Osilodrostat shows promise for Cushing’s Disease

Treatment with the oral 11β-hydroxylase inhibitor osilodrostat continues to maintain a normalized mean urinary free cortisol (mUFC) in patients with Cushing’s Disease (CD) in a phase III trial presented at ENDO 2019.

While pituitary surgery is the first-line treatment recommended for most patients with CD, it is not always effective for all patients, with some patients facing recurrence, which necessitates additional therapy.

The current phase III, multicentre, double-blind LINC-3 study involved patients with CD and mUFC >1.5 times the upper limit of normal (ULN) who had completed a single-arm, open-label treatment phase with osilodrostat 2 mg twice daily for 24 weeks. [ENDO 2019, abstract OR16-2]

At baseline, the median mUFC was 3.5 times the ULN, which is indicative of significant hypercortisolemia, according to Dr Beverly Biller of the Neuroendocrine & Pituitary Tumor Center at Massachusetts General Hospital in Boston, Massachusetts, US. 

At week 26, 71 patients who achieved mUFC ≤ULN at week 24 without a dose increase after week 12 were qualified for randomization to either continue osilodrostat (n=36) or treatment withdrawal by receiving a matching placebo (n=35) for 8 weeks, followed by open-label osilodrostat until week 48. Patients who did not qualified for randomization but remained on treatment at week 26 continued to receive open-label osilodrostat (n=47).

At the end of the randomization phase (week 34), significantly more patients who continued receiving osilodrostat achieved the primary endpoint of maintaining mUFC ≤ULN (without a dose increase after week 26) compared with those who switched to placebo (86 percent vs 29 percent, odds ratio [OR], 13.7; p<0.001).

Also, 53 percent of patients achieved the key secondary endpoint of maintaining mUFC ≤ULN at 24 weeks without osilodrostat uptitration after week 12.

At week 48, 66 percent of the patients enrolled had mUFC ≤ULN. Ninety-six percent of patients overall saw their mUFC levels in the normal range at least once during the study and the median time to first mUFC ≤ULN was 41 days.  

“[Osilodrostat] normalized mUFC in two-thirds of enrolled patients at week 48, with few patients discontinuing treatment because of adverse events,” said Biller, who noted that only 11 percent of patients discontinued study due to AEs.

In general, the most common AEs reported included nausea (42 percent), headache (34 percent), and fatigue (28 percent). During the randomization phase, the AEs most commonly reported in the osilodrostat group vs the placebo group were nausea (11 percent vs 0 percent), anaemia (8 percent vs 9 percent), arthralgia (8 percent vs 0 percent) and headache (8 percent vs 0 percent).

Overall, 51 percent of patients experienced AEs related to hypocortisolism, but most were of mild-to-moderate intensity and were resolved via dose reduction or glucocorticoid supplementation, according to Biller. In addition, AEs associated with accumulation of adrenal hormone precursors were observed in 42 percent of patients.

“This randomized withdrawal study demonstrates osilodrostat to be a highly effective treatment for CD, with good tolerability,” concluded Biller.