With positive phase 2, Neurocrine eyes pivotal trial for rare disease drug

DNA genomics precision medicine
There is currently no FDA-approved, nonsteroid treatment for classic CAH. (Pixabay)

Neurocrine Biosciences' treatment for congenital adrenal hyperplasia (CAH) put up positive interim data in a phase 2 study, significantly lowering levels of two types of hormones linked to the rare genetic disorder in more than half of the patients. 

San Diego-based Neurocrine is developing NBI-74788 to treat classic CAH in adults and children and will meet with the FDA to discuss the path toward registration. The disorder may be caused by a mutation in several different genes; Neurocrine is focused on patients with a mutation that causes a deficiency of the 21-hydroxylase enzyme. This deficiency affects the production of cortisol and other adrenal steroids, which causes adrenal insufficiency, overgrowth of the adrenal glands and excess levels of androgens, or male sex hormones. 

The phase 2 study involved about 30 adults with classic 21-hydroxylase deficiency CAH. The patients were divided into three groups, each of which received a different dose of NBI-74788 for 14 days. After treatment, there was a reduction of at least 50% from baseline in 17-hydroxyprogesterone (17-OHP) and adrenocorticotropic hormone (ACTH) levels in more than half of the patients. 


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"The interim results from this Phase II study of NBI-74788 are encouraging, as they indicate a clinically meaningful reduction in key biomarkers. These data provide encouragement that NBI-74788 has potential as a new treatment option to help patients avoid the complications associated with current therapeutic options for classic CAH,” said lead investigator Richard Auchus, M.D., Ph.D., a professor of internal medicine in the division of metabolism, endocrinology and diabetes at University of Michigan Health System, in a statement. 

The symptoms of classic CAH may vary, depending on the patient’s gender and their age at diagnosis. Girls may have excessive facial or body hair, irregular periods and may be born with ambiguous genitalia, according to the NIH’s Genetic and Rare Disease Information Center. If not treated early, both genders can experience early onset of puberty and short stature as a result of premature completion of growth.

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"Patients with classic CAH currently have limited treatment options besides more and more glucocorticoids,” Auchus said. “The management of their genetic disorder is complex due to the highly variable clinical features and response to therapy, which also changes over time. Most patients receive supraphysiologic doses of glucocorticoids chronically to manage their disease, which frequently leads to serious long-term health consequences.” 

These side effects include bone loss, Cushing’s syndrome and metabolic problems. There is currently no FDA-approved, nonsteroid treatment for classic CAH. NBI-74788 is a non-peptide corticotropin-releasing factor type 1 (CRF1) receptor antagonist. Previous work has shown that blocking CRF receptors can decrease ACTH levels, which could reduce the amount of corticosteroids needed by CAH patients.

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