Assessment of Safety, Tolerability, Pharmacokinetics, and Pharmacological Effect of Orally Administered CORT125134: An Adaptive, Double‐Blind, Randomized, Placebo‐Controlled Phase 1 Clinical Study

Hunt, Hazel; Donaldson, Kirsteen; Strem, Mark; Zann, Vanessa; Leung, Pui; Sweet, Suzanne; Connor, Alyson; Combs, Dan; Belanoff, Joseph K.

doi:10.1002/cpdd.389

Cited by 46 publications

(26 citation statements)

References 12 publications

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“…Dose-related safety, tolerability, pharmacokinetics, and pharmacological effects of CORT125134 were investigated in 81 subjects and it was demonstrated that CORT125134 prevents several effects of the glucocorticoid receptor agonist prednisone ( 140 ). If such potentially safe and well-titratable drugs seem to be an option to limit the effects of a potential and pathologic hyper cortisolism on Earth, we suggest their evaluation regarding immune suppression during spaceflight at least for selected crewmembers.…”

Section: Pharmacological Countermeasuresmentioning

confidence: 99%

Immune System Dysregulation During Spaceflight: Potential Countermeasures for Deep Space Exploration Missions

et al. 2018

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Recent studies have established that dysregulation of the human immune system and the reactivation of latent herpesviruses persists for the duration of a 6-month orbital spaceflight. It appears certain aspects of adaptive immunity are dysregulated during flight, yet some aspects of innate immunity are heightened. Interaction between adaptive and innate immunity also seems to be altered. Some crews experience persistent hypersensitivity reactions during flight. This phenomenon may, in synergy with extended duration and galactic radiation exposure, increase specific crew clinical risks during deep space exploration missions. The clinical challenge is based upon both the frequency of these phenomena in multiple crewmembers during low earth orbit missions and the inability to predict which specific individual crewmembers will experience these changes. Thus, a general countermeasure approach that offers the broadest possible coverage is needed. The vehicles, architecture, and mission profiles to enable such voyages are now under development. These include deployment and use of a cis-Lunar station (mid 2020s) with possible Moon surface operations, to be followed by multiple Mars flyby missions, and eventual human Mars surface exploration. Current ISS studies will continue to characterize physiological dysregulation associated with prolonged orbital spaceflight. However, sufficient information exists to begin consideration of both the need for, and nature of, specific immune countermeasures to ensure astronaut health. This article will review relevant in-place operational countermeasures onboard ISS and discuss a myriad of potential immune countermeasures for exploration missions. Discussion points include nutritional supplementation and functional foods, exercise and immunity, pharmacological options, the relationship between bone and immune countermeasures, and vaccination to mitigate herpes (and possibly other) virus risks. As the immune system has sentinel connectivity within every other physiological system, translational effects must be considered for all potential immune countermeasures. Finally, we shall discuss immune countermeasures in the context of their individualized implementation or precision medicine, based on crewmember specific immunological biases.

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Section: Pharmacological Countermeasuresmentioning

confidence: 99%

Immune System Dysregulation During Spaceflight: Potential Countermeasures for Deep Space Exploration Missions

et al. 2018

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“…Moreover, relacorilant was tested in a rat model of exogenous CS, identifying a significant positive effect on glucocorticoid-induced impairment of glucose metabolism, which was similar to those achieved after mifepristone administration ( 113 ). In a phase I study on healthy subjects, relacorilant showed to be rapidly absorbed, with a half-life of about 11–19 h, allowing therefore a once-daily administration, although a delay in absorption was observed after food intake, and a good safety profile, with gastrointestinal disorders being the most frequently reported AEs after both single dose and multiple doses administration and musculoskeletal disorders essentially reported after multiple doses administration ( 114 ).…”

Section: Glucocorticoid Receptor-directed Drugsmentioning

confidence: 99%

Medical Treatment of Cushing's Disease: An Overview of the Current and Recent Clinical Trials

et al. 2020

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Cushing's disease (CD) is a serious endocrine disorder characterized by chronic hypercortisolism, or Cushing's syndrome (CS), caused by a corticotroph pituitary tumor, which induces an excessive adrenocorticotropic hormone (ACTH) and consequently cortisol secretion. CD presents a severe clinical burden, with impairment of the quality of life and increase in mortality. Pituitary surgery represents the first-line therapy, but it is non-curative in one third of patients, requiring additional treatments. Among second-line treatments, medical therapy is gradually gaining importance, although the current medical treatments are unable to reach optimal efficacy and safety profile. Therefore, new drugs and new formulations of presently available drugs are currently under clinical investigation in international clinical trials, in order to assess their efficacy and safety in CD, or in the general population of CS. Among pituitary-directed agents, pasireotide, in the twice-daily subcutaneous formulation, has been demonstrated to be an effective treatment both in clinical trials and in real-world studies, and extension studies of the phase II and III clinical trials reported evidence of long-term efficacy with general good safety profile, although associated with frequent hyperglycemia, which requires monitoring of glucose metabolism. Moreover, the most recent once-monthly intramuscular formulation, pasireotide long-acting release (LAR), showed similar efficacy and safety, but associated with potential better compliance profile in CD. Roscovitine is an experimental drug currently under investigation. Among adrenal-directed agents, metyrapone is the only historical agent currently under investigation in a prospective, multicenter, international clinical trial, that would likely clarify its efficacy and safety in a large population of patients with CS. Osilodrostat, a novel agent with a mechanism of action similar to metyrapone, seems to offer a rapid, sustained, and effective disease control of CD, according to recently completed clinical trials, whereas levoketoconazole, a different chemical formulation of the historical agent ketoconazole, is still under investigation in clinical trials, with preliminary evidences showing an effective and safe control of CS. ATR-101 is an experimental drug currently under investigation. Among glucocorticoid receptor-directed drugs, mifepristone has been demonstrated to improve clinical syndrome and comorbidities, especially hypertension and impairment of glucose metabolism, but the occurrence of hypokalemia and in women uterine disorders, due to the concomitant action on progestin receptor, requires caution, whereas the preliminary evidence on relacorilant, characterized by high selectivity for glucocorticoid receptor, suggested good efficacy in the control of hypertension and impairment of glucose metabolism, as well as a good safety profile, in CS. Finally, a limited experience has demonstrated that combination therapy might be an interesting approach in the management of CD. The current review provides a summary of the available evidences from current and recent clinical trials on CD, with a specific focus on preliminary data.

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“…New adrenal steroidogenesis blockers and glucocorticoid receptor blockers such as osilodrostat [ 79 ], levoketoconazole [ 80 ], or relacorilant [ 81 ] are currently tested in phase II and phase III studies. There are also trials on new pituitary-directed drugs (for example retinoic acid) [ 82 ].…”

Section: Medical Therapymentioning

confidence: 99%

Recurrence after pituitary surgery in adult Cushing’s disease: a systematic review on diagnosis and treatment

et al. 2020

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Purpose Recurrence after pituitary surgery in Cushing’s disease (CD) is a common problem ranging from 5% (minimum) to 50% (maximum) after initially successful surgery, respectively. In this review, we give an overview of the current literature regarding prevalence, diagnosis, and therapeutic options of recurrent CD. Methods We systematically screened the literature regarding recurrent and persistent Cushing’s disease using the MESH term Cushing’s disease and recurrence. Of 717 results in PubMed, all manuscripts in English and German published between 1980 and April 2020 were screened. Case reports, comments, publications focusing on pediatric CD or CD in veterinary disciplines or studies with very small sample size (patient number < 10) were excluded. Also, papers on CD in pregnancy were not included in this review. Results and conclusions Because of the high incidence of recurrence in CD, annual clinical and biochemical follow-up is paramount. 50% of recurrences occur during the first 50 months after first surgery. In case of recurrence, treatment options include second surgery, pituitary radiation, targeted medical therapy to control hypercortisolism, and bilateral adrenalectomy. Success rates of all these treatment options vary between 25 (some of the medical therapy) and 100% (bilateral adrenalectomy). All treatment options have specific advantages, limitations, and side effects. Therefore, treatment decisions have to be individualized according to the specific needs of the patient.

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Assessment of Safety, Tolerability, Pharmacokinetics, and Pharmacological Effect of Orally Administered CORT125134: An Adaptive, Double‐Blind, Randomized, Placebo‐Controlled Phase 1 Clinical Study

Cited by 46 publications

References 12 publications

Immune System Dysregulation During Spaceflight: Potential Countermeasures for Deep Space Exploration Missions

Immune System Dysregulation During Spaceflight: Potential Countermeasures for Deep Space Exploration Missions

Medical Treatment of Cushing's Disease: An Overview of the Current and Recent Clinical Trials

Recurrence after pituitary surgery in adult Cushing’s disease: a systematic review on diagnosis and treatment

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