LOGICS Trial Supports Recorlev’s Efficacy in Lowering Cortisol Levels

Posted on September 12, 2020 by MaryO

Patients with endogenous Cushing’s syndrome who stopped using Recorlev (levoketoconazole) and moved to a placebo in a study started having their urine cortisol levels rise in response to lack of treatment, compared with those who remained on Recorlev, according to top-line data from the Phase 3 LOGICS trial.

Based on these findings and data from a previous Phase 3 trial of Recorlev called SONICS (NCT01838551), the therapy’s developer, Strongbridge Biopharma, is planning to submit a new drug application requesting its approval to the U.S. Food and Drug Administration (FDA) early next year.

If approved, Recorlev could be available to patients in the U.S. in 2022.

“We are delighted to announce the positive and statistically significant top-line results of the LOGICS study, which add to the growing body of evidence supporting the potential of Recorlev (levoketoconazole) as an effective and well tolerated cortisol synthesis inhibitor to treat Cushing’s syndrome,” Fredric Cohen, MD, chief medical officer of Strongbridge Biopharma, said in a press release.

Recorlev, also known as COR-003, is an investigational oral treatment for endogenous Cushing’s syndrome that inhibits the production of cortisol, the glucocorticoid hormone that is overly produced in patients with the disorder.

The safety, tolerability, effectiveness, and pharmacological properties of Recorlev in people with endogenous Cushing’s syndrome are currently being assessed in the LOGICS trial (NCT03277690).

LOGICS enrolled patients who had never been treated with Recorlev, as well as those given the medication in SONICS.

The study included an initial withdrawal phase, in which patients were assigned randomly to either Recorlev (up to a dose of 1,200 mg), or to a placebo for about 8 weeks. This was followed by a restoration phase, lasting approximately the same time, in which all patients received Recorlev in combination with a placebo. With this design, patients initially assigned to Recorlev continued treatment in the study’s second phase, while those originally assigned to a placebo switched to Recorlev.

Before enrolling in the study’s initial randomized-withdrawal phase, patients completed an open-label titration and maintenance phase lasting 14 to 19 weeks, which determined the best dose of Recorlev they should receive later.

Of the 79 patients who entered the open-label titration and maintenance phase, 44 enrolled in the randomized-withdrawal phase, and 43 completed this initial portion of the trial.

Top-line data now announced by the company showed the proportion of patients having their urine cortisol levels rise by the end of the randomized-withdrawal phase was 54.5% higher among those on a placebo than among those treated with Recorlev (95.5% vs. 40.9%).

All 21 patients who lost their initial treatment response in the open-label portion of the study, and saw their cortisol levels rise after moving to a placebo (withdrawal phase) were given early rescue treatment. Their cortisol levels started to drop after a median of 22 days.

The percentage of patients whose urine cortisol levels were within normal range by the end of the withdrawal phase was 45.5% higher among those treated with Recorlev, compared with those given a placebo (50.0% vs. 4.5%).

In addition to losing benefits related to cortisol control, patients receiving a withdrawal-phase placebo also lost the therapy’s positive cholesterol-lowering effects.

“The Phase 3 LOGICS results complement the long-term efficacy and safety data supplied by the Phase 3 SONICS study, which was published in The Lancet Diabetes & Endocrinology, by confirming that the effects of Recorlev (levoketoconazole) were responsible for the therapeutic response when treatment was continued compared to withdrawing patients to placebo,” said Maria Fleseriu, MD, FACE, professor of Medicine and Neurological Surgery and director of the Oregon Health Sciences University Pituitary Center, and principal investigator of the study. 

 “The LOGICS findings — which build upon the long-term benefit shown during open-label treatment in SONICS — provide robust evidence to support the use of RECORLEV as an important treatment option for this life-threatening rare endocrine disease,” Fleseriu added.

Recorlev was found to be safe and well-tolerated in LOGICS. Of the 79 patients who entered in the study’s open-label titration and maintenance phase, 19% discontinued due to side effects in this phase, and none of the 44 who proceeded to the withdrawal phase stopped treatment for these reasons.

The most common side effects observed during the first two parts of LOGICS included nausea (29%), low blood potassium levels (28%), headache (21%), high blood pressure (19%), and diarrhea (15%).

Some patients saw the levels of their liver enzymes rise above normal levels — a sign of liver inflammation and damage — during the study. However, this and other side effects of special interest, including those associated with adrenal insufficiency, resolved by either lowering the dose or stopping treatment with Recorlev. The proportion of patients experiencing these side effects was similar to that seen in SONICS.

These findings are part of a subset of data from a planned interim analysis of LOGICS. Final study data requires analyses of additional datasets.

Adapted from https://www.globenewswire.com/news-release/2020/09/08/2089872/0/en/Strongbridge-Biopharma-plc-Announces-Positive-and-Statistically-Significant-Top-Line-Results-from-the-Pivotal-Phase-3-LOGICS-Study-of-RECORLEV-levoketoconazole-for-the-Treatment-of.html

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Study Shows Metyrapone Effective for Treating Rare Cushing’s Syndrome

Posted on September 12, 2020 by MaryO

The first ever prospective study to test the safety and efficacy of metyrapone in patients with Cushing’s Syndrome in a real-life setting has shown successful results.

HRA Pharma Rare Diseases SAS, of Paris, has presented data from PROMPT, the first ever prospective study designed to confirm metyrapone efficacy and good tolerance in patients with endogenous Cushing’s Syndrome, with results confirming that metyrapone controlled 80% of the patients at week 12 with either normalisation or at least 50% decrease of urinary free cortisol. These initial results are being published to coincide with HRA Pharma Rare Diseases’ participation in the e-ECE conference 2020.

Cushing’s Syndrome is a rare condition where patients have too much cortisol in their blood. Endogenous Cushing’s Syndrome is most often caused by hormone-releasing tumours of the adrenal or the pituitary glands. To manage this condition, controlling high cortisol levels in patients is important.

Successful results with metyrapone

Metyrapone is an inhibitor of the 11-beta-hydroxylase enzyme, which majorly contributes to cortisol synthesis and is approved in Europe for the treatment of endogenous Cushing’s Syndrome based on observational retrospective studies published over more than 50 years. As this prospective study took place over five years from April 2015 to April 2020, the longitudinal format reduced potential sources of bias and helped determine the risk factors of metyrapone when compared to the previous retrospective studies.

The first results of this study showed that at the end of the 12 weeks, metyrapone therapy is a rapid-onset, effective and safe medical treatment in patients living with the syndrome.

Evelina Paberze, COO of HRA Pharma Rare Diseases, said: “At HRA Pharma Rare Diseases, we are dedicated to building comprehensive evidence of our products. The first results of this prospective study clearly demonstrate the effectiveness of metyrapone in treating Cushing’s Syndrome.”

The next set of data on the six-month optional extension is awaiting confirmation and the full study with the final results will be published next year.

Frederique Welgryn, Managing Director of HRA Pharma Rare Diseases, added: “Cushing’s Syndrome is a chronic disease that can lead to deterioration in patients’ conditions if not treated appropriately. We are thrilled to announce that this first prospective study verifies that metyrapone is both an effective and safe way to treat endogenous Cushing’s Syndrome. This is a big step given the high unmet medical need for patients with endogenous Cushing’s Syndrome.”

From https://www.healtheuropa.eu/study-shows-metyrapone-effective-for-treating-rare-cushings-syndrome/102584/

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High Cortisol Levels in Urine May Be Linked to Changes in Blood Sugar Metabolism

Posted on September 10, 2020 by MaryO

Abnormally high levels of cortisol in the urine — one of the hallmarks of Cushing’s syndrome — seem to be associated with alterations in blood sugar metabolism in obese patients, a study found.

The study, “Hypercortisolism and altered glucose homeostasis in obese patients in the pre-bariatric surgery assessment,” was published in the journal Diabetes/Metabolism Research and Reviews.

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Treatment improved multiple cardiovascular risk and other factors in Cushing’s disease patients

Posted on July 31, 2020 by MaryO

 

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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Smart, Soft Contact Lens For Wireless Immunosensing of Cortisol

Posted on July 18, 2020 by MaryO

Abstract

Despite various approaches to immunoassay and chromatography for monitoring cortisol concentrations, conventional methods require bulky external equipment, which limits their use as mobile health care systems. Here, we describe a human pilot trial of a soft, smart contact lens for real-time detection of the cortisol concentration in tears using a smartphone. A cortisol sensor formed using a graphene field-effect transistor can measure cortisol concentration with a detection limit of 10 pg/ml, which is low enough to detect the cortisol concentration in human tears. In addition, this soft contact lens only requires the integration of this cortisol sensor with transparent antennas and wireless communication circuits to make a smartphone the only device needed to operate the lens remotely without obstructing the wearer’s view. Furthermore, in vivo tests using live rabbits and the human pilot experiment confirmed the good biocompatibility and reliability of this lens as a noninvasive, mobile health care solution.

INTRODUCTION

The steroid hormone, cortisol, which is known as a stress hormone, is secreted by the adrenal gland when people are stressed psychologically or physically (1). This secretion occurs when the adrenal gland is stimulated by adrenocorticotropic hormone, which is secreted by the pituitary gland when it is stimulated by the corticotropin-releasing hormone secreted by the hypothalamus. This serial cortisol secretion system is referred to as a hypothalamus–pituitary gland–adrenal gland axis, which is affected by chronic stress, resulting in abnormal secretion of cortisol (2, 3). The accumulation of cortisol caused by the abnormal secretion of cortisol increases the concentrations of fat and amino acid, which can result in diverse severe diseases (e.g., Cushing’s disease, autoimmune disease, cardiovascular complications, and type 2 diabetes) and neurological disorders (such as depression and anxiety disorders) (2–7). In contrast, abnormally low cortisol levels can lead to Addison’s disease, which results in hypercholesterolemia, weight loss, and chronic fatigue (8). In addition, it was recently reported that plasma cortisol can be correlated to the prognosis of traumatic brain injury (9). Furthermore, the extent of cortisol secretion varies from person to person, and it changes continuously (10, 11). Thus, developing health care systems for real-time monitoring of the cortisol level has been explored extensively over the past decade as the key to the quantitative analysis of stress levels. Although various efforts have led to the development of cortisol sensors that can measure the concentration of cortisol in blood, saliva, sweat, hair, urine, and interstitial fluid (12–17), the accurate measurement of cortisol concentrations has been limited because of the difficulties associated with the transportation and storage of cortisol as well as the instability of the biologically active cortisol in these body fluids at room temperature. In addition, these conventional sensing methods require bulky equipment for the extraction and analysis of these body fluids, which is not suitable for mobile health care systems (12, 18). Therefore, the development of noninvasive and wearable sensors that can monitor cortisol concentration accurately is highly desirable for a smart health care solution. For example, the immunoassay method, which uses an antigen-antibody binding reaction, has been used extensively for electrochemical cortisol immunosensors using saliva and interstitial fluid, except tears (12, 14, 19). However, these immunosensors still require the use of bulky impedance analyzers for the analysis of the Nyquist plot from electrochemical impedance spectroscopy. Although the cyclic voltammetry (CV) technique can be used as an alternative approach for sensing cortisol, additional bulky electrochemical instruments still are necessary for analyzing the CV curves (13, 14, 19). Recently, wearable forms of cortisol sensors that use sweat were developed (15), but they still required bulky measurement equipment (15, 16). Therefore, portable and smart sensors that can monitor the accurate concentration of cortisol in real time are highly desirable for use in mobile health care.

Among the various body fluids, tears, in particular, contain important biomarkers, including cortisol (20, 21). Thus, the integration of biosensors with contact lenses is a potentially attractive candidate for the noninvasive and real-time monitoring of these biomarkers from tears (22–25). However, an approach for fabricating a smart contact lens for sensing the cortisol in tears has not been demonstrated previously. Thus, here, we present an extraordinary approach for the formation of a smart, soft contact lens that enables remote, real-time monitoring of the cortisol level in the wearer’s tears using mobile phones. This smart, soft contact lens is composed of a cortisol sensor, a wireless antenna, capacitors, resistors, and integrated circuit chips that use stretchable interconnects without obstructing the wearer’s view. The components of this device (except the antenna) were protected from mechanical deformations by locating each of the components on discrete, rigid islands and by embedding these islands inside an elastic layer. A graphene field-effect transistor (FET; with the binding of monoclonal antibody) was used as this cortisol immunosensor, which exhibited a sufficiently low detection limit, i.e., 10 pg/ml, for its sensing of cortisol in human tears in which the cortisol concentration ranges from 1 to 40 ng/ml (26). This sensor was integrated with a near-field communication (NFC) chip and antenna inside the soft contact lens for the real-time wireless transmission of the data to the user’s mobile device (e.g., a smart phone or a smart watch). The antenna occupies a relatively large area of this soft lens, so it requires its high stretchability, good transparency, and low resistance for operating a standard NFC chip at 13.56 MHz. In our approach, the hybrid random networks of ultralong silver nanofibers (AgNFs) and fine silver nanowires (AgNWs) enabled high transparency and good stretchability of this antenna and its low sheet resistance for reliable standard NFCs (at 13.56 MHz) inside this smart contact lens. Thus, the fully integrated system of this smart contact lens provided wireless and battery-free operation for the simultaneous detection and transmission of the cortisol concentration from tears to a mobile phone using standard NFC. In addition, a human pilot trial and in vivo tests conducted using live rabbits demonstrated the biocompatibility of this lens, and its safety against inflammation and thermal/electromagnetic field radiation suggests its substantial usability as a noninvasive, mobile health care solution.

RESULTS

Cortisol immunosensor

A graphene FET sensor was fabricated by binding the cortisol monoclonal antibody (C-Mab) to the surface of graphene for the immunosensing of cortisol. Here, graphene acts as a transducer that converts the interaction between cortisol and C-Mab into electrical signals. Figure 1A shows the immobilization process of C-Mab to graphene. Immobilization proceeds through amide bonding of the C-Mab onto the carboxyl group of the graphene surface via the EDC [1-ethyl-3-(3-dimethylaminopropyl) carbodiimide hydrochloride]/NHS (N-hydroxysulfosuccinimide) coupling reaction. A chemical vapor deposition–synthesized graphene layer was transferred onto a desired substrate and exposed to ultraviolet ozone (UVO) to activate the surface of the graphene with the carboxylate group. Figure S1 shows the contact angle between this surface of the graphene and a droplet of deionized (DI) water. Longer exposure time to UVO can decrease the hydrophobicity of graphene with decreasing the contact angle. Table S1 shows the increase in the electrical resistance of graphene that resulted from this UVO treatment. In our experiment, 2 min of exposure time to UVO decreased the contact angle from 70° to 38° without increasing the resistance of the graphene notably. UVO exposure times longer than this threshold time degraded the resistance of the graphene excessively, so the time of exposure of our samples to UVO was limited to 2 min. Figure S2A illustrates the process of immobilizing C-Mab through the EDC/NHS coupling reaction. This two-step coupling reaction of EDC and NHS can mediate the amide bonding between the carboxylate group of the UVO-exposed graphene and the amine group of the protein (12, 17, 27, 28). Here, EDC forms reactive O-acylisourea ester, thereby making the surface unstable. This O-acylisourea ester reacts with the NHS to form amine-reactive NHS ester with the surface still remaining semistable. Then, C-Mab with the amine group reacts with the amine-reactive NHS ester, thereby forming stable amide bonding that can immobilize C-Mab to the NHS on the surface of the graphene. Figure S2B shows the Fourier transform infrared (FTIR) spectroscopy spectra of the DI water after the cortisol sensor had been immersed for 24 hours. The spectra of the DI water in which the sensor was immersed were not significantly different from those of the pristine DI water. However, the C-Mab solution that had a concentration of 1 μg/ml had a significant peak intensity in the range of 3000 to 2800 cm−1, representing the N-H bonding in the C-Mab. These results indicated that C-Mab formed stable bonding on the carboxylated graphene and was negligibly detached by exposure to water.

From https://advances.sciencemag.org/content/6/28/eabb2891

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