Pituitary-targeting seliciclib shows promise in treatment of Cushing disease

In a recent study, seliciclib therapy demonstrates its potential in reversing hypercortisolism by directly targeting pituitary corticotrophs in Cushing disease (CD). However, the agent is associated with liver toxicity, which is resolved by withdrawing treatment.

“Preclinical studies show seliciclib (R-roscovitine) suppresses neoplastic corticotroph proliferation and pituitary adrenocorticotrophic hormone (ACTH) production,” the authors said.

Two prospective, open-label, phase II trials were conducted at a tertiary referral pituitary centre. Adult patients with de novo, persistent, or recurrent CD who received oral seliciclib 400 mg twice daily for 4 consecutive days each week for 4 weeks were included in the study.

Normalization of 24-hour urinary free cortisol (UFC; ≤50 µg/24 hours) at study end was the primary endpoint in the proof-of-concept single-centre study. In the pilot multicentre study, the primary endpoint was UFC normalization or ≥50-percent decrease in UFC from baseline to study end.

Sixteen patients were identified, of which nine received treatment. Mean UFC saw a 42-percent reduction, from 226.4 µg/24 hours at baseline to 131.3 µg/24 hours by study end. Significant UFC decreases were also noted from baseline to each treatment week in the longitudinal model.

Of the patients, three achieved ≥50-percent decrease in UFC (range, 55‒75 percent), while two had a decrease of 48 percent. However, none attained UFC normalization. In patients who achieved ≥48-percent UFC reduction, plasma ACTH decreased by 19 percent (p=0.01).

In terms of safety, grade ≤2 elevated liver enzymes, anaemia, and/or elevated creatinine developed in three patients, but dose interruption or reduction resolved these conditions. Two patients had grade 4 liver-related serious adverse events, which were resolved within 4 weeks of seliciclib cessation.

“The lowest effective dose requires further determination,” the authors said.