Spruce Biosciences is developing what could be the first new therapy treating congenital adrenal hyperplasia (CAH) since the 1960s, and a new therapy for women with polycystic ovary syndrome.
Courtesy of Spruce Biosciences
Spruce Biosciences is on the verge of developing what potentially could be the first new therapy treating congenital adrenal hyperplasia (CAH) since the 1960s, as well as a new therapy for women with polycystic ovary syndrome (PCOS).
“We’re using the same compound, tildacerfont, for both indications,” Javier Szwarcberg, M.D., CEO of Spruce Biosciences, told BioSpace. “The drug is a second-generation small molecule that binds to the CRF1 receptors in the pituitary gland and acts as an antagonist. Studies show it diminishes secretion of adrenocorticotropic hormone (ACTH) by the pituitary and androstenedione (A4), and therefore has the potential to control the disease without the need for supraphysiological doses of glucocorticoids.” Consequently, this molecule may reduce the risk of steroid-associated comorbidities, such as cardiometabolic obesity and osteoporosis.
Two Phase IIb studies are underway to treat adults with classic CAH: CAHmelia-203 and CAHmelia-204.
“The 203 study brings in classic CAH patients who have higher levels of A4, which means their condition is not controlled. It wouldn’t be appropriate to immediately glucocorticoid dose-reduce those patients. The hope is that with tildacerfont, through its CRF1 receptor antagonist (action), we will see control of A4,” which will enable glucocorticoid dose reductions later on. Szwarcberg said he expects a readout in the second half of 2023.
The 204 study is designed for classic CAH patients with normal or near-normal levels of A4, with the intent to reduce glucocorticoid doses. “With tildacerfont, the A4 levels ought to remain at a control level as the patient goes through glucocorticoid dose reductions,” Szwarcberg said, adding that he expects a read out for this study in the latter half of 2024. A Phase II study of tildacerfont has also started to treat pediatric CAH, he noted.
Data from the Phase II clinical trials of tildacerfont in adult classic CAH indicate “profound biochemical improvements in adrenal androgens such as A4, and ACTH,” Szwarcberg revealed.
Supraphysiologic levels of corticosteroids have been the traditional treatment for CAH, but they carry significant long-term comorbidities. Patients with classic CAH have a genetic mutation in the CYP21A2 gene leading to deficiencies in the 21-hydroxylase enzyme that impair a person’s ability to produce cortisol, a hormone necessary for life. As the body’s demand for cortisol increases, the disease becomes life-threatening.
Tildacerfont initially was developed to address depression and anxiety. Spruce realized it could reduce adrenal androgen production and therefore treat CAH, leading the company to buy all rights to the molecule from Eli Lilly. “Developing tildacerfont makes great sense to me. CAH biology is well-understood, the mechanism of action is clear and the clinical and regulatory pathway to approval appears feasible,” Szwarcberg said.
Today’s clinical trials mark the beginning of a turning point for Spruce. “The trials that began in 2020 did not meet their timelines,” he said. Since becoming CEO in January, Szwarcberg has made several staffing changes and added a new chief medical officer, head of clinical operations and chief regulatory and quality officer. He also has revamped the protocols in ways that make it easier for clinical sites to recruit patients into the Phase IIb trials. “We have simplified the protocols and have added sites for the clinical studies.” The company originally targeted 70 trial sites and would like to increase that to a maximum of about 130 sites globally.
Tildacerfont also may prove valuable in treating polycystic ovary syndrome for patients with adrenally sourced androgens. “PCOS is the number one cause of female infertility in the world,” Szwarcberg said. “The underlying cause is unknown but genetic and epigenetic factors play a role in the disease.”
Until recently, scientists believed the source of androgens originated solely from the ovaries. Now they understand that about 5% of the approximately 116 million patients worldwide have androgens that solely originate from the adrenals. This is termed functional adrenal hyperandrogenism (FAH). About 30% of PCOS patients have androgens of mixed origin.
“In the context of FAH-PCOS, scientists believe the adrenals are hypersensitive to normal or near-normal levels of ACTH. Therefore, by modulating ACTH levels, adrenals will see less of that stimulant and potentially produce less androgens,” Szwarcberg said. To test that, Spruce is conducting a proof of mechanism trial that assesses efficacy from very low doses to a peak of 200 milligrams a day. “We hope to have that trial fully enrolled by Q4 of this year and release data in the first half of 2023.”
Spruce’s focus is on completing the CAHmelia program – the 203 and 204 studies – and advancing programs in pediatrics (for CAH) and in PCOS. Tildacerfont holds orphan drug status from the U.S. Food and Drug Administration and from the European Medicines Agency.
