FDA Releases Corrected Rejection Letter for Corcept NDA

FDA has released a corrected version of a 12/30 Complete Response Letter issued to Corcept Therapeutics, indicating that the agency had repeatedly warned the company against submitting its NDA seeking approval of relacorilant for treating hypertension associated with endogenous Cushing’s syndrome. FDA said that during the pre-submission meetings, “we informed you on several occasions of our concerns about the adequacy of the clinical development program to assess the effect of relacorilant on hypertension in the intended population, including the design of CORT125134-455 [study], and to expect significant review issues if you were to submit your application.”

According to the letter, relacorilant failed to demonstrate superior efficacy over placebo in its main clinical trial, showing virtually no meaningful difference in blood pressure outcomes between treatment and control groups. FDA’s review also raised significant safety concerns, citing four cases of probable drug-induced liver injury. One patient experienced liver enzyme elevations more than 50 times the upper limit of normal, a level the agency associated with increased risk of serious liver complications.

UBS analyst Ashwani Verma said the language used in the corrected letter was unusually direct. He noted that Corcept’s management had indicated the company submitted the application based on advice from regulatory consultants, but said the FDA appeared to hold a strong opposing view, as reflected in the wording of the CRL, according to Reuters.

The CORT125134-455 trial included a 22-week open-label treatment phase followed by a 12-week randomized, placebo-controlled withdrawal phase. While the trial met its primary endpoint — loss of blood pressure response during the withdrawal phase — FDA said the results were derived from a “highly enriched population” that limited their interpretability.

Of 102 patients with hypertension at baseline, 39% discontinued during the open-label phase, and only 46 patients entered the randomized withdrawal period, according to the agency. As a result, the FDA said the observed treatment effect likely overestimated relacorilant’s benefit in the intended population. Although the agency acknowledged a mean systolic blood pressure reduction of 5.2 mm Hg at the end of the open-label phase, it said the estimate was unreliable due to extensive missing data and the absence of a control group.

The second pivotal study, CORT125134-456, was a randomized, double-blind, placebo-controlled trial in patients with autonomous cortisol secretion or Cushing’s syndrome and uncontrolled systolic hypertension and/or glucose abnormalities. That trial failed to meet its primary endpoint, showing no meaningful difference between relacorilant and placebo in 24-hour systolic blood pressure reduction at Week 22, FDA says. The between-arm difference was less than 1 mm Hg and was not statistically significant, it adds.

Corcept also conducted a post-hoc subgroup analysis in a small subset of patients with Cushing’s syndrome that showed a nominally significant blood pressure reduction with relacorilant. However, FDA said the analysis was not pre-specified, relied on a small sample size with substantial missing data, and failed to show significance when the agency applied its own imputation methods.

The 1/28 corrected version of the letter was issued following additional communications between Corcept and FDA, according to the letter.