Isturisa found to be safe, effective in long-term trial extension
Most participants achieved normal cortisol levels by the end of the study
Long-term treatment with Isturisa (osilodrostat) led to a sustained normalization in cortisol levels, symptom relief, and improved quality of life for people with Cushing’s disease, according to the full results from the LINC 4 clinical trial and its extension phase.
“These data provide further evidence of the durable clinical benefit of long-term [Isturisa] treatment in patients with persistent, recurrent or de novo [newly-diagnosed] Cushing’s disease,” the scientists wrote in “Long-term efficacy and safety of osilodrostat in patients with Cushing’s disease: results from the LINC 4 study extension,” which was published in Frontiers in Endocrinology.
In Cushing’s disease, a tumor in the brain’s pituitary gland leads to excessive amounts of the hormone cortisol being produced by the adrenal glands, which sit atop the kidneys. Surgery to remove the tumor is the first-line treatment, but it’s not always effective and some patients aren’t eligible.
For those patients, Isturisa, which blocks cortisol production, is approved in the U.S. It’s also approved for endogenous Cushing’s syndrome and Cushing’s disease in Europe and Japan. The therapy was developed by Novartis and its rights were acquired by Recordati in 2019.
The Novartis-sponsored Phase 3 LINC 4 trial (NCT02697734), was designed to evaluate Isturisa’s safety and effectiveness in 73 people with Cushing’s disease.
Isturisa’s effect on cortisol levels, other parameters
In the main trial, participants were randomly assigned to receive Isturisa or a placebo for 12 weeks (about three months), after which all were given Isturisa through week 48 (about a year). The starting dose was 2 mg twice a day, with adjustments permitted based on how it was tolerated and clinical responses, up to 30 mg twice a day.
Top-line trial data indicated Isturisa rapidly lowered urinary cortisol levels, with a significantly higher proportion of patients (77%) achieving normal urinary levels after 12 weeks over those on a placebo (8%). These gains were sustained up to 36 weeks.
Treatment was also associated with normalized metabolic parameters, including blood pressure, blood sugar, and cholesterol. Physical features of Cushing’s, such as flushing and fat accumulation as well as body weight and waist circumference, were reduced and quality of life improved.
Results from open-label extension
After the first year, 60 patients entered an open-label extension period, where all would continue to receive Isturisa at their optimized dose for up to an additional year.
In the recent publication, the scientists reported the long-term data from this extension. From the start of the main trial, the median Isturisa exposure was 87.1 weeks, or a little over 1.5 years.
As reported, 68.5% of patients had normal urinary cortisol levels at the end of the 48-week core period.
This was maintained in the extension phase, with 40 of 60 people (66.7%) having normalized cortisol levels by week 72 (1.5 years). As of each person’s end-of-trial visit, 72.4% achieved normal urinary cortisol levels.
Given the wide range of cortisol levels at the start of the trial, “this indicates that patients can benefit from [Isturisa] treatment regardless of their baseline [urinary cortisol] level,” the researchers wrote.
Mean blood cortisol levels declined to within a normal range in the main trial and were sustained throughout the extension, while late-night salivary cortisol levels decreased and remained stable, but were still above the upper limit of normal.
Metabolic improvements and reductions in physical manifestations of Cushing’s were maintained or improved in the extension. Very few patients reported that any Cushing’s manifestations got worse, according to the researchers. Likewise, measures of quality of life, which steadily improved during the core trial, continued to improve in the extension.
Side effects with Isturisa
Isturisa was generally well tolerated, with no new safety signals identified. The most common side effects were decreased appetite (46.6%), joint pain (45.2%), and fatigue (39.7%). Most were mild or moderate in severity.
Given Isturisa’s mechanism of action, it’s expected that side effects associated with low cortisol levels or high adrenal hormone precursors may occur. Still, the frequency of these side effects was reduced in the extension relative to the core trial. Testosterone increases in female patients observed during the main trial were also reduced over the long term.
The treatment didn’t adversely affect pituitary tumor size, with similar proportions of patients reporting a decrease, increase, or stable tumor size throughout the study.
“The data presented here … reinforce previous reports demonstrating that [Isturisa] is effective and well tolerated during long-term treatment of Cushing’s disease,” the researchers wrote.