Avacopan (CCX168)

Avacopan (CCX168) is an experimental oral therapy that ChemoCentryx is developing to treat anti-neutrophil cytoplasmic autoantibody (ANCA) vasculitis.

ChemoCentryx holds all rights to avacopan in the U.S. Its partner, Vifor Pharma, will have marketing rights for the treatment in the rest of the world should it be approved.

ChemoCentryx submitted a new drug application (NDA) to the U.S. Food and Drug Administration (FDA) for avacopan in September 2020. A response is expected from the FDA by June.

Avacopan also is under review with the European Medicines Agency (EMA) for the treatment of granulomatosis with polyangiitis (GPA) and microscopic polyangiitis (MPA), two specific types of ANCA vasculitis. The EMA is expected to respond by the second half of 2021.

What is ANCA vasculitis?

ANCA vasculitis is an autoimmune disease in which a type of immune cell called neutrophils become overactive and attack small blood vessels in the body. This causes inflammation and damage.

In normal inflammation, the complement system (a family of proteins that play an important role in the immune response) is activated. This signals immune cells to come to the area where there is an injury or infection. Immune cells defend the body against invasion by infectious agents and promote healing.

In ANCA vasculitis, the complement system can be activated by mistake. This means that immune cells “are called” to areas where there is no injury or infection. The accumulation of inflammatory signals damages the blood vessels and tissues where this occurs.

One important signaling protein of the complement system is C5a. Released by cells in distress, it binds to C5a receptors (C5aR) on immune cells and on cells that line blood vessels. When bound to its receptor, C5a signals to immune cells to come to that site. 

How avacopan works

Avacopan contains a small molecule that binds to C5a preventing it from binding to its receptor. This reduces the number of immune cells that wrongly rush to sites. This way, avacopan should reduce inflammation and damage to small blood vessels in ANCA vasculitis.

Avacopan in clinical trials

Researchers tested avacopan in two Phase 2 clinical trials, called CLEAR (NCT01363388) and CLASSIC (NCT02222155), and a Phase 3 trial (NCT02994927) called ADVOCATE.

The goal of the CLEAR trial was to determine whether avacopan would allow people with ANCA vasculitis to lower the dose of steroids they use to control their disease. ANCA vasculitis patients can be on high doses of steroids to decrease inflammation. However, this can have serious side effects. Steroids also suppress a healthy immune response, leaving patients vulnerable to infections.

During the trial, researchers randomly assigned 67 patients to one of three treatment regimens over 12 weeks: a high dose of the corticosteroid prednisone plus a placebo, avacopan plus a lower dose of prednisone, or avacopan plus a placebo. All participants also received standard doses of cyclophosphamide or Rituxan (rituximab), which also are medications used to treat ANCA vasculitis. Researchers measured the effectiveness of avacopan by assessing changes in the Birmingham vasculitis activity score (BVAS), a measure of vasculitis.

Results were published in the Journal of the American Society of Nephrology in April 2017. They showed that avacopan without prednisone was as effective as a standard therapy that included prednisone.

The main goal of the CLASSIC trial was to test the safety of adding avacopan to the standard-care regimen used for ANCA vasculitis. This includes prednisone plus either cyclophosphamide or Rituxan. Researchers randomly assigned patients to a high dose of avacopan plus standard of care, a low dose of avacopan plus standard care, or a placebo plus standard care.

ChemoCentryx reported that the combination of avacopan and the standard regimen was safe.

The Phase 3 ADVOCATE trial randomly assigned 331 people with ANCA vasculitis to either avacopan or prednisone in combination with the standard care for 52 weeks.

ChemoCentryx reported that the study met both of its primary goals: disease remission at 26 weeks and sustained remission at 52 weeks (as determined by changes in BVAS from the study’s start to week 26 or 52).

Avacopan was not worse statistically than the current standard care. Of patients receiving avacopan treatment, 72.3% achieved remission at 26 weeks. This percentage was 70.1% in patients receiving standard care (control group). Sustained remission at 52 weeks occurred in 65.7% of the avacopan-treated group versus 54.9% in the control group, which was a significant improvement.

Additional benefits in patients who received avacopan included a reduction in glucocorticoid-related toxicity, significant improvement in kidney function in those with kidney disease, and improvements in health-related quality of life. Researchers reported serious adverse side effects in fewer patients in the avacopan group (42%) than in the standard care group (45%). Most adverse events were related to ANCA vasculitis and were similar to rates in previous trials.

Additional information

The FDA granted avacopan orphan drug status, a designation that helps speed the approval process for medicines in development to treat rare diseases.

The EMA added avacopan to its priority medicines, or PRIME, initiative list. The initiative is aimed at accelerating regulatory approval of therapies addressing unmet medical needs. The EMA also granted avacopan orphan drug designation for the treatment of GPA and MPA.


Last updated: Jan. 13, 2021


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