And then we found it—in KORLYM, the first FDA-approved treatment for endogenous Cushing's syndrome, a serious, debilitating
metabolic disorder caused by the overproduction of cortisol, a stress hormone, the effects of which can include hypertension,
heart disease, diabetes, depression, chronic fatigue, obesity, and bone loss. An estimated 20,000 people in the US, mostly
women, have Cushing's, which qualifies it for rare disease status. However, the real incidence is considered to be higher
because it is frequently undiagnosed; many clinicians are unfamiliar with the disease and confuse it with other conditions
that are often less lethal.
Signs and symptoms of Cushing’s syndrome
In addition, Cushing's has a strong co-morbidity profile: an estimated 3-5% of all type II diabetic patients have that condition
due to the effect of uncontrolled cortisol proliferation on blood sugar levels; cortisol also erodes bone mass and is thus
a contributing factor in osteoporosis.
KORLYM does not by itself decrease cortisol production but reduces its dangerous side-effects, especially the high blood sugar
levels that usually lead to diabetes in patients with long-term exposure to excess levels of the hormone. Approved by the
FDA in February 2012, the KORLYM label is a relatively narrow one, covering Cushing's syndrome patients with type 2 diabetes
or glucose intolerance who are not candidates for or who have failed the most common treatment for Cushing's, which is surgery
to remove the benign tumors that stimulate overproduction of cortisol.
A hormone that matters: Cortisol's big footprint
However, research indicates that KORLYM's main mechanism of action as a glucocorticoid receptor (GR-II) antagonist, which
blocks cortisol from binding in the bloodstream, can improve clinical symptoms for other life-threatening conditions where
excess cortisol has been identified as a causative factor. In this regard, KORLYM has potential value above and beyond its
current status as one drug for a single rare disease. Could it be instead the vanguard of a much larger therapeutic franchise,
one built around medicines that mediate the destructive effects of a single aberrant hormone on the nerves and tissues that
keep us whole and healthy?
Corcept Therapeutics, the small, California Bay Area company that brought KORLYM to market, thinks it is. "KORLYM is the first
step toward a business that we are creating around a unifying scientific theme, which is to understand how excess cortisol
levels influence the incidence and progression of not just one, but potentially dozens, of different conditions," Corcept
CEO Joe Belanoff told Pharm Exec.
From a purely medical perspective, the model makes sense: cortisol, which is found in more than 80% of all bodily tissues,
is an essential regulator of system metabolism and proper organ function. A review of the clinical literature finds that,
in addition to endocrine and metabolic disorders like Cushing's and diabetes, the effects of aberrant high cortisol are felt
in CNS diseases, including psychotic depression, post-traumatic stress disorder, alcoholism, and early-stage Alzheimer's;
ophthalmologic conditions like glaucoma and central serous retinopathy; osteoporosis; and even oncology, where research shows
that cortisol can, in some cases, control the way tumors grow. Corcept is focusing its development pipeline on three main
applications, covering psychiatry, metabolics. and cancer.
"The potential indications around this ubiquitous and clinically underrated hormone take us beyond the rare disease state
to those chronic areas where we still see large numbers of patients with unmet medical needs," says Belanoff. The implicit
message here is KORLYM exists as a prototype for something bigger—a new, multi-platform approach to identifying and treating