Efzofitimod for Sarcoidosis

Last updated June 20, 2022, by Lindsey Shapiro, PhD

Fact-checked by José Lopes, PhD


What is efzofitimod for sarcoidosis?

Efzofitimod (formerly known as ATYR1923) is a first-in-class immunomodulatory therapy, designed to resolve inflammation and prevent subsequent scarring (fibrosis), that’s being investigated for people with pulmonary sarcoidosis.

aTyr Pharma, which is developing the therapy, also is testing it for systemic sclerosis and to treat severe pneumonia related to COVID-19 infection.

A potential disease-modifying therapy, Efzofitimod was granted orphan drug status by the U.S. Food and Drug Administration in 2022 for sarcoidosis and systemic sclerosis.

How does efzofitimod work in sarcoidosis?

Sarcoidosis is characterized by an over-active immune system that leads to the formation of small clumps of inflammatory cells — called granulomas — in the body’s organs. When such granulomas form in the lungs, it’s called pulmonary sarcoidosis.

Efzofitimod works to dampen immune responses associated with lung inflammation by binding to and selectively modulating a protein called neuropilin-2 (NRP2). During inflammation, levels of NRP2 are increased in immune cells, including ones that form granulomas.

Studies in mouse models of lung injury have shown that efzofitmod is able to decrease the infiltration of some immune cell subsets into the lungs, thereby potentially easing inflammation. In cell cultures, it’s been shown to modulate the activity of T-cells, a type of immune cell, and prevent granulomas from forming.

How will efzofitimod be administered in sarcoidosis?

In clinical trials, efzofitimod has been given as into-the-vein (intravenous) infusions at doses ranging from 0.03 milligrams per kilogram of body weight (mg/kg) to 5 mg/kg. In studies of sarcoidosis, the therapy has been given monthly.

Efzofitimod in clinical trials

Trials in healthy volunteers

A first-in-human Phase 1 clinical trial (ACTRN12617001446358) was launched in 2017 and involved 36 healthy adults, ages 18–55. It was designed to evaluate efzofitimod’s safety, tolerability, pharmacokinetics — its movement into, through, and out of the body — and immunogenicity, or its ability to provoke an immune response.

Participants were given a single infusion of efzofitimod at doses ranging from 0.03 mg/kg to 5.0 mg/kg or a placebo, and were monitored for one month.

Results showed that the therapy was generally well-tolerated at all tested doses. No significant adverse events or unwanted immune responses against the therapy were observed throughout the follow-up period.

Pharmacokinetic analyses showed that the treatment stayed above the expected therapeutic levels in the bloodstream at the end of the month, supporting a monthly dosing regimen.

Kyorin Pharmaceutical, aTyr’s partner for the development of efzofitimod in Japan — where the therapy is known as KRP-R120 — conducted a similar trial in that country. That Phase 1 study involved 32 healthy Japanese volunteers. Efzofitimod was found to be generally safe and well-tolerated, and the pharmacokinetics were similar to those observed in the previous study.

Trial in pulmonary sarcoidosis

aTyr then sponsored a Phase 1/2 trial (NCT03824392) of efzofitimod in the U.S., conducted in partnership with the Foundation for Sarcoidosis Research. A total of 37 people with pulmonary sarcoidosis were enrolled at multiple U.S. sites. Participants were randomly assigned to receive one of three intravenous doses of efzofitimod (1, 3 or 5 mg/kg), or a placebo, every four weeks.

The trial’s main goal was to assess the treatment’s safety at 24 weeks, or about six months. In agreement with the earlier Phase 1 trial, efzofitimod was found to be generally safe and well-tolerated, with no drug-related serious adverse events or signs of unwanted immune responses reported.

A number of exploratory efficacy goals also were examined, including changes in corticosteroid use, lung function, clinical symptoms, and levels of inflammatory biomarkers.

Participants in the highest dose group (5 mg/kg) reduced their corticosteroid use by 58% from the study’s start — a 22% greater reduction than in the placebo group. Moreover, one-third of participants in that group became entirely corticosteroid-free, whereas no patients in any other group did.

This highest dose also led to clinically meaningful improvements in lung function compared with a placebo group, as measured by forced vital capacity (FVC) — a measure of how much air can be forcibly exhaled in a single breath. Clinically meaningful reductions also were observed in shortness of breath, cough, fatigue, and lung and general health, as measured by the King’s Sarcoidosis Questionnaire (KSQ).

Patients treated with efzofitimod showed dose-dependent declines in inflammatory and sarcoidosis biomarkers, with the greatest drops occurring in the 5 mg/kg group.

Ongoing trials

A Phase 3 trial (NCT05415137) dubbed EFZO-FIT will evaluate efzofitimod’s safety and efficacy in adults ages 18-75 with pulmonary sarcoidosis who are using oral corticosteroids. The trial will enroll an estimated 264 patients at multiple sites in North America, Europe, and Japan.

Participants will be randomly assigned to receive monthly infusions of efzofitimod (3 or 5 mg/kg) or a placebo for a total of 12 doses — about a year of treatment.

The trial’s main goal will be to achieve reductions in the use of corticosteroids, with secondary objectives including changes in lung function (FVC) and other sarcoidosis symptoms (KSQ).

EFZO-FIT is expected to begin in September 2022 and finish in January 2025.

Common side effects of efzofitimod

No serious side effects from efzofitimod’s use have been reported in sarcoidosis clinical trials. Experienced side effects were deemed mild or moderate in severity, but the nature of these side effects have not been reported.


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