Spruce Biosciences' tildacerfont (SPR-001) for congenital adrenal hyperplasia (CAH), a rare endocrine disorder, passed muster in a phase II experiment. Proof-of-concept data were disclosed at the Endocrine Society's annual meeting in New Orleans, ENDO 2019, for the oral corticotrophin-releasing factor type 1 receptor antagonist.

As yet there is no FDA-approved therapy for CAH, which affects as many as one in every 15,000 people in the U.S. and Europe, many of them children.

The phase II results involved 18 classic CAH patients, 10 of whom received six weeks of treatments, and eight patients received two weeks of treatments. The results from both cohorts showed tildacerfont was well-tolerated and exhibited a predictable, dose-dependent pharmacokinetic profile. The results also showed tildacerfont reduced excess adrenal androgens, progestins and adrenocorticotropic hormones.

"We have been collecting great feedback from the physician, patient, and advocacy community at ENDO 2019," Spruce CEO Alexis Howerton told BioWorld. "We look forward to initiating the next stage of development, which we expect to be a double-blind, placebo-controlled program."

The phase II multiple-dose, dose-escalation, open-label, interventional clinical trial began on Sept. 6, 2018, and is set to finish on June 20. The estimated study completion date is July 3. There is a screening period of ≤30 days, and a safety follow-up period of 30 days.

Top-line results indicate that the first of the two cohorts showed reductions in adrenal androgens were found in 10 out of the 10 patients in the cohort. Also, improvements in progestins and adrenocorticotropic hormones, the primary driver of adrenal tissue hyperplasia, were found in eight of the 10 patients in the cohort.

In the second cohort, six of the eight patients showed improvements in androstenedione. Improvement in 17-hydroxyprogesterone was found in six of seven patients, and adrenocorticotropic hormone improvement was found in five of seven patients.

Primary endpoints were safety and change in 17-hydroxyprogesterone at six weeks compared to baseline. The study also is evaluating pharmacokinetic and pharmacodynamic measures.

The primary outcome measure of the study was the incidence of treatment-emergent adverse events, including any serious adverse events, dose-limited toxicities, and adverse events leading to the discontinuation of the study drug. The secondary outcome measures, over the course of 12 weeks, were the change from baseline in 17-hydroxyprogesterone (17-OHP), change from baseline to week 12 in 17-OHP following dosing of SPR-001 in subjects with CAH, change from baseline in androstenedione, change from baseline to week 12 in androstenedione following dosing of SPR-001 in subjects with CAH, change from baseline in adrenocorticotropic hormone (ACTH), and change from baseline to week 12 in ACTH following dosing of SPR-001 in subjects with CAH.

One of the male patients, with confirmed testicular adrenal rest tumors at baseline, had a notable tumor-size reduction after six weeks of therapy in the phase II trial. That type of tumor is adrenocorticotropic hormone responsive lesions of the testes that can lead to pain and infertility in men and boys.

Competitive spaces heats up

The FDA granted orphan designation to tildacerfont in December 2017. The Committee for Orphan Medicinal Products of the European Medicines Agency recommended granting orphan designation to tildacerfont in January 2018.

Competitors include Millendo Therapeutics Inc., Diurnal Group plc, and Neurocrine Biosciences Inc. Millendo is developing nevanimibe (ATR-101), an ACAT1 inhibitor that designed to prevent pathological accumulation of steroid intermediates in CAH. Its phase II interventional, open-label clinical trial began in August 2018 and its top-line phase IIb results are expected in March 2020. Diurnal recruited its first patients for its phase III clinical trial in October 2018. Diurnal plans to recruit up to 150 patients for the study and they will be treated for 52 weeks. The study is expected to the completed in late 2020 and an NDA filing in the U.S. is said to be planned for 2021.

Neurocrine began its phase II clinical trial in April 2018 and its estimated study completion date is next month. Other companies with discovery-stage programs that have not entered phase I yet for a similar treatment are Adrenas Therapeutics Inc., Ferring Pharmaceuticals Inc. and Sentia Medical Sciences Inc.

CAH is caused by genetic mutations leading to the inability to produce the stress hormone cortisol. The current standard of care is the life-long use of high-dose steroids replace the body's cortisol and to shut down pathways leading to overproduction of adrenal androgens. Spruce is looking to replace the steroids, which are administered three to four times daily, with a once-daily small molecule.

Spruce received $20 million series A in 2016, led by Novo Holdings A/S with additional investment from Rivervest Venture Partners.