HB-1614 may increase exercise capacity in PH-ILD: Clinical trial
Adults with disease may also see quality-of-life improvements
A Phase 2a study of HB-1614, an oral therapy candidate, suggested the medication is safe and may improve exercise capacity and quality of life in adults with pulmonary hypertension associated with interstitial lung disease (PH-ILD).
This is according to Halo Biosciences, developer of HB-1614, which announced the publication of results from the SATURN clinical trial (NCT05128929).
“We are proud to see the SATURN study featured in Thorax, validating our translational approach and marking a key milestone in our development of HB-1614,” Anissa Kalinowski, Halo’s CEO, said in a company press release. The Thorax article’s title is “Randomised, placebo-controlled trial of oral hymecromone in adults with pulmonary hypertension.”
Although the study included participants with PH-ILD and pulmonary arterial hypertension (PAH), the medication appeared more effective in PH-ILD. HB-1614 failed to meet the primary efficacy goal of changes in pulmonary vascular resistance (PVR) — a measure of the resistance to blood flow in the lungs — but other effects suggest routes for further testing. HB-1614 was safe and well tolerated.
“This represents a meaningful step forward for individuals living with PH-ILD, a condition with limited treatment options and a high burden of disease,” said Paul Bollyky, MD, professor of medicine at Stanford University and scientific co-founder of Halo.
Halo aims to inhibit hyaluronan synthesis
In interstitial lung diseases, inflammation and scarring in the lungs may cause increased blood pressure in the lungs. This pulmonary hypertension (PH) can, in turn, overstrain the heart and lead to symptoms including shortness of breath and fatigue.
Vascular remodeling, in which blood vessels change structure and arrangement, is a central process driving PH. Hyaluronan, a component of the extracellular matrix (ECM), a structural support network surrounding cells, plays a role in vascular remodeling, inflammation, and scarring, or fibrosis. High hyaluronan levels have been reported in PAH and PH-ILD.
With HB-1614, Halo aims to inhibit hyaluronan synthesis. The medication is a formulation of 4-methylumbelliferone (4-MU, or hymecromone), a small molecule that blocks hyaluronan production. According to Halo, this may be a disease-modifying approach for PH-ILD.
“We hypothesised that inhibition of HA [hyaluronan] synthesis with hymecromone could serve as a reverse-remodelling therapy in PH,” the research team wrote. To test this, they recruited eight adults with PH-ILD and eight with PAH for a 24-week study. These participants, who had a median age of 62, received two oral doses of HB-1614, or a placebo, each day.
PH-ILD participants on HB-1614 could walk farther relative to study’s start
Results showed no statistically significant differences in PVR at 24 weeks (almost six months) when comparing treatment to the placebo. Likewise, the two groups did not differ in analyses of pulmonary arterial pressure, a 6-minute walk test — a standard measure of exercise capacity — and quality of life.
But in exploratory analyses in specific PH subtypes, five PH-ILD participants treated with HB-1614 could walk a mean of 66 m (216 feet) farther in 6 minutes relative to the study’s start. This difference is double the difference previously deemed clinically significant in adults with PAH, according to the researchers.
These clinical data reinforce the scientific rationale for targeting hyaluronan in fibrotic and inflammatory lung disease and highlight 4-MU’s potential as a first-in-class, disease-modifying [extracellular matrix]-modulator for patients with serious conditions like PH-ILD.
Quality of life measures also improved significantly in this group.
“These results suggest that hymecromone provided a symptomatic benefit in patients with PH-ILD, but this was not associated with improvements in PVR,” the investigators wrote. No such benefits were seen in PAH patients.
“These clinical data reinforce the scientific rationale for targeting hyaluronan in fibrotic and inflammatory lung disease and highlight 4-MU’s potential as a first-in-class, disease-modifying [extracellular matrix]-modulator for patients with serious conditions like PH-ILD,” Bollyky said.
However, the team noted the PH-ILD group had particularly low results in this test before treatment, which could explain the large effect size. With the small number of participants, they couldn’t draw statistically meaningful conclusions, but suggested “further investigations in larger patient cohorts are warranted.”
“We hypothesise that through improved metabolic effects, there may be improved musculoskeletal function [bones, joints, ligaments, skeletal muscles, tendons] and that future studies should consider the assessment of muscle biopsy or validated functional measures to better understand the effect of hymecromone in patients with PH-ILD,” the scientists wrote. They also said the six-minute walk test would be an appropriate primary outcome measure of a future trial in PH-ILD.
As for safety, no adverse event was deemed related to treatment and no treatment interruptions or discontinuations were reported.
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