First IPF Patient Enrolled in Phase 2b Trial of Oral HZN-825

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by Patricia Inacio PhD |

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The first patient has been enrolled in a pivotal Phase 2b trial investigating the safety and effectiveness of Horizon Therapeutics’ oral medicine candidate HZN-825 in people with idiopathic pulmonary fibrosis (IPF).

The trial (NCT05032066) aims to enroll approximately 360 people with IPF, ages 18–80, whose disease symptoms first became evident more than one but less than seven years ago, among additional criteria.

Enrollment, which is expected to proceed over the course of two years, is now open at three U.S. clinical sites — two in Florida and one in Texas. More information is available here.

“The enrollment of the first patient in this pivotal study marks an important milestone for development of this potential therapy for these patients and our commitment to fibrotic conditions,” Theresa Podrebarac, MD, senior vice president of clinical development at Horizon, said in a press release.

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Patients will be randomly divided into three groups: one will be given 300 mg of HZN-825 once daily, and the two other groups will receive either 300 mg of HZN-825 or a placebo, twice daily. All participants will be treated for a total of 52 weeks, or one year.

The main goal is to assess the effects of treatment on forced vital capacity (FVC), a lung function parameter that measures how much air a person is able to forcibly exhale after a deep breath.

Additional goals include assessing the effects of treatment on the 6-Minute Walk Test (6MWT), the King’s Brief Interstitial Lung Disease (K-BILD) questionnaire, and the rate of hospitalization due to respiratory distress. Of note, the 6MWT measures the distance a patient is able to walk in six minutes and is often used as an indicator of endurance capacity, while the K-BILD questionnaire is used to assess an individual’s health status.

The trial also will assess progression-free survival — the time during which a patient lives with the disease without getting worse — as one of its goals.

The therapy’s effects will be evaluated, in part, based on patients’ prior use, or not, of approved IPF therapies Ofev (nintedanib) or Esbriet (pirfenidone). Their degree of FVC% predicted at the start of the trial — below 70% or higher — also will be taken into account.

HZN-825 was designed to block the activity of the lysophosphatidic acid 1 receptor, known as LPAR1. This receptor protein has been implicated in the scarring (fibrosis) that underlies IPF and other fibrotic disorders.

“Preclinical studies have demonstrated that targeting LPAR1 has the potential to prevent and possibly reverse the underlying pathologies [disease mechanisms] characteristic of idiopathic pulmonary fibrosis,” said Podrebarac.

That means that therapies such as HZN-825 possibly may slow disease progression in IPF.

“Patients with idiopathic pulmonary fibrosis know their condition will only worsen over time and deserve therapies that will stabilize or slow the progression of this disease,” said Martin Kolb, MD, PhD, division director of respirology at McMaster University, in Canada, and the trial’s lead investigator.

“This trial will help determine the safety, efficacy and tolerability of Horizon’s LPAR1 antagonist in slowing the decline of lung function due to inflammation and fibrosis from this disease,” he added.

HZN-825 was initially tested in people with diffuse cutaneous systemic sclerosis (dcSSc), a form of systemic sclerosis, an autoimmune disease characterized by widespread tissue scarring and skin thickening. People with dcSSc often have impaired lung function due to scarring in the lungs.

Data from a Phase 2a trial (NCT01651143) showed HZN-825 reduced skin thickening in people with early dcSSc after treatment for eight weeks, in comparison with those receiving a placebo. Those who completed this trial were eligible to enroll in a 16-week (about four-month) open-label extension study, during which all participants received the experimental treatment.

According to Horizon, 79% of patients treated for 24 weeks (about six months) with HZN-825 showed clinically meaningful improvements in skin thickening, as assessed by the modified Rodnan skin score (mRSS).

Following these early data, Horizon launched a pivotal Phase 2b trial (NCT04781543) to continue assessing the safety and effectiveness of HZN-825 in people with dcSSc. That trial is still recruiting participants; more information is available here.

HZN-825 was originally developed by Sanofi under the name SAR100842. It was acquired by Curzion Pharmaceuticals and rebranded as CZN001. When Horizon acquired Curzion in April 2020, it renamed the investigational therapy HZN-825.