AVACOPAN: A New Adjunctive Therapy for Antineutrophil Cytoplasmic Antibody-Associated Vasculitis : Cardiology in Review

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AVACOPAN: A New Adjunctive Therapy for Antineutrophil Cytoplasmic Antibody-Associated Vasculitis

Garg, Jasmine BA*; Frishman, William H. MD

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Cardiology in Review 31(1):p 3-6, January/February 2023. | DOI: 10.1097/CRD.0000000000000496
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Abstract

Avacopan (TAVNEOS, ChemoCentryx, San Carlos, California) is an orally administered, novel, targeted therapy that was approved by the United States Food and Drug Administration in October 2021 as an adjunctive treatment for patients with severe antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis. Specifically, avacopan is indicated for granulomatosis with polyangiitis and microscopic polyangiitis. Additionally, avacopan is currently in late-stage clinical development for the treatment of C3 glomerulopathy and hidradenitis suppurativa. Even though avacopan has only been approved as a supplemental medication, it provides a necessary advancement in treatment with current primary therapies possibly leading to serious adverse side effects. This article reviews the pharmacology and clinical manifestations, including pertinent scientific data, of avacopan.

CHEMISTRY AND PHARMACODYNAMIC PROFILE

Avacopan (Fig. 1) has a chemical name of (2R,3S)-2-[4- (acyclopentylamino)phenyl]-1-(2-fluoro-6-methylbenzoyl)-N-[4-methyl-3- (trifluoromethyl)phenyl]piperidine-3-carboxamide with a molecular formula of C33H35F4N3O2.1 This drug is a chiral molecule with 2 stereocenters and a pale crystalline solid that is considerably insoluble in water, but soluble in organic solvents.1

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FIGURE 1.:
Avacopan chemical structure.

Avacopan (CCX168) selectively inhibits the complement 5a receptor (CD88), thus blocking neutrophil chemoattraction, activation, and adhesion with an overall anti-inflammatory effect (Fig. 2).2 Although avacopan’s exact mechanism in ANCA-vasculitis has not been well established, it is presumed to work by blocking the proinflammatory complement system that is irregularly overstimulated in complement-driven autoimmune diseases such as ANCA-associated vasculitis. ANCA-associated vasculitis is a relatively rare group of disorders involving self-reactive antibodies that overstimulate the complement pathway and neutrophils, which causes inflammation of small blood vessels and has severe systemic manifestations.3 A novel aspect of avacopan is its precise selectivity of C5a receptor inhibition that still allows for the beneficial C5L2 receptor pathway to function normally.2 Avacopan also obstructs the anaphylatoxin C5a-induced upregulation of CD11b (integrin alpha M), but this mechanism has not been fully understood.2 Currently, first-line treatment includes immunosuppressants plus a high-dose corticosteroid. Although corticosteroids and immunosuppressants are effective in this disease, prolonged use of high-dose corticosteroids have several known harmful side effects, including a diminished quality of life, toxicity, and can lead to a relapsing course.4 Therefore, avacopan is a breakthrough in treatment for patients with vasculitis with the potential of living with a better quality of life.

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FIGURE 2.:
The Complement System with Avacopan (CCX168) point of intervention.2

PHARMACOKINETICS

Avacopan’s mean steady state plasma exposure is about 3466 ± 1921 ng × h/mL for AUC0-12hr and 349 ± 169 ng/mL for Cmax in patients with ANCA-vasculitis taking the recommended dosage.1 The drug’s steady state is achieved by 13 weeks and has a 4-fold accumulation.1 Avacopan is a well-absorbed drug that is highly affected by food intake.1 Ingesting a high-fat and high-caloric meal increases the AUC and Cmax by about 72% and 8%, respectively, and postpones the tmax from 2 to 6 hours.1 The volume of distribution of avacopan is approximated at 345 L and binds to plasma protein greater than 99.9%.1

After ingesting 30 mg of avacopan with food, the mean elimination half-life of avacopan was estimated at 97.6 hours with a total apparent body clearance of 16.3 L/h.1 Avacopan primarily undergoes hepatic first-pass metabolism by cytochrome P450 3A4. Therefore, CYP3A4 inducers such as rifampin decrease avacopan efficacy, whereas CYP3A4 inhibitors such as itraconazole increase avacopan exposure (Table 1).1 Hepatic metabolism of this drug forms a mono-hydroxylated circulating metabolite called M1 that has similar activity to avacopan on the C5a receptor.1 Mild to moderate hepatic impairment does not seem to affect the clearance of avacopan, and no adjustment of dosage is needed for these patients.1 After metabolism occurs, avacopan is primarily cleared by biliary excretion of the metabolites into the feces.1 ChemoCentryx is currently conducting a drug interaction study to further investigate the effects of CYP3A4 substrates and food on avacopan.

TABLE 1. - Clinical Study of the Pharmacokinetics of Avacopan and M1 in the Presence of Coadministered Drugs1
Coadministered Drug Regimen of Coadministered Drug Ratio (90% CI)*
Cmax AUC
Strong CYP3A4 inhibitor: itraconazole 200 mg once daily for 4 days Avacopan 1.87 (1.70, 2.06) 2.19 (2.00, 2.41)
M1 1.03 (0.95, 1.11) 1.19 (1.11, 1.28)
Strong CYP3A4 inducer: rifampin 600 mg once daily for 11 days Avacopan 0.21 (0.18, 0.25) 0.07 (0.06, 0.10)
M1 0.27 (0.23, 0.31) 0.07 (0.06, 0.09)
*Ratios for Cmax and AUC comparing coadministration of the medication with avacopan versus administration of avacopan alone.
CI indicates confidence interval; M1, mono-hydroxylated circulating metabolite.

CLINICAL TRIALS

The CLEAR trial was a randomized, double-blind, placebo-controlled phase II clinical trial with the primary objective of testing avacopan’s efficacy, and for the possibility of replacing glucocorticoids as the mainstay treatment.5 First, all patients were treated with 5 infusions of cyclophosphamide spread out from day 1 to week 12 followed by azathioprine from weeks 14 to 24, with a small group also treated with rituximab as well.5 Then 3 groups were created: placebo plus prednisone 60 mg (control group); avacopan 30 mg twice daily plus prednisone 20 mg; and avacopan 30 mg twice daily without prednisone.5 The primary end point or efficacy was designated if a group achieved a treatment response by week 12 (decrease in Birmingham Vasculitis Activity Score from baseline by at least 50%). Efficacy was seen in 70% of the control group, 86.4% in avacopan plus prednisone, and 81% of avacopan without prednisone. This clinical trial showed the substantial potential of avacopan and the need for additional studies for its efficacy, durability, and safety.

The Avacopan Development in Vasculitis to Obtain Corticosteroid Elimination and Therapeutic Efficacy (ADVOCATE) trial (2017–2019) was a randomized, double-blind, active controlled phase III clinical trial to test avacopan’s efficacy in sustaining remission in patients with ANCA-vasculitis when used concurrently with cyclophosphamide followed by azathioprine or in combination with rituximab.6,7 A total of 331 patients with ANCA-associated vasculitis were treated with either cyclophosphamide (followed by azathioprine) or rituximab, and then randomly assigned into 2 halves of Group A and B (Fig. 3). Group A (control group) included 164 patients who received avacopan-matched placebo twice daily for 52 weeks and a full starting dose of prednisone taper (60 mg per day to 0 per day over 20 weeks). Group B included 166 patients who received avacopan 30 mg twice daily for 52 weeks and prednisone-matched placebo for 20 weeks.

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FIGURE 3.:
ADVOCATE Trial screening, randomization and follow-up. Reprinted with permission from Massachusetts Medical Society from Jayne et al.6 Copyright Massachusetts Medical Society. All permission requests for this image should be made to the copyright holder.

Two primary end points of week 26 and week 52 were used to determine efficacy of avacopan with sustained remission of ANCA-vasculitis. Sustained remission for both end points was defined as a Birmingham Vasculitis Activity Score of 0 at week 26 and at week 52 with no glucocorticoid use from week 22 to week 26 and week 48 to week 52.6 In the avacopan group, remission was observed in 120 of 166 patients (72.3%) at week 26 and 109 of the 166 patients (65.7%), whereas in the prednisone group remission was at 70.1% at week 26 and 54.9% at week 52 (Table 2).6

TABLE 2. - ADVOCATE Trial Sustained Remission at Week 526
Prednisone (N = 164) n (%) TAVNEOS (N = 166) n (%) Estimate of Treatment Difference P*
Sustained Remission at Week 52 90 (54.9%) 109 (64.7%) 12.5%† 0.013
95% CI (46.9, 62.6)‡ (57.9, 72.8)‡ (2.6 22.3)§
*2-sided P value of Summary Score Test (Agresti 2013).
†Summary Score estimate of the common difference in remission rates (Agresti 2013) by using inverse-variance stratum weights.
‡Clopper and Pearson exact CI.
§Miettinen-Nurminen (Score) confidence limits for the common difference in remission rates.
CI, confidence interval; N, number of patients in the analysis population for the specified treatment group; n, number of patients with disease remission; %= 100*n/N.

Secondary end points were glucocorticoid-induced toxic effects graded by Glucocorticoid Toxicity Index (GTI) during the first 26 weeks, and a change in quality of life assessed by the EuroQoL Group 5-Dimensions 5-Level Questionnaire (EQ-5D-5L). As expected, the prednisone control group had an increased GTI and a decreased EQ-5D-5L score, indicating more glucocorticoid toxicity and decreased quality of life.6 This is consistent with prednisone and other glucocorticoids having worsening quality of life and increased risk for other morbidities.

This trial6 investigated whether avacopan could be an effective first-line treatment for ANCA-vasculitis not taken with prednisone. The avacopan group was neither noninferior nor superior to the prednisone taper group regarding remission at week 26 but demonstrated superiority to prednisone taper with sustained remission at week 52. For this study, noninferior was defined if at the first primary efficacy point, the lower bound of the 2-sided 95% confidence interval was greater than the noninferior margin of −0.20 and the control group disease remission rate was at least 40% at week 26 (avacopan fell in this category). A superiority test was positive if the lower bound of the 95% confidence interval was greater than 0.0, which avacopan passed for the secondary end point of week 52. This clinical trial was defined as a successful study since it passed the successful study requirement of avacopan treatment group achieving noninferior versus the control group. Importantly, the avacopan treatment group had a lower risk of relapse for vasculitis than the prednisone group, which is the key benefit of adding avacopan.5,6

Serious adverse events were observed to be 33% higher in group A than group B, which is consistent with glucocorticoids causing an increased risk of adverse effects and life-threatening events including infections, metabolic disorders, and even an increased risk of cardiac morbidity.5,8 This trial indicates that avacopan could be a potential breakthrough in the treatment of ANCA-associated vasculitis; however, longer trials are mandated with United States Food and Drug Administration approval to establish avacopan’s efficacy and safety as the first-line treatment.

ADVERSE EFFECTS

The most common serious adverse drug reactions of avacopan in comparison to prednisone were also assessed from the safety data in the ADVOCATE trial. Pneumonia was the most frequent adverse side effect that was reported in avacopan (4.8%) over prednisone (3.7%).1,6 Granulomatosis with polyangiitis, acute kidney injury, and urinary tract infections were other occurring adverse side effects in avacopan over prednisone.1,6 Common adverse reactions, higher in avacopan than prednisone, were reported in more than 5% of patients and included nausea, headache, hypertension, diarrhea, vomiting, rash, fatigue, upper abdominal pain, dizziness, and paresthesia.1,6 However, these were reported under a multitude of circumstances in a short period of time of the clinical trial, and may not represent clinical practice.

Hepatic-related adverse reactions were reported in 22 patients (13.3%) in the avacopan treatment group and 19 (11.6%) patients in the prednisone control group.1,6 In this trial, 7 patients in the avacopan treatment group and 2 patients in the prednisone control group had to discontinue the trial due to hepatobiliary adverse reactions.1,6 Since there were reported cases of severe hepatic dysfunction from taking avacopan, patients are recommended to obtain a liver panel before starting avacopan and every 4 weeks for the first 6 months of treatment at least, and a HBV serology test. Avacopan is contraindicated in patients with active and untreated hepatitis B, hepatitis C, autoimmune hepatitis, and cirrhosis.1,6 Angioedema was reported in 2 patients (1.2%) taking avacopan.1,6 Although this was a small portion of the patient population, hypersensitivity reactions such as angioedema should be monitored closely, as this could lead to hospitalization.

DOSING AND ADMINISTRATION

Avacopan comes as 10 mg pale yellow capsules with CCX168 printed in Black. The standard recommended dose of avacopan is 30 mg (three 10 mg capsules) twice daily in the morning and evening with food. This drug should be taken in whole without crushing or chewing the tablet.1 Patients are advised against doubling up on a dose of avacopan even if they miss a dose previously.1 Because avacopan is a CYP3A4 substrate, doses may have to be adjusted depending on drug interactions. For instance, the avacopan dose should be adjusted to only 30 mg once daily when using a CYP3A4 inhibitor such as itracanozole or clarithromycin.1 As mentioned previously, mild to moderate hepatic disease does not seem to affect dosing or administration of the drug, but severe hepatic impairment has yet to be tested. The cost of avacopan has a wholesale price of approximately $150,000 per patient per year.

CONCLUSION

In conclusion, avacopan is a remarkable adjunctive treatment option for patients suffering from ANCA-vasculitis that directly inhibits the overreactive neutrophil migration and activation while still allowing for other beneficial pathways of the complement system. Although it has not been approved for solo treatment, when combined with first-line treatment, it mitigates the need for a prolonged course of high-dose corticosteroids that come with extensive side effects and decreased quality of life. Moreover, avacopan was proven to lower the risk of relapse, which remains one of the main issues with a prolonged course of glucocorticoids. As a newer approved drug, longer trials are warranted to establish its durability and all the potential benefits. Additionally, further studies are indicated to test the potential of avacopan to treat other inflammatory disorders, such as C3 glomerulopathy and hidradenitis suppurativa.

REFERENCES

1. “Highlights of Prescribing Information. See Full Prescribing Information for TAVNEOS. Tavneos (Avacopan) Capsules, for Oral Use Initial U.S. Approval: 2021.” U.S. National Library of Medicine, National Institutes of Health. https://dailymed.nlm.nih.gov/ dailymed/medguide.cfm?setid=c93cbc0b-29a3-46a5-9c85-41815ea5cf4a. Accessed March 10, 2022.
2. Bekker P, Dairaghi D, Seitz L, et al. “Characterization of Pharmacologic and Pharmacokinetic Properties of CCX168, a Potent and Selective Orally Administered Complement 5A Receptor Inhibitor, Based on Preclinical Evaluation and Randomized Phase 1 Clinical Study.”. PLoS One. 2016;11:e0164646.
3. Yates M, Watts R. ANCA-associated vasculitis. Clin Med (Lond). 2017;17:60–64.
4. Jayne D. Complement inhibition in ANCA vasculitis. Nephrol Ther. 2019;15:409–412.
5. Harigai M, Takada H. Avacopan, a Selective C5a Receptor Antagonist, for Anti-Neutrophil Cytoplasmic Antibody-Associated Vasculitis. Mod Rheumatol. 2022;32:475–483.
6. Jayne DRW, Merkel PA, Schall TJ, et al. Avacopan for the treatment of ANCA-associated vasculitis. N Engl J Med. 2021; 384:599–609. https://www.nejm.org/doi/full/10.1056/nejmoa2023386. Accessed March 15, 2022.
7. ChemoCentryx. A Phase 3 Clinical Trial of CCX168 (Avacopan) in Patients with ANCA-Associated Vasculitis (ADVOCATE). ClinicalTrials.gov. 2016. https://clinicaltrials.gov/ct2/show/NCT02994927.
8. Osman M, Cohen Tervaert JW, Pagnoux C. Avacopan for the treatment of ANCA-associated vasculitis. Expert Rev Clin Immunol. 2021;17:717–726.
Keywords:

avacopan; C5a receptor antagonist; ANCA-vasculitis

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