SPI-62, now clofutriben, normalizes cortisol levels in Phase 2 trial

Appears to work well without need to adjust doses or risk adrenal insufficiency

Margarida Maia, PhD avatar

by Margarida Maia, PhD |

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Sparrow Pharmaceuticals’ oral small molecule SPI-62, now being called clofutriben, can lower the levels of free cortisol in the urine of people with Cushing’s syndrome caused by a tumor outside the adrenal glands, including those with Cushing’s disease.

Unlike other cortisol-lowering medications, which require careful dosing to prevent cortisol from dropping to levels too low, clofutriben appears to work well without the need for dose adjustments, posing a low risk for adrenal insufficiency, or too little cortisol.

That’s according to interim results from RESCUE (NCT05307328), an ongoing Phase 2 clinical trial that’s testing how safe clofutriben is against a placebo and how well it works when given as oral tablets every day in the morning for 12 weeks, or about three months.

David Katz, PhD, Sparrow’s chief scientific officer, shared these results during a presentation, “HSD11B1 inhibition reducing toxicities of glucocorticoids,” at the Endocrine Society (ENDO) 2024 conference, held recently in Boston. Full trial results are expected later this year.

“Most of the first trial participants have experienced various clinical benefits, including recovery of muscle strength, or being able to discontinue other medications for diabetes, weight loss, and improved sleep,” Katz said in an email exchange with Cushing’s Disease News.

“These results are early and based on a small number of trial participants who received clofutriben,” Katz added. “If similar results continue to be observed, clofutriben could become a future treatment option for patients with Cushing’s that has no need for dose titration and low risk for adrenal insufficiency.”

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Phase 3 trial planned for 2025

“The Sparrow team looks forward to learning if these promising interim results hold for the larger number of patients in the now fully enrolled clinical trial in endogenous Cushing’s syndrome,” Frank Czerwiec, MD, PhD, Sparrow’s chief medical officer, said in a press release. “In anticipation, our team is planning for the initiation of a Phase 3 trial in 2025.”

Endogenous Cushing’s syndrome occurs when the body produces too much of the hormone cortisol. This hormone is released by the adrenal glands atop the kidneys to help the body respond to stress. It increases blood pressure and blood sugar, and suppresses the immune system and inflammation.

Tumors can cause the body to produce excess cortisol by releasing adrenocorticotropic hormone (ACTH) into the bloodstream. ACTH then travels to the adrenal glands, causing them to produce cortisol. In Cushing’s disease, the source of ACTH is a tumor in the brain’s pituitary gland. 

However, “much or most of the cortisol inside liver, fat, bone, brain, and other cells where excess cortisol causes the signs and symptoms of Cushing’s doesn’t come directly from the adrenal,” Katz said. “Rather, cortisol levels inside cells are largely controlled by a metabolic cycle between active cortisol and inactive cortisone.”

Inactive cortisone circulates in the bloodstream and is taken up by cells, where it can be converted into cortisol, its active form, by the action of an enzyme called HSD-1. Clofutriben is designed to inhibit HSD-1, which is expected to reduce the buildup of cortisol inside cells and ease symptoms of Cushing’s.

A single or multiple doses of clofutriben, given once daily for 14 days, or two weeks, lowered the levels of cortisol in the blood of healthy adults compared with a placebo, according to results presented at ENDO 2024.

As part of the RESCUE trial, adults with endogenous Cushing’s syndrome were randomly assigned to clofutriben or a placebo for 12 weeks. Patients initially assigned to clofutriben are then switched to the placebo, and vice versa, for 12 weeks more, making a total of 24 weeks, or six months.

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Most patients treated with clofutriben saw cortisol levels return to normal

More than 60% of patients treated with clofutriben saw their levels of cortisol in the urine return to normal, compared with none in the placebo group. There were no signs of adrenal insufficiency, with blood cortisol in the morning remaining 10 micrograms per deciliter or higher.

“Reducing cortisol levels within cells secondarily influences circulating cortisol levels, as cortisol diffuses between cells and the bloodstream. In turn, the amount of cortisol excreted in urine depends on circulating cortisol levels,” Katz said.

There were no safety signals, but “some patients experienced non-specific symptoms (e.g., fatigue, nausea) consistent with cortisol withdrawal syndrome, which is to be expected when cortisol levels shift rapidly from high to normal,” Katz said.

After completing the RESCUE trial, patients have the option to enter a long-term extension where they continue to receive treatment with clofutriben. “All patients who completed the 24-week trial thus far elected to continue in the long-term extension,” Katz said.