Avacopan for antineutrophil cytoplasmic antibody–associated vasculitis

Approved indication: treatment of adults with antineutrophil cytoplasmic antibody (ANCA)–associated vasculitis (granulomatosis with polyangiitis and microscopic polyangiitis), in combination with a rituximab- or cyclophosphamide-based regimen
Tavneos (Seqirus)
10 mg capsules

Antineutrophil cytoplasmic antibody (ANCA)–associated vasculitis is characterised by the presence of antibodies that target neutrophils and can lead to multisystem autoimmune vasculitis of small blood vessels.¹ ANCA‑associated vasculitis can be categorised into 3 types: granulomatosis with polyangiitis (GPA), microscopic polyangiitis (MPA) and eosinophilic granulomatosis with polyangiitis (EGPA). Standard therapy consists of glucocorticoids (e.g. prednisone) and immunosuppressants (e.g. rituximab, cyclophosphamide).²

Avacopan is an orally administered small‑molecule selective complement C5a receptor antagonist. It reduces the pro-inflammatory effects of complement C5a such as neutrophil activation and release of lysosomal proteases and oxidative free radicals.³ Avacopan is approved for use as an alternative to glucocorticoids for the treatment of adults with ANCA‑associated vasculitis of the GPA and MPA types, in combination with a rituximab- or a cyclophosphamide-based treatment regimen.⁴

A phase 3 randomised controlled trial compared the efficacy of avacopan (30 mg twice daily for 52 weeks) with prednisone (60 mg daily, tapered to discontinuation by week 21), in combination with standard immunosuppressant treatment, in patients with ANCA‑associated vasculitis (n=331, mean age 61 years).⁵ Standard immunosuppressant treatment was either intravenous rituximab for 4 weeks or cyclophosphamide (intravenous or oral) for 13 to 14 weeks, followed by oral azathioprine from week 15. Disease remission was defined as a Birmingham Vasculitis Activity Score of zero and no administration of glucocorticoids within 4 weeks prior to week 26 of the study. Sustained remission was defined as remission at weeks 26 and 52 with no relapse in between, and no glucocorticoids within 4 weeks prior to week 52.⁵

The study reported that avacopan was statistically noninferior to prednisone in achieving remission; 72.3% of patients treated with avacopan achieved remission compared with 70.1% of patients treated with prednisone (estimated common difference 3.4%, 95% confidence interval [CI] −6.0 to 12.8%, p<0.001). Avacopan was superior to prednisone in sustaining remission at week 52; 65.7% of patients had sustained remission with avacopan compared with 54.9% with prednisone (estimated common difference 12.5%, 95% CI 2.6 to 22.3%, p<0.001). Glucocorticoids were used in both groups; the mean daily dose in the avacopan group was one-third of that in the prednisone group.⁵

The adverse effects that were more common in the avacopan group were nausea, diarrhoea, vomiting, upper abdominal pain, paraesthesia, fatigue, rash, headache, dizziness, increased serum creatinine and hypertension. The most common serious adverse effects were liver function abnormalities and pneumonia;⁶ the incidences of serious adverse events were similar between the avacopan and prednisone groups.⁵

A patient’s white blood cell count and liver enzymes should be checked prior to initiating avacopan and monitored throughout treatment.⁴ Treatment should be temporarily stopped if a patient has elevated liver enzymes, develops leukopenia, neutropenia or lymphopenia, or has a serious active infection that requires hospitalisation. The drug may be resumed upon normalisation of liver function tests or permanently stopped if elevated liver enzymes persist.⁶

Avacopan is a substrate of the cytochrome P450 (CYP) enzyme CYP3A4; therefore, concurrent administration of drugs that interact with this isoenzyme should be avoided where possible. Because of this interaction, patients should be advised to avoid consuming grapefruit or grapefruit juice while on treatment. As avacopan is also a weak CYP3A4 inhibitor, there is a potential for interaction with other drugs that are CYP3A4 substrates.⁶

Currently, there are no data on the effects of avacopan on fertility. It is not recommended for use during pregnancy (Therapeutic Goods Administration category D) and in women for whom pregnancy is possible, due to teratogenicity and other adverse pregnancy outcomes observed in animal studies. Animal studies have also shown that avacopan is likely to be secreted into breastmilk; no data are currently available on the effects of avacopan on the breastfed child.⁶

Dose adjustment is not needed in mild to moderate hepatic or renal impairment, but there are no safety data in patients with severe hepatic impairment or an estimated glomerular filtration rate below 15 mL/min/1.73 m². Caution should be taken when treating patients with hepatitis B, hepatitis C, human immunodeficiency virus or tuberculosis, because of a lack of data.⁶

In summary, avacopan may be used as an alternative treatment to glucocorticoids, in combination with standard immunosuppressive drugs, for adults with ANCA‑associated vasculitis.

This new drug comment was finalised on 12 August 2024.

🅃 manufacturer provided the AusPAR and the product information. The Transparency Score is explained in New drugs: transparency, Vol 37 No 1, Aust Prescr 2014;37:27.

At the time the comment was prepared, information about this drug was available on the websites of the Food and Drug Administration in the USA, the European Medicines Agency and the Therapeutic Goods Administration.

 

References

1. Jarrot PA, Kaplanski G. Pathogenesis of ANCA-associated vasculitis: An update. Autoimmun Rev 2016;15:704-13.
2. Almaani S, Fussner LA, Brodsky S, Meara AS, Jayne D. ANCA-Associated Vasculitis: An Update. J Clin Med 2021;10.
3. Bekker P, Dairaghi D, Seitz L, Leleti M, Wang Y, Ertl 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.
4. Therapeutic Goods Administration. Australian Public Assessment Report for Tavneos. Department of Health and Aged Care; 2023. [cited 2024 Jul 26]
5. Jayne DRW, Merkel PA, Schall TJ, Bekker P, Group AS. Avacopan for the Treatment of ANCA-Associated Vasculitis. N Engl J Med 2021;384:599-609.
6. Therapeutic Goods Administration. Australian Product Information - Tavneos (avacopan) capsules. Department of Health and Aged Care; 2024. [cited 2024 Aug 12]

 The new drug commentaries in Australian Prescriber are prepared by the editors and reviewed by the Editorial Advisory Committee. Some of the views expressed on newly approved products should be regarded as preliminary, as there may be limited published data at the time of publication, and little experience in Australia of their safety or efficacy. However, the Editorial Advisory Committee believes that comments made in good faith at an early stage may still be of value. Before new drugs are prescribed, the Committee believes it is important that more detailed information is obtained from the manufacturer's approved product information, a drug information centre or some other appropriate source.