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Osilodrostat therapy was found to be effective in improving blood pressure parameters, health-related quality of life, depression, and other signs and symptoms in patients with Cushing disease, regardless of the degree of cortisol control, according to study results presented at the 30th Annual Scientific and Clinical Congress of the American Association of Clinical Endocrinologists (ENVISION 2021). Investigators of the LINC 3 study (ClinicalTrials.gov Identifier: NCT02180217), a phase 3, multicenter study with a double-blind, randomized withdrawal period, sought to assess the effects of twice-daily osilodrostat (2-30 mg) on signs, symptoms, and health-related quality of life in 137 patients with Cushing disease. Study endpoints included change in various parameters from baseline to week 48, including mean urinary free cortisol (mUFC) status, cardiovascular-related measures, physical features, Cushing Quality-of-Life score, and Beck Depression Inventory score. Participants were assessed every 2, 4, or 12 weeks depending on the study period, and eligible participants were randomly assigned 1:1 to withdrawal at week 24. The median age of participants was 40.0 years, and women made up 77.4% of the cohort. Of 137 participants, 132 (96%) achieved controlled mUFC at least once during the core study period. At week 24, patients with controlled or partially controlled mUFC showed improvements in blood pressure that were not seen in patients with uncontrolled mUFC; at week 48, improvement in blood pressure occurred regardless of mUFC status. Cushing Quality-of-Life and Beck Depression Inventory scores, along with other metabolic and cardiovascular risk factors, improved from baseline to week 24 and week 48 regardless of degree of mUFC control. Additionally, most participants reported improvements in physical features of hypercortisolism, including hirsutism, at week 24 and week 48. The researchers indicated that the high response rate with osilodrostat treatment was sustained during the 48 weeks of treatment, with 96% of patients achieving controlled mUFC levels; improvements in clinical signs, physical features, quality of life, and depression were reported even among patients without complete mUFC normalization. Disclosure: This study was sponsored by Novartis Pharma AG; however, as of July 12, 2019, osilodrostat is an asset of Recordati AG. Please see the original reference for a full list of authors’ disclosures. Visit Endocrinology Advisor‘s conference section for complete coverage from the AACE Annual Meeting 2021: ENVISION. Reference Pivonello R, Fleseriu M, Newell-Price J, et al. Effect of osilodrostat on clinical signs, physical features and health-related quality of life (HRQoL) by degree of mUFC control in patients with Cushing’s disease (CD): results from the LINC 3 study. Presented at: 2021 AACE Virtual Annual Meeting, May 26-29, 2021. From https://www.endocrinologyadvisor.com/home/conference-highlights/aace-2021/osilodrostat-improves-blood-pressure-hrqol-and-depression-in-patients-with-cushing-disease/-
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Data from LINC3 and LINC4 provide insight into the impact of dosing titration schedules on risk of hypocortisolism-related adverse events associated with osilodrostat use in patients with Cushing's disease. Data from a pair of phase 3 studies presented at the American Academy of Clinical Endocrinology’s 30th Annual Meeting (AACE 2021) is providing insight into the effect of dose titration schedules with use of osilodrostat (Isturisa) in patients with Cushing’s disease. Presented by Maria Fleseriu, MD, of Oregon Health and Science University, the analysis of the LINC3 and LINC4 demonstrated the more gradual titration occurring in LINC4 resulted in a lower proportion of hypocortisolism-related adverse events, suggesting up-titration every 3 weeks rather than every 2 weeks could help lower event risk without compromising mean urinary free cortisol (mUFC) control. “For patients with Cushing’s disease, osilodrostat should be initiated at the recommended starting dose with incremental dose increases, based on individual response/tolerability aimed at normalizing cortisol levels,” concluded investigators. With approval from the US Food and Drug Administration in March 2020 for patients not eligible for pituitary surgery or have undergone the surgery but still have the disease, osilodrostat became the first FDA-approved therapy address cortisol overproduction by blocking 11β-hydroxylase. Based on results of LINC3, data from the trial, and the subsequent LINC4 trial, provide the greatest available insight into use of the agent in this patient population. The study presented at AACE 2021 sought to assess whether slow dose up titration might affect rates of hypocortisolism-related adverse events by comparing titration schedules from both phase 3 trials. Median osilodrostat exposure was 75 (IQR, 48-117) weeks and 70 (IQR, 49-87) weeks in LINC3 and LINC4, respectively. The median time to first mUFC equal to or less than ULN was 41 (IQR, 30-42) days in LINC3 and 35 (IQR, 34-52) days in LINC4. Adverse events potentially related to hypocortisolism were more common among patients in LINC3 (51%, n=70) than LINC4 (27%, n=20). Upon analysis of adverse events, investigators found the most commonly reported type of adverse event was adrenal insufficiency, which included events of glucocorticoid deficiency, adrenocortical insufficiency, steroid withdrawal syndrome, and decreased urinary free cortisol. Results incited the majority of hypocortisolism-related adverse events occurred during the dos titration periods of each trial. In LINC3, 54 of the 70 (77%) hypocortisolism-related adverse events occurred by week 26. In comparison, 58% of hypocortisolism-related adverse events occurring in LINC4 occurred prior to week 12. Investigators noted most of events that occurred were mild or moderate and managed with dose interruption or reduction of osilodrostat or concomitant medications. This study, “Effect of Dosing and Titration of Osilodrostat on Efficacy and Safety in Patients with Cushing's Disease (CD): Results from Two Phase III Trials (LINC3 and LINC4),” was presented at AACE 2021. From https://www.endocrinologynetwork.com/view/fda-panels-votes-to-support-teplizumab-potential-for-delaying-type-1-diabetes
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— Gradual dose escalation had fewer adverse events, same therapeutic benefit, as quicker increases by Kristen Monaco, Staff Writer, MedPage Today May 27, 2021 A more gradual increase in oral osilodrostat (Isturisa) dosing was better tolerated among patients with Cushing's disease, compared with those who had more accelerated increases, a researcher reported. Looking at outcomes from two phase III trials assessing osilodrostat, only 27% of patients had hypocortisolism-related adverse events if dosing was gradually increased every 3 weeks, said Maria Fleseriu, MD, of Oregon Health & Science University in Portland, in a presentation at the virtual meeting of the American Association of Clinical Endocrinology (AACE). On the other hand, 51% of patients experienced a hypocortisolism-related adverse event if osilodrostat dose was increased to once every 2 weeks. Acting as a potent oral 11-beta-hydroxylase inhibitor, osilodrostat was first approved by the FDA in March 2020 for adults with Cushing's disease who either cannot undergo pituitary gland surgery or have undergone the surgery but still have the disease. The drug is currently available in 1 mg, 5 mg, and 10 mg film-coated tablets. The approval came based off of the positive findings from the complementary LINC3 and LINC4 trials. The LINC3 trial included 137 adults with Cushing's disease with a mean 24-hour urinary free cortisol concentration (mUFC) over 1.5 times the upper limit of normal (50 μg/24 hours), along with morning plasma adrenocorticotropic hormone above the lower limit of normal (9 pg/mL). During the open-label, dose-escalation period, all the participants were given 2 mg of osilodrostat twice per day, 12 hours apart. Over this 12-week titration phase, dose escalations were allowed once every 2 weeks if there were no tolerability issues to achieve a maximum dose of 30 mg twice a day. After this 12-week dose-escalation schedule, additional bumps up in dose were permitted every 4 weeks. The median daily osilodrostat dose was 7.1 mg. The LINC4 trial included 73 patients with Cushing's disease with an mUFC over 1.3 times the upper limit of normal. The 48 patients randomized to receive treatment were likewise started on 2 mg bid of osilodrostat. However, this trial had a more gradual dose-escalation schedule, as doses were increased only every 3 weeks to achieve a 20 mg bid dose. After the 12-week dose-escalation phase, patients on a dose over 2 mg bid were restarted on 2 mg bid at week 12, where dose escalations were permitted once every 3 weeks thereafter to achieve a maximum 30 mg bid dose during this additional 36-week extension phase. Patients in this trial achieved a median daily osilodrostat dose of 5.0 mg. In both studies, patients' median age was about 40 years, the majority of patients were female, and about 88% had undergone a previous pituitary surgery. When comparing the adverse event profiles of both trials, Fleseriu and colleagues found that more than half of patients on the 2-week dose-escalation schedule experienced any grade of hypercortisolism-related adverse events. About 10.2% of these events were considered grade 3. About 28% of these patients had adrenal insufficiency -- the most common hypercortisolism-related adverse event reported. This was a catch-all term that include events like glucocorticoid deficiency, adrenocortical insufficiency, steroid withdrawal syndrome, and decreased cortisol, Fleseriu explained. Conversely, only 27.4% of patients on a 3-week dose escalation schedule experienced a hypercortisolism-related adverse event, and only 2.7% of these were grade 3. No grade 4 events occurred in either trial, and most events were considered mild or moderate in severity. "These adverse events were not associated with any specific osilodrostat dose of mean UFC level," Fleseriu said, adding that most of these events occurred during the initial dose-escalation periods. About 60% and 58% of all hypocortisolism-related adverse events occurred during the dose titration period in the 2-week and 3-week dose-escalation schedules, respectively. These events were managed via dose reduction, a temporary interruption in medication, and/or a concomitant medication. Very few patients in either trial permanently discontinued treatment due to these adverse events, Fleseriu noted. "Despite differences in the frequency of dose escalation, the time to first mUFC normalization was similar in the LINC3 and LINC4 studies," she said, adding that "gradual increases in osilodrostat dose from a starting dose of 2 mg bid can mitigate hypocortisolism-related adverse events without affecting mUFC control." "For patients with Cushing's disease, osilodrostat should be initiated at the recommended starting dose with incremental dose increases, based on individual response and tolerability aimed at normalizing cortisol levels," Fleseriu concluded. Kristen Monaco is a staff writer, focusing on endocrinology, psychiatry, and dermatology news. Based out of the New York City office, she’s worked at the company for nearly five years. Disclosures The LINC3 and LINC4 trials were funded by Novartis. Fleseriu reported relationships with Novartis, Recordati, and Strongbridge Biopharma. Primary Source American Association of Clinical Endocrinology Source Reference: Fleseriu M, et al "Effect of dosing and titration of osilodrostat on efficacy and safety in patients with Cushing's disease (CD): Results from two phase III trials (LINC3 and LINC4)" AACE 2021. From https://www.medpagetoday.com/meetingcoverage/aace/92824?xid=nl_mpt_DHE_2021-05-28&eun=g1406328d0r&utm_source=Sailthru&utm_medium=email&utm_campaign=Daily Headlines Top Cat HeC 2021-05-28&utm_term=NL_Daily_DHE_dual-gmail-definition
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Osilodrostat treatment was found to be associated with a rapid and sustained reduction in mean concentration of urinary free cortisol (UFC) and improved clinical symptoms in patients with Cushing’s disease, according to the results of a prospective, multicenter, open-label, phase 3 study published in the Lancet Diabetes Endocrinology. Osilodrostat is an oral inhibitor of 11-β hydroxylase cytochrome P450. Adults aged 18 to 75 years of age with diagnosed persistent or recurrent Cushing’s disease were recruited between 2014 and 2017 at 66 hospitals in 19 countries. Cushing’s disease was defined by a mean UFC concentration over a 24-hour period >1.5 times greater than the upper limit of normal (ULN) and morning plasma adrenocorticotropic hormone level above normal limits. Participants (n=137) received 30 mg osilodrostat twice daily, dose which was adjusted every 2 weeks until week 12 on the basis of mean 24-hour UFC concentration. The determined maintenance dose was continued until week 24. At week 26, participants who had achieved 24-hour UFC concentration ≤ ULN and did not need titration after week 12 were randomly assigned in an equal ratio to maintain osilodrostat treatment or were switched to a placebo for 8 weeks. This 8-week period of the study was double-blinded. During weeks 35 to 48, all patients were returned to osilodrostat treatment. In this cohort, mean age was 40.0 years (range, 19.0-70.0 years), 77% of participants were women, the average time since diagnosis was 47.2 months (interquartile range [IQR], 19.0-88.3), 88% had previous pituitary surgery, 16% had pituitary radiation therapy, and 74% had medicinal therapy. At baseline, the mean 24-hour UFC concentration was 1006±1590 nmol/24 h. At week 24, 53% of participants achieved a mean 24-hour UFC concentration ≤ULN without increases in dose after week 12 and were eligible for randomization (osilodrostat, n=36; placebo, n=35). At week 34, more patients receiving osilodrostat vs placebo maintained a complete response (86% vs 29%, respectively; odds ratio [OR], 13.7; 95% CI, 3.7-53.4; P <.0001). Improvements in cardiovascular-related metabolic parameters associated with hypercortisolism and overall measures of well-being were observed. Levels of high-density lipoprotein decreased by week 48 (-0.3 mmol/L; 95% CI, .0.3 to -0.2), mean Cushing’s quality of life score increased by 52.4% (95% CI, 32.3-72.7), and Beck Depression Inventory score decreased by 31.8% (95% CI, -44.3 to -19.3). Adverse events were hypocortisolism (51%), adverse events related with adrenal hormone precursors (42%), nausea (42%), headache (34%), fatigue (28%), and adrenal insufficiency (28%). A total of 18% of participants dropped out of the study due to adverse events. The major limitation of this study was the short withdrawal period (8 weeks) which may not have permitted to observe symptoms of hypercortisolism. “Alongside careful dose adjustments and monitoring of known risks associated with osilodrostat, our findings indicate a positive benefit– risk consideration of treatment for most patients with Cushing’s disease,” concluded the study authors. Disclosure: Multiple authors declared affiliations with industry. Please refer to the original article for a full list of disclosures. Reference Pivonello R, Fleseriu M, Newell-Price J, et al. Efficacy and safety of osilodrostat in patients with Cushing’s disease (LINC 3): a multicentre phase III study with a doubleblind, randomised withdrawal phase. Lancet Diabetes Endocrinol. 2020;S2213-8587(20)30240-0. doi:10.1016/S2213-8587(29)30240-0 From https://www.endocrinologyadvisor.com/home/topics/general-endocrinology/osilodrostat-sustained-reduction-mean-ufc-concentration-cushings-disease/
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Hypercortisolism Quickly Reversed With Oral Tx Oral osilodrostat (Isturisa) normalized cortisol levels in Cushing's disease patients who were ineligible for or not cured with pituitary surgery, according to the phase III LINC 3 trial. After 24 weeks of open-label treatment with twice-daily osilodrostat, 53% of patients (72 of 137; 95% CI 43.9-61.1) were able to maintain a complete response -- marked by mean 24-hour urinary free cortisol concentration of the upper limit of normal or below -- without any uptitration in dosage after the initial 12-week buildup phase, reported Rosario Pivonello, MD, of the Università Federico II di Napoli in Italy, and colleagues. As they explained in their study online in The Lancet Diabetes & Endocrinology, following the 24-week open-label period these complete responders to treatment were then randomized 1:1 to either remain on osilodrostat or be switched to placebo. During this 10-week randomization phase, 86% of patients maintained their complete cortisol response if they remained on osilodrostat versus only 29% of those who were switched to placebo (odds ratio 13.7, 95% CI 3.7-53.4, P<0.0001) -- meeting the trial's primary endpoint. As for adverse events, more than half of patients experienced hypocortisolism, and the most common adverse events included nausea (42%), headache (34%), fatigue (28%), and adrenal insufficiency (28%). "Alongside careful dose adjustments and monitoring of known risks associated with osilodrostat, our findings indicate a positive benefit-risk consideration of treatment for most patients with Cushing's disease," the researchers concluded. This oral inhibitor of 11β-hydroxylase -- the enzyme involved in the last step of cortisol synthesis -- was FDA approved in March 2020 based on these findings, and is currently available in 1 mg, 5 mg, and 10 mg film-coated tablets. The prospective trial, consisting of four periods, included individuals between the ages of 18 and 75 with confirmed persistent or recurrent Cushing's disease -- marked by a mean 24-h urinary free cortisol concentration over 1.5 times the upper limit of normal (50 μg/24 hours), along with morning plasma adrenocorticotropic hormone above the lower limit of normal (9 pg/mL). All individuals had either undergone prior pituitary surgery or irradiation, were not deemed to be candidates for surgery, or had refused to have surgery. During the first open-label study period, all participants took 2 mg of oral osilodrostat twice daily, spaced 12 hours apart. This dose was then titrated up if the average of three 24-h urinary free cortisol concentration samples exceeded the upper limit of normal. During the second study period, which spanned weeks 12 through 24, all participants remained on their osilodrostat therapeutic dose. By week 24, about 62% of the participants were taking a therapeutic dose of 5 mg or less twice daily; only about 6% of patients needed a dose higher than 10 mg twice daily. In the third study period, which spanned weeks 26 through 34, "complete responders" who achieved normal cortisol levels were then randomized to continue treatment or be switched to placebo, while those who did not fully respond to treatment continued on osilodrostat. For the fourth study period, from weeks 24 through 48, all participants were switched back to active treatment with osilodrostat. Overall, 96% of participants were able to achieve a complete response at some point while on osilodrostat treatment, with two-thirds of these responders maintaining this normalized cortisol level for at least 6 months. The median time to first complete response was 41 days. Metabolic profiles also improved along with this reduction in cortisol levels. These included improvements in body weight, body mass index, fasting plasma glucose, both systolic and diastolic blood pressures, and total cholesterol levels. "Given the known clinical burden of cardiovascular risk associated with Cushing's disease, the improvement in clinical features shown here indicates important benefits of osilodrostat," the researchers said. "By improving multiple cardiovascular risk factors, our findings are likely to be clinically relevant." Along with metabolic improvements, patients also had "clinically meaningful improvements" in quality of life, as well as reductions in depressive symptoms measured by the Beck Depression Inventory score, the investigators reported. One limitation to the trial, they noted, was an inability to control for concomitant medications, since nearly all participants were taking other medications, particularly antihypertensive and antidiabetic therapies. "Further examination of the effects of osilodrostat on the clinical signs of Cushing's disease, and the reasons for changes in concomitant medications and the association between such medications and clinical outcomes would be valuable," Pivonello's group said. From https://www.medpagetoday.com/endocrinology/generalendocrinology/87827
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Cushing syndrome, a rare endocrine disorder caused by abnormally excessive amounts of the hormone cortisol, has a new pharmaceutical treatment to treat cortisol overproduction. Osilodrostat (Isturisa) is the first FDA approved drug who either can’t undergo pituitary gland surgery or have undergone the surgery but still have the disease. The oral tablet functions by blocking the enzyme responsible for cortisol synthesis, 11-beta-hydroxylase. “Until now, patients in need of medications…have had few approved options, either with limited efficacy or with too many adverse effects. With this demonstrated effective oral treatment, we have a therapeutic option that will help address patients' needs in this underserved patient population," said Maria Fleseriu, MD, FACE, professor of medicine and neurological surgery and director of the Pituitary Center at Oregon Health Sciences University. Cushing disease is caused by a pituitary tumor that releases too much of the hormone that stimulates cortisol production, adrenocorticotropin. This causes excessive levels of cortisol, a hormone responsible for helping to maintain blood sugar levels, regulate metabolism, help reduce inflammation, assist in memory formulation, and support fetus development during pregnancy. The condition is most common among adults aged 30-50 and affects women 3 times more than men. Cushing disease can lead to a number of medical issues including high blood pressure, obesity, type 2 diabetes, blood clots in the arms and legs, bone loss and fractures, a weakened immune system, and depression. Patients with Cushing disease may also have thin arms and legs, a round red full face, increased fat around the neck, easy bruising, striae (purple stretch marks), or weak muscles. Side effects of osilodrostat occurring in more than 20% of patients are adrenal insufficiency, headache, nausea, fatigue, and edema. Other side effects can include vomiting, hypocortisolism (low cortisol levels), QTc prolongation (heart rhythm condition), elevations in adrenal hormone precursors (inactive substance converted into hormone), and androgens (hormone that regulated male characteristics). Osilodrostat’s safety and effectiveness was evaluated in a study consisting of 137 patients, of which about 75% were women. After a 24-week period, about half of patients had achieved normal cortisol levels; 71 successful cases then entered an 8-week, double-blind, randomized withdrawal study where 86% of patients receiving osilodrostat maintained normal cortisol levels, compared with 30% who were taking a placebo. In January 2020, the European Commission also granted marketing authorization for osilodrostat. From https://www.ajmc.com/newsroom/patients-with-cushing-have-new-nonsurgical-treatment-option
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NEW ORLEANS — The investigational drug osilodrostat (Novartis) continues to show promise for treating Cushing's disease, now with new phase 3 trial data. The data from the phase 3, multicenter, double-blind randomized withdrawal study (LINC-3) of osilodrostat in 137 patients with Cushing's disease were presented here at ENDO 2019: The Endocrine Society Annual Meeting by Beverly M.K. Biller, MD, of the Neuroendocrine & Pituitary Tumor Center at Massachusetts General Hospital, Boston. "Osilodrostat was effective and shows promise for the treatment of patients with Cushing's disease," Biller said. Osilodrostat is an oral 11β-hydroxylase inhibitor, the enzyme that catalyzes the last step of cortisol biosynthesis in the adrenal cortex. Its mechanism of action is similar to that of the older Cushing's drug metyrapone, but osilodrostat has a longer plasma half-life and is more potent against 11β-hydroxylase. Significantly more patients randomized to osilodrostat maintained a mean urinary free cortisol (mUFC) response versus placebo at 34 weeks following a 24-week open-label period plus 8-week randomized phase, with rapid and sustained mUFC reduction in most patients. Patients also experienced improvements in clinical signs of hypercortisolism and quality of life. The drug was generally well-tolerated and had no unexpected side effects. Asked to comment, session comoderator Julia Kharlip, MD, associate medical director of the Pituitary Center at the University of Pennsylvania, Philadelphia, told Medscape Medical News, "This drug is incredibly exciting because over 80% of people were controlled fairly rapidly. People could get symptom relief but also a reliable response. You don't have to wonder when you're treating a severely affected patient if it's going to work. It's likely going to work." However, Kharlip cautioned that it remains to be seen whether osilodrostat continues to work long-term, given that the older drug metyrapone — which must be given four times a day versus twice daily for osilodrostat — is known to become ineffective over time because the pituitary tumor eventually overrides the enzyme blockade. "Based on how osilodrostat is so much more effective at smaller doses, there's more hope that it will be effective long term...If the effectiveness and safety profile that we're observing now continues to show the same performance years in a row, then we've got our drug." Osilodrostat Potentially Addresses an Unmet Medical Need Cushing's disease is a rare disorder of chronic hypercortisolism with significant burden, increased mortality, and decreased quality of life. Pituitary surgery is the recommended first-line treatment for most patients, but not all patients remit with surgery and some require additional treatment. Pasireotide (Signifor, Novartis), an orphan drug approved in the United States and Europe for the treatment of Cushing's disease in patients who fail or are ineligible for surgical therapy, is also only effective in a minority of patients. "There hasn't been a medicine effective for long-term treatment, so a lot of patients end up getting bilateral adrenalectomy, thereby exchanging one chronic medical disease for another," Kharlip explained. Biller commented during the question-and-answer period, "I think because not all patients are placed in remission with surgery initially and because other patients subsequently recur — a problem that is more common than we used to believe — we do need medical therapies." She continued, "I think it's important to have a large choice of medical therapies that work in different places in the hypothalamic-pituitary-adrenal axis. "Even though surgery is the right initial therapy for everyone, I think in terms of subsequent medical therapy we have to tailor that to the individual circumstances of the patient in terms of the goals of treatment, and perhaps what other medicines they're on, the degree of cortisol excess [and other factors]." Highly Significant Normalization in Mean UFC Versus Placebo In a prior 22-week phase 2 study (LINC-2), osilodrostat normalized mUFC in most patients. Results of the extension phase were reported by Medscape Medical News 2 years ago. The current phase 3 study, LINC-3, was conducted on the basis of that proof-of-concept study, Biller said. The trial was conducted in 19 countries across four continents in patients with persistent or recurrent Cushing's disease screened for mUFC > 1.5 times the upper limit of normal and other entry criteria. In total, 137 patients were enrolled and randomized. Participants were a median age of 40 years, 77% were female, and 88% had undergone prior pituitary surgery. Nearly all (96%) had received at least one previous treatment for Cushing's. At baseline, patients' mean mUFC (364 µg/24 hours) was 7.3 times the upper limit of normal, which is "quite significant hypercortisolemia," Biller noted. All patients initially received osilodrostat, with a rapid dose uptitration every 2 weeks from 2 to 30 mg orally twice daily until they achieved a normal UFC. They continued on open-label medication until week 24, when urine samples were collected. Patients who had an mUFC less than the upper limit of normal and had not had a dose increase in the prior 12 weeks were eligible for the double-blind phase. Those who were ineligible continued taking open-label drug. The 70 eligible patients were randomized to continue taking osilodrostat (n = 36) or were switched to placebo (n = 34) for another 8 weeks. After that, the patients taking placebo were switched back to osilodrostat until week 48. A total of 113 patients completed the 48 weeks. The primary efficacy endpoint was mUFC at 34 weeks (the end of the 8-week randomized phase). For those randomized to continue on the drug, mUFC remained in the normal range in 86.1% of patients versus just 29.4% of those who had been switched to placebo for the 8 weeks. The difference was highly significant (odds ratio, 13.7; P < .001), Biller reported. A key secondary endpoint, proportion of patients with an mUFC at or below the ULN at 24 weeks without up-titration after week 12, was achieved in 53%. The mean dose at 48 weeks was 11.0 mg/day, "a fairly low dose," she noted. Clinical features were also improved at week 48, including systolic and diastolic blood pressure (percentage change –6.8 and –6.6, respectively), weight (–4.6), waist circumference (–4.2), fasting plasma glucose (–7.1), and HbA1c (–5.4). Scores on the Cushing Quality of Life scale improved by 52.4 points, and Beck Depression Inventory scores dropped by 31.8 points. Most Adverse Events Temporary, Manageable The most commonly reported adverse events were nausea (41.6%), headache (33.6%), fatigue (28.5%), and adrenal insufficiency (27.7%), and 10.9% of patients overall discontinued because of an adverse event. Adverse events related to hypocortisolism occurred in 51.1% of patients overall, with 10.2% being grade 3 or 4. However, most of these were single episodes of mild-to-moderate intensity and mainly occurred during the initial 12-week titration period. Most patients responded to dose reduction or glucocorticoid supplementation. Adverse events related to accumulation of adrenal hormone precursors occurred in 42.3% of patients overall, with the most common being hypokalemia (13.1%) and hypertension (12.4%). No male patients had signs or symptoms related to increased androgens or estrogens. However, 12 female patients experienced hirsutism, most of those patients also had acne, and one had hypertrichosis. None discontinued because of those symptoms. Kharlip commented, "What's really inspiring was that even though half of the patients had symptoms related to adrenal insufficiency, it sounded as if they were quickly resolved with treatment and none discontinued because of it." "And it may have been related to study design where the medication was titrated very rapidly. There is probably a way to do this more gently and get the good results without the side effects." Kharlip also praised the international consortium that devised the protocol and collaborated in the research effort. "It's incredibly exciting and gratifying to see the world come together to get these data. It's such a rare disease. To be able to have something like that in the field is a dream, to have a working consortium. The protocol was effective in demonstrating efficacy. It's just a win on so many levels for a disease that currently doesn't have a good therapy...I struggle with these patients all the time so I'm thrilled that there is hope." An ongoing confirmatory phase 3 study, LINC-4, is evaluating patients up to 48 weeks. Biller is a consultant for and has received grants from Novartis and Strongbridge. Kharlip has reported no relevant financial relationships. For more diabetes and endocrinology news, follow us on Twitter and on Facebook. From https://www.medscape.com/viewarticle/910864#vp_1
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CLCI699C2302: A Phase III, Multi-center, Randomized, Double-blind, 48 Week Study with an Initial 12 Week Placebo-controlled Period to Evaluate the Safety and Efficacy of Osilodrostat in Patients with Cushing’s Disease Purpose In people with a disorder known as Cushing’s disease, levels of the hormone cortisol are very high in the urine and blood. Lowering cortisol levels relieves the symptoms of Cushing’s disease. Osilodrostat is an investigational drug that inhibits an enzyme needed for cortisol to be made. In this study, researchers are assessing the safety and effectiveness of osilodrostat in patients with Cushing¿s disease and observing its ability to reduce cortisol levels. In the first 12 weeks of the study, patients will receive osilodrostat or a placebo (inactive drug). After week 12 and continuing through week 48, all patients will receive osilodrostat. Patients will then have the option to continue taking osilodrostat for up to 100 weeks into the study, if they wish. Osilodrostat is taken orally (by mouth). Eligibility To be eligible for this study, patients must meet several criteria, including but not limited to the following: Patients must have Cushing¿s disease with elevated levels of cortisol in the urine. An acceptable amount of time must have passed between the completion of prior therapies and entry into the study, to allow for a sufficient “washout” period. This study is for patients ages 18 to 75. For more information about this study and to inquire about eligibility, please contact Dr. Eliza Geer at 646-888-2627. Protocol 17-351 Phase III Investigator Eliza B. Geer Co-Investigators Monica Girotra Diseases Pituitary Tumor Locations Memorial Sloan Kettering Memorial Hospital From https://www.mskcc.org/cancer-care/clinical-trials/17-351
