Cushing’s Disease Patients are More Likely to Have Ocular Hypertension

Posted on December 29, 2022 by MaryO

The following is the summary of “Increased Risk of Ocular Hypertension in Patients With Cushing’s Disease” published in the December 2022 issue of Glaucoma by Ma, et al.

Ocular hypertension was more common in people with Cushing’s illness. The usage of steroids in the body is a major contributor to high intraocular pressure (IOP). Topical or systemic glucocorticoid use may increase the prevalence of ocular hypertension in the general population from 30–40%. The prevalence of ocular hypertension in endogenous hypercortisolemia and the ophthalmological consequences following endocrine remission after surgical resection are unknown. During the period of January 2019 through July 2019, all patients with Cushing’s disease (CD) who were hospitalized at a tertiary pituitary facility for surgical intervention had their intraocular pressure (IOP), vision field, and peripapillary retinal nerve fiber layer thickness recorded.

Nonfunctioning pituitary adenoma (NFPA) patients and acromegaly patients from the same time period were used as comparison groups. Researchers showed postoperative changes in IOP, estimated the odds ratio (OR), and identified risk variables for the development of ocular hypertension. About 52 patients with CD were included in the study (mean age 38.4±12.4 years). Patients with CD had an IOP that was 19.4±5.4 mm Hg in the left eye and 20.0±7.1 mm Hg in the right eye, which was significantly higher than that of patients with acromegaly (17.5±2.3 mm Hg in the left eye and 18.6±7.0 mm Hg in the right eye, P=0.033) and NFPA (17.8±2.6 mm Hg in the left eye and 17.4±2.4 mm Hg in the right eye, Ocular hypertension was diagnosed in 21 eyes (20.2%) of CD patients, but only 4 eyes (4.7%) of acromegaly patients and 4 eyes (4.5%) of NFPA patients. Patients with CD had an odds ratio (OR) of 5.1 [95% CI, 1.3-25.1, P=0.029] and 6.6 [95% CI, 1.8-30.3, P=0.007] for developing ocular hypertension compared with the 2 control groups.

Higher levels of urine-free cortisol were associated with an increased risk of ocular hypertension in CD patients (OR=19.4, 95% CI, 1.7-72.6). Patients with CD saw a decrease in IOP at 1 month following surgery, and this improvement was maintained for another 2 months. Researchers conclude that endogenous hypercortisolemia should be included as part of the glaucoma assessment due to the increased risk of ocular hypertension in CD. Ophthalmologists and neuroendocrinologists should use their judgment in light of this finding.

Source:  journals.lww.com/glaucomajournal/Fulltext/2022/12000/Increased_Risk_of_Ocular_Hypertension_in_Patients.3.aspx

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Levoketoconazole Treatment in Endogenous Cushing’s Syndrome

Posted on November 9, 2022 by MaryO

Objective: This extended evaluation (EE) of the SONICS study assessed effects of levoketoconazole for an additional 6 months following open-label, 6-month maintenance treatment in endogenous Cushing’s syndrome.

Design/Methods: SONICS included dose-titration (150–600 mg BID), 6-month maintenance, and 6-month EE phases. Exploratory efficacy assessments were performed at Months 9 and 12 (relative to start of maintenance). For pituitary MRI in patients with Cushing’s disease, a threshold of ≥2 mm denoted change from baseline in largest tumor diameter.

Results: Sixty patients entered EE at Month 6; 61% (33/54 with data) exhibited normal mean urinary free cortisol (mUFC). At Months 9 and 12, respectively, 55% (27/49) and 41% (18/44) of patients with data had normal mUFC. Mean fasting glucose, total and LDL-cholesterol, body weight, body mass index, abdominal girth, hirsutism, CushingQoL, and BDI-II scores improved from study baseline at Months 9 and 12. Forty-six patients completed Month 12; 4 (6.7%) discontinued during EE due to adverse events. The most common adverse events in EE were arthralgia, headache, hypokalemia, and QT prolongation (6.7% each). No patient experienced ALT or AST >3× ULN, QTcF interval >460 msec, or adrenal insufficiency during EE. Of 31 patients with tumor measurements at baseline and Month 12 or follow-up, largest tumor diameter was stable in 27 (87%) patients, decreased in 1, and increased in 3 (largest increase 4 mm).

Conclusion: In the first long-term levoketoconazole study, continued treatment through 12-month maintenance period sustained the early clinical and biochemical benefits in most patients completing EE, without new adverse effects.

Read the whole article at https://eje.bioscientifica.com/configurable/content/journals$002feje$002faop$002feje-22-0506$002feje-22-0506.xml?t%3Aac=journals%24002feje%24002faop%24002feje-22-0506%24002feje-22-0506.xml&body=pdf-45566

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Sparrow Pharmaceuticals Presents New Clinical Trial Data Analyses on HSD-1 Inhibitor SPI-62 at the 24th European Congress of Endocrinology

Posted on June 1, 2022 by MaryO

Clinical trial analyses focus on the human body’s homeostatic response to potent HSD-1 inhibition by SPI-62

Results highlight that urinary free cortisol is distinct from intracellular cortisol that causes symptoms in patients with Cushing’s syndrome or autonomous cortisol secretion

PORTLAND, Ore.–(BUSINESS WIRE)–Sparrow Pharmaceuticals, an emerging, clinical-stage biopharmaceutical company developing novel, targeted therapies for disorders of glucocorticoid excess, today presented new pharmacological data during a poster session and a Rapid Communications session titled, “HPA axis modulation by a potent inhibitor indicates 11β-hydroxysteroid dehydrogenase type 1 (HSD-1) is a main source of cortisol that can bind intracellular receptors” at the 24th European Congress of Endocrinology (ECE 2022). Sparrow scientists examined the steroid hormone changes after administration of its lead therapeutic candidate, SPI-62, an HSD-1 inhibitor, to healthy adults.

“Normalized urinary free cortisol, or UFC, is a standard therapeutic target for patients with Cushing’s syndrome,” said David A. Katz, Ph.D., CSO at Sparrow Pharmaceuticals, “But that biomarker doesn’t measure the cortisol that can access intracellular receptors and cause symptoms. UFC normalization has been shown not to correlate with clinical endpoints in patients with Cushing’s syndrome. Many patients with autonomous cortisol secretion have normal UFC, yet substantial cortisol morbidity. As we conduct clinical trials for patients with those diseases, we’re in search of better ways to measure the cortisol that makes patients ill.”

The study analyzed historical clinical trial data to better characterize how SPI-62 impacts cortisol levels and the body’s homeostatic response to those changes.

Conclusions of the study include:

  • Half of hepatocellular cortisol with access to intracellular receptors is generated in healthy adults by HSD-1.
  • ACTH increase compensates for the effect of HSD-1 inhibition on systemic cortisol levels.
  • Secondary increases of androgen levels have not been associated to date with clinical consequences.
  • Large changes of the amount of cortisol that can bind intracellular receptors, and thus cause cortisol-related morbidity, can occur independently of urinary free cortisol levels.

HSD-1 converts cortisone to cortisol in tissues in which cortisol excess is associated with morbidity including liver, adipose, bone, and brain. SPI-62 is a potent HSD-1 inhibitor in clinical development for treatment of Cushing’s syndrome and autonomous cortisol secretion, and as adjunctive therapy to prednisolone in polymyalgia rheumatica. In Phase 1 clinical trials SPI-62 was generally well tolerated and associated with maximal liver and brain HSD-1 inhibition.

To register and view the abstracts, visit ECE’s website here.

From https://www.businesswire.com/news/home/20220524005465/en/Sparrow-Pharmaceuticals-Presents-New-Clinical-Trial-Data-Analyses-on-HSD-1-Inhibitor-SPI-62-at-the-24th-European-Congress-of-Endocrinology

 

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Osilodrostat Effective for Patients With Cushing Disease

Posted on May 7, 2022 by MaryO

Osilodrostat is associated with rapid normalization of mean urinary free cortisol (mUFC) excretion in patients with Cushing disease and has a favorable safety profile, according to the results of a study published in the Journal of Clinical Endocrinology & Metabolism.

The phase 3 LINC-4 study (ClinicalTrials.gov Identifier: NCT02697734) evaluated the safety and efficacy of osilodrostat, a potent, orally available 11β­-hydroxylase inhibitor, compared with placebo in patients with Cushing disease.

The trial, which was conducted at 40 centers in 14 countries, included a 12-week, randomized, double-blind, placebo-controlled period that was followed by a 36-week, open-label osilodrostat treatment period with an optional extension.

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Osilodrostat Normalizes Urinary Free Cortisol in Most Adults with Cushing’s Disease

Posted on April 13, 2022 by MaryO

More than three-quarters of adults with Cushing’s disease assigned osilodrostat had a normalized mean urinary free cortisol level at 12 weeks and maintained a normal level at 36 weeks, according to data from the LINC 4 phase 3 trial.

In findings published in The Journal of Clinical Endocrinology & Metabolism, 77% of adults with Cushing’s disease randomly assigned to osilodrostat (Isturisa, Recordati) had mean urinary free cortisol (UFC) levels reduced to below the upper limit of normal at 12 weeks compared with 8% of adults assigned to placebo.

Osilodrostat normalizes UFC in most people with Cushing's disease at 12 weeks
Most adults with Cushing’s disease taking 2 mg twice daily osilodrostat had normalized mean UFC levels at 12 weeks compared with placebo. Data were derived from Gadelha M, et al. J Clin Endocrinol Metab. 2022;doi:10.1210/clinem/dgac178.

“Osilodrostat is a highly effective treatment for Cushing’s disease, normalizing urinary free cortisol excretion in 77% of patients after 12 weeks’ treatment,” Mônica Gadelha, MD, professor of endocrinology at The Federal University of Rio de Janeiro, and colleagues wrote. “Cortisol reductions were maintained throughout 48 weeks of treatment and were accompanied by improvements in clinical signs of hypercortisolism and quality of life.”

Gadelha and colleagues enrolled 73 adults aged 18 to 75 years with Cushing’s disease from 40 centers in 14 countries into the LINC 4 phase 3 trial. Participants were randomly assigned to 2 mg osilodrostat twice daily (n = 48) or placebo (n = 25) for 12 weeks. Urinary samples were collected at weeks 2, 5 and 8 to measure mean UFC, and dosage was adjusted based on efficacy and tolerability. After 12 weeks, participants from both groups received osilodrostat in a 36-week open-label treatment period. All participants restarted the open-label portion of the trial at 2 mg osilodrostat unless they were on a lower dose at week 12. Dose adjustments in the open-label phase were made using the same guidelines in the randomized, double-blind, placebo-controlled trial. The primary endpoint was the efficacy of osilodrostat at achieving a mean UFC below the upper limit of normal of 138 nmol per 24 hours at 12 weeks vs. placebo; the key secondary endpoint was the percentage of participants achieving a normal mean UFC at 36 weeks.

At 12 weeks, the percentage of adults with a normalized mean UFC level was higher in the osilodrostat group compared with placebo (77.1% vs. 8%; P < .0001).

At 36 weeks, 80.8% of all participants had a normal mean UFC level. The overall response rate was 79.5% at 48 weeks.

Median time to first controlled mean UFC response was 35 days for those randomly assigned to osilodrostat as well as those randomly assigned to placebo who crossed over to osilodrostat for the open-label phase. At 48 weeks, 84% of participants were receiving 10 mg or less of osilodrostat per day, including 56% receiving 4 mg or less daily.

At 12 weeks, the osilodrostat group had several cardiovascular and metabolic-related improvements, including systolic and diastolic blood pressure, HbA1c, HDL cholesterol, body weight and waist circumference. No changes were observed in the placebo group.

“The improvements in cardiovascular and metabolic parameters were sustained throughout osilodrostat treatment and have the potential to alleviate the burden of comorbidities in many patients with Cushing’s disease,” the researchers wrote.

At 12 weeks, 52.5% of those receiving osilodrostat had a reduction in supraclavicular fat pad and 50% had a reduction in dorsal fat pad. At least 25% of participants also had improvements in facial redness, striae, proximal muscle atrophy and central obesity. Improvements were sustained through week 48.

During the placebo-controlled trial, grade 3 and 4 adverse events occurred for about 20% of participants in both groups. For the entire study, 38.4% of adults reported grade 3 and 4 adverse events, with the most common being hypertension. Eight participants discontinued the study due to adverse events.

From https://www.healio.com/news/endocrinology/20220408/osilodrostat-normalizes-urinary-free-cortisol-in-most-adults-with-cushings-disease

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