Therapy base	214 (64.8%)
IV/oral cyclophosphamide Standard Therapy base	116 (35.2%)

The baseline mean eGFR (mL/min/1.73 m²) was 45.6 in the Active Control arm and 44.6 in the TAVNEOS® arm²

Patients’ mean duration of GPA and MPA was 21.54 months²

ACR/VF guidelines define “active” as new, persistent, or worsening signs and/or symptoms attributed to GPA or MPA, and not related to prior damage⁶

ACR/VF guidelines define “severe” as life- or organ-threatening vasculitis, inclusive of multi-organ and localized symptoms⁶

^||Birmingham Vasculitis Activity Score (BVAS) provides a standardized measure of current and recent systemic vasculitis disease activity. There are 56 clinical features, grouped into 9 organ systems plus an “Other” category, each of which is given a numerical value according to its perceived clinical relevance as decided by expert consensus.^2,7

ACR = American College of Rheumatology; VF = Vasculitis Foundation; eGFR = estimated glomerular filtration rate; GPA = granulomatosis with polyangiitis; IV = intravenous; MPA = microscopic polyangiitis.

See oral dosing for TAVNEOS®

Important safety information

Contraindications

Serious hypersensitivity to avacopan or to any of the excipients.

Warnings and Precautions

Hepatotoxicity: Serious cases of hepatic injury have been observed in patients taking TAVNEOS, including life-threatening events. Obtain liver test panel before initiating TAVNEOS, every 4 weeks after start of therapy for 6 months and as clinically indicated thereafter. Monitor patients closely for hepatic adverse reactions, and consider pausing or discontinuing treatment as clinically indicated (refer to section 5.1 of the Prescribing Information). TAVNEOS is not recommended for patients with active, untreated, and/or uncontrolled chronic liver disease (e.g., chronic active hepatitis B, untreated hepatitis C, uncontrolled autoimmune hepatitis) and cirrhosis. Consider the risks and benefits before administering this drug to a patient with liver disease.

Serious Hypersensitivity Reactions: Cases of angioedema occurred in a clinical trial, including 1 serious event requiring hospitalization. Discontinue immediately if angioedema occurs and manage accordingly. TAVNEOS must not be readministered unless another cause has been established.

Hepatitis B Virus (HBV) Reactivation: Hepatitis B reactivation, including life-threatening hepatitis B, was observed in the clinical program. Screen patients for HBV. For patients with evidence of prior infection, consult with physicians with expertise in HBV and monitor during TAVNEOS therapy and for 6 months following. If patients develop HBV reactivation, immediately discontinue TAVNEOS and concomitant therapies associated with HBV reactivation, and consult with experts before resuming.

Serious Infections: Serious infections, including fatal infections, have been reported in patients receiving TAVNEOS. The most common serious infections reported in the TAVNEOS group were pneumonia and urinary tract infections. Avoid use of TAVNEOS in patients with active, serious infection, including localized infections. Consider the risks and benefits before initiating TAVNEOS in patients with chronic infection, at increased risk of infection, or who have been to places where certain infections are common.

Adverse Reactions

The most common adverse reactions (≥5% of patients and higher in the TAVNEOS group vs. prednisone group) were nausea, headache, hypertension, diarrhea, vomiting, rash, fatigue, upper abdominal pain, dizziness, blood creatinine increased, and paresthesia.

Drug Interactions

Avoid co-administration of TAVNEOS with strong and moderate CYP3A4 enzyme inducers. Reduce TAVNEOS dose when co-administered with strong CYP3A4 enzyme inhibitors to 30 mg once daily. Consider dose reduction of CYP3A4 substrates when coadministering TAVNEOS. Co-administration of avacopan and 40 mg simvastatin increases the systemic exposure of simvastatin. While taking TAVNEOS, limit simvastatin dosage to 10 mg daily (or 20 mg daily for patients who have previously tolerated simvastatin 80 mg daily for at least one year without evidence of muscle toxicity). Consult the concomitant CYP3A4 substrate product information when considering administration of such products together with TAVNEOS.

TAVNEOS is available as a 10 mg capsule.

INDICATION

TAVNEOS (avacopan) is indicated as an adjunctive treatment of adult patients with severe active anti-neutrophil cytoplasmic autoantibody (ANCA)-associated vasculitis (granulomatosis with polyangiitis [GPA] and microscopic polyangiitis [MPA]) in combination with standard therapy including glucocorticoids. TAVNEOS does not eliminate glucocorticoid use.

Please see Full Prescribing Information and Medication Guide for TAVNEOS.

To report a suspected adverse event, call 1-833-828-6367. You may report to the FDA directly by visiting www.fda.gov/medwatchor calling 1-800-332-1088.