Welcome to Cushing's New Drugs!

Compiled and organized by Yimaitong, please do not reprint without authorization
.

The U.
S.
Food and Drug Administration (FDA) has approved the steroidogenesis inhibitor levoketoconazole for the treatment of Cushing's syndrome in adults who cannot undergo surgery or have not been treated, according to news from the Healio website
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Approval was based on two Phase 3 studies - SONICS and LOGICS - conducted in multiple countries
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The studies described above evaluated the efficacy of levokeconazole as a potential treatment for endogenous hypercortisolemia in adults with Cushing's syndrome and achieved positive efficacy and safety results
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 However, some experts have pointed out that despite the approval of new treatments, the management of Cushing's disease remains challenging, the disease is often associated with severe comorbidities and, if left uncontrolled, has a high mortality rate
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 Cushing's Syndrome and Unmet Need for Treatment Cushing's syndrome is a rare endocrine disorder that can cause death in severe cases
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Common clinical symptoms include full moon face, supraclavicular fat pad, buffalo back, central obesity, proximal muscle weakness, easy skin bruising, weight gain, hirsutism, and growth retardation in children, which may also be secondary A series of symptoms such as hypertension, osteopenia, diabetes and impaired immune function
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 Common treatment options for Cushing's syndrome include surgery, radiation therapy, and medication
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After surgical treatment, the cortisol concentration of some patients is still at a high level, and there are still symptoms and side effects related to the cortisol level, and the surgical effect is often not ideal
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However, the current drugs for the treatment of Cushing's syndrome have some shortcomings, and drugs with better effects and lower side effects are expected to appear in clinical practice
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In recent years, a new drug, levoketoconazole, has received attention as a possible alternative treatment option for endogenous Cushing's syndrome
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 Efficacy and Safety of Levoketoconazole Levoketoconazole, the pure (2S,4R) isomer of ketoconazole, is a cortisol synthesis inhibitor and is expected to be used in the treatment of endogenous Cushing's syndrome
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The drug has been approved by the FDA and the European Medicines Agency as a rare disease drug.
At present, the safety and efficacy of the drug have been evaluated by two phase III clinical trials of SONICS and LOGICS
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Overview of the SONICS and LOGICS studies A total of 166 adults with Cushing's syndrome were evaluated in both studies
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The SONICS study met its primary and key secondary endpoints, significantly reducing and normalizing mean urinary free cortisol concentrations without increasing the dose
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LOGICS, a double-blind, placebo-controlled, randomized drop-out study, met its primary and key secondary endpoints, demonstrating the efficacy and efficacy of levoketoconazole compared with placebo in normalizing treatment response and maintaining treatment security
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  Take the SONICS study as an example: SONICS is a single-arm, open-label study that studies different dose groups of the drug
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The study enrolled a total of 94 participants, including 77 women and 17 men, who had 24-hour mean urinary free cortisol (mUFC) levels at or above 1.
5 times the upper limit of normal
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 The initial oral dose of L-ketoconazole is 300 mg each time, bid
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The researchers will adjust the dose according to the participant's mUFC level, the maximum dose is 600mg each time, bid (if the patient cannot tolerate, the daily oral dose can be reduced to 150mg), once the participant's mUFC reaches normal levels, The drug dose is no longer adjusted, that is, the target therapeutic dose is reached
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 ➤ Drug efficacy: 77 of the 94 participants completed dose adjustment, and 61 of them reached the 6-month maintenance period
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Data on the secondary study endpoint showed a significant decrease in mean free testosterone levels in female participants during the maintenance phase (from 0.
32 ng/dL to 0.
12 ng/dL; P < 0.
0001)
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At the same time, the drug significantly reduced clinical symptoms caused by androgen excess, such as acne (P=0.
0063), peripheral edema (P=0.
0295) and hirsutism (P=0.
0008)
.

In male participants, mean free testosterone did not increase significantly (from 5.
1 ng/dL to 5.
8 ng/dL)
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Quality of life and depression scores improved for all participants
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 The primary endpoint of the study (no dose increase during the 6-month maintenance period while participants maintained normal mUFC levels) was achieved in 30% of participants
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In addition, 8% of participants maintained normalization of mUFC levels with increasing doses
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 ➤Drug safety: The study showed that the main adverse reactions related to levketoconazole were nausea (31.
9%), headache (27.
7%), peripheral edema (19.
1%), hypertension (17.
0%) and fatigue (16.
0%)
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Four of the participants had serious adverse reactions (1 case of elevated liver function indicators, 2 cases of QTc interval prolongation, and 1 case of adrenal insufficiency)
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In addition, mild-to-moderate liver enzyme elevations were detected in 15% of participants, and 13% discontinued medication due to treatment-related adverse events
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Studies have shown that L-ketoconazole can inhibit the synthesis of cortisol and testosterone and improve clinical symptoms associated with excess cortisol
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And it is safe and well tolerated
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Yimaitong compiled and compiled from: [1]Press release.
FDA approves levoketoconazole for Cushing's syndrome[EB/OL].
[2022-1-3].
https:// -approves-levoketoconazole-for-cushings-syndrome.
[2]https://