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    Home > Active Ingredient News > Endocrine System > "Ketoconazole + Octreotide", "Osilodrostat"... Will these become new methods of Cushing's treatment?

    "Ketoconazole + Octreotide", "Osilodrostat"... Will these become new methods of Cushing's treatment?

    • Last Update: 2021-04-21
    • Source: Internet
    • Author: User
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    Author: Medical team doctors report NMT NMT ENDO compile reports, please do not reprint without authorization.

    Introduction: The 2021 American Endocrine Society Annual Meeting (ENDO) released a number of research progress on "Cushing" therapeutic drugs, including Osilodrostat, Metyrapone, and "Ketoconazole + Octreotide" sequential therapy.
    We are one Get up and take a look.

     About Cushing's syndrome Cushing's syndrome, also known as hypercortisolism, is a clinical syndrome caused by long-term excessive secretion of glucocorticoids in the adrenal cortex due to various reasons.
    It is a rare disease with an incidence of 1-2 /1000000.

     Patients usually present with full moon face, bloody appearance, central obesity, acne, purple streaks, hypertension, secondary diabetes, and osteoporosis.

    The high incidence of this type of disease is 20-50 years old, and the incidence of women is three times that of men.

    The normalization of cortisol levels is the primary goal of the treatment of Cushing’s syndrome.

     1.
    Phase 3 clinical LINC 4 study: Osilodrostat is effective and well tolerated in the treatment of Cushing's disease 1.
    What is Osilodrostat? Osilodrostat is an oral 11β-hydroxylase inhibitor that can directly block the synthesis of adrenal cortisol, and can quickly and continuously normalize the average urinary free cortisol (mUFC) level in most patients with CD.

    At this ENDO conference, Dr.
    Mônica Gadelha from the University of Rio de Janeiro, Federal Republic of Rio de Janeiro, Brazil, introduced to us the results of the Phase 3 clinical LINC 4 study on "Osilodrostat for the treatment of Cushing's disease".

     2.
    Study description In this study, the researchers randomly divided adult CD patients with mUFC>1.
    3 x ULN into 2:1 groups, and were given osilodrostat 2mg bid or a matching placebo for a double-blind period of 12 weeks.
    And tolerability, adjust the drug dose (range 1-20 mg bid) at 2, 5, and 8 weeks respectively.

    From week 12 to week 48, all patients received open-label osilodrostat, allowing dose adjustments (range 1-30 mg bid).

    The primary endpoint of the study was: the proportion of patients in the osilodrostat group and the placebo group randomly assigned when mUFC≤ULN at 12 weeks.

     3.
    Osilodrostat is effective.
    A total of 73 CD patients were enrolled in this study, 48 in the Osilodrostat group and 25 in the placebo group.
    The baseline mUFC was 2.
    5 x ULN (0.
    7-12.
    5) vs.
    2.
    2 x ULN (0.
    2-18.
    9), respectively.

     ➤At 12 weeks, 77% of subjects in the osilodrostat group achieved mUFC≤ULN, compared with 8% in the control group (OR 43.
    4; P<0.
    0001).

     ➤At 36 weeks, 81% of subjects in the osilodrostat group achieved mUFC ≤ ULN (primary and secondary endpoint), and the average time to control the mUFC response for the first time was 35 days.

     ➤In the 12th and 48th weeks, improvements in cardiovascular and metabolic related parameters (including systolic and diastolic blood pressure and HbA1c) were observed in the osilodrostat group.

     3.
    Exploration of the safety of Osilodrostat During the entire study period, the most common adverse events of osilodrostat treatment were arthralgia (45%), loss of appetite (45%), fatigue (38%), nausea (37%) and headache (33%) ).

    The incidence of adverse events related to hypocortisolemia and pre-adrenal hormone accumulation was 15% and 0%, 44% and 36% in the treatment group and placebo group, respectively, and most were grade 1/2.
    Interrupt the dose and/or combination medication to resolve.

     4.
    Conclusion The rate of mUFC level returning to normal in the Osilodrostat group at 12 weeks was significantly better than that in the placebo group (77% vs.
    8%).
    The mUFC level continued to improve at 36 weeks, and a small number of patients were discontinued due to adverse events; low cortisol Adverse events related to hyperemia are rare and controllable.

    In conclusion, osilodrostat is an effective and well-tolerated CD treatment.

     Phase III/IV study: Treatment of endogenous Cushing’s syndrome, metirapone is safe and effective, Dr.
    Lynnette K.
    Nieman from the Institute of Diabetes and Digestive and Kidney Diseases of the National Institutes of Health shared with us the relevant beauty Results of Phase III/IV study of Metyrapone in the treatment of endogenous Cushing syndrome.

     1.
    About metyrapone metyrapone is a steroid production inhibitor and is approved in Europe for the treatment of endogenous Cushing syndrome (CS).
    The main evidence is an observational retrospective published over 50 years.
    the study.

    This study provides the first prospective study data, confirming the good efficacy and tolerability of metyrapone.

     2.
    Study description This single-arm, open-label, multi-center, international trial included 50 CS patients whose 24-hour urine free cortisol (UFC) value was at least higher than the upper limit of normal (ULN=165 nmol/24h) 50% higher.

    Gradually titrate the dose of metyrapone within 12 weeks to achieve normal urine and serum cortisol levels.

    Patients whose mUFC does not exceed 2 times the ULN can enter a 6-month extended period.

    The primary efficacy endpoint is the proportion of patients with mUFC≤ULN at 12 weeks; the key secondary endpoint is the proportion of patients with mUFC falling ≥50% at 12 weeks.

     3.
    The effectiveness of metyrapone was good.
    At 12 weeks, 47% of subjects reached the primary endpoint; another 40% of subjects had mUFC ≤ 2 times the ULN.

    The final median dose of metyrapone is 1500 mg/day.

    In 66% of patients, signs and symptoms were normalized or improved.

    Cholesterol, glycosylated hemoglobin, fasting blood glucose, and insulin all improved, with a median decrease of 12%, 3%, 5%, and 9%, respectively.
    The median systolic and diastolic blood pressure also decreased by 4mmHg and 5mmHg, respectively.

     Of the patients receiving antihypertensive treatment, 31% decreased their drug use during the study period, and 16% increased their drug use during the study period.

    The median ACTH increased by 11% from baseline.

    The Cushing Quality of Life Questionnaire increased by 10 points from the baseline.

     4.
    Safety exploration 52% of patients had mild to moderate study drug-related adverse events.

    The most common adverse reactions were nausea (24%), loss of appetite (18%), fatigue (14%), headache (10%), peripheral edema (6.
    0%), hypokalemia (6.
    0%) and hypertension ( 6.
    0%).

    In addition, 12% of subjects had reversible adrenal insufficiency.

     5.
    Conclusion This prospective study for CS patients confirmed that at the 12th week, metyrapone can effectively reduce UFC levels, tolerability is similar to previously reported safety, and improves the quality of life.

     3.
    Prospective study: In patients with mild Cushing’s disease, the sequential therapy of “ketoconazole + octreotide” seems to be effective.
    Dr.
    Ticiana Paes from the Erasmus Medical Center in Rotterdam, the Netherlands, introduced an “initial prescription ketone” The effectiveness of sequential therapy maintained with octreotide after conazole for the treatment of Cushing’s disease (CD)" study results.

     1.
    Study description This is a prospective study involving 14 adult CD patients.

    Initially, all patients received ketoconazole (600-800 mg/day) treatment.
    After the cortisol level returned to normal, combined with octreotide 20 mg/4 weeks, the dose could be increased to 30 mg/4 weeks.

    After two months of combination therapy, the patient continued to receive octreotide monotherapy until the end of the study (9 months).

    The treatment success rate is evaluated by the average of the two urine free cortisol (UFC) levels.

     2.
    Sequential therapy seems to be more effective for patients with mild CD.
    The average age of the subjects was 48.
    6 years, women accounted for 64%, and 85% were newly diagnosed patients who had not received treatment.

    Ketoconazole restored normal UFC levels in 11 patients (79%).
    Octreotide effectively maintained normal UFC levels in 3 of these patients (complete responders).
    In addition, 4 patients had partial responses to octreotide treatment (partial responses).
    By).

    In the above three patients, the normal UFC level was maintained for 1-2 months after ketoconazole was discontinued.
    Among the partial responders, the UFC level decreased by at least 50% from the baseline.

    The remaining 4 patients developed hypercortisolism (non-responders) immediately after ketoconazole was discontinued.

     Compared with some and non-responders, 3 octreotide responders had lower UFC levels at baseline (1.
    40±0.
    06 vs.
    2.
    05±0.
    20 ULN, p=0.
    08), and 2 of them had weight, waist circumference, systolic blood pressure and diastole The pressure has improved.

     In terms of adverse reactions, 1 patient discontinued ketoconazole due to gastrointestinal intolerance, and 5 patients experienced transient elevation of liver enzymes.

     3.
    Conclusion This study shows that in patients with mild CD, octreotide seems to be effective in maintaining normal cortisol production after initial ketoconazole reduction of cortisol levels.

    The ongoing study aims to assess whether the results of this study are related to increased expression of SST2 in ACTH adenomas.


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