nevanimibe (ATR-101) / Tempest Therap - LARVOL DELTA

Pharmacologic Alteration of Meibum Lipid Composition Alleviates Dry Eye Phenotype in Awat2-/- Mice. (PubMed, Invest Ophthalmol Vis Sci) - "Awat2-/- mice, an animal model of EDE, were treated systemically with ATR101 (nevanimibe), a selective sterol O-acyltransferase 1 (SOAT1) inhibitor that suppresses cholesteryl ester (CE) synthesis...Pharmacologic intervention in meibogenesis corrects a pathogenic lipid imbalance in Awat2-deficient MGs and improves tear film and MG function. These findings identify lipid metabolic remodeling of meibum as a mechanistically grounded therapeutic strategy for obstructive MG dysfunction and evaporative dry eye."

Journal • Preclinical • Dry Eye Disease • Ophthalmology

The role of dimensionality and extracellular matrix formation in 3D bioprinted breast cancer models (EACR 2026) - "Sensitivity to metabolic inhibitors (including rapamycin, Atpenin-A5, ATR-101, 3-BP, and BPTES) was also evaluated.Result and Each model system exhibited a distinct proteomic signature, allowing clear discrimination among culture conditions even in the absence of pharmacological treatment. These findings demonstrate that culture dimensionality and extracellular context strongly influence tumor cell metabolism and intracellular signaling. The resulting differences in drug sensitivity and resistance mechanisms emphasize the importance of developing preclinical models that more closely approximate in situ tumor biology."

Preclinical • Breast Cancer • Oncology • Solid Tumor

Radiosynthesis and initial preclinical evaluation of 18F-labeled nevanimibe analog for PET imaging of SOAT1-mediated cholesterol metabolism (SNMMI 2026) - "In summary, we have developed the radiosynthesis of a fluorinated analog of nevanimibe and assessed its initial biodistribution in vivo. The data for this analog aligns with the biodistribution of the parent tracer, [11C]nevanimibe. Current studies are underway with male Sprague-Dawley rats as female rats have a greater variability in uptake due to differences in menstrual cycles."

Preclinical • Cardiovascular • Endocrine Disorders • Hypertension

First-in-human PET imaging of cholesterol trafficking in overactive adrenal glands with [11C]Nevanimibe (SNMMI 2026) - "Of the subjects, six were healthy controls (3M, 3F), and three patients were previously diagnosed with hypercortisolism (see figure) via an elevated urine free cortisol (UFC) test as well as failure to respond to adrenal suppression with dexamethasone phosphate. In this study, we performed first-in-human PET imaging of the SOAT1 targeted ligand, [11C]Nevanimibe. We have translated a preclinically developed tracer into clinical studies and assessed its initial kinetics in patients with hyperactive adrenal glands. This initial data suggests that SOAT1 imaging may be used to stratify patients with hypertension and suspected PA to avoid unnecessary invasive screening."

First-in-human • P1 data • Cardiovascular • Endocrine Disorders • Hypertension

Radiosynthesis and initial preclinical evaluation of 18F-labeled nevanimibe analog for PET imaging of SOAT1-mediated cholesterol metabolism (SNMMI 2026) - "In summary, we have developed the radiosynthesis of a fluorinated analog of nevanimibe and assessed its initial biodistribution in vivo. The data for this analog aligns with the biodistribution of the parent tracer, [11C]nevanimibe. Current studies are underway with male Sprague-Dawley rats as female rats have a greater variability in uptake due to differences in menstrual cycles."

Preclinical • Cardiovascular • Endocrine Disorders • Hypertension

Validation of [11C]Nevanimibe Radiosynthesis for Clinical Translation: A SOAT1 Inhibitor for PET Imaging of Atherosclerosis and Endocrine Diseases (SNMMI 2025) - "Synthesis from [11C]CH3OTf (900 mCi) resulted in an average of 4.25% non-decay corrected activity yield of [11C]nevanimibe (32.4, 30.8, 51.5 mCi; n=3) from EOB (34, 44, 34 minutes). Radiochemical purities higher than 94% and a mean molar activity of 17028 Ci/mmol were observed for all three sequential syntheses. All quality control tests met the specifications for release."

Clinical • Adrenal Cortex Carcinoma • Atherosclerosis • Cardiovascular • Congenital Adrenal Hyperplasia • Endocrine Disorders • Genito-urinary Cancer • Nephrology • Oncology • Solid Tumor

Validation of [11C]Nevanimibe Radiosynthesis for Clinical Translation: A SOAT1 Inhibitor for PET Imaging of Atherosclerosis and Endocrine Diseases (SNMMI 2025) - "Synthesis from [11C]CH3OTf (900 mCi) resulted in an average of 4.25% non-decay corrected activity yield of [11C]nevanimibe (32.4, 30.8, 51.5 mCi; n=3) from EOB (34, 44, 34 minutes). Radiochemical purities higher than 94% and a mean molar activity of 17028 Ci/mmol were observed for all three sequential syntheses. All quality control tests met the specifications for release."

Clinical • Adrenal Cortex Carcinoma • Atherosclerosis • Cardiovascular • Congenital Adrenal Hyperplasia • Endocrine Disorders • Genito-urinary Cancer • Nephrology • Oncology • Solid Tumor

The impact of acyl-CoA:cholesterol transferase (ACAT) inhibitors on biophysical membrane properties depends on membrane lipid composition. (PubMed, Mol Cell Endocrinol) - "At present, mitotane is the only inhibitor of this class of enzymes in clinical use for the treatment of adrenocortical carcinoma but associated with common and severe adverse effects...In the present study, the interaction of the three ACAT inhibitors nevanimibe, Sandoz 58-035, and AZD 3988 with membranes has been investigated using lipid model membranes in conjunction with biophysical experimental (NMR, ESR, fluorescence) and theoretical (MD simulations) approaches. The data show, that the drugs (i) incorporate into lipid membranes, (ii) differently influence the structure of lipid membranes; (iii) affect membrane structure depending on the lipid composition; and (iv) do not cause hemolysis of red blood cells. The results are discussed with regard to the use of the drugs, in particular to better understand their efficacy and possible side effects."

Journal • Adrenal Cortex Carcinoma • Alzheimer's Disease • Atherosclerosis • Cardiovascular • CNS Disorders • Dyslipidemia • Genito-urinary Cancer • Hematological Disorders • Oncology • Solid Tumor

Dysregulation of cholesterol homeostasis in human lung cancer tissue and tumour-associated macrophages. (PubMed, EBioMedicine) - "Our data show an opposite dysregulation of cholesterol homeostasis in tumour tissue vs. TAMs. Polarization of in vitro differentiated macrophages by tumour cell-conditioned medium recapitulates key features of ex vivo TAMs."

Journal • Lung Adenocarcinoma • Lung Cancer • Non Small Cell Lung Cancer • Oncology • Solid Tumor

Molecular structures of human ACAT2 disclose mechanism for selective inhibition. (PubMed, Structure) - "Here, we report cryogenic electron microscopy structures of human ACAT2 bound to its specific inhibitor pyripyropene A or the general ACAT inhibitor nevanimibe...Enzymatic assays show that mutations within sites of cholesterol entry or allosteric activation attenuate ACAT2 activity in vitro. Together, these results reveal mechanisms for ACAT2-mediated esterification of cholesterol, providing a blueprint to design new ACAT2 inhibitors for use in the prevention of cardiovascular disease."

Journal • Atherosclerosis • Cardiovascular • Dyslipidemia • Metabolic Disorders • ACAT1

Clinical outcomes in 21-hydroxylase deficiency. (PubMed, Curr Opin Endocrinol Diabetes Obes) - "The various clinical outcomes need regular monitoring. Negative consequencies are to large extent the result of the unphysiological glucocorticoid replacement. Modern management with improved follow-up and future addition of new drugs may improve outcomes."

Clinical • Clinical data • Journal • Adrenal Cortex Carcinoma • Diabetes • Endocrine Cancer • Gestational Diabetes • Immunology • Metabolic Disorders • Oncology • Solid Tumor

Medical Treatment of Cushing's Disease: An Overview of the Current and Recent Clinical Trials. (PubMed, Front Endocrinol (Lausanne)) - "Osilodrostat, a novel agent with a mechanism of action similar to metyrapone, seems to offer a rapid, sustained, and effective disease control of CD, according to recently completed clinical trials, whereas levoketoconazole, a different chemical formulation of the historical agent ketoconazole, is still under investigation in clinical trials, with preliminary evidences showing an effective and safe control of CS. ATR-101 is an experimental drug currently under investigation. Among glucocorticoid receptor-directed drugs, mifepristone has been demonstrated to improve clinical syndrome and comorbidities, especially hypertension and impairment of glucose metabolism, but the occurrence of hypokalemia and in women uterine disorders, due to the concomitant action on progestin receptor, requires caution, whereas the preliminary evidence on relacorilant, characterized by high selectivity for glucocorticoid receptor, suggested good efficacy in the control of hypertension and..."

Clinical • Journal • Review • Diabetes • Endocrine Disorders • Hypertension • Oncology

A Phase 2, Multicenter Study of Nevanimibe for the Treatment of Congenital Adrenal Hyperplasia. (PubMed, J Clin Endocrinol Metab) - No abstract available

Clinical • Journal • P2 data • Endocrine Disorders • CYP17A1

Nevanimibe HCl for the Treatment of Classic CAH (clinicaltrials.gov) - P2; N=15; Terminated; Sponsor: Millendo Therapeutics US, Inc.; N=24 ➔ 15; Trial completion date: Dec 2020 ➔ Jul 2020; Recruiting ➔ Terminated; Trial primary completion date: Dec 2020 ➔ Jun 2020; Following an interim data review, further investment in nevanimibe has been discontinued

Clinical • Enrollment change • Trial completion date • Trial primary completion date • Trial termination • Endocrine Disorders

Structure of nevanimibe-bound tetrameric human ACAT1. (PubMed, Nature) - "Each monomer contains nine transmembrane helices (TMs), six of which (TM4-TM9) form a cavity that accommodates nevanimibe and an endogenous acyl-coenzyme A. This cavity also contains a histidine that has previously been identified as essential for catalytic activity. Our structural data and biochemical analyses provide a physical model to explain the process of cholesterol esterification, as well as details of the interaction between nevanimibe and ACAT1, which may help to accelerate the development of ACAT1 inhibitors to treat related diseases."

Journal • Alzheimer's Disease • Atherosclerosis • Cardiovascular • CNS Disorders • Dyslipidemia • Endocrine Disorders • Oncology

A Phase 2, Multicenter Study of Nevanimibe for the Treatment of Congenital Adrenal Hyperplasia. (PubMed, J Clin Endocrinol Metab) - "Nevanimibe decreased 17-OHP levels within 2 weeks of treatment. Larger studies of longer duration are needed to further evaluate its efficacy as add-on therapy for CAH."

Clinical • Journal • P2 data • Endocrine Disorders • ATR • CYP17A1

"$MLND to discontinue livoletide program in PWS and focus on development of pipeline assets nevanimibe and MLE-301" (,@BioStocks)

Nevanimibe HCl for the Treatment of Classic CAH (clinicaltrials.gov) - P2; N=24; Recruiting; Sponsor: Millendo Therapeutics US, Inc.; Trial completion date: Mar 2020 ➔ Dec 2020; Trial primary completion date: Mar 2020 ➔ Dec 2020

Clinical • Trial completion date • Trial primary completion date

A Study of ATR-101 for the Treatment of Congenital Adrenal Hyperplasia (clinicaltrials.gov) - P2; N=10; Completed; Sponsor: Millendo Therapeutics, Inc.; N=15 ➔ 10

Enrollment change

A phase 1 study of nevanimibe HCl, a novel adrenal-specific sterol O-acyltransferase 1 (SOAT1) inhibitor, in adrenocortical carcinoma. (PubMed, Invest New Drugs) - P1; "Results 63 patients with metastatic ACC, all of whom had previously failed systemic chemotherapy and only 2 of whom were mitotane-naïve, were dosed with oral nevanimibe at doses ranging from 1.6 mg/kg/day to 158.5 mg/kg/day. As the total number of tablets required to achieve an MTD exceeded practical administration limits, a maximum feasible dose was defined. Given that the expected exposure levels necessary for an apoptotic effect could not be achieved, the current formulation of nevanimibe had limited efficacy in patients with advanced ACC."

Journal • P1 data