Vlad Coric

Pharmacodynamics of Selective Inhibition of γ -Secretase by Avagacestat

A hallmark of Alzheimer’s disease (AD) pathology is the accumulation of brain amyloid β-peptide (Aβ), generated by γ-secretase-mediated cleavage of the amyloid precursor protein (APP). Therefore, γ-secretase inhibitors (GSIs) may lower brain Aβ and offer a potential new approach to treat AD. As γ-secretase also cleaves Notch proteins, GSIs can have undesirable effects due to interference with Notch signaling. Avagacestat (BMS-708163) is a GSI developed for selective inhibition of APP over Notch cleavage. Avagacestat inhibition of APP and Notch cleavage was evaluated in cell culture by measuring levels of Aβ and human Notch proteins. In rats, dogs, and humans, selectivity was evaluated by measuring plasma blood concentrations in relation to effects on cerebrospinal fluid (CSF) Aβ levels and Notch-related toxicities. Measurements of Notch-related toxicity included goblet cell metaplasia in the gut, marginal-zone depletion in the spleen, reductions in B cells, and changes in expression of the Notch-regulated hairy and enhancer of split homolog-1 from blood cells. In rats and dogs, acute administration of avagacestat robustly reduced CSF Aβ40 and Aβ42 levels similarly. Chronic administration in rats and dogs, and 28-day, single- and multiple-ascending–dose administration in healthy human subjects caused similar exposure-dependent reductions in CSF Aβ40. Consistent with the 137-fold selectivity measured in cell culture, we identified doses of avagacestat that reduce CSF Aβ levels without causing Notch-related toxicities. Our results demonstrate the selectivity of avagacestat for APP over Notch cleavage, supporting further evaluation of avagacestat for AD therapy.

Functional differences between PD-1+ and PD-1- CD4+ effector T cells in healthy donors and patients with glioblastoma multiforme

Immune checkpoint inhibitors targeting programmed cell death protein 1 (PD-1) have been highly successful in the treatment of cancer. While PD-1 expression has been widely investigated, its role in CD4+ effector T cells in the setting of health and cancer remains unclear, particularly in the setting of glioblastoma multiforme (GBM), the most aggressive and common form of brain cancer. We examined the functional and molecular features of PD-1+CD4+CD25—CD127+Foxp3—effector cells in healthy subjects and in patients with GBM. In healthy subjects, we found that PD-1+CD4+ effector cells are dysfunctional: they do not proliferate but can secrete large quantities of IFNγ. Strikingly, blocking antibodies against PD-1 did not rescue proliferation. RNA-sequencing revealed features of exhaustion in PD-1+ CD4 effectors. In the context of GBM, tumors were enriched in PD-1+ CD4+ effectors that were similarly dysfunctional and unable to proliferate. Furthermore, we found enrichment of PD-1+TIM-3+ CD4+ effectors in tumors, suggesting that co-blockade of PD-1 and TIM-3 in GBM may be therapeutically beneficial. RNA-sequencing of blood and tumors from GBM patients revealed distinct differences between CD4+ effectors from both compartments with enrichment in multiple gene sets from tumor infiltrating PD-1—CD4+ effectors cells. Enrichment of these gene sets in tumor suggests a more metabolically active cell state with signaling through other co-receptors. PD-1 expression on CD4 cells identifies a dysfunctional subset refractory to rescue with PD-1 blocking antibodies, suggesting that the influence of immune checkpoint inhibitors may involve recovery of function in the PD-1—CD4+ T cell compartment. Additionally, co-blockade of PD-1 and TIM-3 in GBM may be therapeutically beneficial.

The Gamma Secretase Inhibitor, BMS-708163 Increases Alpha Secretase Abeta Peptide Cleavage Fragments and Decreases the Gamma Secretase Abeta Peptide 1-34 Fragment in Cerebrospinal Fluid

to investigate the role of the innate immune system inAlzheimer’s disease (AD) bymeasuring complement factors in cerebrospinal fluid (CSF) of subjects with mild cognitive impairment (MCI), AD and other dementias (oDem).Methods: We selected healthy controls (n1⁄4 19, age1⁄4 63, MMSE1⁄4 29.1), subjects with MCI (n 1⁄4 56, age 1⁄4 70, MMSE 1⁄4 26.9), AD (n 1⁄4 45, age 1⁄4 72, MMSE 1⁄4 22.9) and oDem (n 1⁄4 31, age 1⁄4 69 MMSE 1⁄4 24.1) from the EDAR study (www.edarstudy.eu). We measured C3a, central to the classical, alternative and lectin complement pathways, C5a involved in the lytic complement pathway, and the soluble C5b-9 terminal complement complex (TCC). We also measured in CSF abeta 1-42, total tau, and serum amyloid P (SAP, an acute response protein which activates complement). We compared groups and correlated complement markers with other biomarkers, neuropsychological markers, andmarkers of functional impairment using non-parametric tests.Results: Complement data are shown in the table. C3a was decreased by 50-60% in subjects with MCI, AD, and oDem relative to controls (p < 0.003 all comparisons). C5a was increased 3-6 fold in AD relative to controls (p 1⁄4 0.077), MCI (p1⁄4 0.016), and oDem(p1⁄4 0.07). TCCdid not differ between the groups, although subjects with AD had higher concentrations than the other groups. In the combined sample of subjects with MCI, AD, and oDem, higher levels of C3a correlated with higher levels of TCC (r 1⁄4 0.51, p < 0.001), SAP (r 1⁄4 0.40, p< 0.001), and tau (r1⁄4 0.18, p1⁄4 0.048). Higher levels of C5a correlated with more impairment on memory, executive functioning, and the MMSE (r1⁄4 0.22-0.30, p 1⁄4 0.05-0.002). Higher levels of TCC correlated with higher SAP levels (r 1⁄4 0.41, p < 0.001) and more functional impairment (r 1⁄4 0.25, p 1⁄4 0.018).Conclusions: The innate immune system is actively involved in neurodegeneration and may provide diagnostic and prognostic information for AD. The large reduction of C3a in subjects with MCI, AD and oDem, suggests increased use of this factor, regardless of the cause of neurodegeneration. Alternatively, increased C3a levels may protect against neurodegeneration. The increase of C5a in AD suggests a disease specific activation of the lytic complement pathway. Since this measure correlated with clinical measures of severity, C5a activation may be a relatively late event in the disease process.

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

the safety and tolerability of avagacestat in patients with PDAD. Key entry criteria for subjects included: memory complaints documented by subject or study partner, objective memory loss on the Wechsler Memory Scale Logical Memory II or the Free & Cued Selective Reminding Test, a CDR-global score of 0.5 with a memory box score of 0.5, and a MMSE of 24-30. Entry criteria required that subjects not meet DSM-IV criteria for dementia, and their MRI findings show no alternative cause for cognitive impairment. After meeting all key criteria, subjects underwent lumbar puncture and were included if their CSF amyloid-beta42 levels < 200pg/mL or total tau/amyloid-beta42 ratio of 0.39. Co-medication with a stable dose of a marketed cholinesterase inhibitor or memantine was permitted. Results: Randomization completed in September 2011, approximately 24 months after first patient visit. Of 1350 subjects enrolled at 72 centers in North America and Europe; 263 (19%) were randomized. Nearly 800 enrolled subjects (approximately 60%) were excluded prior to CSF testing due to clinical criteria. Of nearly 550 subjects whomet the clinical inclusion criteria and completed the lumbar puncture, approximately one-half met the CSF biomarker criteria for study entry. There were 104 subjects who met entry requirements except the CSF criteria, whowere enrolled into a nonrandomized observational cohort. The major reasons for exclusion were cognitive criteria, abnormal laboratory tests, meeting dementia criteria, compliance to protocol issues, MRI findings, or concurrent medications. Conclusions: The recruitment of this study population of subjects with PDAD demonstrates both the feasibility and challenges of trials, which require both clinical phenotypic features as well as CSF criteria. Efforts are warranted to refine entry criteria and decrease screen failures.

Cerebral microbleeds in a phase 2 clinical trial of mild-to-moderate Alzheimer's disease with the gamma secretase inhibitor BMS-708163

three cohorts (equal sample size) according to their rates of change in ADAS-Cog total scores. Patients with most positive rates of change in ADAS-cog total scores (i.e., worsening) showed significantly more rapid hippocampal atrophy as compared with to patients that showed the most negative rates of change in ADAS-Cog total scores (i.e., improving), and patients with intermediate, near-zero, rates of change in ADAS-cog total scores (i.e., stable) (trend). Conclusions: The rate of hippocampal degeneration may be altered in DAT patients who respond to treatment with memantine or donepezil as compared to patients who are treated with these drugs but who do not respond. However, we were not able to detect drug-specific changes in hippocampal degeneration. Cognitive improvement and slowing of disease progression in AD as a result of drug treatment may be dependent upon neuroanatomical factors that influence who will respond to treatment. Improving our understanding of these factors way lead to the development of more effective therapies.