Tavneos: New Drug for ANCA-Associated Vasculitis

Highlights

Tavneos (avacopan) is a new drug indicated as an adjunctive treatment of adult patients with severe active antineutrophil 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.

Tavneos is approved by the U.S. Food and Drug Administration (FDA) in October 2021.

In Europe, Tavneos, approved in January 2022, is used in combination with rituximab or cyclophosphamide in the treatment of adult patients with severe active granulomatosis with polyangiitis or microscopic polyangiitis.

Tavneos is developed by ChemoCentryx.

For U.S. patients, an annual course of treatment for ANCA-associated vasculitis with Tavneos costs approximately $180,000.

According to industry forecasts, annual sales of Tavneos will cross the $600 million mark by 2026.

 

What Is ANCA-Associated Vasculitis

Vasculitis is a group of diseases characterized by the presence of inflammatory white blood cells in the walls of blood vessels, causing reactive damage to the latter. Both loss of vessel integrity, resulting in bleeding, and disruption of its lumen can cause ischemia and necrosis of tissues downstream of the bloodstream. Vasculitis can be either primary or secondary to another disease. Vasculitis is often serious and requires immediate treatment. The exact pathogenetic mechanisms remain unknown.

The classification of non-infectious vasculitis is predominantly based on the caliber of the affected vessels, although there are some forms of vasculitis that do not involve any one predominant vascular size. Thus, in the case of small vessels, vasculitis may be associated with antineutrophil cytoplasmic antibodies (ANCA, ANCA) — autoantibodies against antigens in the cytoplasm of neutrophil granulocytes and monocytes: for example, against myeloperoxidase (MPO-ANCA) or proteinase 3 (PR3-ANCA). In turn, ANCA-associated vasculitis is subdivided into the following major clinicopathological variants, all of which are necrotizing:

• Microscopic polyangiitis (MPA). Predominantly affects the capillaries, venules or arterioles (small and medium-sized arteries may be involved), most often manifests with necrotizing glomerulonephritis and/or pulmonary capillaritis, granulomatous inflammation is usually absent, ANCA is present in more than 90% of cases.

• Granulomatosis with polyangiitis (GPA), previously known as Wegener’s granulomatosis (WG). Predominantly affects small and medium-sized vessels (capillaries, venules, arterioles, arteries, veins), characterized by typical granulomatous inflammation of the upper and lower airways, necrotizing mildly immune glomerulonephritis, ANCA present in more than 80% of cases.

• Eosinophilic granulomatosis with polyangiitis (EGPA, Churg–Strauss syndrome), formerly known as allergic granulomatosis. Predominantly affects small and medium-sized vessels, characterized by eosinophilic saturation, patients often present with rhinosinusitis, asthma and marked peripheral blood eosinophilia; ANCA present in about 40% of cases.

Therapy of ANCA-associated vasculitis involves administration of immunosuppressants (cyclophosphamide, rituximab, methotrexate, mycophenolate mofetil) with high doses of glucocorticoids, use of plasmapheresis, kidney transplantation. Following initiation of treatment, up to one-third of patients relapse within 6–18 months and half relapse within 3–5 years. A serious problem is mortality, reaching up to 11%–16% in the first year after diagnosis; the reason lies in glucocorticoids, which open the gates to potentially lethal infections and contribute to the progressive damage of internal organs. It is the prolonged use of glucocorticoids that is responsible for 60% of deaths in ANCA-associated vasculitis.

In December 2017, Nucala (mepolizumab), a monoclonal antibody against interleukin 5 (IL-5) by GlaxoSmithKline, added adult patients with eosinophilic granulomatosis with polyangiitis.

 

Tavneos: Mechanism of Action of Avacopan

Avacopan (CCX168) is an oral small-molecule selective blocker of complement component 5a receptor 1 (C5aR1, CD88) that inhibits C5a-mediated neutrophil activation and migration.

Protein fragment C5a, which is a product of cleavage of component 5 (C5) of the complement system, acts as a powerful mediator of inflammation: through promotion of complement activation, formation of membrane attack complex (MAC), engagement of cells of the innate immune system, and release of histamine.

The role of activation of the alternative complement pathway in the pathogenesis of ANCA-associated vasculitis is as follows. Neutrophils primed by infection or proinflammatory cytokines release properdin, which activates the alternative complement cascade, leading to the cleavage of C5 into C5a and C5b. The latter combines with C6-9 to form MAC, whereas C5a binds to C5a receptors expressed on the surface of neutrophils and other cells. When C5a binds to C5aR1, a neutrophil-activating receptor, an amplification loop is created: the activation of the alternative complement cascade is enhanced by the properdin released by neutrophils, resulting in the generation of more C5a that contributes to additional neutrophil activation. The latter process not only causes severe necrotizing inflammation of the vessel wall, but also leads to the expression of myeloperoxidase (MPO) and proteinase 3 (PR3) on the surface of neutrophils, thereby increasing MPO-ANCA and PR3-ANCA autoantibody binding, which is manifested by further disease progression. C5a also directly activates vascular endothelial cells, promoting their retraction and increased permeability, which is represented by tissue edema.

Importantly, avacopan, which suppresses C5aR1, does not affect the complement component 5a receptor 2 (C5aR2, C5L2), a neutrophil-inhibitory receptor whose degradation is associated with, for example, worsening acute lung injury, aggravation of inflammation in contact dermatitis, exacerbation of ANCA-associated vasculitis.

The highly selective blockade of C5a activity means that avacopan — unlike drugs such as Soliris (eculizumab) or Ultomiris (ravulizumab), which Alexion Pharmaceuticals, acquired by AstraZeneca, invented and which block C5 cleavage — does not affect the C5b fragment and MAC formation. Otherwise, there would be a risk of developing life-threatening acute infections caused by encapsulated bacteria like meningococcus; that is, appropriate pre-vaccination against meningococcus is not required.

The rights to market avacopan in the United States belong to ChemoCentryx itself, while outside of them it is owned by Vifor Fresenius Medical Care Renal Pharma (VFMCRP) within the Vifor Pharma Group, which in mid-December 2021 was intended to buy by Australia’s CSL for 11.7 billion dollars. In Japan, the drug is promoted by the local Kissei Pharmaceutical.

 

Tavneos: Efficacy and Safety of Avacopan in Treatment of ANCA-Associated Vasculitis

The ADVOCATE (NCT02994927) phase 3 (randomized, double-blind, active-controlled, multicenter, international) clinical trial invited adult patients (n=331) with ASCA-associated vasculitis (granulomatosis with polyangiitis or microscopic polyangiitis), newly diagnosed or relapsed, with the presence of autoantibodies against MPO or PR3.

Participants were given experimental avacopan (30 mg twice daily) or prednisone (for 20 weeks, 60 mg daily with gradual dose reduction to zero). Both groups received either intravenous rituximab or cyclophosphamide (intravenous or oral) followed by oral azathioprine (or, if the latter was intolerant, mycophenolate mofetil).

In the case of worsening or relapsing of vasculitis, patients may have received maintenance therapy with intravenous and/or oral glucocorticoids.

Two primary points of treatment efficacy were established: remission of the disease after 26 weeks of therapy and sustained remission of the disease after 52 weeks of therapy.

Remission was defined as a Birmingham Vasculitis Activity Score (BVAS) of zero and no need for glucocorticoids for at least the four preceding weeks. Sustained remission implied remission at weeks 26 and 52 with no relapse during this period.

Remission was achieved in 72.3% of patients in the avacopan group — versus 70.1% in the prednisone group: estimated common difference 3.4% (95% CI: −6.0 to 12.8), p<0.001 for non-inferiority, p=0.24 for superiority.

Sustained remission was recorded for 65.7% of subjects in the avacopan group — vs. 54.9% among those receiving standard treatment: estimated common difference 12.5% (95% CI: 2.6 to 22.3), p<0.001 for non-inferiority, p=0.007 for superiority.

In terms of the therapeutic efficacy of avacopan in the task of achieving sustained remission among individual subgroups of subjects, the results are as follows:

• newly diagnosed disease: 60.9% of patients in the avacopan group went into sustained remission of the disease — versus 57.9% in the control group
• recurrent disease: 76.5% — 48.0%
• granulomatosis with polyangiitis: 61.5% — 57.8%
• microscopic polyangiitis: 70.7% — 51.4%
• presence of antibodies against MPO: 70.2% — 53.2%
• presence of antibodies against PR3: 59.7% — 57.1%
• background therapy with rituximab: 71.0% — 56.1%
• background therapy with cyclophosphamide: 55.9% — 52.6%.

10.1% of patients in the avacopan group experienced a relapse during treatment, compared to 21.0% in the prednisone group. Administration of Tavneos reduced the risk of ANCA-associated vasculitis relapse by 54% relative to prednisone: hazard ratio (HR) 0.46 (95% CI: 0.25 to 0.84).

Noted benefits of Tavneos in the treatment of ANCA-associated vasculitis compared with standard prednisone therapy include:

• Significant attenuation of glucocorticoid toxicity, according to the glucocorticoid toxicity index (GTI 2.0): at week 26 of treatment, the cumulative worsening score (GTI-CWS) was 39.7 — versus 56.6 in the control group (p=0.0002), the aggregate improvement score (GTI-AIS) was 11.2 — vs. 23.4 (p=0.0082), and a statistically significant reduction in the rate of glucocorticoid-related adverse events (in 66.3% of patients versus 80.5%).

• Significant improvement in renal function in patients with their disease, according to the mean change in estimated glomerular filtration rate (eGFR) [mL/min/1.73 m²]: after 26 weeks of treatment, this index increased by 5.8 — vs. 2.9 in the control group (p=0.0413), after 52 weeks by 7.3 — vs. 4.1 (p=0.0259).

• Significant improvement in health-related quality of life according to the SF-36 and EQ-5D-5L questionnaires.

Common adverse reactions to avacopan use included nausea (in 24% of patients — versus 21% in the prednisone group), headache (21% vs. 14%), hypertension (18% vs. 18%), diarrhea (15% vs. 15%), vomiting (15% vs. 13%), rash (11% vs. 8%), fatigue (10% vs. 9%).

Serious adverse reactions reported more frequently in the Tavneos group than in the prednisone group included pneumonia (in 4.8% of patients —versus 3.7%), granulomatosis with polyangiitis (3.0% vs. 0.6%), acute kidney injury (1.8% vs. 0.6%), and urinary tract infection (1.8% vs. 1.2%).

Administration of Tavneos may be accompanied by hepatotoxicity (periodic monitoring is recommended), serious hypersensitivity reactions (one case of serious angioedema has been reported), reactivation of viral hepatitis B, and serious infections.

 

Avacopan for ANCA-Associated Vasculitis: Expert Comments

During the discussion of Tavneos’s New Drug Application (NDA), the FDA advisory committee was divided, with one-half of the experts confirming the efficacy of avacopan and the other half expressing doubts.

Yes, avacopan demonstrated superiority over prednisone in the task of reaching sustained remission after 52 weeks of treatment for ANCA-associated vasculitis. However, according to the subgroup analysis, this superiority was true only for those who received background induction therapy with rituximab; no significant difference with prednisone was reported among those receiving cyclophosphamide. Although the results of the subgroup analysis should be interpreted with caution because they are often characterized by low precision and considerable uncertainty, this inconsistency raises concerns about the strength of the evidence for the effectiveness of avacopan.

The BVAS analysis performed by the Investigator did not confirm the superiority of avacopan over standard treatment on either of the two primary efficacy endpoints. Superiority was shown only in an analysis performed by an Adjudication Committee that relied on a different attribution of persistent vasculitis. The discrepancy underscores the lack of reliability of the demonstrated effectiveness of avacopan.

Because both the avacopan and prednisone groups received background treatment with rituximab or cyclophosphamide (although the usefulness of glucocorticoids in addition to the latter is not well understood), it cannot be stated with certainty that remission was due to avacopan rather than rituximab or cyclophosphamide.

Since 87% of patients in the avacopan group also received glucocorticoids (for the reasons outlined in the trial design), the assessment of non-inferiority was actually a comparison between avacopan with a lower dose of glucocorticoids and a higher dose of glucocorticoids.

Finally, the increased use of glucocorticoids in the prednisone group compared with the avacopan group was limited to the first 20 weeks of the study. Therefore, the differences in glucocorticoid doses used from week 0 to week 26 between the prednisone group and the avacopan group may be an artifact of the study design rather than a reflection of better control of disease activity in the avacopan group.

Avacopan showed no impressive advantage over prednisone on secondary efficacy endpoints including urine albumin to creatinine ratio, eGFR, need for dialysis, and Vasculitis Damage Index (VDI).

Again, prior phase 2 clinical trials have not documented additional evidence of benefit for treatment of ANCA-associated vasculitis with avacopan without concomitant glucocorticoids.

 

Avacopan: What’s Next

ChemoCentryx continues to study the applicability of avacopan in the treatment of C3 glomerulopathy (C3G) and hydradenitis suppurativa (HS; inverse acne). However, the treatment of these pathologies has not proven to be particularly effective at this stage of the clinical trials of avacopan.

Thus, the ACCOLADE (NCT03301467) phase 2 clinical trial testing avacopan in the treatment of C3 glomerulopathy (in the form of dense deposit disease [DDD] or C3 glomerulonephritis [C3GN]) ended, strictly speaking, unsuccessfully. Despite achieving a target delta of 35% compared with placebo in terms of assessing disease activity by renal biopsy, the large variability in patient responses did not allow for a statistically significant difference. Secondary endpoints, including those assessing renal function (eGFR, proteinuria, fibrosis), were successful, but they can only be considered exploratory. However, given that, first, no other drug has yet improved renal function in C3 glomerulopathy, second, the progressive nature of this disease leads to renal failure, and third, no approved treatment for this condition has yet been proposed, ChemoCentryx intends to discuss with the FDA the future of avacopan for C3 glomerulopathy.

The AURORA (NCT03852472) phase 2 clinical trial, which evaluated avacopan in the treatment of hydradenitis suppurativa, ended unsuccessfully because the experimental treatment could not statistically significantly diverge from placebo in terms of clinical response. Nevertheless, ChemoCentryx has planned a phase 3 clinical trial that will invite severe patients (Hurley stage III), as higher-dose avacopan worked on this population. Again, there is something to fight for, as only Humira (adalimumab), a tumor necrosis factor (TNF) blocker, is approved to treat hydradenitis suppurativa, bringing AbbVie over $1 billion a year in revenue in this indication.

Along the way, ChemoCentryx is contemplating starting a clinical trial of avacopan for the treatment of lupus nephritis.

 

Extras

Tavneos (avacopan). Prescribing information. U.S. [PDF]

Avacopan for the treatment of ANCA-associated vasculitis. N Engl J Med. 2021 Feb 18;384(7):599-609. [source]

ChemoCentryx. Corporate presentation. January 2022. [PDF]

ChemoCentryx. Topline results of ACCOLADE trial of avacopan for C3 glomerulopathy (C3G). December 21, 2020. [PDF]

Avacopan. Multi-disciplinary review and evaluation. FDA CDER. October 12, 2018. [PDF]

ChemoCentryx. Avacopan for the treatment of anti-neutrophil cytoplasmic autoantibody (ANCA)-associated vasculitis. Presentation slides for Meeting of the Arthritis Advisory Committee. May 6, 2021. [PDF]

FDA. Avacopan for treatment of adult patients with anti‐neutrophil cytoplasmic autoantibody (ANCA) vasculitis. Overview of the clinical program. Presentation slides for Meeting of the Arthritis Advisory Committee. May 6, 2021. [PDF]

FDA. Avacopan for the treatment of adult patients with anti‐neutrophil cytoplasmic autoantibody (ANCA)‐associated vasculitis (granulomatosis with polyangiitis [GPA] and microscopic polyangiitis [MPA]). Opening remarks. Presentation slides for Meeting of the Arthritis Advisory Committee. May 6, 2021. [PDF]