RARE Daily

Spruce Cuts Staff as CAH Study Misses Primary Endpoint

March 14, 2024

Rare Daily Staff

Spruce Biosciences said topline results from its phase 2b study of tildacerfont in adult classic congenital adrenal hyperplasia failed to meet the primary efficacy endpoint while its study of tildacerfont in pediatric classic congenital adrenal hyperplasia supports further dose-ranging across additional dosing cohorts.

The biotech’s shares sank as much as 75 percent on the news and Spruce said it would cut 21 percent of its staff as part of cost-cutting measures. It is terminating the CAHmelia-203 study and a workforce reduction of approximately 21percent. The company currently has more than $81 million in cash and cash equivalents, which is anticipated to fund its current operating plan through the end of 2025, including through the CAHmelia-204 topline results and CAHptain-205 topline results from additional dosing cohorts.

Congenital Adrenal Hyperplasia (CAH) is a rare, autosomal recessive disease, driven by a mutation in the gene that encodes an enzyme necessary for the synthesis of key adrenal hormones. In CAH patients, the body is not able to produce cortisol, which alters the normal feedback cycle of the hypothalamic-pituitary-adrenal axis and leads to excess secretion of adrenocorticotropic hormone, hyperplasia of the adrenal gland, and consequently high levels of adrenal androgen production. As a result, CAH patients may suffer from premature puberty, impaired fertility, hirsutism, acne, the development of adrenal rest tumors, and an impaired quality of life, and additionally for females, virilized genitalia and menstrual irregularities.

Currently, the only way to downregulate the production of excess androgens in CAH patients is to administer supraphysiologic doses of glucocorticoids, which increases the risks of developing diabetes, cardiovascular disease, stunted growth, osteoporosis, thin skin, gastrointestinal disorders, and decreased lifespan.

Tildacerfont is a second generation, once-daily oral antagonist of the CRF1 receptor, being developed for the treatment of classic CAH. The global CAHmelia program in adult classic CAH is comprised of two phase 2b studies of two distinct populations of adult CAH patients. CAHmelia-203 assesses androstenedione (A4) reduction in adult CAH patients with severe hyperandrogenemia, while CAHmelia-204 assesses glucocorticoid (GC) reduction, a potentially registrational endpoint, in adult CAH patients on supraphysiologic GC doses with normal or near normal levels of A4.

The phase 2 CAHptain-205 study is focused on addressing the unmet medical need in pediatric CAH patients, which represents approximately 25 percent of the total patient population.

The CAHmelia-203 clinical trial, which enrolled 96 subjects with a mean baseline A4 level more than five times above the upper limit of normal, did not achieve the primary efficacy endpoint of the assessment of dose response for the change in A4 from baseline to week 12. Compliance with study medication and GC was low resulting in lower-than-expected tildacerfont exposure. Tildacerfont was generally safe and well tolerated at all doses with no treatment-related serious adverse events. Most adverse events were reported as mild to moderate.

“CAHmelia-203 is the first study of its kind to address a difficult-to-treat CAH patient population with severe and more refractory hyperandrogenemia, which is often attributed to challenging real-life compliance with daily GCs,” said Javier Szwarcberg, CEO of Spruce Biosciences. “We garnered important data from this study which will inform ongoing development of tildacerfont in adult classic CAH.”

Spruce anticipates reporting topline results in the third quarter of 2024 from CAHmelia-204, which is focused on assessing GC reduction, a potentially registrational endpoint, in a different population of adult CAH patients with relatively controlled A4 levels and historically better adherence to GC therapy. Assuming positive results from CAHmelia-204 and CAHptain-205, the company plans to meet with the U.S. Food and Drug Administration and comparable foreign regulatory authorities to outline the design of a registrational clinical program in adult and pediatric classic CAH.

The CAHptain-205 study of tildacerfont in pediatric classic CAH enrolled 30 children between two and 17 years of age with a mean baseline GC dose of 14 mg/m2/day and mean baseline A4 level of 372 ng/dL. The study characterized the safety and pharmacokinetic profiles of tildacerfont, as well as changes in androgen levels over 12 weeks of treatment, and the ability to reduce daily GC dose upon A4 normalization.

Tildacerfont was generally safe and well tolerated at all dose ranges with no treatment-related SAEs reported. Seventy three percent of all patients met the efficacy endpoint of A4 or GC reduction from baseline at 12 weeks of treatment with tildacerfont and 70 percent of patients with elevated baseline A4 values demonstrated an A4 reduction at week 4. Preliminary pharmacokinetic analysis suggests that tildacerfont is cleared more rapidly in children than in adult CAH patients.

Photo: Javier Szwarcberg, CEO of Spruce Biosciences

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