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Genetic disease that prevents natural synthesis of certain hormones

Classic congenital adrenal hyperplasia (CAH) is a rare inherited endocrine disorder caused by a genetic mutation in a crucial enzyme for cortisol synthesis, and is characterized by overgrowth of the adrenal glands, adrenal insufficiency, mineralocorticoid deficiency, and androgen excess. The most frequent form of CAH, responsible for 95% of cases, is a deficiency in the enzyme 21-hydroxylase, which is required for the production of cortisol and aldosterone in the adrenal glands. There are two main types, classic and non-classical CAH. Classic CAH is diagnosed at birth and is characterized by adrenal insufficiency. It can lead to severe virilization in women, testicular tumors in men, and infertility. Non-classical CAH is a milder form of CAH, usually not diagnosed until adolescence, but with a larger prevalence of 0.1-0.2% of the general population. Classic CAH is the current focus of ATR-101.

CAH is an orphan disease with universal screening

Classic CAH has an incidence of 1 in 10,000-15,000 births in North American and European populations1. CAH occurs in both males and females, but its presentation from patient to patient can be quite different. Adrenal crisis, a life-threatening condition that occurs when the body cannot produce sufficient cortisol in response to stress, is a risk in both males and females with classic CAH. For this reason, all newborns in the US and in many other countries are screened for CAH at birth and treated as appropriate with corticosteroid replacement (glucocorticoids and, in many cases, mineralocorticoids) to make up for their inability to synthesize these hormones. CAH also causes hormonal imbalances in adults.

Despite taking corticosteroids, most patients are unable to achieve hormonal balance

Corticosteroids are the current standard of care for classic CAH and are used to address the endogenous cortisol deficiency of CAH patients. Such exogenous cortisol administration, however, has its own complications and side effects, and it is difficult to mimic normal glucocorticoid levels. Elevated ACTH levels can result and cause excess adrenal production of various androgens, including testosterone. In women, these excess androgens cause hirsutism, alopecia, acne, and irregular menstruation. In men, testicular adrenal rest tumors occur at a high rate that, in turn leads to a high rate of infertility. Increasing exogenous corticosteroids is the current means of addressing such issues, but often results in iatrogenic Cushing’s syndrome. The patient and the physician are often trapped between over-treating with corticosteroids and suffering from elevated levels of androgens.


  1. Speiser PW, et al. Congenital adrenal hyperplasia due to steroid 21-hydroxylase deficiency: an endocrine society clinical practice guideline. J Clin Endocrinol Metab. 2010 Sep;95(9):4133-60. (PMID: 20823466)

A rare disease with limited treatment options

Endogenous Cushing's syndrome (CS) is a rare endocrine disorder characterized by increased cortisol production from the adrenal gland, which is the result of a pituitary, adrenal or ectopic tumor. Cushing's syndrome caused by a pituitary tumor is called Cushing's disease. The incidence of endogenous CS is about two persons per million annually1. It most commonly affects people who are 20 to 50 years of age, and women are three times more likely than men to have CS. Many cases of CS can be cured through surgery, but for those cases that are refractory to surgery, medical management can be quite challenging. New broad-acting agents are needed, as currently approved treatments are only for subsets of CS patients and are limited by side effects.

Impact to the patient goes beyond cortisol

The chronic cortisol excess in Cushing's syndrome can cause a multitude of issues for the patient such as weight gain, fatigue, hypertension, diabetes, bone loss, purple stretch marks, and a range of neurologic symptoms. In men, symptoms can also include decreased fertility and erectile dysfunction, while women may demonstrate menstrual irregularities and facial hair growth. With chronic exposure to higher than normal levels of cortisol, patients also exhibit cognitive impairment and mood disorders. The cumulative impact of these symptoms decreases the quality of life of the patients to an extent comparable to multiple sclerosis and cancer2. Untreated CS can be life-threatening.


  1. Sharma ST, et al. Cushing’s syndrome: epidemiology and developments in disease management. Clin Epidemiol. 2015 Apr; 17(7):281-93. (PMID: 25945066)
  2. Feelders RA, et al. The burden of Cushing’s disease: clinical and health-related quality of life aspects. Eur J Endocrinol. 2012 Sep;167(3):311-26. (PMID: 22728347)

ACC has a poor prognosis

Adrenocortical carcinoma (ACC), also called adrenal cancer, is a cancer that develops from the adrenal glands, which are located above the kidneys. ACC occurs when cancer cells form in the outer layer (cortex) of the adrenal gland, the organ responsible for releasing hormones in response to stress. ACC frequently impacts the body's secretion of adrenal hormones and patients are often diagnosed when they seek medical attention due to symptoms associated with excess hormone production. These symptoms can include fluctuations in weight, fluid retention and rapid onset of diabetes. Other patients experience severe fatigue, pain or a feeling of fullness, which can be caused by the size of a large adrenal tumor. ACC is often diagnosed in the late stages of disease, when there is very poor patient prognosis. Patients with metastatic disease have a median overall survival of 15 months1.

ACC is an ultra-rare orphan disease

ACC is a rare, aggressive cancer with an incidence of 1-2 per million population2. Approximately 600 new patients are diagnosed in the U.S. each year. While ACC can occur at any age, most people diagnosed with the disease are between 40 and 50 years of age, and the disease is more common in women. It has also been shown to affect clusters of pediatric patients under 5 years of age.

Only approved drug is mitotane

While tumor resections may provide a cure, often this is only a temporary remission as the disease frequently reoccurs. The only approved drug for ACC is mitotane, a derivative of the pesticide DDT. Mitotane is associated with tolerability issues that often prevent the achievement of therapeutic blood levels3. Mitotane is sometimes combined with the cytotoxic chemotherapies etoposide, doxorubicin and cisplatin (EDP-M) for patients at advanced stages of the disease. These options are extremely limited and can be toxic, poorly tolerated and often ineffective.

  1. Fassnacht M, et al. Combination chemotherapy in advanced adrenocortical carcinoma. N Engl J Med. 2012 Jun;366(23):2189-97. (PMID: 22551107)
  2. Allolio B, et al. Clinical review: adrenocortical carcinoma: clinical update . J Clin Endocrinol Metab. 2006 Jun;91(6):2027-37. (PMID: 16551738)
  3. Kerkhofs TM, et al. Comparison of two mitotane starting dose regimens in patients with advanced adrenocortical carcinoma. J Clin Endocrinol Metab. 2013 Dec;98(12):4759-67. (PMID: 24057287)