avagacestat (BMS-708163) / BMS - LARVOL DELTA

RHOGTPase-Related Gene Signature Predicts Prognosis, Immunotherapy Response, and Chemotherapy Sensitivity in Colon Cancer. (PubMed, Appl Biochem Biotechnol) - "Tumor Immune Dysfunction and Exclusion (TIDE) analysis revealed an association between high Rho GTPase risk scores and immune dysfunction, suggesting potential resistance to immune checkpoint inhibitors in high-risk patients. Additionally, differential sensitivity to 59 chemotherapeutics was observed: high-risk patients showed greater sensitivity to CCT007093, CGP.082996, and AS601245, while low-risk patients were more sensitive to BMS.708163, NSC.87877, and Cisplatin, informing potential treatment choices. The Rho GTPase-related 12-gene signature offers a valuable tool for predicting prognosis and therapeutic response in colon cancer, supporting personalized treatment strategies and improved patient outcomes."

Gene Signature • IO biomarker • Journal • Colon Cancer • Colorectal Cancer • Oncology • Solid Tumor

The role of SEC14L4 in esophageal squamous cell cancer: insights into clinical relevance and molecular pathways. (PubMed, Transl Cancer Res) - "Drug sensitivity analysis indicated the association of SEC14L4 expression with sensitivity of ESCC to the common chemotherapy drugs AICAR, BMS.708163, GNF.2, Nutlin.3a, PD.0325901, and RDEA119. Verification of the high expression of SEC14L4 in KYSE520 and KYSE150 was conducted, thereby confirming the study's findings. High expression of SEC14L4 is associated with poorer clinical outcomes, highlighting its potential as a therapeutic target and suggesting its involvement in the molecular mechanisms underlying ESCC."

Journal • Esophageal Cancer • Esophageal Squamous Cell Carcinoma • Oncology • Squamous Cell Carcinoma

Androgen effects on alcohol-induced liver fibrosis are controlled by a Notch-dependent epigenetic switch. (PubMed, Cell Mol Gastroenterol Hepatol) - "Male sex hormone signaling can promote or prevent alcohol-associated liver fibrosis depending on the KDM5-dependent epigenetic state."

Journal • Addiction (Opioid and Alcohol) • Fibrosis • Hepatology • Immunology • Liver Cirrhosis • AR • JAG1 • KDM5B • KDM5C • NOTCH3

Gamma Secretase as an Important Drug Target for Management of Alzheimer's Disease: A Comprehensive Review. (PubMed, Curr Top Med Chem) - "Examples of GSI are Semagacestat and Avagacestat while GSM includes E2012; which inhibits the cleavage activity of GS. In this report, each of the four subunits of GS is described in detail, along with the interactions between GS and its inhibitors or modulators. In addition, the FDA-approved drugs are enlisted."

Journal • Review • Alzheimer's Disease • CNS Disorders • APP

Bioluminescence Imaging with Functional Amyloid Reservoirs in Alzheimer's Disease Models. (PubMed, Anal Chem) - "Lastly, we demonstrated that this method could be used to monitor AD progression and the therapeutic effectiveness of avagacestat, a well-studied gamma-secretase inhibitor. Importantly, a good correlation (R = 0.81) was established between in vivo bioluminescence signals and Aβ burdens of the tested AD mice. We believe that our approach can be easily implemented into daily imaging experiments and has tremendous potential to change the daily practice of preclinical AD research."

Journal • Alzheimer's Disease • CNS Disorders • Oncology

Gamma secretase inhibition: Effects on fertility and embryo-fetal development in rats. (PubMed, Toxicol Appl Pharmacol) - "These findings are not considered a risk for late-onset AD where the patient population is ≥65 years old most with women who are post-menopausal. However, for treatment of early onset AD with a younger patient population, there are risks for reproductive or developmental toxicities with treatment with gamma secretase inhibitors like avagacestat."

Journal • Preclinical • Alzheimer's Disease • CNS Disorders • APP

A novel cell-based assay for the high-throughput screening of epithelial-mesenchymal transition inhibitors: Identification of approved and investigational drugs that inhibit epithelial-mesenchymal transition. (PubMed, Lung Cancer) - "We systematically screened approved, investigational, and druggable compounds with inhibitory effects using a reporter assay, and identified candidate drugs for EMT inhibition."

Journal • Lung Cancer • Non Small Cell Lung Cancer • Oncology • Solid Tumor • CDH1 • TGFB1 • VIM

Role of Sodium Channel β1 Subunits in Transcriptional Regulation of SCN1A (NaV1.1) Expression (AES 2022) - "CHLs were treated with γ-secretase inhibitors Avagacestat (10 μM) or L-685,458 (10 μM) for 24h, followed by western blotting to examine V5 (β1) expression... RT-qPCR experiments demonstrated that Scn1a (NaV1.1) gene expression was significantly downregulated in Scn1b null mouse somatosensory cortex (p 0.05)."

CNS Disorders • Epilepsy • Targeted Protein Degradation • SCN8A

A novel cell-based assay for the high-throughput screening of epithelial–mesenchymal transition inhibitors: Identification of approved and investigational drugs that inhibit epithelial–mesenchymal transition (Lung Cancer) - "We generated a luciferase reporter cell line using A549 human lung cancer cells and E-cadherin or vimentin as EMT markers....Values obtained by the assay were adjusted for the number of viable cells and scored by determining the difference between mean values of the positive and negative control groups. Four compounds were identified as novel candidate drugs. Among those, one (avagacestat) and two compounds (GDC-0879 and levothyroxine) improved the expression of E-cadherin and vimentin, respectively, in epithelial cells. GDC-0879 and levothyroxine also significantly inhibited the invasive capacity of cells."

Preclinical • Lung Cancer • Non Small Cell Lung Cancer • Oncology

[VIRTUAL] Reporting amyloid beta levels via bioluminescence imaging with amyloid reservoirs (AAIC 2021) - "Lastly, we demonstrated that this method could be used to monitor AD progression and therapeutic effectiveness of avagacestat, a well-studied gamma-secretase inhibitor. Our approach can be easily implanted into daily imaging experiments. We believe that our method has tremendous potential to change daily practice of preclinical AD research."

Alzheimer's Disease • CNS Disorders • Oncology

"(3/6) These are: Semagacestat, Avagacestat, Solanezumab, CAD106, Crenezumab, Gantenerumab, Avagacestat, Verubecestat, Atabecestat, Lanabecestat, Crenezumab, Elenbecestat, Umibecestat, Donanemab." (@AlbertoEspay)

Structural Analysis of the Simultaneous Activation and Inhibition of γ-Secretase Activity in the Development of Drugs for Alzheimer's Disease. (PubMed, Pharmaceutics) - "Semagacestat and avagacestat are two biphasic drugs that can facilitate cognitive decline in patients with Alzheimer's disease... Biphasic drugs and pathogenic mutations can affect the same dynamic protein structures that control processive catalysis. Successful drug-design strategies must incorporate transient changes in the γ-secretase structure in the development of specific modulators of its catalytic activity."

Journal • Alzheimer's Disease • CNS Disorders

Systematic Evaluation for the Influences of the SOX17/Notch Receptor Family Members on Reversing Enzalutamide Resistance in Castration-Resistant Prostate Cancer Cells. (PubMed, Front Oncol) - "The γ secretase inhibitors, BMS-708163, GSI-IX, PF-3084014, and RO4929097 abrogated the enzalutamide resistance by inhibiting Notch1 or/and Notch4 in vitro, with GSI-IX and RO4929097 being more effective than BMS-708163 and PF-3084014 in reliving bone metastasis in vivo. In conclusion, the Notch1 and Notch4 inhibitors GSI-IX and RO4929097 are promising therapeutic agents for the treatment of CRPC."

Journal • Genito-urinary Cancer • Oncology • Prostate Cancer • Solid Tumor • NOTCH1 • NOTCH4 • SOX17

Structural basis of γ-secretase inhibition and modulation by small molecule drugs. (PubMed, Cell) - "Here, we report the cryoelectron microscopy (cryo-EM) structures of human γ-secretase bound individually to two GSI clinical candidates, Semagacestat and Avagacestat, a transition state analog GSI L685,458, and a classic GSM E2012, at overall resolutions of 2.6-3.1 Å. E2012 binds to an allosteric site of γ-secretase on the extracellular side, potentially explaining its modulating activity. Structural analysis reveals a set of shared themes and variations for inhibitor and modulator recognition that will guide development of the next-generation substrate-selective inhibitors."

Journal • Alzheimer's Disease • CNS Disorders • Oncology • APP

Serotonin modulates AKT-mTOR and Notch signaling pathways, promotes liver cancer cell steatosis and cell survival (AACR 2018) - "...Notch inhibitors Avagacestat 2 and FLI-06 inhibited serotonin-mediated Notch signaling and cellular autophagy...In addition, treatment of serotonin also induced autophagy modulator proteins such as SIRT1 and Tumor Necrosis Factor Alpha Inducing Protein 8 (TNFAIP8) which participate in the modulation of cellular autophagy and cell survival. Taken together our data suggested that peripheral serotonin regulates liver cancer cell steatosis, cells survival and may promote liver carcinogenesis by the modulation of AKT/mTOR and Notch signaling pathways."

Hepatocellular Cancer

Effects of single doses of avagacestat (BMS-708163) on cerebrospinal fluid Aβ levels in healthy young men (Clin Drug Investig) - P=NA, N=34; Avagacestat was quickly absorbed into the systemic circulation, with a mean time to reach maximum plasma concentration (t(max)) of approximately 1-2h, and a CSF T(max) of approximately 3h

Clinical data • Alzheimer's Disease

Randomized, placebo-controlled, double blind, single- and multiple-dose study to evaluate the pharmacokinetics, safety and tolerability of avagacestat (BMS-708163) in healthy young male and elderly male and female Chinese subjects (AAICAD 2012) - P1, N=32; NCT01079819; Geometric mean AUC (INF) was higher in elderly subjects (123% higher for 50mg & 57% higher for 125mg) following single doses of avagacestat; Avagacestat reached steady-state between days 7-11 following multiple doses of 50mg & 125mg for 14 days; Mean half-life of avagacestat was somewhat longer in elderly subjects vs. healthy males

P1 data • Alzheimer's Disease

Randomized, double-blinded, placebo-controlled study to evaluate the safety, pharmacokinetics, and pharmacodynamics of avagacestat (BMS 708163) in healthy Japanese and non-Japanese subjects (AAICAD 2012) - P1, N=22; NCT01057030; The pharmacokinetic rate of avagacestat was similar between Japanese and non-Japanese subjects; Avagacestat was rapidly absorbed, with peak plasma concentrations achieved at 1-2 hours post-dose; The plasma concentration of avagacestat declined in a biphasic manner with the mean terminal elimination half-life values ranging from 32-36 hours

P1 data • Alzheimer's Disease

Bristol-Myers drops Alzheimer’s drug on little benefit (Bloomberg.com) - BMS ended development of avagacestat after the data from a completed trial and a current study showed the therapy wasn’t effective enough to move into the final phase; No new safety issues emerged in this interim analysis, but, the efficacy observed did not justify further development when evaluated in context of all avagacestat data.

Discontinued • Alzheimer's Disease

Examining recruitment in a phase 2 multisite industry sponsored interventional trial in mild to moderate Alzheimer’s disease (CTAD 2011) - P2, N=338; CN156-013; The primary study objective was to assess the safety and tolerability of BMS-708163 in patients with mild-to-moderate AD four doses of BMS-708163 were tested against placebo; Results of latest analysis presented at conference

P2 data • Alzheimer's Disease

Data on Bristol-Myers Squibb’s investigational treatment for Alzheimer’s disease demonstrate potential therapeutic window at doses below 100 mg in phase II safety and tolerability study (Businesswire) - P2, N=209; BMS-708163 doses below 100mg/day demonstrated acceptable tolerability profiles for further development and were associated with discontinuation rates comparable with PBO; BMS-708163 doses at or above 100mg were associated with higher discontinuation rates, most commonly due to GI and dermatological side effects

P2 data • Alzheimer's Disease

The effect of concomitant administration of multiple doses of avagacestat on the pharmacokinetics of either donepezil or galantamine in healthy subjects (AAICAD 2012) - P1, N=32, NCT01042314; P1, N=34, NCT01039194; Coadministration of avagacestat & donepezil or galantamine was associated with an increase in the geometric mean Cmax (14-21%) & AUC(TAU) (24-26%) of donepezil &/or galantamine; Co-administration of avagacestat with either donepezil or galantamine in healthy subjects for short periods of time was associated with a higher frequency of AEs than administration of donepezil or galantamine alone

P1 data • Alzheimer's Disease

Baseline clinical scores and volumetric MRI parameters across subjects randomized in mild-to-moderate (BMS CN156-013) and predementia (BMS CN156-018) Alzheimer's disease clinical trials of avagacestat (AAICAD 2012) - P2, N=209; BMS CN156-013; P2, N=263; CN156-018 AD; Between the two study populations clinical scores (total MMSE, ADAS-cog, CDR-sb, & ADCS-ADL) were all different (p<0.0001); In PDAD subjects, normalized BPVs were significantly higher while normalized LVV & WMLV were lower; In an analysis of the combined population correlations (r<0.3) were found between all MRI volumetric measures & all clinical scores

P2 data • Alzheimer's Disease

Safety and tolerability of the γ-secretase inhibitor avagacestat in a phase 2 study of mild to moderate Alzheimer disease (Arch Neurol) - P2, N=209; NCT00810147; Avagacestat dosed at 25mg and 50mg daily was relatively well tolerated and had low discontinuation rates; The 100mg and 125mg dose arms were poorly tolerated with trends for cognitive worsening; Exploratory cerebrospinal fluid biomarker substudies provide preliminary support for γ-secretase target engagement, but additional studies are warranted to better characterize pharmacodynamic effects at the 25mg and 50mg doses

P2 data • Alzheimer's Disease

Multicenter, randomized, double-blind, placebo-controlled, single-ascending dose study of the oral γ-secretase inhibitor BMS-708163 (avagacestat): Tolerability profile, pharmacokinetic parameters, and pharmacodynamic markers (Clin Ther) - P1, N=116; NCT01454115; Avagacestat concentrations peaked quickly after oral administration & then had a biphasic decrease in concentrations with a prolonged terminal phase; Exposures were proportional with doses up to 200mg; Avagacestat was well tolerated at single oral doses up to 800mg, with a biphasic effect on plasma Aβ(1-40)

P1 data • Alzheimer's Disease