LOGICS Trial Supports Recorlev’s Efficacy in Lowering Cortisol Levels

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

Clinical Trial: Multicenter Study of Seliciclib (R-roscovitine) for Cushing Disease

Sponsor:
Information provided by (Responsible Party):
Shlomo Melmed, MD, Cedars-Sinai Medical Center
Brief Summary:

This phase 2 multicenter, open-label clinical trial will evaluate safety and efficacy of 4 weeks of oral seliciclib in patients with newly diagnosed, persistent, or recurrent Cushing disease.

Funding Source – FDA Office of Orphan Products Development (OOPD)

Condition or disease  Intervention/treatment  Phase 
Cushing Disease Drug: Seliciclib Phase 2
Detailed Description:
This phase 2 multicenter, open-label clinical trial will evaluate safety and efficacy of two of three potential doses/schedules of oral seliciclib in patients with newly diagnosed, persistent, or recurrent Cushing disease. Up to 29 subjects will be treated with up to 800 mg/day oral seliciclib for 4 days each week for 4 weeks and enrolled in sequential cohorts based on efficacy outcomes. The study will also evaluate effects of seliciclib on quality of life and clinical signs and symptoms of Cushing disease.
Ages Eligible for Study: 18 Years and older   (Adult, Older Adult)
Sexes Eligible for Study: All
Accepts Healthy Volunteers: No
Criteria

Inclusion criteria:

  • Male and female patients at least 18 years old
  • Patients with confirmed pituitary origin of excess adrenocorticotropic hormone (ACTH) production:
    • Persistent hypercortisolemia established by two consecutive 24 h UFC levels at least 1.5x the upper limit of normal
    • Normal or elevated ACTH levels
    • Pituitary macroadenoma (>1 cm) on MRI or inferior petrosal sinus sampling (IPSS) central to peripheral ACTH gradient >2 at baseline and >3 after corticotropin-releasing hormone (CRH) stimulation
    • Recurrent or persistent Cushing disease defined as pathologically confirmed resected pituitary ACTH-secreting tumor or IPSS central to peripheral ACTH gradient >2 at baseline and >3 after CRH stimulation, and 24 hour UFC above the upper limit of normal reference range beyond post-surgical week 6
    • Patients on medical treatment for Cushing disease. The following washout periods must be completed before screening assessments are performed:
      • Inhibitors of steroidogenesis (metyrapone, ketoconazole): 2 weeks
      • Somatostatin receptor ligand pasireotide: short-acting, 2 weeks; long-acting, 4 weeks
      • Progesterone receptor antagonist (mifepristone): 2 weeks
      • Dopamine agonists (cabergoline): 4 weeks
      • CYP3A4 strong inducers or inhibitors: varies between drugs; minimum 5-6 times the half-life of drug

Exclusion criteria:

  • Patients with compromised visual fields, and not stable for at least 6 months
  • Patients with abutment or compression of the optic chiasm on MRI and normal visual fields
  • Patients with Cushing’s syndrome due to non-pituitary ACTH secretion
  • Patients with hypercortisolism secondary to adrenal tumors or nodular (primary) bilateral adrenal hyperplasia
  • Patients who have a known inherited syndrome as the cause for hormone over secretion (i.e., Carney Complex, McCune-Albright syndrome, Multiple endocrine neoplasia (MEN) 1
  • Patients with a diagnosis of glucocorticoid-remedial aldosteronism (GRA)
  • Patients with cyclic Cushing’s syndrome defined by any measurement of UFC over the previous 1 months within normal range
  • Patients with pseudo-Cushing’s syndrome, i.e., non-autonomous hypercortisolism due to overactivation of the hypothalamic-pituitary-adrenal (HPA) axis in uncontrolled depression, anxiety, obsessive compulsive disorder, morbid obesity, alcoholism, and uncontrolled diabetes mellitus
  • Patients who have undergone major surgery within 1 month prior to screening
  • Patients with serum K+< 3.5 while on replacement treatment
  • Diabetic patients whose blood glucose is poorly controlled as evidenced by HbA1C >8%
  • Patients who have clinically significant impairment in cardiovascular function or are at risk thereof, as evidenced by congestive heart failure (NYHA Class III or IV), unstable angina, sustained ventricular tachycardia, clinically significant bradycardia, high grade atrioventricular (AV) block, history of acute MI less than one year prior to study entry
  • Patients with liver disease or history of liver disease such as cirrhosis, chronic active hepatitis B and C, or chronic persistent hepatitis, or patients with alanine aminotransferase (ALT) or aspartate aminotransferase (AST) more than 1.5 x ULN, serum total bilirubin more than ULN, serum albumin less than 0.67 x lower limit of normal (LLN) at screening
  • Serum creatinine > 2 x ULN
  • Patients not biochemically euthyroid
  • Patients who have any current or prior medical condition that can interfere with the conduct of the study or the evaluation of its results, such as
    • History of immunocompromise, including a positive HIV test result (ELISA and Western blot). An HIV test will not be required, however, previous medical history will be reviewed
    • Presence of active or suspected acute or chronic uncontrolled infection
    • History of, or current alcohol misuse/abuse in the 12 month period prior to screening
  • Female patients who are pregnant or lactating, or are of childbearing potential and not practicing a medically acceptable method of birth control. If a woman is participating in the trial then one form of contraception is sufficient (pill or diaphragm) and the partner should use a condom. If oral contraception is used in addition to condoms, the patient must have been practicing this method for at least two months prior to screening and must agree to continue the oral contraceptive throughout the course of the study and for 3 months after the study has ended. Male patients who are sexually active are required to use condoms during the study and for three month afterwards as a precautionary measure (available data do not suggest any increased reproductive risk with the study drugs)
  • Patients who have participated in any clinical investigation with an investigational drug within 1 month prior to screening or patients who have previously been treated with seliciclib
  • Patients with any ongoing or likely to require additional concomitant medical treatment to seliciclib for the tumor
  • Patients with concomitant treatment of strong CYP3A4 inducers or inhibitors.
  • Patients who were receiving mitotane and/or long-acting somatostatin receptor ligands octreotide long-acting release (LAR) or lanreotide
  • Patients who have received pituitary irradiation within the last 5 years prior to the baseline visit
  • Patients who have been treated with radionuclide at any time prior to study entry
  • Patients with known hypersensitivity to seliciclib
  • Patients with a history of non-compliance to medical regimens or who are considered potentially unreliable or will be unable to complete the entire study
  • Patients with presence of Hepatitis B surface antigen (HbsAg)
  • Patients with presence of Hepatitis C antibody test (anti-HCV)

The Relationship of Mitochondrial Dysfunction and the Development of Insulin Resistance in Cushing’s Syndrome

Authors Ježková J, Ďurovcová V, Wenchich LHansíková H, Zeman J, Hána V, Marek J, Lacinová Z, Haluzík M, Kršek M

Received 18 March 2019

Accepted for publication 13 June 2019

Published 19 August 2019 Volume 2019:12 Pages 1459—1471

DOI https://doi.org/10.2147/DMSO.S209095

Checked for plagiarism Yes

Review by Single-blind

Peer reviewers approved by Dr Melinda Thomas

Peer reviewer comments 3

Editor who approved publication: Dr Antonio Brunetti

 

Jana Ježková,1 Viktória Ďurovcová,1 Laszlo Wenchich,2,3 Hana Hansíková,3 Jiří Zeman,3Václav Hána,1 Josef Marek,1 Zdeňka Lacinová,4,5 Martin Haluzík,4,5 Michal Kršek1

1Third Department of Medicine, First Faculty of Medicine, Charles University and General University Hospital, Prague, Czech Republic; 2Institute of Rheumatology, Prague, Czech Republic; 3Department of Pediatrics and Adolescent Medicine, First Faculty of Medicine, Charles University and General University Hospital, Prague, Czech Republic; 4Institute of Medical Biochemistry and Laboratory Diagnostic, First Faculty of Medicine, Charles University and General University Hospital, Prague, Czech Republic; 5Centre for Experimental Medicine, Institute for Clinical and Experimental Medicine, Prague, Czech Republic

Correspondence: Jana Ježková
Third Department of Medicine, First Faculty of Medicine, Charles University and General University Hospital, U Nemocnice 1128 02 Praha 2, Prague, Czech Republic
Tel +420 60 641 2613
Fax +420 22 491 9780
Email fjjezek@cmail.cz

Purpose: Cushing’s syndrome is characterized by metabolic disturbances including insulin resistance. Mitochondrial dysfunction is one pathogenic factor in the development of insulin resistance in patients with obesity. We explored whether mitochondrial dysfunction correlates with insulin resistance and other metabolic complications.

Patients and methods: We investigated the changes of mRNA expression of genes encoding selected subunits of oxidative phosphorylation system (OXPHOS), pyruvate dehydrogenase (PDH) and citrate synthase (CS) in subcutaneous adipose tissue (SCAT) and peripheral monocytes (PM) and mitochondrial enzyme activity in platelets of 24 patients with active Cushing’s syndrome and in 9 of them after successful treatment and 22 healthy control subjects.

Results: Patients with active Cushing’s syndrome had significantly increased body mass index (BMI), homeostasis model assessment of insulin resistance (HOMA-IR) and serum lipids relative to the control group. The expression of all investigated genes for selected mitochondrial proteins was decreased in SCAT in patients with active Cushing’s syndrome and remained decreased after successful treatment. The expression of most tested genes in SCAT correlated inversely with BMI and HOMA-IR. The expression of genes encoding selected OXPHOS subunits and CS was increased in PM in patients with active Cushing’s syndrome with a tendency to decrease toward normal levels after cure. Patients with active Cushing’s syndrome showed increased enzyme activity of complex I (NQR) in platelets.

Conclusion: Mitochondrial function in SCAT in patients with Cushing’s syndrome is impaired and only slightly affected by its treatment which may reflect ongoing metabolic disturbances even after successful treatment of Cushing’s syndrome.

Keywords: Cushing’s syndrome, insulin resistance, mitochondrial enzyme activity, gene expression

Creative Commons License This work is published and licensed by Dove Medical Press Limited. The full terms of this license are available at https://www.dovepress.com/terms.php and incorporate the Creative Commons Attribution – Non Commercial (unported, v3.0) License. By accessing the work you hereby accept the Terms. Non-commercial uses of the work are permitted without any further permission from Dove Medical Press Limited, provided the work is properly attributed. For permission for commercial use of this work, please see paragraphs 4.2 and 5 of our Terms.

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Imaging Agent Effectively Detects, Localizes Tumors in Cushing’s Syndrome

Wannachalee T, et al. Clin Endocrinol. 2019;doi:10.1111/cen.14008.
May 20, 2019

A radioactive diagnostic agent for PET imaging effectively localized primary tumors or metastases in most adults with ectopic Cushing’s syndrome, leading to changes in clinical management for 64% of patients, according to findings from a retrospective study published in Clinical Endocrinology.

As Endocrine Today previously reported, the FDA approved the first kit for the preparation of gallium Ga-68 dotatate injection (Netspot, Advanced Accelerator Applications USA Inc.), a radioactive diagnostic agent for PET scan imaging, in June 2016. The radioactive probe is designed to help locate tumors in adult and pediatric patients with somatostatin receptor-positive neuroendocrine tumors. Ga-68 dotatate, a positron-emitting analogue of somatostatin, works by binding to the hormone.

In a retrospective review, Richard Auchus, MD, PhD, professor of pharmacology and internal medicine in the division of metabolism, endocrinology and diabetes at the University of Michigan, and colleagues analyzed data from 28 patients with ectopic Cushing’s syndrome who underwent imaging with gallium Ga-68 dotatate for identification of the primary tumor or follow-up between November 2016 and October 2018 (mean age, 50 years; 22 women). All imaging was completed at tertiary referral centers at Mayo Clinic, University of Michigan and The University of Texas MD Anderson Cancer Center. Researchers assessed patient demographics, imaging modalities, histopathological results and treatment data. Diagnosis of Cushing’s syndrome was confirmed by clinical and hormonal evaluation. The clinical impact of gallium Ga-68 dotatate was defined as the detection of primary ectopic Cushing’s syndrome or new metastatic foci, along with changes in clinical management.

Within the cohort, 17 patients underwent imaging with gallium Ga-68 dotatate for identification of the primary tumor and 11 underwent the imaging for follow-up. Researchers found that gallium Ga-68 dotatate identified suspected primary ectopic Cushing’s syndrome in 11 of 17 patients (65%), of which seven tumors were solitary and four were metastatic. Diagnosis was confirmed by pathology in eight of the 11 patients: Five patients had a bronchial neuroendocrine tumor, one patient had a thymic tumor, one had a pancreatic neuroendocrine tumor, and one metastatic neuroendocrine tumor was of unknown primary origin. One patient had a false positive scan, according to researchers.

Among the 11 patients with ectopic Cushing’s syndrome who underwent gallium Ga-68 dotatate imaging to assess disease burden or recurrence, the imaging led to changes in clinical management in seven cases (64%), according to researchers.

“Our study demonstrates the high sensitivity of [gallium Ga-68 dotatate] in the localization of [ectopic Cushing’s syndrome], for both occult primary tumors and metastatic lesions,” the researchers wrote. “Importantly, the use of [gallium Ga-68 dotatate] impacted clinical management in 64% of patients with [ectopic Cushing’s syndrome] overall.”

The researchers noted that the high cost and limited availability of PET/CT imaging might preclude the widespread use of gallium Ga-68 dotatate for imaging in patients with suspected ectopic Cushing’s syndrome, and that experience with the scans remains limited vs. other imaging studies.

“Nevertheless, combing the experience of three large referral centers, our study gathers the largest number of [patients with ectopic Cushing’s syndrome] imaged with [gallium Ga-68 dotatate] to date and provides a benchmark for the utility of this diagnostic modality for this rare but highly morbid condition,” the researchers wrote. – by Regina Schaffer

DisclosuresThe authors report no relevant financial disclosures.

From https://www.healio.com/endocrinology/adrenal/news/online/%7B69e458a8-e9a0-4567-a786-00868118b435%7D/imaging-agent-effectively-detects-localizes-tumors-in-cushings-syndrome

Sosei Heptares Starts New Clinical Development Program

TOKYO and LONDONFeb. 20, 2019 /PRNewswire/ — Sosei Group Corporation (“the Company”; TSE: 4565), announces that the first healthy subject has been dosed with a novel small molecule HTL0030310 in a Phase I clinical study, marking the start of a new in-house clinical program targeting endocrine disorders, including Cushing’s disease.

HTL0030310 is a potent and selective agonist of the SSTR5 (somatostatin 5) receptor and the sixth molecule designed by the Company using its GPCR Structure-Based Drug Design (SBDD) platform to enter clinical development.

HTL0030310 has been designed to modulate the excess release of hormones from adenomas (benign tumors) of the pituitary gland. Highly elevated plasma levels of pituitary hormones result in a number of serious endocrine disorders, including Cushing’s Disease. Cushing’s disease is characterized by excessive cortisol release, crucial in regulating metabolism, maintaining cardiovascular function and helping the body respond to stress.

A key design feature of HTL0030310 is its significant selectivity for SSTR5 over SSTR2. This selectivity is expected to improve the balance of efficacy vs. dose-limiting side effects and therefore, presents an opportunity to develop a best-in-class medicine for patients with Cushing’s disease, in particular.

The clinical trial with HTL0030310 is a double-blind, randomised, placebo-controlled first-in-human study in which single ascending subcutaneous doses of HTL0030310 will be administered to healthy male and female adult subjects. The study is being conducted in the UK and will assess the safety, tolerability, pharmacokinetics and pharmacodynamics of HTL0030310 in up to 64 subjects. Preliminary results are expected in the second half of 2019 and will provide a first insight into the effects of HTL0030310 on the control of glucose and other endocrine hormones and the potential to target Cushing’s disease and other endocrine disorders.

Dr. Malcolm Weir, Executive VP and Chief R&D Officer, said: “HTL0030310 is a novel and highly selective molecule, and is the sixth candidate originating from our SBDD platform to advance into human trials. We are not only pleased to begin this new study but also delighted with the productivity of our unique platform to generate attractive candidates targeting GPCRs involved in multiple diseases. These candidates present new prospects for our emerging proprietary pipeline, as well as unique opportunities for partnering, and provide a solid foundation to execute our strategy.”

About Cushing’s disease

Cushing’s disease is a debilitating endocrine disorder caused by the overproduction of the hormone cortisol and is often triggered by a pituitary adenoma (benign tumour) secreting excess adrenocorticotropic hormone (ACTH). Cortisol has a crucial role regulating metabolism, maintaining cardiovascular function and helping the body respond to stress. Symptoms may include weight gain, central obesity, a round, red full face, severe fatigue and weakness, striae (purple stretch marks), high blood pressure, depression and anxiety. Cushing’s disease affects 10-15 million people per year, most commonly adults between 20 to 50 years and women more often than men. The first line and most common treatment approach for Cushing’s disease is surgical removal of the pituitary tumor followed by radiotherapy and drug therapy designed to reduce cortisol production.

Ref: American Association of Neurological Surgeons (AANS) 

About Sosei Heptares

We are an international biopharmaceutical group focused on the design and development of new medicines originating from its proprietary GPCR-targeted StaR® technology and structure-based drug design platform capabilities. The Company is advancing a broad and deep pipeline of partnered and wholly owned product candidates in multiple therapeutic areas, including CNS, immuno-oncology, gastroenterology, inflammation and other rare/specialty indications. Its leading clinical programs include partnered candidates aimed at the symptomatic treatment of Alzheimer’s disease (with Allergan) and next generation immuno-oncology approaches to treat cancer (with AstraZeneca). Our additional partners and collaborators include Novartis, Pfizer, Daiichi-Sankyo, PeptiDream, Kymab and MorphoSys. The Company is headquartered in Tokyo, Japan with R&D facilities in Cambridge, UK and Zurich, Switzerland.

“Sosei Heptares” is the corporate brand of Sosei Group Corporation, which is listed on the Tokyo Stock Exchange (ticker: 4565).

For more information, please visit https://www.soseiheptares.com/

LinkedIn: @soseiheptaresco | Twitter: @soseiheptaresco | YouTube: @soseiheptaresco

Forward-looking statements

This press release contains forward-looking statements, including statements about the discovery, development and commercialization of products. Various risks may cause Sosei Group Corporation’s actual results to differ materially from those expressed or implied by the forward-looking statements, including: adverse results in clinical development programs; failure to obtain patent protection for inventions; commercial limitations imposed by patents owned or controlled by third parties; dependence upon strategic alliance partners to develop and commercialize products and services; difficulties or delays in obtaining regulatory approvals to market products and services resulting from development efforts; the requirement for substantial funding to conduct research and development and to expand commercialization activities; and product initiatives by competitors. As a result of these factors, prospective investors are cautioned not to rely on any forward-looking statements. We disclaim any intention or obligation to update or revise any forward-looking statements, whether as a result of new information, future events or otherwise.

View original content:https://www.prnewswire.com/news-releases/sosei-heptares-starts-new-clinical-development-program-300798591.html

SOURCE Sosei Heptares

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