Clofutriben shows promise in trial for endogenous Cushing’s syndrome
All patients completing RESCUE trial chose to continue on treatment
All patients who completed a Phase 2 clinical trial of clofutriben, an oral small molecule that Sparrow Pharmaceuticals is developing for endogenous Cushing’s syndrome, chose to continue on the experimental treatment as part of a planned open-label extension.
Overall, the results of the trial, dubbed RESCUE, showed promise, Sparrow stated in a company press release.
“One of the most encouraging observations is that, given the option to continue clofutriben or switch to another treatment at the end of the trial, patients chose to continue clofutriben in the [open-label extension],” said Frank Czerwiec, MD, PhD, Sparrow’s chief medical officer.
Interim results from RESCUE (NCT05307328), which tested how well clofutriben works compared with a placebo, showed that the treatment candidate can normalize the levels of free cortisol in the urine of adults with Cushing’s disease and other forms of Cushing’s syndrome caused by a tumor outside the adrenal glands.
Based on these positive results, the company plans to move forward with further clinical testing of clofutriben next year. “We are working closely with our medical, scientific, and patient advisors on plans to present these data and on designs for our next phase of clinical trials to [start] next year,” Czerwiec said.
In a move to support clofutriben’s clinical development, the U.S. Food and Drug Administration (FDA) has granted the therapy orphan drug designation for treating endogenous Cushing’s syndrome. This designation is granted to potential treatments for rare diseases, defined as conditions affecting fewer than 200,000 people in the U.S.
Jamie MacPherson, Sparrow’s senior vice president of regulatory affairs and quality, noted that orphan drug designation “qualifies [drug developers] for incentives including tax credits for qualified clinical trials, exemption from user fees, and a potential seven years of market exclusivity” if the treatment is ultimately approved.
Clofutriben also named an orphan drug for endogenous Cushing’s syndrome
Endogenous Cushing’s syndrome occurs when the body produces too much cortisol, a hormone from the adrenal glands that helps the body respond to stress. The adrenal glands are located on top of each kidney. Too much cortisol, however, can cause a range of symptoms, from excess weight to extreme fatigue.
Some tumors that form in the body release high levels of adrenocorticotropic hormone, known as ACTH, which signals the adrenal glands to produce more cortisol. In Cushing’s disease — the most common form of endogenous Cushing’s syndrome — ACTH is released by a tumor that forms in the brain’s pituitary gland.
Inactive cortisone can be converted in cells into cortisol with the help of an enzyme called HSD-1. Clofutriben, previously known as SPI-62, inhibits HSD-1. This is expected to lower the levels of cortisol and ease symptoms of Cushing’s syndrome.
Unlike other cortisol-lowering medications, clofutriben cuts off the source of cortisol within cells. According to Sparrow, the risk of cortisol reaching dangerously low levels is minimal, helping skirt the need for careful titration to prevent adrenal insufficiency or adrenal crisis, its life-threatening complication. Drug titration is the process of adjusting a medication’s dose slowly over time to ensure its maximum benefit without adverse effects.
HSD-1 inhibition with clofutriben is a completely novel approach to the treatment of endogenous Cushing’s syndrome … [that] may overcome many of the serious problems with current therapies, including major safety, tolerability, and complexity issues such as the risk of adrenal insufficiency and adrenal crisis.
Czerwiec noted that “HSD-1 inhibition with clofutriben is a completely novel approach to the treatment of endogenous Cushing’s syndrome.” He said its use “may overcome many of the serious problems with current therapies, including major safety, tolerability, and complexity issues such as the risk of adrenal insufficiency and adrenal crisis.”
As part of the RESCUE trial, adults with ACTH-dependent Cushing’s syndrome were randomly assigned to daily tablets of clofutriben or the placebo for 12 weeks, or about three months. Patients initially assigned to clofutriben were then switched to the placebo, and vice versa, for 12 weeks more, making this phase a total of 24 weeks, or about six months.
An interim analysis showed that more than 60% of patients assigned to clofutriben had normal levels of free cortisol in the urine, while none on the placebo did. Morning levels of cortisol in the blood stayed safely higher than 10 micrograms per deciliter, indicating no signs of adrenal insufficiency.
The full results are still being awaited. But in the meantime, per MacPherson, the company is happy to have received orphan drug designation for its treatment candidate from the FDA.
“We are pleased that the FDA has recognized the potential for clofutriben to treat this devastating disease,” MacPherson said.
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