Sparrow Pharmaceuticals' clofutriben, an oral small molecule, has shown promising results in a Phase 2 clinical trial (RESCUE) for endogenous Cushing's syndrome. All patients who completed the trial opted to continue the experimental treatment in a planned open-label extension, according to a company press release. This suggests a potential benefit and tolerability that warrants further investigation.
RESCUE Trial Results
The RESCUE trial (NCT05307328) evaluated clofutriben against placebo in adults with ACTH-dependent Cushing's syndrome. Interim results indicated that clofutriben can normalize free cortisol levels in urine in patients with Cushing's syndrome caused by tumors outside the adrenal glands. Specifically, more than 60% of patients on clofutriben achieved normal urinary free cortisol levels, compared to none in the placebo group. Morning cortisol blood levels remained above 10 micrograms per deciliter, suggesting a low risk of adrenal insufficiency.
"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.
Orphan Drug Designation
The FDA has granted clofutriben orphan drug designation for treating endogenous Cushing's syndrome, a rare condition affecting fewer than 200,000 people in the U.S. This designation provides incentives, including tax credits for clinical trials, exemption from user fees, and potential seven years of market exclusivity upon approval, according to Jamie MacPherson, Sparrow’s senior vice president of regulatory affairs and quality.
Mechanism of Action
Endogenous Cushing's syndrome results from excessive cortisol production. In Cushing's disease, the most common form, a pituitary tumor releases ACTH, stimulating the adrenal glands to overproduce cortisol. Clofutriben (formerly SPI-62) inhibits HSD-1, an enzyme that converts inactive cortisone to cortisol within cells. This mechanism is designed to lower cortisol levels and alleviate Cushing’s syndrome symptoms.
According to Sparrow, clofutriben's mechanism, cutting off cortisol production within cells, may minimize the risk of dangerously low cortisol levels, potentially avoiding the need for careful dose titration to prevent adrenal insufficiency or adrenal crisis.
"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 stated.
Sparrow Pharmaceuticals plans further clinical testing of clofutriben next year and is working with advisors to finalize the study design.
