Posted by: Chris Maloney | October 9, 2012

Will Solanezumab Or a Drug Like It Cure Alzheimers Disease?

English: PET scan of a human brain with Alzhei...

English: PET scan of a human brain with Alzheimer’s disease (Photo credit: Wikipedia)

For those who want the direct medical research, I’ve attached the abstracts.

When I open up the paper and read about anything that may be effective for Alzheimers, I take notice.  Being who I am, I go to medline and look up what the effect is and how soon I should start talking to patients about it.

We aren’t there with Solanezumab yet.  It is an injected antibody that is effective at attacking the plaques in the brain.  So far it hasn’t shown any effect on cognitive decline, only that it does attack the plaques.  Combining studies to tweak out some benefit doesn’t hold water.  It’s still hopeful, but we’ve been down this road before.

The first trial was a vaccine against the plaques.  “the
first active vaccine was abandoned because it caused meningoencephalitis in
approximately 6% of treated patients.”  (All abstracts below the article).

Now “Anti- monoclonal antibodies (bapineuzumab and solanezumab) are now being developed.”  If you wonder what happened to bapineuzumab, it didn’t help with cognitive decline and caused edema and “microhemorrhages.”

The current solanezumab doesn’t seem to share the side effects, but I suspect they are being very cautious about dosing.  The trouble is that the bapineuzumab was strong enough to cause problems but still wasn’t strong enough to reverse the disease process.

At this point we don’t even have animal studies on this particular approach for treating Alzheimers.

Treating the plaques directly is problematic, because “the
histopathological hallmark lesions of this disease, the extracellular Aβ
plaques and the intraneuronal neurofibrillary tangles, start as early as
childhood in the affected individuals. AD is multifactorial and probably
involves many different etiopathogenic mechanisms.”

So I won’t be holding my breath that this particular antibody will be the solution.  We need to look at treating from a variety of directions, including diet, to maximize the effects of any drug like this one at preventing disease progression.

Alzheimers Dement. 2012 Jul;8(4):261-71. Epub 2012 Jun 5.

Safety and biomarker effects of solanezumab in patients with Alzheimer’s disease.

Farlow M, Arnold SE, van Dyck CH, Aisen PS, Snider BJ, Porsteinsson AP, Friedrich S, Dean RA, Gonzales C, Sethuraman G, DeMattos RB, Mohs R, Paul SM, Siemers ER.


Department of Neurology, Indiana University School of Medicine, Indianapolis, USA.



To assess the safety, tolerability, pharmacokinetics, and pharmacodynamics of 12 weekly infusions of solanezumab, an anti-β-amyloid (Aβ) antibody, in patients with mild-to-moderate Alzheimer’s disease. Cognitive measures were also obtained.


In this phase 2, randomized, double-blind, placebo-controlled clinical trial, 52 patients with Alzheimer’s disease received placebo or antibody (100 mg every 4 weeks, 100 mg weekly, 400 mg every 4 weeks, or 400 mg weekly) for 12 weeks. Safety and biomarker evaluations continued until 1 year after randomization. Both magnetic resonance imaging and cerebrospinal fluid (CSF) examinations were conducted at baseline and after the active treatment period. The Aβ concentrations were measured in plasma and CSF, and the Alzheimer’s Disease Assessment Scale-cognitive portion was administered.


Clinical laboratory values, CSF cell counts, and magnetic resonance imaging scans were unchanged by treatment, and no adverse events could be clearly related to antibody administration. Total (bound to antibody and unbound) Aβ(1-40) and Aβ(1-42) in plasma increased in a dose-dependent manner. Antibody treatment similarly increased total Aβ(1-40) and Aβ(1-42) in CSF. For patients taking 400 mg weekly, antibody treatment decreased unbound Aβ(1-40) in CSF (P < .01), but increased unbound Aβ(1-42) in CSF in a dose-dependent manner. The Alzheimer’s Disease Assessment Scale-cognitive portion was unchanged after the 12-week antibody administration.


Antibody administration was well tolerated with doses up to 400 mg weekly. The dose-dependent increase in unbound CSF Aβ(1-42) suggests that this antibody may shift Aβ equilibria sufficiently to mobilize Aβ(1-42) from amyloid plaques.

Copyright © 2012 The Alzheimer’s Association. Published by Elsevier Inc. All rights reserved.

PMID: 22672770

Clin Neuropharmacol. 2010 Mar-Apr;33(2):67-73.

Safety and changes in plasma and cerebrospinal fluid amyloid beta after a single administration of an amyloid beta monoclonal antibody in subjects with Alzheimer disease.

Siemers ER, Friedrich S, Dean RA, Gonzales CR, Farlow MR, Paul SM, Demattos RB.


Eli Lilly and Company, Lilly Research Laboratories, Indianapolis, Indiana 46285, USA.



Active and passive immunization strategies have been suggested as possible options for the treatment of Alzheimer disease (AD). LY2062430 (solanezumab) is a humanized monoclonal antibody being studied as a putative disease-modifying treatment of AD.


Patients with mild to moderate AD were screened and selected for inclusion. Initial screening was performed for 54 subjects, and 29 of these underwent additional screening; after this second screening, a total of 19 subjects were included. Single doses of solanezumab using 0.5, 1.5, 4.0, and 10.0 mg/kg were administered. Safety assessments included gadolinium-enhanced magnetic resonance imaging of the brain and cerebrospinal fluid (CSF) analyses at baseline and 21 days after dosing. Plasma and CSF concentrations of solanezumab and amyloid beta (Abeta) and cognitive evaluations were obtained.


Administration of solanezumab was generally well tolerated except that mild self-limited symptoms consistent with infusion reactions occurred for 2 of 4 subjects given 10 mg/kg. No evidence of meningoencephalitis, microhemorrhage, or vasogenic edema was present based on magnetic resonance image and CSF analyses. A substantial dose-dependent increase in total (bound plus unbound) Abeta was demonstrated in plasma; CSF total Abeta also increased. No changes in cognitive scores occurred.


A single dose of solanezumab was generally well tolerated, although infusion reactions similar to those seen with administration of other proteins may occur with higher doses. A dose-dependent change in plasma and CSF Abeta was observed, although changes in cognitive scores were not noted. Further studies of solanezumab for the treatment of AD are warranted.

PMID: 20375655

Immunotherapy. 2012 Feb;4(2):213-38.

Immunotherapy for Alzheimer’s disease: from anti-β-amyloid to tau-based immunization strategies.

Panza F, Frisardi V, Solfrizzi V, Imbimbo BP, Logroscino G, Santamato A, Greco A, Seripa D, Pilotto A.


Geriatric Unit & Gerontology-Geriatric Research Laboratory, IRCCS Casa Sollievo della Sofferenza, Foggia, Italy.


The exact mechanisms leading to Alzheimer’s disease (AD) are largely unknown, limiting the identification of effective disease-modifying therapies. The two principal neuropathological hallmarks of AD are extracellular β-amyloid (Aβ), peptide deposition (senile plaques) and intracellular neurofibrillary tangles containing hyperphosphorylated tau protein. During the last decade, most of the efforts of the pharmaceutical industry were directed against the production and accumulation of Aβ. The most innovative of the pharmacological approaches was the stimulation of Aβ clearance from the brain of AD patients via the administration of Aβ antigens (active vaccination) or anti-Aβ antibodies (passive vaccination). Several active and passive anti-Aβ vaccines are under clinical investigation. Unfortunately, the first active vaccine (AN1792, consisting of preaggregate Aβ and an immune adjuvant, QS-21) was abandoned because it caused meningoencephalitis in approximately 6% of treated patients. Anti-Aβ monoclonal antibodies (bapineuzumab and solanezumab) are now being developed. The clinical results of the initial studies with bapineuzumab were equivocal in terms of cognitive benefit. The occurrence of vasogenic edema after bapineuzumab, and more rarely brain microhemorrhages (especially in Apo E ε4 carriers), has raised concerns on the safety of these antibodies directed against the N-terminus of the Aβ peptide. Solanezumab, a humanized anti-Aβ monoclonal antibody directed against the midregion of the Aβ peptide, was shown to neutralize soluble Aβ species. Phase II studies showed a good safety profile of solanezumab, while studies on cerebrospinal and plasma biomarkers documented good signals of pharmacodynamic activity. Although some studies suggested that active immunization may be effective against tau in animal models of AD, very few studies regarding passive immunization against tau protein are currently available. The results of the large, ongoing Phase III trials with bapineuzumab and solanezumab will tell us if monoclonal anti-Aβ antibodies may slow down the rate of deterioration of AD. Based on the new diagnostic criteria of AD and on recent major failures of anti-Aβ drugs in mild-to-moderate AD patients, one could argue that clinical trials on potential disease-modifying drugs, including immunological approaches, should be performed in the early stages of AD.

PMID: 22339463

Int Psychogeriatr. 2002;14 Suppl 1:51-75.

The ABC of Alzheimer’s disease: cognitive changes and their management in Alzheimer’s disease and related dementias.

Corey-Bloom J.


Neurology Service, UCSD School of Medicine, San Diego, California 92161, USA.


Cognitive decline, commonly first recognized as memory impairment, is a typical feature of Alzheimer’s disease (AD). Neuropathological changes in the cerebral cortex and limbic system lead to deficits in learning, memory, language, and visuospatial skills. The precise nature of cognitive dysfunction reflects the distribution of pathological changes in AD. These will vary along the disease severity continuum and may also depend on where the disease sits in the spectrum of dementia. For example, AD-related disorders such as Lewy body dementia (LBD) and Parkinson’s disease dementia (PDD) also show symptoms of cognitive decline and share several pathological features, including degeneration of cortical cholinergic and striatal dopaminergic neurons. In vascular dementia (VaD), there is often an unequal distribution of cognitive deficit, with severe impairment in some functions and relative sparing of others. Cholinesterase (ChE) inhibitors, which help restore acetylcholine levels in the brain, are licensed for the symptomatic treatment of AD and have shown additional benefit in related dementias. Physiological correlates of cholinergic function/dysfunction in the brain include regional cerebral blood flow, glucose metabolism, and cerebrospinal fluid levels of ChE enzymes. These variables represent valuable markers of the clinical efficacy of ChE inhibitors. However, direct assessment of cognitive improvement, stabilization or decline is usually considered the key efficacy parameter in clinical studies of ChE inhibitors in AD and related dementias. Large-scale, placebo-controlled clinical studies of ChE inhibitors have demonstrated efficacy in treating the cognitive impairments associated with AD. Randomized comparative studies of ChE inhibitors are now under way to directly compare symptomatic efficacy and effects on disease progression. Clinical trial data of the cognitive effects of ChE inhibitors in AD, LBD, PDD, and VaD are discussed in detail in this article. The benefits of long-term treatment on symptomatic improvement in cognition and further potential disease-modifying effects are highlighted.

PMID: 12636180

J Neuroinflammation. 2012 May 29;9:106.

Tumor necrosis factor-α synthesis inhibitor 3,6′-dithiothalidomide attenuates markers of inflammation, Alzheimer pathology and behavioral deficits in animal models of neuroinflammation and Alzheimer’s disease.

Tweedie D, Ferguson RA, Fishman K, Frankola KA, Van Praag H, Holloway HW, Luo W, Li Y, Caracciolo L, Russo I, Barlati S, Ray B, Lahiri DK, Bosetti F, Greig NH, Rosi S.


Laboratory of Neurosciences, Intramural Research Program, National Institute on Aging, National Institutes of Health, Baltimore, MD 21224, USA.



Neuroinflammation is associated with virtually all major neurodegenerative disorders, including Alzheimer’s disease (AD). Although it remains unclear whether neuroinflammation is the driving force behind these disorders, compelling evidence implicates its role in exacerbating disease progression, with a key player being the potent proinflammatory cytokine TNF-α. Elevated TNF-α levels are commonly detected in the clinic and animal models of AD.


The potential benefits of a novel TNF-α-lowering agent, 3,6′-dithiothalidomide, were investigated in cellular and rodent models of neuroinflammation with a specific focus on AD. These included central and systemic inflammation induced by lipopolysaccharide (LPS) and Aβ(1-42) challenge, and biochemical and behavioral assessment of 3xTg-AD mice following chronic 3,6′-dithiothaliodmide.


3,6′-Dithiothaliodmide lowered TNF-α, nitrite (an indicator of oxidative damage) and secreted amyloid precursor protein (sAPP) levels in LPS-activated macrophage-like cells (RAW 264.7 cells). This translated into reduced central and systemic TNF-α production in acute LPS-challenged rats, and to a reduction of neuroinflammatory markers and restoration of neuronal plasticity following chronic central challenge of LPS. In mice centrally challenged with A(β1-42) peptide, prior systemic 3,6′-dithiothalidomide suppressed Aβ-induced memory dysfunction, microglial activation and neuronal degeneration. Chronic 3,6′-dithiothalidomide administration to an elderly symptomatic cohort of 3xTg-AD mice reduced multiple hallmark features of AD, including phosphorylated tau protein, APP, Aβ peptide and Aβ-plaque number along with deficits in memory function to levels present in younger adult cognitively unimpaired 3xTg-AD mice. Levels of the synaptic proteins, SNAP25 and synaptophysin, were found to be elevated in older symptomatic drug-treated 3xTg-AD mice compared to vehicle-treated ones, indicative of a preservation of synaptic function during drug treatment.


Our data suggest a strong beneficial effect of 3,6′-dithiothalidomide in the setting of neuroinflammation and AD, supporting a role for neuroinflammation and TNF-α in disease progression and their targeting as a means of clinical management.

PMID: 22642825

Acta Neuropathol. 2011 Nov;122(5):543-9. Epub 2011 Sep 30.

Opportunities and challenges in developing Alzheimer disease therapeutics.

Iqbal K, Grundke-Iqbal I.


Department of Neurochemistry, New York State Institute for Basic Research in Developmental Disabilities, Staten Island, 10314-6399, USA.


Alzheimer disease (AD) is a chronic, progressive disorder with an average disease progression of 7-10 years. However, the histopathological hallmark lesions of this disease, the extracellular Aβ plaques and the intraneuronal neurofibrillary tangles, start as early as childhood in the affected individuals. AD is multifactorial and probably involves many different etiopathogenic mechanisms. Thus, while AD offers a wide window of opportunity that practically includes the whole life span of the affected individuals, and numerous therapeutic targets, the multifactorial nature of this disease also makes the selection of the therapeutic targets an immensely challenging task. In addition to β-amyloidosis and neurofibrillary degeneration, the AD brain also is compromised in its ability to regenerate by enhancing neurogenesis and neuronal plasticity. An increasing number of preclinical studies in transgenic mouse models of AD show that enhancement of neurogenesis and neuronal plasticity can reverse cognitive impairment. Development of both drugs that can inhibit neurodegeneration and drugs that can increase the regenerative capacity of the brain by enhancing neurogenesis and neuronal plasticity are required to control AD.

PMID: 21959585




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