tildacerfont (SPR001) / Spruce Biosciences, Kaken Pharma - LARVOL DELTA

Glucocorticoid (GC) Dosing Across Adults and Children with Congenital Adrenal Hyperplasia (CAH) (ENDO 2025) - "To provide GC replacement and suppress adrenal androgen production, GC doses higher than daily physiologic replacement (~7 mg/m2 hydrocortisone or equivalent) are usually required... Phase 2 studies CAHmelia-203 (N=96; adults), CAHmelia-204 (N=100; adults), and CAHptain-205 (N=62; 2-65 yr) examined effectiveness of tildacerfont, an oral non-steroidal antagonist of the corticotropin-releasing factor type-1 receptor, in treating CAH... In the pooled dataset (N=258; 143 females; 185 salt-wasting), mean (SD) age was 27 (14) yr; 30, 26, and 202 patients were in the 2-10 (pediatric), 11-17 (adolescent) and >17 yr (adult) groups, respectively. North America (NA), Europe (EU), and the rest of world (ROW) contributed 133, 74, and 51 patients, respectively. Mean BMI was 29.6 kg/m2 (8.3)."

Clinical • Congenital Adrenal Hyperplasia • Endocrine Disorders • Pediatrics

A Phase 2 Study to Evaluate the Safety, Efficacy and PK of Tildacerfont in Children with CAH (clinicaltrials.gov) - P2 | N=65 | Terminated | Sponsor: Spruce Biosciences | Active, not recruiting ➔ Terminated; The SPR001-203 clinical trial did not achieve the primary efficacy endpoint of the absolute change in daily GC dose from baseline at week 24. It was decided to terminate the SPR001-205 in response to the SPR001-203 efficacy data.

Trial termination • Congenital Adrenal Hyperplasia • Endocrine Disorders

A Ph2b to Evaluate Tildacerfont in the Reduction of Glucocorticoid Steroid Doses in Adult CAH (clinicaltrials.gov) - P2 | N=100 | Terminated | Sponsor: Spruce Biosciences | Active, not recruiting ➔ Terminated; Study did not meet its primary endpoint.

Trial termination • Congenital Adrenal Hyperplasia • Endocrine Disorders • CYP1A2 • CYP21A2

A Phase 2 Study to Evaluate the Safety, Efficacy and PK of Tildacerfont in Children with CAH (clinicaltrials.gov) - P2 | N=70 | Active, not recruiting | Sponsor: Spruce Biosciences | Recruiting ➔ Active, not recruiting | Trial completion date: Dec 2024 ➔ Apr 2025 | Trial primary completion date: Dec 2024 ➔ Mar 2025

Enrollment closed • Trial completion date • Trial primary completion date • Congenital Adrenal Hyperplasia • Endocrine Disorders

A Ph2b to Evaluate Tildacerfont in the Reduction of Glucocorticoid Steroid Doses in Adult CAH (clinicaltrials.gov) - P2 | N=100 | Active, not recruiting | Sponsor: Spruce Biosciences | Trial completion date: Sep 2029 ➔ Jan 2025

Trial completion date • Congenital Adrenal Hyperplasia • Endocrine Disorders • CYP1A2 • CYP21A2

Innovations in pharmacotherapy of CAH (ESPE 2024) - "Circadian delivery of hydrocortisone improves control of 21OHD compared to conventional hydrocortisone and over time results in lower glucocorticoid exposure...The P450 17A1 inhibitor abiraterone acetate directly blocks androgen production but at the expense of progesterone accumulation. The corticotropin-releasing factor type 1 receptor (CRF1) antagonists crinecerfont and tildacerfont have shown efficacy in suppressing ACTH and adrenal biomarkers in phase 2 trials...Gene therapy is also under study with an AAV5 vector (BBP-631). These modern approaches to deliver cortisol replacement and the suppress adrenal androgen production should simplify management, improve disease control, and mitigate the long-term consequences of 21OHD and chronic non-physiologic glucocorticoid exposure."

Congenital Adrenal Hyperplasia • Endocrine Disorders • Gene Therapies

A Ph2b to Evaluate Clinical Efficacy and Safety of Tildacerfont in Adult CAH (clinicaltrials.gov) - P2 | N=96 | Terminated | Sponsor: Spruce Biosciences | Trial completion date: Nov 2029 ➔ May 2024 | Active, not recruiting ➔ Terminated; Study SPR001-203 did not meet its primary and secondary endpoints therefore Spruce Biosciences has decided to terminate the study

Trial completion date • Trial termination • Congenital Adrenal Hyperplasia • Endocrine Disorders • CYP1A2

A Randomized, Placebo-Controlled, Dose Escalation Study to Evaluate the Safety and Efficacy of Tildacerfont in Adult Subjects with Polycystic Ovary Syndrome (PCOS) and Elevated Adrenal Androgens (ENDO 2024) - "Abstracts presented at a news conference are embargoed until the date and time of the news conference. The Endocrine Society reserves the right to lift the embargo on specific abstracts that are selected for promotion prior to or during ENDO."

Clinical • Congenital Adrenal Hyperplasia • Endocrine Disorders • Pancreatitis • Polycystic Ovary Syndrome

A Phase 2 Study to Evaluate the Safety, Efficacy and PK of Tildacerfont in Children With CAH (clinicaltrials.gov) - P2 | N=55 | Recruiting | Sponsor: Spruce Biosciences | N=20 ➔ 55 | Trial completion date: Mar 2024 ➔ Dec 2024 | Trial primary completion date: Mar 2024 ➔ Dec 2024

Enrollment change • Trial completion date • Trial primary completion date • Congenital Adrenal Hyperplasia • Endocrine Disorders

A Ph2b to Evaluate Clinical Efficacy and Safety of Tildacerfont in Adult CAH (clinicaltrials.gov) - P2 | N=96 | Active, not recruiting | Sponsor: Spruce Biosciences | N=72 ➔ 96 | Trial completion date: Nov 2024 ➔ Nov 2029 | Trial primary completion date: Dec 2023 ➔ Mar 2024

Enrollment change • Trial completion date • Trial primary completion date • Congenital Adrenal Hyperplasia • Endocrine Disorders • CYP1A2

A Ph2b to Evaluate Tildacerfont in the Reduction of Glucocorticoid Steroid Doses in Adult CAH (clinicaltrials.gov) - P2 | N=90 | Active, not recruiting | Sponsor: Spruce Biosciences | Trial completion date: Sep 2025 ➔ Sep 2029 | Trial primary completion date: Dec 2024 ➔ Sep 2024

Trial completion date • Trial primary completion date • Congenital Adrenal Hyperplasia • Endocrine Disorders • CYP1A2

A Ph2b to Evaluate Tildacerfont in the Reduction of Glucocorticoid Steroid Doses in Adult CAH (clinicaltrials.gov) - P2 | N=90 | Active, not recruiting | Sponsor: Spruce Biosciences | Recruiting ➔ Active, not recruiting

Enrollment closed • Congenital Adrenal Hyperplasia • Endocrine Disorders • CYP1A2

Spruce Biosciences Reports Third Quarter 2023 Financial Results and Provides Corporate Updates (Businesswire) - "CAHptain-205 Study in Pediatric Classic CAH Completes Enrollment: Enrollment in the CAHptain study is complete with 30 patients, surpassing the target enrollment of 20 patients; Target enrollment of 72 patients in the company’s CAHmelia-203 clinical trial is complete...Due to substantial patient interest in CAHmelia-203, final enrollment in the study will exceed its original target of 72 patients; Enrollment in the CAHmelia-204 clinical trial surpassed 75% enrollment and remains on track to complete enrollment in the early first quarter of 2024."

Trial status • Congenital Adrenal Hyperplasia

Spruce Biosciences Reports Third Quarter 2023 Financial Results and Provides Corporate Updates (Businesswire) - "Anticipated Upcoming Milestones...Topline results from the CAHmelia-203 clinical trial in adult classic CAH patients with highly elevated levels of A4 in the first quarter of 2024; Topline results from all cohorts in the CAHptain-205 clinical trial in pediatric classic CAH patients in the first quarter of 2024; Topline results from the CAHmelia-204 clinical trial in adult classic CAH patients on supraphysiologic doses of glucocorticoids with normal or near normal levels of A4 in the third quarter of 2024"

Clinical data • Congenital Adrenal Hyperplasia

A Ph2b to Evaluate Clinical Efficacy and Safety of Tildacerfont in Adult CAH (clinicaltrials.gov) - P2 | N=72 | Active, not recruiting | Sponsor: Spruce Biosciences | Recruiting ➔ Active, not recruiting

Enrollment closed • Endocrine Disorders • CYP1A2

A Study of Safety and Efficacy of Tildacerfont in Females With Polycystic Ovary Syndrome and Elevated Adrenal Androgens (clinicaltrials.gov) - P2 | N=27 | Completed | Sponsor: Spruce Biosciences | Active, not recruiting ➔ Completed | N=39 ➔ 27 | Trial primary completion date: May 2023 ➔ Aug 2023

Enrollment change • Trial completion • Trial primary completion date • Polycystic Ovary Syndrome

Crinecerfont in a First Clinical Application of a CRH Antagonist: Further Potential Uses are still an Open Chapter! (PubMed, J Clin Endocrinol Metab) - No abstract available

Journal

Effect of tildacerfont on gonadotropins and testicular steroidogenesis in men with classic 21-hydroxylase deficiency (ENDO 2023) - "Abstracts presented at a news conference are embargoed until the date and time of the news conference. The Endocrine Society reserves the right to lift the embargo on specific abstracts that are selected for promotion prior to or during ENDO.*"

Endocrine Disorders • Oncology

Corticotropin releasing factor-1 receptor antagonism associated with favorable outcomes of male reproductive health biochemical parameters. (PubMed, Front Endocrinol (Lausanne)) - "Tildacerfont treatment demonstrated clinically meaningful reductions in A4 levels, and A4/T with concomitant increased LH levels indicating increased testicular T production. The data suggests improvement in hypothalamic-pituitary-gonadal axis function, but more data is required to confirm favorable male reproductive health outcomes."

Journal • Endocrine Disorders • Oncology

A Study of Safety and Efficacy of Tildacerfont in Females With Polycystic Ovary Syndrome and Elevated Adrenal Androgens (clinicaltrials.gov) - P2 | N=39 | Active, not recruiting | Sponsor: Spruce Biosciences | Recruiting ➔ Active, not recruiting

Enrollment closed • Polycystic Ovary Syndrome

A Study of Safety and Efficacy of Tildacerfont in Females With Polycystic Ovary Syndrome and Elevated Adrenal Androgens (clinicaltrials.gov) - P2 | N=39 | Recruiting | Sponsor: Spruce Biosciences | Trial primary completion date: Dec 2022 ➔ May 2023

Trial primary completion date • Polycystic Ovary Syndrome

A Phase 2 Study to Evaluate the Safety, Efficacy and PK of Tildacerfont in Children With CAH (clinicaltrials.gov) - P2 | N=20 | Recruiting | Sponsor: Spruce Biosciences | Trial completion date: Jun 2023 ➔ Mar 2024 | Trial primary completion date: Jun 2023 ➔ Mar 2024

Trial completion date • Trial primary completion date • Endocrine Disorders

Association between glucocorticoid dose with BMI and glucocorticoid-related comorbidities: Data from tildacerfont Phase 2a trials in classic congenital adrenal hyperplasia (ICE 2022) - No abstract available

P2a data • Endocrine Disorders

A Ph2b to Evaluate Clinical Efficacy and Safety of Tildacerfont in Adult CAH (clinicaltrials.gov) - P2 | N=72 | Recruiting | Sponsor: Spruce Biosciences | Trial primary completion date: Nov 2024 ➔ Dec 2023

Trial primary completion date • Endocrine Disorders • CYP1A2

A Ph2b to Evaluate Tildacerfont in the Reduction of Glucocorticoid Steroid Doses in Adult CAH (clinicaltrials.gov) - P2 | N=90 | Recruiting | Sponsor: Spruce Biosciences | Trial completion date: Nov 2022 ➔ Sep 2025 | Trial primary completion date: Jun 2022 ➔ Dec 2024

Trial completion date • Trial primary completion date • Endocrine Disorders • CYP1A2