Avacopan (CCX168) is an experimental therapy being developed by ChemoCyntryx to treat anti-neutrophil cytoplasmic autoantibody (ANCA) vasculitis.
ChemoCyntryx holds all rights to avacopan in the U.S., while its partner, Vifor Pharma, will have marketing rights for avacopan in the rest of the world should it be approved.
What is ANCA vasculitis?
ANCA vasculitis is an autoimmune disease in which the immune system mistakenly attacks a type of white blood cell that are called neutrophils. As a result of such attacks, small blood vessels in the body become inflamed and damaged.
In normal inflammation, the complement system (a family of proteins that play an important role in the immune response) is activated. This signals white blood cells to come to the area where an injury or infection has occurred. The white blood cells defend the body against invasion by infectious agents and promote healing.
In ANCA vasculitis, the complement system can be activated by mistake, meaning that white blood 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 the endothelial cells that line blood vessels. When bound to its receptor, C5a signals to immune cells to come to that site.
How does avacopan work?
Avacopan contains a small molecule that inhibits C5a, preventing the activation of inflammatory pathways.
By blocking C5a, avacopan prevents 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
The goal of the CLEAR trial was to determine whether avacopan would allow people with ANCA vasculitis to lower the dose of steroids used to control their disease.
ANCA vasculitis patients can be on high doses of steroids to decrease inflammation, but such use can have serious side effects. Steroids also suppress a healthy immune response, leaving patients vulnerable to infections.
In the CLEAR trial, researchers randomized 67 patients to one of three treatment regimens over 12 weeks: high dose of the corticosteroid prednisone plus a placebo, avacopan plus a lower dose of prednisone, or avacopan with a steroid placebo. All also received standard doses of cyclophosphamide or Rituxan (rituximab), medications also used to treat ANCA vasculitis. The research team measured the effectiveness of avacopan by assessing changes in the Birmingham Vasculitis Activity Score, or BVAS, a measure of vasculitis.
The main goal of the CLASSIC trial was to test the safety of adding avacopan to the standard-of-care regimen used forANCA vasculitis, which includes prednisone plus either cyclophosphamide or Rituxan. Patients were randomly assigned to a high dose of avacopan plus standard of care, a low dose of avacopan plus standard of care, or placebo plus standard of care.
ChemoCyntryx reported that the combination of avacopan and the standard regimen was safe.
The Phase 3 ADVOCATE trial (NCT02994927) randomly assigned 331 people with ANCA vasculitis to either avacopan or prednisone in combination with the standard-of-care for 52 weeks.
ChemoCyntryx reported that the study met both of its primary endpoints: 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).
Use of avacopan was statistically non-inferior to the current standard of care, with 72.3% of avacopan-treated patients and 70.1% of standard-of-care patients (control group) achieving remission at 26 weeks. Sustained remission at 52 weeks was observed in 65.7% of the avacopan-treated group versus 54.9% in the control group, which was a significant improvement.
Additional benefits observed in avacopan group patients 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. Serious adverse events were reported in fewer patients in the avacopan group (42%) than in the standard-of-care group (45%). Most adverse events were related to ANCA vasculitis, and were similar to rates reported in previously published ANCA vasculitis trials.
The U.S. Food and Drug Administration (FDA) granted avacopan orphan drug status, a designation that helps speed the approval process for medicines being developed to treat rare diseases.
The European Medicines Agency (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.
Last updated: Nov. 27, 2019
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