Phase 2 trial planned to test oral therapy izicopan in AAV
Developer InflaRx believes drug could be more convenient alternative to Tavneos
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InflaRx plans to launch a Phase 2 clinical trial to evaluate its experimental oral treatment, izicopan, in people with ANCA-associated vasculitis (AAV).
The company believes izicopan has the potential to be a safer, faster, and more convenient alternative to Tavneos (avacopan), an oral therapy with a similar mechanism of action that’s approved for the most common types of AAV.
“We have elected to pursue development in ANCA-associated vasculitis following our thorough evaluation of the high unmet need in this life-threatening disease and izicopan’s promise as a significantly differentiated [suppressor] of C5aR [C5a receptor], with potential advantages in efficacy, safety and convenience,” Niels C. Riedemann, MD, PhD, InflaRx’s founder and CEO, said in a company press release.
InflaRx recently shared its development strategy for izicopan in a webcast. It includes evaluating several approaches to shorten the path to regulatory approval.
Izicopan designed to bind to key protein
AAV is a group of autoimmune diseases typically caused by self-reactive antibodies called ANCAs, which overly activate neutrophils, a type of immune cell. This results in inflammation and damage to small blood vessels. AAV symptoms may affect several organs, but kidney damage is common.
The damaging effects of these autoimmune attacks are partially driven by activation of a group of immune proteins called the complement system. This leads to the production of the complement protein C5a, which binds to receptor proteins at the surface of neutrophils, further promoting their abnormal activation.
Izicopan is a small oral molecule designed to selectively bind to the C5a receptor (C5aR) protein and prevent its interaction with C5a, thereby reducing neutrophil activation, inflammation, and damage to small blood vessels.
It works similarly to Tavneos, a twice-daily oral treatment approved as an add-on to standard glucocorticoids for adults with severe and active microscopic polyangiitis (MPA) and granulomatosis with polyangiitis (GPA), the two most common AAV types.
Notably, the U.S. Food and Drug Administration is considering withdrawing Tavneos from the market following allegations of manipulated data in its regulatory application, suggesting the treatment was not shown to be effective for its approved use. There are also concerns about liver toxicity. Regulators in the European Union, where the therapy is approved for the same indication, are also taking a second look at Tavneos.
Drug shows promising results in preclinical studies
According to InflaRx, preclinical studies, including in animal models, have shown that izicopan results in higher drug exposure in the body and superior C5aR activity to Tavneos.
In a separate press release, the company also announced additional preclinical study results. Specifically, a head-to-head study showed that izicopan led to lower reactive metabolite formation than Tavneos, indicating a potentially better safety profile for izicopan. Reactive metabolites are potentially toxic breakdown products of a medication formed when the body, primarily the liver, processes drugs.
“These data provide additional insight into the mechanistic profile of izicopan,” said Renfeng Guo, MD, InflaRx’s chief scientific officer and founder. “We believe that, if supported by clinical data, such properties may contribute to its overall differentiation within the C5aR [suppressor] class.”
Results from a first-in-human Phase 1 trial demonstrated that the treatment was well tolerated in healthy volunteers, with no safety concerns at single doses between 3 mg and 240 mg, or multiple doses ranging from 30 mg once daily to 90 mg twice daily for 14 days.
Izicopan also led to a significantly higher blockade of C5a-induced neutrophil activation than that reported for Tavneos, and resulted in about 10 times higher drug exposure in the body and about three times higher maximum drug levels.
The experimental treatment may also be formulated with a higher drug strength per capsule (30 mg vs. 10 mg in Tavneos), reducing pill burden, and has potential for once-daily dosing. Tavneos is taken as three 10 mg capsules twice daily.
These data provide additional insight into the mechanistic profile of izicopan. We believe that, if supported by clinical data, such properties may contribute to its overall differentiation within the C5aR [suppressor] class.
In a Phase 2a trial involving people with skin conditions driven, at least in part, by activation of the C5a-C5aR axis, izicopan was found to be generally safe and well-tolerated and to reduce disease severity.
In the planned Phase 2 trial in AAV, participants, including those with severe kidney problems, will be randomly assigned to receive either izicopan or a placebo, twice daily, together with glucocorticoid tapering and rituximab, for 26 weeks (about six months) to induce disease remission. Rituximab (sold as Rituxan and others, with biosimilars available) is a therapy approved for MPA and GPA.
In the maintenance phase of treatment, patients will continue to receive their assigned treatment plus rituximab for six months, but some of those on izicopan will transition to receiving it once daily.
The primary goal is to assess izicopan’s safety. Secondary goals include evaluating izicopan’s efficacy at improving kidney function and reducing disease activity, as well as time to clinical remission, effects on markers of kidney damage, and the treatment’s pharmacological properties.
The company also aims to develop proof-of-concept studies in kidney diseases where early evidence already exists for the therapeutic potential of C5a/C5aR suppression.
