Christopher Carlson

Phase 3 solanezumab trials: Secondary outcomes in mild Alzheimer's disease patients

EXPEDITION and EXPEDITION2 were identically designed placebo‐controlled phase 3 studies assessing effects of solanezumab, an antiamyloid monoclonal antibody binding soluble amyloid‐β peptide, on cognitive and functional decline over 80 weeks in patients with mild‐to‐moderate Alzheimers disease (AD). Primary findings for both studies have been published.

Amantadine for weight gain associated with olanzapine treatment

Patients with schizophrenia (Sch), schizoaffective, schizophreniform, or bipolar (BP) I disorders [Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition (DSM-IV)]; not manic or acutely psychotic [Brief Psychiatric Rating Scale (BPRS) total score < or =45]; treated with olanzapine for 1-24 months; and who had gained > or =5% of their initial body weight were examined to determine whether amantadine could attenuate weight gain or promote weight loss. Olanzapine (Olz; 5-20 mg/day) was co-administered with double-blind treatment of 100-300 mg/day amantadine (Olz+Amt, n=60) or placebo (Olz+Plc, n=65). Visit-wise analysis of weight showed that weight change from baseline [last-observation-carried-forward (LOCF)] in the Olz+Amt group was significantly different from the Olz+Plc group at weeks 8 (P=0.042), 12 (P=0.029), and 16 (primary endpoint, mean+/-S.D.: -0.19+/-4.58 versus 1.28+/-4.26 kg, P=0.045). Mean BPRS total score, positive subscale, and anxiety-depression scores improved comparably in both groups, and Montgomery-Asberg Depression Rating Scale (MADRS) total score improved in the Olz+Amt group. Overall, amantadine was safe, was well tolerated, and attenuated weight gain or promoted weight loss in some patients who had gained weight during olanzapine therapy.

Trial of Solanezumab for Mild Dementia Due to Alzheimer’s Disease

BACKGROUND Alzheimers disease is characterized by amyloid‐beta (Aβ) plaques and neurofibrillary tangles. The humanized monoclonal antibody solanezumab was designed to increase the clearance from the brain of soluble Aβ, peptides that may lead to toxic effects in the synapses and precede the deposition of fibrillary amyloid. METHODS We conducted a double‐blind, placebo‐controlled, phase 3 trial involving patients with mild dementia due to Alzheimers disease, defined as a Mini–Mental State Examination (MMSE) score of 20 to 26 (on a scale from 0 to 30, with higher scores indicating better cognition) and with amyloid deposition shown by means of florbetapir positron‐emission tomography or Aβ1‐42 measurements in cerebrospinal fluid. Patients were randomly assigned to receive solanezumab at a dose of 400 mg or placebo intravenously every 4 weeks for 76 weeks. The primary outcome was the change from baseline to week 80 in the score on the 14‐item cognitive subscale of the Alzheimers Disease Assessment Scale (ADAS‐cog14; scores range from 0 to 90, with higher scores indicating greater cognitive impairment). RESULTS A total of 2129 patients were enrolled, of whom 1057 were assigned to receive solanezumab and 1072 to receive placebo. The mean change from baseline in the ADAS‐cog14 score was 6.65 in the solanezumab group and 7.44 in the placebo group, with no significant between‐group difference at week 80 (difference, ‐0.80; 95% confidence interval, ‐1.73 to 0.14; P=0.10). As a result of the failure to reach significance with regard to the primary outcome in the prespecified hierarchical analysis, the secondary outcomes were considered to be descriptive and are reported without significance testing. The change from baseline in the MMSE score was ‐3.17 in the solanezumab group and ‐3.66 in the placebo group. Adverse cerebral edema or effusion lesions that were observed on magnetic resonance imaging after randomization occurred in 1 patient in the solanezumab group and in 2 in the placebo group. CONCLUSIONS Solanezumab at a dose of 400 mg administered every 4 weeks in patients with mild Alzheimers disease did not significantly affect cognitive decline. (Funded by Eli Lilly; EXPEDITION3 ClinicalTrials.gov number, NCT01900665.)

Prevalence of asymptomatic vasogenic edema in pretreatment Alzheimer's disease study cohorts from phase 3 trials of semagacestat and solanezumab

Cerebral vasogenic edema (VE) has been reported to occur during antiamyloid immunotherapy. VE may be associated with central nervous system pathology with blood–brain barrier disruptions; however, less is known about the prevalence of naturally occurring VE in patients with Alzheimers disease (AD).

Delayed-start analysis: Mild Alzheimer's disease patients in solanezumab trials, 3.5 years

Solanezumab is an anti‐amyloid monoclonal antibody in clinical testing for treatment of Alzheimers disease (AD). Its mechanism suggests the possibility of slowing the progression of AD.

Regulation of Cytokine Secretion and Amyloid Precursor Protein Processing by Proinflammatory Amyloid Beta (Aβ)

Abstract: Neurodegenerative processes in Alzheimers disease (AD) are thought to be driven, in part, by the deposition of amyloid beta (Aβ), a 39‐43‐aminoacid peptide product resulting from an alternative cleavage of amyloid precursor protein (APP). In addition to its neurotoxic properties, Aβ may influence neuropathology by stimulating glial cell cytokine and acute phase protein secretion in affected areas of the brain (e.g., cortex, hippocampus). Using an in vitro human astrocyte model (U‐373 MG astrocytoma cells), the effects of Aβ treatment on acute phase protein (APP and alpha‐1‐antichymot rypsin [α1‐ACT]) and interleukin‐8 (IL‐8) were examined. U‐373 MG cells secreted increased levels of α1‐ACT and neurotrophic/neuroprotective alpha‐cleaved APP (αAPP) after exposure to interleukin‐1β (IL‐1β) for 24 hours. Aβ treatment resulted in a similar, but modest increase in α1‐ACT secretion, a two‐ to threefold stimulation of IL‐8 production, and, conversely, a profound reduction in the levels of secreted αAPPs. Aβ inhibited αAPP secretion by U‐373 MG cells in a concentration‐ and conformation‐dependent manner. Moreover, the reduction in αAPP secretion was accompanied by an increase in cell‐associated APP. Another proinflammatory amyloidogenic peptide, human amylin, similarly affected APP processing in U‐373 astrocytoma cells. These data suggest that Aβ may contribute to Alzheimers‐associated neuropathology by lowering the production of neuroprotective/neurotrophic αAPPs. Moreover, the concomitant increase in cell‐associated APP may provide increased substrate for the generation of amyloidogenic peptides within astrocytes.

Human amylin stimulates inflammatory cytokine secretion from human glioma cells.

Chronic neurodegeneration in the brains of Alzheimer’s disease (AD) patients may be mediated, at least in part, by the ability of amyloid beta (Aβ) to exacerbate inflammatory pathways in a conformation-dependent manner. In this regard, we previously reported that the Aβ-peptide-mediated potentiation of inflammatory cytokine secretion from interleukin-1β (IL-1β)-stimulated human astrocytoma cells was conformation dependent. Other amyloidogenic peptides, such as human amylin, which display similar conformation-dependent neurotoxic effects, may also elicit inflammatory cytokine secretion from glial cells. To test this hypothesis, we compared human and rat amylin for the effects on cytokine production in U-373 MG human astrocytoma cells. Human amylin alone stimulated U-373 MG cells to secrete IL-6 and IL-8 in a concentration-dependent manner with maximum effects seen at 10–25 μM peptide. In addition, human amylin markedly potentiated IL-1β-stimulated cytokine production with a similar concentration dependence. In contrast, nonamyloidogenic rat amylin modestly stimulated cytokine secretion, either alone or combined with IL-1β. Aging human amylin resulted in diminished cytokine secretion, probably due to the formation of large, less active aggregates. In agreement with our previous studies using Aβ, extracellular Ca2+ was necessary for human amylin stimulation of cytokine secretion. Our data suggest that amyloidogenic peptides promote cytokine secretion through similar β-sheeted secondary-structure- and extracellular-Ca2+-dependent mechanisms.

Regulation of amyloid precursor protein processing by Aβ in human glioma cells

Amyloid precursor protein (APP) is cleaved to neurotoxic/proinflammatory amyloid beta protein (Abeta) or to the neuroprotective secreted alpha-APPs. A balance in APP metabolism may influence the outcome between toxicity and protection to central nervous system (CNS) neurons in Alzheimers disease. Treatment of U-373 MG astrocytoma cells with aggregated Abeta (1-40) decreases APP secretion into the medium to 10-30% of control values. This decreased secretion appears to be specific for APP since Abeta treatment causes an approximately 2-fold increase in interleukin-8 (IL-8) secretion. Abeta treatment also causes a 4- to 9-fold increase in total cell-associated APP. This increase is due to cellular retention of alpha secretase-cleaved APP and a 2-fold increase in mature full-length APP. These data suggest that deposition of aggregated Abeta may contribute to Alzheimers-associated neurotoxicity by altering the metabolism of the APP protein. Abeta may exert harmful effects by decreasing the secretion of neuroprotective or neurotrophic APP and, in addition, by increasing intracellular full-length APP; thereby providing increased substrate for generation of amyloidogenic peptide within astrocytes.

Amyloid-related imaging abnormalities from trials of solanezumab for Alzheimer's disease

Solanezumab, a humanized monoclonal antibody that binds soluble amyloid beta peptide, is being developed for treatment of Alzheimers disease (AD).

Vasogenic edema in the setting of ß-amyloid lowering therapy, adverse event: what is it and how is it detected?

trease level. Results: Chronic administration of D-galactose or six weeks significantly impaired behavioral (Morris water maze, elevated plus maze and locomotor activity), oxidative defense and impaired mitochondrial enzymes complex (I, II and III) activities as compared to sham group. Six weeks Centella asiatica treatment significantly improved behavioral alterations, oxidative damage and mitochondrial enzyme complex activities as compared to control (D-galactose). Centella asiatica also attenuated enhanced acetylcholine esterase enzyme level in D-galactose senescence mice. Conclusions: In conclusion, results of this study illustrate that Centella asiatica ameliorates memory dysfunction and biochemical, mitochondrial dysfunction in D-galactose induced senescence mice.