RARE DISEASE
Primary adrenal insufficiency
Primary adrenal insufficiency
Primary adrenal insufficiency
Drug discovery
5
drugs
With orphan designations
Overview
Primary adrenal insufficiency (PAI) is a rare, life-threatening disorder caused by inadequate cortisol and aldosterone production, most commonly due to autoimmune adrenalitis [1][3][9]. Diagnosis involves low morning cortisol with elevated ACTH and requires lifelong glucocorticoid (hydrocortisone/prednisone) and mineralocorticoid (fludrocortisone) replacement [1][7][14]. Delayed diagnosis increases mortality risk from adrenal crises [1][4][6]. Patient education on medication adherence and stress-dose adjustments is critical [1][5][14].
Burden
Mortality: 2× higher than general population, driven by adrenal crises/infections [2][4][17]
Adrenal crises: Incidence 6–8/100 patient-years requiring hospitalization [4][6][17]
Chronic morbidity: Reduced quality of life, frequent healthcare visits, comorbidities (autoimmune thyroid disease) [4][6][10]
Therapies
Hormone replacement:
Hydrocortisone (10–25 mg/day divided) + fludrocortisone (0.05–0.2 mg/day) [1][7][14]
Emergency protocols: Stress-dose steroids (IV hydrocortisone) during illness/surgery [1][5][14]
Patient education: Sick-day rules, steroid emergency cards, injectable hydrocortisone kits [1][5][14]
Categories: rare endocrine diseases
Research Papers
772 drug discovery papers about Primary adrenal insufficiency, with 3 first-in-class and 26 next-in-class emerging drug candidates forecasted to outperform the average preclinical success rate. Recent publications:
772 drug discovery papers about Primary adrenal insufficiency, with 3 first-in-class and 26 next-in-class emerging drug candidates forecasted to outperform the average preclinical success rate. Recent publications:
2026-08-09 | IFNG-producing self-reactive CD4+ T cells induce autoimmune adrenalitis in a mouse model of Addison's disease.
Autoimmune Addison's disease (AD) is a rare but life-threatening disorder caused by immune-mediated destruction of the adrenal cortex, and progress in therapy has been limited by insufficient mechanistic insight. Here, we establish a model of Experimental Autoimmune Adrenalitis (EAA) that recapitulates key features of AD and reveals sex-dependent differences in disease manifestation within the model. Immunization with peptides derived from the adrenal self-antigen CYP11A1 induces corticosterone insufficiency. We show that autoimmune adrenalitis is driven by IFNG produced by self-reactive CD4+ T cells, promoting granulomatous inflammation in the adrenal cortex. Together, these findings identify IFNG as a central effector of autoimmune adrenalitis and suggest that targeting the IFNG pathway may represent a potential therapeutic strategy for AD.
2026-08-06 | Infectious Diseases Targeting the Adrenal Glands: A Review.
100 years ago in the U.S., tuberculosis was the most common cause of primary adrenal insufficiency (AI) (Addison's disease). Autoimmune adrenalitis is now responsible for 80-90% of AI in this country and Europe; nevertheless today, in the U.S. and certainly abroad, diverse infections can involve the adrenals in both the immunocompetent and immunocompromised and potentially produce AI. Such infections range widely: bacterial (e.g., Mycobacterium tuberculosis, in particular), fungal (e.g., histoplasmosis), viral and even protozoal (e.g., severe Plasmodium falciparum malaria). Suspecting AI, especially if chronic, is not straightforward, delays in AI diagnosis may reach > 6 months in 50%, and 50-75% of patients initially present in overt adrenal crisis. Diagnosing adrenal involvement by an infection may be drawn out, typically requires careful imaging, a thorough infectious disease evaluation, and may require adrenal biopsy.
2026-08-06 | Congenital adrenal hyperplasia in children: a comprehensive review of clinical spectrum, diagnostic strategies, and management approaches.
Congenital adrenal hyperplasia (CAH) comprises a group of rare autosomal recessive disorders and is a leading cause of primary adrenal insufficiency in children. Most cases are due to classic 21-hydroxylase deficiency. Earlier diagnosis has been made possible with newborn screening, which has also reduced the risk of adrenal crises. This review is based on a search of PubMed, Embase, Scopus, and Medline for articles published from 2000 to 2025, using the terms "congenital adrenal hyperplasia", "21-hydroxylase deficiency", "primary adrenal insufficiency", and "steroidogenesis" with a focus on paediatric studies, clinical trials, systematic reviews, and consensus guidelines. The aims of clinical management are appropriate glucocorticoid and mineralocorticoid replacement, prevention of adrenal crises, monitoring of growth, puberty, and metabolic health. The main challenges include balancing androgen suppression with minimising glucocorticoid overexposure and monitoring for long-term complications such as early bone maturation and testicular adrenal rest tumours. Diagnostic accuracy and genotype-phenotype correlations have improved through advances in biochemical testing and molecular genetics. Newer and adjunctive therapies, including modified-release hydrocortisone, CRF1 receptor antagonists, adrenal-targeted drugs, and experimental gene therapies, may further improve disease management and simplify treatment. Effective management of CAH in children requires balancing optimal hormonal control with minimising treatment-related adverse effects. Newer and future therapies are expected to improve physiological management and long-term outcomes. Further research is needed to enhance individualised care and support transition to adult services.
2026-08-04 | Pharmacokinetics of inhaled prednisolone for adrenal crisis: an exploratory study.
An adrenal crisis is a potentially life-threatening medical emergency, which requires rapid treatment with glucocorticoids. Guidelines advise immediate self-administration of hydrocortisone by intramuscular injection using an emergency management kit in case an adrenal crisis is suspected. However, self-injection is often not performed due to administration complexity or patient anxiety. Pulmonary administration of glucocorticoids may be a more patient-friendly and suitable alternative, especially when administered using a dry powder inhaler. Before advancing to the development of a dry powder inhaler, we aimed to evaluate whether the pharmacokinetics of inhaled prednisolone sodium succinate are suitable for the outpatient treatment of adrenal crisis. Twelve healthy participants (aged 23-31 years, 50% females) received two separate doses of prednisolone sodium succinate, equivalent to 56.1 and 112.2 mg prednisolone on separate occasions, administered via a nebulizer. The primary outcome was the time to reach a target plasma concentration of 200 nmol/L. The median times to achieve this plasma concentration (excluding the nebulization time of approximately 10 minutes) were 17 (13 - 23) minutes and 9 (5-11) minutes for the 56.1 and 112.2 mg doses, respectively. Furthermore, pulmonary administered prednisolone sodium succinate was well tolerated. The results of this study, particularly the short time to the target plasma concentration, indicate that prednisolone sodium succinate is rapidly absorbed via the lungs and that the pharmacokinetics of inhaled nebulized prednisolone sodium succinate are suitable for the outpatient treatment of adrenal crisis.
2026-07-28 | Delay in Diagnosis of Addison's Disease: A Case Report and Literature Review.
Primary adrenal insufficiency is a rare disorder prone to delay in diagnosis after initial presentation. Multiple factors including a wide range of presentations, slow onset of symptoms, and other human factors may be contributing to challenges with the diagnosis.
2026-08-09 | IFNG-producing self-reactive CD4+ T cells induce autoimmune adrenalitis in a mouse model of Addison's disease.
Autoimmune Addison's disease (AD) is a rare but life-threatening disorder caused by immune-mediated destruction of the adrenal cortex, and progress in therapy has been limited by insufficient mechanistic insight. Here, we establish a model of Experimental Autoimmune Adrenalitis (EAA) that recapitulates key features of AD and reveals sex-dependent differences in disease manifestation within the model. Immunization with peptides derived from the adrenal self-antigen CYP11A1 induces corticosterone insufficiency. We show that autoimmune adrenalitis is driven by IFNG produced by self-reactive CD4+ T cells, promoting granulomatous inflammation in the adrenal cortex. Together, these findings identify IFNG as a central effector of autoimmune adrenalitis and suggest that targeting the IFNG pathway may represent a potential therapeutic strategy for AD.
2026-08-06 | Infectious Diseases Targeting the Adrenal Glands: A Review.
100 years ago in the U.S., tuberculosis was the most common cause of primary adrenal insufficiency (AI) (Addison's disease). Autoimmune adrenalitis is now responsible for 80-90% of AI in this country and Europe; nevertheless today, in the U.S. and certainly abroad, diverse infections can involve the adrenals in both the immunocompetent and immunocompromised and potentially produce AI. Such infections range widely: bacterial (e.g., Mycobacterium tuberculosis, in particular), fungal (e.g., histoplasmosis), viral and even protozoal (e.g., severe Plasmodium falciparum malaria). Suspecting AI, especially if chronic, is not straightforward, delays in AI diagnosis may reach > 6 months in 50%, and 50-75% of patients initially present in overt adrenal crisis. Diagnosing adrenal involvement by an infection may be drawn out, typically requires careful imaging, a thorough infectious disease evaluation, and may require adrenal biopsy.
2026-08-06 | Congenital adrenal hyperplasia in children: a comprehensive review of clinical spectrum, diagnostic strategies, and management approaches.
Congenital adrenal hyperplasia (CAH) comprises a group of rare autosomal recessive disorders and is a leading cause of primary adrenal insufficiency in children. Most cases are due to classic 21-hydroxylase deficiency. Earlier diagnosis has been made possible with newborn screening, which has also reduced the risk of adrenal crises. This review is based on a search of PubMed, Embase, Scopus, and Medline for articles published from 2000 to 2025, using the terms "congenital adrenal hyperplasia", "21-hydroxylase deficiency", "primary adrenal insufficiency", and "steroidogenesis" with a focus on paediatric studies, clinical trials, systematic reviews, and consensus guidelines. The aims of clinical management are appropriate glucocorticoid and mineralocorticoid replacement, prevention of adrenal crises, monitoring of growth, puberty, and metabolic health. The main challenges include balancing androgen suppression with minimising glucocorticoid overexposure and monitoring for long-term complications such as early bone maturation and testicular adrenal rest tumours. Diagnostic accuracy and genotype-phenotype correlations have improved through advances in biochemical testing and molecular genetics. Newer and adjunctive therapies, including modified-release hydrocortisone, CRF1 receptor antagonists, adrenal-targeted drugs, and experimental gene therapies, may further improve disease management and simplify treatment. Effective management of CAH in children requires balancing optimal hormonal control with minimising treatment-related adverse effects. Newer and future therapies are expected to improve physiological management and long-term outcomes. Further research is needed to enhance individualised care and support transition to adult services.
2026-08-04 | Pharmacokinetics of inhaled prednisolone for adrenal crisis: an exploratory study.
An adrenal crisis is a potentially life-threatening medical emergency, which requires rapid treatment with glucocorticoids. Guidelines advise immediate self-administration of hydrocortisone by intramuscular injection using an emergency management kit in case an adrenal crisis is suspected. However, self-injection is often not performed due to administration complexity or patient anxiety. Pulmonary administration of glucocorticoids may be a more patient-friendly and suitable alternative, especially when administered using a dry powder inhaler. Before advancing to the development of a dry powder inhaler, we aimed to evaluate whether the pharmacokinetics of inhaled prednisolone sodium succinate are suitable for the outpatient treatment of adrenal crisis. Twelve healthy participants (aged 23-31 years, 50% females) received two separate doses of prednisolone sodium succinate, equivalent to 56.1 and 112.2 mg prednisolone on separate occasions, administered via a nebulizer. The primary outcome was the time to reach a target plasma concentration of 200 nmol/L. The median times to achieve this plasma concentration (excluding the nebulization time of approximately 10 minutes) were 17 (13 - 23) minutes and 9 (5-11) minutes for the 56.1 and 112.2 mg doses, respectively. Furthermore, pulmonary administered prednisolone sodium succinate was well tolerated. The results of this study, particularly the short time to the target plasma concentration, indicate that prednisolone sodium succinate is rapidly absorbed via the lungs and that the pharmacokinetics of inhaled nebulized prednisolone sodium succinate are suitable for the outpatient treatment of adrenal crisis.
2026-07-28 | Delay in Diagnosis of Addison's Disease: A Case Report and Literature Review.
Primary adrenal insufficiency is a rare disorder prone to delay in diagnosis after initial presentation. Multiple factors including a wide range of presentations, slow onset of symptoms, and other human factors may be contributing to challenges with the diagnosis.
Access all drug discovery papers and probability of success in trials forecasts:
Access all drug discovery papers and probability of success in trials forecasts:
Drug Discovery Landscape
5 orphan drug designations for Primary adrenal insufficiency.
5 orphan drug designations for Primary adrenal insufficiency.
Drug | Therapy type | Regulator | Orphan designation | Approval | Sponsor |
|---|---|---|---|---|---|
hydrocortisone modified release capsules | small molecules | FDA | 2015-09-03 | — | Diurnal Limited |
hydrocortisone modified release tabs | small molecules | FDA | 2008-06-18 | — | Takeda Development Center Americas, Inc. |
Hydrocortisone [Chronocort] | small molecules | EMA | 2007-03-20 | — | Immedica Netherlands B.V. |
Dehydroepiandrosterone (DHEA) | small molecules | FDA | 2003-08-19 | — | Paladin Labs, Inc. |
Prasterone | small molecules | EMA | 2003-07-28 | — | Medicom Healthcare BV |
Let's accelerate rare disease drug discovery
Let's accelerate drug discovery
Get access to Explority AI's forecasts to outperform average preclinical success rates. Whether you're expanding your R&D pipeline, evaluating a partnership, or simply have a question — we'd love to hear from you.