Use of levoketoconazole improved several clinical features of Cushing’s disease

LOS ANGELES – Following 6 months of treatment with the investigational agent levoketoconazole, several clinical signs and symptoms of Cushing’s disease improved, including acne, hirsutism, and peripheral edema, as did patient-reported quality of life and symptoms of depression.

The findings come from an analysis of secondary endpoints among patients enrolled in SONICS, an open-label, phase 3 study of levoketoconazole as a treatment for endogenous Cushing’s disease (CD) that enrolled 94 patients at centers in North America, Europe and the Middle East. An investigational cortisol synthesis inhibitor, levoketoconazole is being developed by Strongbridge Biopharma and is not yet approved by the Food and Drug Administration.

“Despite the availability of approved treatments, the medical needs in Cushing’s [disease] remain very high,” the study’s principal investigator, Maria Fleseriu, MD, FACE, said in an interview in advance of the annual scientific and clinical congress of the American Association of Clinical Endocrinologists, where the data were presented. “This study demonstrates that levoketoconazole has the potential to address several clinical features of Cushing’s, owing to its clinically translated novel mechanism of action to suppress both cortisol and androgen syntheses (the latter elevated in many women with CD). Interestingly, there was no evidence of clinically important free-T reduction in men, and more studies are needed to elucidate this mechanism.”

In SONICS, adults with confirmed CD and mean 24-hour urinary free-cortisol (mUFC) value at least 1.5 times the upper limit of normal were treated with levoketoconazole in three phases: 2- to 21-week dose-titration phase (150-600 mg BID, as needed, to target mUFC normalization); 6-month maintenance phase (primary endpoint); and 6-month extended evaluation phase. The end of maintenance phase findings that focused on reductions in mUFC and safety had been previously reported. The current analysis focused on secondary endpoints, including changes from baseline to end of maintenance in investigator-assessed CD clinical signs and symptoms (acne score [range: 0-44]; hirsutism score [women only; range: 0-36]; and peripheral edema score [range: 0-12]), and patient-reported outcomes of quality of life (Cushing QoL questionnaire score [range: 0-100]) and depression (Beck Depression Inventory II score [range: 0-63]). The researchers also assessed hormones including free testosterone levels, and they used paired t-tests to infer statistical significance of the mean changes from baseline to end of maintenance for all measures.

Of the 94 patients enrolled in SONICS, 77 entered the maintenance phase, said Dr. Fleseriu, professor of medicine and neurological surgery and director of the pituitary center at Oregon Health and Science University, Portland. The patients’ mean age was 44 years and mean baseline mUFC was 243.3 mcg/day; 82% of patients were female, and 96% were white. Between baseline and the end of maintenance, the researchers observed significant mean improvements in acne scores (from 2.8 to –1.8, respectively; P = .0063), hirsutism scores (women only, from 7.8 to –2.6; P = .0008), and peripheral edema scores (from 1.0 to –0.4; P = .0295). They also observed significant mean improvements in quality of life and depression scores between baseline and end of maintenance (P less than .0001 and P = .0043, respectively). Mean free-testosterone levels increased nonsignificantly between baseline and end of maintenance in men (from 5.1 to 5.8 ng/dL) yet decreased significantly in women (from 0.3 to 0.1 ng/dL; P less than 0.0001; reference). Overall, 33 patients (35%) discontinued taking levoketoconazole by the end of the maintenance phase. Twelve (13%) discontinued because of adverse events.

“I wasn’t necessarily surprised with any of the data in this poster as I had experience with the drug in clinical trials, but I was definitely pleased to see overall significant improvements in acne score, hirsutism score in women, and peripheral edema score,” Dr. Fleseriu said. “Those are benefits that could potentially increase long-term adherence to treatment and quality-of-life improvements, particularly in women. It’s also exciting to see that quality of life and depression improved in these patients as well.”

These types of patient-reported outcomes are so important to how our patients feel about their disease and should be more of a focus for us physicians; it’s important to look at efficacy, safety and patient reported outcomes when we decide for an individualized treatment for each patient,” she noted.

Dr. Fleseriu reported that she has received research funding for Oregon Health and Science University from Novartis, Millendo, and Strongbridge. She has also received scientific consulting fees from Novartis and Strongbridge.

[email protected]

LOS ANGELES – Following 6 months of treatment with the investigational agent levoketoconazole, several clinical signs and symptoms of Cushing’s disease improved, including acne, hirsutism, and peripheral edema, as did patient-reported quality of life and symptoms of depression.

The findings come from an analysis of secondary endpoints among patients enrolled in SONICS, an open-label, phase 3 study of levoketoconazole as a treatment for endogenous Cushing’s disease (CD) that enrolled 94 patients at centers in North America, Europe and the Middle East. An investigational cortisol synthesis inhibitor, levoketoconazole is being developed by Strongbridge Biopharma and is not yet approved by the Food and Drug Administration.

“Despite the availability of approved treatments, the medical needs in Cushing’s [disease] remain very high,” the study’s principal investigator, Maria Fleseriu, MD, FACE, said in an interview in advance of the annual scientific and clinical congress of the American Association of Clinical Endocrinologists, where the data were presented. “This study demonstrates that levoketoconazole has the potential to address several clinical features of Cushing’s, owing to its clinically translated novel mechanism of action to suppress both cortisol and androgen syntheses (the latter elevated in many women with CD). Interestingly, there was no evidence of clinically important free-T reduction in men, and more studies are needed to elucidate this mechanism.”

In SONICS, adults with confirmed CD and mean 24-hour urinary free-cortisol (mUFC) value at least 1.5 times the upper limit of normal were treated with levoketoconazole in three phases: 2- to 21-week dose-titration phase (150-600 mg BID, as needed, to target mUFC normalization); 6-month maintenance phase (primary endpoint); and 6-month extended evaluation phase. The end of maintenance phase findings that focused on reductions in mUFC and safety had been previously reported. The current analysis focused on secondary endpoints, including changes from baseline to end of maintenance in investigator-assessed CD clinical signs and symptoms (acne score [range: 0-44]; hirsutism score [women only; range: 0-36]; and peripheral edema score [range: 0-12]), and patient-reported outcomes of quality of life (Cushing QoL questionnaire score [range: 0-100]) and depression (Beck Depression Inventory II score [range: 0-63]). The researchers also assessed hormones including free testosterone levels, and they used paired t-tests to infer statistical significance of the mean changes from baseline to end of maintenance for all measures.

Of the 94 patients enrolled in SONICS, 77 entered the maintenance phase, said Dr. Fleseriu, professor of medicine and neurological surgery and director of the pituitary center at Oregon Health and Science University, Portland. The patients’ mean age was 44 years and mean baseline mUFC was 243.3 mcg/day; 82% of patients were female, and 96% were white. Between baseline and the end of maintenance, the researchers observed significant mean improvements in acne scores (from 2.8 to –1.8, respectively; P = .0063), hirsutism scores (women only, from 7.8 to –2.6; P = .0008), and peripheral edema scores (from 1.0 to –0.4; P = .0295). They also observed significant mean improvements in quality of life and depression scores between baseline and end of maintenance (P less than .0001 and P = .0043, respectively). Mean free-testosterone levels increased nonsignificantly between baseline and end of maintenance in men (from 5.1 to 5.8 ng/dL) yet decreased significantly in women (from 0.3 to 0.1 ng/dL; P less than 0.0001; reference). Overall, 33 patients (35%) discontinued taking levoketoconazole by the end of the maintenance phase. Twelve (13%) discontinued because of adverse events.

“I wasn’t necessarily surprised with any of the data in this poster as I had experience with the drug in clinical trials, but I was definitely pleased to see overall significant improvements in acne score, hirsutism score in women, and peripheral edema score,” Dr. Fleseriu said. “Those are benefits that could potentially increase long-term adherence to treatment and quality-of-life improvements, particularly in women. It’s also exciting to see that quality of life and depression improved in these patients as well.”

These types of patient-reported outcomes are so important to how our patients feel about their disease and should be more of a focus for us physicians; it’s important to look at efficacy, safety and patient reported outcomes when we decide for an individualized treatment for each patient,” she noted.

Dr. Fleseriu reported that she has received research funding for Oregon Health and Science University from Novartis, Millendo, and Strongbridge. She has also received scientific consulting fees from Novartis and Strongbridge.

[email protected]

LOS ANGELES – Following 6 months of treatment with the investigational agent levoketoconazole, several clinical signs and symptoms of Cushing’s disease improved, including acne, hirsutism, and peripheral edema, as did patient-reported quality of life and symptoms of depression.

The findings come from an analysis of secondary endpoints among patients enrolled in SONICS, an open-label, phase 3 study of levoketoconazole as a treatment for endogenous Cushing’s disease (CD) that enrolled 94 patients at centers in North America, Europe and the Middle East. An investigational cortisol synthesis inhibitor, levoketoconazole is being developed by Strongbridge Biopharma and is not yet approved by the Food and Drug Administration.

“Despite the availability of approved treatments, the medical needs in Cushing’s [disease] remain very high,” the study’s principal investigator, Maria Fleseriu, MD, FACE, said in an interview in advance of the annual scientific and clinical congress of the American Association of Clinical Endocrinologists, where the data were presented. “This study demonstrates that levoketoconazole has the potential to address several clinical features of Cushing’s, owing to its clinically translated novel mechanism of action to suppress both cortisol and androgen syntheses (the latter elevated in many women with CD). Interestingly, there was no evidence of clinically important free-T reduction in men, and more studies are needed to elucidate this mechanism.”

In SONICS, adults with confirmed CD and mean 24-hour urinary free-cortisol (mUFC) value at least 1.5 times the upper limit of normal were treated with levoketoconazole in three phases: 2- to 21-week dose-titration phase (150-600 mg BID, as needed, to target mUFC normalization); 6-month maintenance phase (primary endpoint); and 6-month extended evaluation phase. The end of maintenance phase findings that focused on reductions in mUFC and safety had been previously reported. The current analysis focused on secondary endpoints, including changes from baseline to end of maintenance in investigator-assessed CD clinical signs and symptoms (acne score [range: 0-44]; hirsutism score [women only; range: 0-36]; and peripheral edema score [range: 0-12]), and patient-reported outcomes of quality of life (Cushing QoL questionnaire score [range: 0-100]) and depression (Beck Depression Inventory II score [range: 0-63]). The researchers also assessed hormones including free testosterone levels, and they used paired t-tests to infer statistical significance of the mean changes from baseline to end of maintenance for all measures.

Of the 94 patients enrolled in SONICS, 77 entered the maintenance phase, said Dr. Fleseriu, professor of medicine and neurological surgery and director of the pituitary center at Oregon Health and Science University, Portland. The patients’ mean age was 44 years and mean baseline mUFC was 243.3 mcg/day; 82% of patients were female, and 96% were white. Between baseline and the end of maintenance, the researchers observed significant mean improvements in acne scores (from 2.8 to –1.8, respectively; P = .0063), hirsutism scores (women only, from 7.8 to –2.6; P = .0008), and peripheral edema scores (from 1.0 to –0.4; P = .0295). They also observed significant mean improvements in quality of life and depression scores between baseline and end of maintenance (P less than .0001 and P = .0043, respectively). Mean free-testosterone levels increased nonsignificantly between baseline and end of maintenance in men (from 5.1 to 5.8 ng/dL) yet decreased significantly in women (from 0.3 to 0.1 ng/dL; P less than 0.0001; reference). Overall, 33 patients (35%) discontinued taking levoketoconazole by the end of the maintenance phase. Twelve (13%) discontinued because of adverse events.

“I wasn’t necessarily surprised with any of the data in this poster as I had experience with the drug in clinical trials, but I was definitely pleased to see overall significant improvements in acne score, hirsutism score in women, and peripheral edema score,” Dr. Fleseriu said. “Those are benefits that could potentially increase long-term adherence to treatment and quality-of-life improvements, particularly in women. It’s also exciting to see that quality of life and depression improved in these patients as well.”

These types of patient-reported outcomes are so important to how our patients feel about their disease and should be more of a focus for us physicians; it’s important to look at efficacy, safety and patient reported outcomes when we decide for an individualized treatment for each patient,” she noted.

Dr. Fleseriu reported that she has received research funding for Oregon Health and Science University from Novartis, Millendo, and Strongbridge. She has also received scientific consulting fees from Novartis and Strongbridge.

[email protected]