clofutriben (SPI-62) / Sparrow Pharma - LARVOL DELTA

Clofutriben Pharmacokinetics in Patients With Impaired Renal Function (clinicaltrials.gov) - P1 | N=16 | Recruiting | Sponsor: Sparrow Pharmaceuticals | Not yet recruiting ➔ Recruiting

Enrollment open • Renal Disease

Human Adipose Tissue 11β-Hydroxysteroid Dehydrogenase Type 1 Inhibition Without Tachyphylaxis by Clofutriben, a Pseudo-Irreversible Enzyme Inhibitor. (PubMed, Clin Transl Sci) - "Molecular docking revealed that clofutriben can form a ternary complex with nicotinamide-adenine dinucleotide phosphate (NADPH) cofactor and the human HSD-1 active site. The higher activation energy to dissociate that trimolecular interaction, compared to a bimolecular drug-enzyme interaction characteristic of other HSD-1 inhibitors, is posited to be responsible for the enzyme kinetic and favorable pharmacological properties of clofutriben."

Journal • Diabetes • Genetic Disorders • Metabolic Disorders • Obesity • Oncology • Type 2 Diabetes Mellitus

Effects of clofutriben, a selective 11β-hydroxysteroid dehydrogenase type 1 inhibitor, on the efficacy and toxicity of prednisolone in patients with polymyalgia rheumatica: a single-blind controlled trial with sequential cohorts. (PubMed, Ann Rheum Dis) - "Further trials to assess clofutriben's potential to improve the benefit-risk profile of prednisolone are warranted."

Journal • Cardiovascular • Giant Cell Arteritis • Immunology • Metabolic Disorders • Musculoskeletal Pain • Pain • Rheumatology

Clofutriben Pharmacokinetics in Patients With Impaired Renal Function (clinicaltrials.gov) - P1 | N=16 | Not yet recruiting | Sponsor: Sparrow Pharmaceuticals

New P1 trial • Renal Disease

DDI: Pharmacokinetic Interaction Trial of Clofutriben With Midazolam and Prednisolone (clinicaltrials.gov) - P1 | N=16 | Active, not recruiting | Sponsor: Sparrow Pharmaceuticals

New P1 trial

RESCUE: SPI-62 as a Treatment for Adrenocorticotropic Hormone-dependent Cushing's Syndrome (clinicaltrials.gov) - P2 | N=26 | Completed | Sponsor: Sparrow Pharmaceuticals | Active, not recruiting ➔ Completed | Trial completion date: Dec 2025 ➔ Aug 2025 | Trial primary completion date: Dec 2025 ➔ Aug 2025

Trial completion • Trial completion date • Trial primary completion date • Cushing’s Disease • Endocrine Disorders

A Trial of Prednisolone in Combination With SPI-62 in Participants With Polymyalgia Rheumatica (PMR) (clinicaltrials.gov) - P1 | N=1 | Terminated | Sponsor: Sparrow Pharmaceuticals | N=24 ➔ 1 | Suspended ➔ Terminated; lack of enrollment

Enrollment change • Trial termination • Giant Cell Arteritis • Immunology • Musculoskeletal Pain • Pain • Rheumatology

A Trial of Prednisolone in Combination With SPI-62 or Placebo in Subjects With Polymyalgia Rheumatica (PMR) (clinicaltrials.gov) - P2 | N=66 | Completed | Sponsor: Sparrow Pharmaceuticals | Recruiting ➔ Completed | Trial completion date: Jul 2025 ➔ Apr 2025

Trial completion • Trial completion date • Giant Cell Arteritis • Immunology • Musculoskeletal Pain • Pain • Rheumatology

RESCUE: SPI-62 As a Treatment for Adrenocorticotropic Hormone-dependent Cushing's Syndrome (clinicaltrials.gov) - P2 | N=26 | Active, not recruiting | Sponsor: Sparrow Pharmaceuticals | Trial primary completion date: Dec 2024 ➔ Dec 2025

Trial primary completion date • Cushing’s Disease • Endocrine Disorders

ACSPIRE: SPI-62 As a Treatment for Hypercortisolism Related to a Benign Adrenal Tumor (clinicaltrials.gov) - P2 | N=30 | Terminated | Sponsor: Sparrow Pharmaceuticals | Trial completion date: Dec 2025 ➔ Feb 2025 | Active, not recruiting ➔ Terminated; Data does not demonstrate a clear benefit for this patient population, and we therefore cannot justify continuing this trial.

Trial completion date • Trial termination • Adrenal Cortex Carcinoma • Cushing’s Disease • Endocrine Cancer • Endocrine Disorders • Oncology • Solid Tumor

A Trial of Prednisolone in Combination With SPI-62 in Participants With Polymyalgia Rheumatica (PMR) (clinicaltrials.gov) - P1 | N=24 | Suspended | Sponsor: Sparrow Pharmaceuticals | Trial completion date: Oct 2024 ➔ Apr 2025 | Trial primary completion date: Oct 2024 ➔ Apr 2025

Combination therapy • Trial completion date • Trial primary completion date • Giant Cell Arteritis • Immunology • Musculoskeletal Pain • Pain • Rheumatology • CRP

A Trial of Prednisolone in Combination With SPI-62 or Placebo in Subjects With Polymyalgia Rheumatica (PMR) (clinicaltrials.gov) - P2 | N=72 | Recruiting | Sponsor: Sparrow Pharmaceuticals | N=48 ➔ 72 | Trial completion date: Jul 2024 ➔ Jul 2025 | Trial primary completion date: Apr 2024 ➔ Apr 2025

Combination therapy • Enrollment change • Trial completion date • Trial primary completion date • Giant Cell Arteritis • Immunology • Musculoskeletal Pain • Pain • Rheumatology • CRP

A Trial of Prednisolone in Combination With SPI-62 in Participants With Polymyalgia Rheumatica (PMR) (clinicaltrials.gov) - P1 | N=24 | Suspended | Sponsor: Sparrow Pharmaceuticals | Recruiting ➔ Suspended

Combination therapy • Trial suspension • Giant Cell Arteritis • Immunology • Musculoskeletal Pain • Pain • Rheumatology • CRP

THE 11Β-HYDROXYSTEROID DEHYDROGENASE TYPE 1 INHIBITOR SPI-62 DIFFERENTIALLY MODULATES PREDNISOLONE IMMUNE AND MUSCULOSKELETAL EFFICACY AND BONE FORMATION/RESORPTION BIOMARKERS IN PATIENTS WITH POLYMYALGIA RHEUMATICA (PMR): AN INTERIM REPORT (EULAR 2024) - "SPI-62 achieved full HSD-1 inhibition. SPI PSL 10 attenuated PMR disease control, which was partly restored by SPI PSL 15 and further by SPI PSL 20. Relapses, ESR, IL-6, stiffness intensity, and pain chronicity were numerically the same with SPI PSL 20 as PBO PSL 10."

Biomarker • Clinical • Fatigue • Giant Cell Arteritis • Immunology • Muscular Atrophy • Musculoskeletal Diseases • Musculoskeletal Pain • Obesity • Pain • Rheumatology • CRP • IL6

A Trial of Prednisolone in Combination With SPI-62 in Participants With Polymyalgia Rheumatica (PMR) (clinicaltrials.gov) - P1 | N=24 | Recruiting | Sponsor: Sparrow Pharmaceuticals | Not yet recruiting ➔ Recruiting

Enrollment open • Giant Cell Arteritis • Immunology • Musculoskeletal Pain • Pain • Rheumatology • CRP

ACSPIRE: SPI-62 as a Treatment for Hypercortisolism Related to a Benign Adrenal Tumor (clinicaltrials.gov) - P2 | N=30 | Active, not recruiting | Sponsor: Sparrow Pharmaceuticals | Recruiting ➔ Active, not recruiting | N=150 ➔ 30

Enrollment change • Enrollment closed • Adrenal Cortex Carcinoma • Cushing’s Disease • Endocrine Cancer • Endocrine Disorders • Oncology • Solid Tumor

RESCUE: SPI-62 as a Treatment for Adrenocorticotropic Hormone-dependent Cushing's Syndrome (clinicaltrials.gov) - P2 | N=26 | Active, not recruiting | Sponsor: Sparrow Pharmaceuticals | Recruiting ➔ Active, not recruiting

Enrollment closed • Cushing’s Disease • Endocrine Disorders

A Trial of Prednisolone in Combination With SPI-62 in Participants With Polymyalgia Rheumatica (PMR) (clinicaltrials.gov) - P1 | N=24 | Not yet recruiting | Sponsor: Sparrow Pharmaceuticals

New P1 trial • Giant Cell Arteritis • Immunology • Musculoskeletal Pain • Pain • Rheumatology • CRP

RESCUE: SPI-62 as a Treatment for Adrenocorticotropic Hormone-dependent Cushing's Syndrome (clinicaltrials.gov) - P2 | N=26 | Recruiting | Sponsor: Sparrow Pharmaceuticals | Trial primary completion date: Dec 2023 ➔ Dec 2024

Trial primary completion date • Cushing’s Disease • Endocrine Disorders

A Trial of Prednisolone in Combination With SPI-62 or Placebo in Subjects With Polymyalgia Rheumatica (PMR) (clinicaltrials.gov) - P2 | N=48 | Recruiting | Sponsor: Sparrow Pharmaceuticals | Trial completion date: Dec 2023 ➔ Jul 2024 | Trial primary completion date: Sep 2023 ➔ Apr 2024

Trial completion date • Trial primary completion date • Giant Cell Arteritis • Immunology • Musculoskeletal Pain • Pain • Rheumatology • CRP

Characterization of Numeric Rating Scales for Symptom Assessment in Polymyalgia Rheumatica (ACR Convergence 2023) - "Clinical trial participants with PMR, no or low disease activity, and who received prednisolone 10 mg for = 1 week prior to entry were treated with prednisolone 10 mg for 4 weeks and received each of SPI-62 and matching placebo as adjunctive therapy for 2 weeks... The results provide necessary initial evidence to encourage further examination of these NRS' psychometrics. They suggest high patient compliance for daily symptom report and moderate test-retest reliability. Patient ability to recall accurately their most severe symptoms during 7 days prior to a trial visit was strong for stiffness and fatigue, whilst moderate for pain."

Fatigue • Giant Cell Arteritis • Immunology • Musculoskeletal Pain • Pain • Rheumatology

Population Target-Mediated Pharmacokinetic/Pharmacodynamic Modeling to Evaluate SPI-62 Exposure and Hepatic 11β-Hydroxysteroid Dehydrogenase Type 1 (HSD-1) Inhibition in Healthy Adults. (PubMed, Clin Pharmacokinet) - "A population TMDD-PD model that explains SPI-62 nonlinear PK and hepatic HSD-1 inhibition following different dose regimens in healthy adults was successfully established. Our simulation results provide a solid foundation for model-informed development of SPI-62."

Journal • PK/PD data

ACSPIRE: SPI-62 as a Treatment for Hypercortisolism Related to a Benign Adrenal Tumor (clinicaltrials.gov) - P2 | N=150 | Recruiting | Sponsor: Sparrow Pharmaceuticals | Trial completion date: Dec 2023 ➔ Dec 2025 | Initiation date: Jun 2022 ➔ Jul 2023 | Trial primary completion date: Nov 2023 ➔ Dec 2024

Trial completion date • Trial initiation date • Trial primary completion date • Adrenal Cortex Carcinoma • Endocrine Cancer • Endocrine Disorders • Oncology • Solid Tumor

RESCUE: SPI-62 as a Treatment for Adrenocorticotropic Hormone-dependent Cushing's Syndrome (clinicaltrials.gov) - P2 | N=26 | Recruiting | Sponsor: Sparrow Pharmaceuticals | Trial completion date: Aug 2023 ➔ Dec 2025 | Trial primary completion date: Mar 2023 ➔ Dec 2023

Trial completion date • Trial primary completion date • Endocrine Disorders

Intracellular Cortisol Control: An Approach to Reduce Cushing's Syndrome Morbidity With Minimal Adrenal Insufficiency Risk? (ENDO 2023) - "Morning serum (293.9 +/- 18.9 v 273.4 +/- 39.3 nM) and 24h urinary (100.7 +/- 6.9 v 89.6 +/- 14.0 nmol) cortisol did not differ between SPI-62 and placebo...In situations that require GC rescue dosing during HSD-1 inhibitor administration, prodrug GCs (i.e., cortisone acetate, prednisone) will not be effective a. s they require HSD-1 for activation. Those patients require active agents (e.g., hydrocortisone, prednisolone).*Unless otherwise noted, all abstracts presented at ENDO must not be released to the press or the public until the date and time of presentation...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.*"

Cardiovascular • Endocrine Disorders • Giant Cell Arteritis • Hypertension • Immunology • Musculoskeletal Pain • Myositis • Nephrology • Obesity • Osteoporosis • Pain • Renal Disease • Rheumatology