HZN-825 is a therapy being developed by Horizon Therapeutics to possibly treat people with diffuse cutaneous scleroderma, a subtype of systemic scleroderma. This rare disease is caused by an overactive immune system, which leads to the accumulation of scar tissue in the skin and various other tissues and organs.

The potential therapy was originally developed by Sanofi under the name SAR100842 and later by Curzion Pharmaceuticals under the name CZN001. Curzion was purchased by Horizon in 2020.

How HZN-825 works

While the development and progression of systemic scleroderma remains uncertain, the levels of a protein called lysophosphatidic acid (LPA) are known to be higher than normal in the blood of systemic scleroderma patients. LPA is suspected to play a role in disease processes.

LPA is normally produced at sites of inflammation or cell injury, and it binds to LPA receptors present on the surface of many cells. The activation of LPA receptors results in the expression of several genes involved in the development of fibrosis.

HZN-825 is a molecule that binds to LPA receptors, blocking LPA from doing so. It is hoped that this may reduce the formation and build-up of scar tissue in scleroderma patients.

HZN-825 in clinical trials

The safety and tolerability of HZN-825 has been evaluated, to date, in one double-blind and placebo-controlled Phase 2a study (NCT01651143) in 32 people with early diffuse cutaneous scleroderma patients that lasted eight weeks. A second phase followed: a 16-week open-label extension that enrolled 30 of these patients.

In the first part, patients were randomly assigned to receive oral HZN-825 or placebo twice a day for eight weeks. All had a baseline, or study start, Rodnan skin score (a measure of skin thickness) of at least 15.

Trial results, published published in the Arthritis & Rheumatology journal in 2018, showed the trial met its primary goal, that of safety. The treatment was well-tolerated through both study phases (24 weeks of total treatment), with most frequent adverse events reported being mild or moderate. They included headaches, diarrhea, nausea, and falls.

Exploratory outcomes included the assessment of genes activated by LPA that might play a role in fibrosis, and the clinical efficacy of the treatment, measured using the Rodnan skin score.

Improved skin scores were seen in people treated with HZN-825 compared to those on placebo at week eight. A decrease in the expression of fibrosis-linked genes activated by LPA was also seen in these patients, suggesting that HZN-825 may effectively block the action of LPA.



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