New data further support novel treatment for Cushing’s syndrome
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The steroidogenesis inhibitor levoketoconazole improved and normalized morning urinary free cortisol concentrations for adults with endogenous Cushing’s disease compared with placebo, according to an industry press release.
In announcing topline findings from the phase 3 LOGICS study, Strongbridge Biopharma noted that levoketoconazole (Recorlev) was generally well tolerated, with safety data mirroring those from the earlier phase 3 SONICS trial.
“We are delighted to announce the positive and statistically significant top-line results of the LOGICS study, which add to the growing body of evidence supporting the potential of Recorlev (levoketoconazole) as an effective and well-tolerated cortisol synthesis inhibitor to treat Cushing’s syndrome,” Fredric Cohen, MD, chief medical officer of Strongbridge Biopharma, said in the release. “We believe that these results, coupled with the previously reported positive results from our Phase 3 SONICS study, will support a new drug application in the U.S., which we plan to submit to the FDA in the first quarter of 2021.”
Study design
As Healio previously reported, in the phase 3 SONICS study, levoketoconazole was effective in reducing and normalizing morning urinary free cortisol concentrations and biomarkers of cardiovascular risk among a large cohort of adults with endogenous Cushing’s syndrome, as well as improving clinical signs of the disease and quality of life measures.
The phase 3 LOGICS study accepted adults with Cushing’s syndrome with baseline mean urinary free cortisol (mUFC) at least 1.5 times the upper limit of normal. Participants who had previously completed the SONICS study were also permitted to be considered for entry into the LOGICS study. Prior to the randomized-withdrawal phase, 79 participants entered a single-arm, open-label titration and maintenance phase of approximately 14 to 19 weeks, with 44 participants (including five from SONICS) entered into the 8-week randomized-withdrawal portion of the trial; 22 were randomly assigned levoketoconazole and 22 assigned placebo.
At the end of the randomized-withdrawal phase of the LOGICS study, 54.5% more participants who were withdrawn to placebo had a loss of mUFC response vs. those who remained on levoketoconazole (95.5% vs. 40.9%; P = .0002). All 21 participants who lost response after receiving placebo received early rescue treatment within the 8-week randomized-withdrawal phase (median time to early rescue, 22 days).
The secondary endpoint of normalization of mUFC at the end of the randomized-withdrawal phase was also highly statistically significant; 45.5% more participants treated with levoketoconazole maintained normalized mUFC in the active arm vs. placebo (50% vs. 4.5%; P = .0015).
“The reporting of top-line data from our phase 3 LOGICS study marks a critical milestone for the company and represents the culmination of years of hard work and dedication by the Strongbridge team,” John H. Johnson, CEO of Strongbridge Biopharma, said in the release. “As a rare disease organization, we are focused on developing treatments for underserved patient populations, and today’s announcement is a major step forward in our mission to help address the needs of the estimated 8,000 Cushing’s syndrome patients in the U.S. who are treated with prescription therapy, many of whom are not well-controlled with current therapies.”
Additionally, the mean changes from the randomized-withdrawal baseline to the end of the randomized-withdrawal phase for both total and LDL cholesterol were significantly different between the treatment groups (adjusted P = .0004 and .0056, respectively), indicating rapid reversibility of the levoketoconazole treatment benefits on cholesterol following the switch to placebo.
“The phase 3 LOGICS results complement the long-term efficacy and safety data supplied by the phase 3 SONICS study, which was published in The Lancet Diabetes & Endocrinology, by confirming that the effects of Recorlev were responsible for the therapeutic response when treatment was continued compared to withdrawing patients to placebo,” Maria Fleseriu, MD, FACE, professor of medicine and neurological surgery and director of the Oregon Health Sciences University Pituitary Center and a principal investigator of the study, said in the release. “The LOGICS findings — which build upon the long-term benefit shown during open-label treatment in SONICS — provide robust evidence to support the use of Recorlev as an important treatment option for this life-threatening, rare endocrine disease.”
Safety data
Levoketoconazole was well tolerated; 19% of the 79 participants who initially received doses discontinued during titration-maintenance due to adverse events. None of the 44 randomized patients discontinued because of adverse events. The most common adverse events reported in both phases among 80 participants who received levoketoconazole continuously were nausea (29%), hypokalemia (28%), headache (21%), hypertension (19%) and diarrhea (15%).
Throughout both study phases, three levoketoconazole-treated participants had at least one serum alanine aminotransferase measurement greater than five times the upper limit of normal, and nine participants had at least one measurement that was greater than three times the upper limit of normal. The findings are comparable to data reported during the SONICS trial. All liver abnormalities greater than three times the upper limit of normal resolved without clinical sequelae.
Adverse events of special interest in LOGICS, aside from those that were liver-related, were those relating to adrenal insufficiency reported for eight participants (10%) and those related to QT interval prolongation. Of 80 levoketoconazole-treated participants across both phases, two patients experienced QT prolongation of more than 500 milliseconds, the threshold of clinical importance. These adverse events were all resolved after dose reduction or permanent drug discontinuation. Similar observations were reported in SONICS.
Currently, the azole antifungal ketoconazole, a racemic mixture of two enantiomers, is approved only in Europe and is used off-label for Cushing’s syndrome in the U.S., Fleseriu, who is also an Endocrine Today Editorial Board member, previously told Healio. Ketoconazole has been associated with risk for hepatotoxicity in observational studies, for which weekly monitoring is recommended by the FDA. Levoketoconazole is the pure 2S,4R enantiomer of ketoconazole and may be a more potent inhibitor of cortisol secretion compared with ketoconazole, Fleseriu said.
In the release, Strongbridge Pharma noted that top-line results from the LOGICS trial represent a subset of analyzed data from a planned interim analysis. Final study results are subject to a detailed assessment of the full LOGICS trial.
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