Elan Pharmaceuticals Research Articles

Long‐term neuropathological effects of amyloid‐β immunization revealed by spatial transcriptomics

AbstractBackgroundModern Alzheimer’s disease (AD) therapeutics include immunization against amyloid‐β (Aβ). Intriguingly, neuropathological examination of the first active Aβ vaccination trial (Elan Pharmaceuticals’ AN1792) showed some patients with evidence of Aβ clearance 15 years post‐vaccination. Yet, these patients progressed to severe dementia before death, possibly due to ongoing tau propagation. The AN1792 trial was halted when some participants developed aseptic meningoencephalitis driven by auto‐aggressive T cells. Imaging features of meningoencephalitis experienced by AN1792 subjects are pathologically reminiscent of amyloid‐related imaging abnormalities (ARIA) that currently hamper clinical trials and the therapeutic use of passive Aβ immunotherapy for AD.MethodHere, we utilized spatial transcriptomics to sequence RNA from formalin‐fixed paraffin‐embedded (FFPE) cortical brain sections from a unique neuropathological cohort of 14 immunized AD cases and a placebo‐control from AN1792. Additional controls included 6 naïve (unimmunized) AD cases and 3 non‐neurological disease controls.ResultWe reveal a cytotoxic and migratory phenotype of infiltrating T cells in the meninges of AD patients immunized against Aβ. Specifically, brain infiltrating T cells express cytotoxic genes (e.g. GZMA), activation genes (e.g. CD74 and B2M), and migratory genes (e.g. ITGAL and VCAM1). Additionally, we discovered genetic signatures that distinguish cortical areas cleared of Aβ in immunized AN1792 subjects.ConclusionWe show that active Aβ immunotherapy induces long‐term adaptive immune effects in the AD cortex.

Amyloid‐beta immunotherapy induces novel methylomic changes in Alzheimer’s disease brain

AbstractBackgroundPost‐mortem neuropathological examinations following the first active immunotherapy strategy (AN‐1792, Elan Pharmaceuticals, 2000) for Alzheimer’s disease (AD) have evidenced amyloid‐β (Aβ) plaque clearance and increased microglial phagocytic activity in immunised individuals. This study characterises the epigenetic profiles of individuals who underwent Aβ immunotherapy with the aim of discovering novel therapeutic targets and biomarkers.MethodDNA was isolated from post‐mortem prefrontal cortex tissue of 16 immunised AD cases who received varying doses (ug) and number of doses during the trial period, including placebos. DNA methylation was quantified using methylation arrays and the raw intensity values processed and normalised for subsequent statistical analysis to identify differentially methylated positions (DMPs) across the genome associated with Aβ immunotherapy. Additional analyses included regions of enrichment analysis for identification of differentially methylated regions (DMRs) and weighted gene co‐expression network analysis to identify gene clusters with highly correlated methylation levels.ResultAfter correcting for known (age, sex, cell type composition) and unknown variables, a DMP located within Chromosome 19 Open Reading Frame 12 (C19Orf12) at the genome‐wide significance level (P < 9.00E−08) was associated with Aβ immunisation. 10 DMRs were further associated with immunisation, with three regions consisting of ≥ 3 CpG sites and having a Sidak‐corrected P < 0.05. These regions were located within the CRISP2 (chr6; 49681178:49681391 [8 probes], Sidak‐corrected P = 8.29E‐05), CTTNA1 (chr5; 138210906:138211184 [8 probes], Sidak‐corrected P = 5.96E‐06), and RNF39 (chr6; 30038859:30039025 [12 probes], Sidak‐Corrected P = 2.60E‐05) genes.ConclusionIndicating better inflammatory markers can help inform of effective preventative care strategies for elders. This study provides evidence for altered epigenetic processes in the pathophysiology of AD and identifies novel processes specific to Aβ immunotherapy. The next step for this project includes analysing RNA sequencing data, to determine if observed methylomic changes correlate with gene expression, and genotyping array data.

For director-at-large: Lee M. Latimer

California Section. Consultant, LHLatimer Consulting, Oakland, California. Academic record: Tulane University, BS, chemistry, 1971; University of Wisconsin, PhD, organic chemistry, 1976; University of California, Berkeley, postdoctoral research in organic chemistry, 1976–77; University of Wisconsin School of Pharmacy, postdoctoral research in organic chemistry, 1977–79. Honors: ACS Division of Chemical Health and Safety, Howard Fawcett Chemical Health Award, 2016; ACS Santa Clara Valley Section, Shirley B. Radding Award, 2014; ACS Fellow, 2012; ACS California Section, Walter B. Petersen Award, 2010; ACS Rochester Section, Rochester Section Award, 1991; Elan Pharmaceuticals, Chemical Sciences Excellence Award, 2009; Kodak Research Labs, Gold Team Achievement Award, 1992; National Institutes of Health, Postdoctoral Fellowship, 1977–79; Phi Beta Kappa, 1971; Sigma Xi, 1971. Professional positions (for past 10 years): LHLatimer Consulting, drug development consultant, 2011–; NeurOp, head of chemistry, 2014–16; Elan Pharmaceuticals, 1995–2011, senior director of process and analytical chemistry, 2005–11, chemical hygiene officer, 2004–10; San Francisco State University,

A\u03b243 in human Alzheimer\u2019s disease: effects of active A\u03b242 immunization

Neuropathological follow-up of patients with Alzheimer’s disease (AD) who participated in the first clinical trial of Amyloid-β 42 (Aβ42) immunization (AN1792, Elan Pharmaceuticals) has shown that immunization can induce removal of Aβ42 and Aβ40 from plaques, whereas analysis of the cerebral vessels has shown increased levels of these Aβ peptides in cerebral amyloid angiopathy (CAA). Aβ43 has been less frequently studied in AD, but its aggregation propensity and neurotoxic properties suggest it may have an important pathogenic role. In the current study we show by using immunohistochemistry that in unimmunized AD patients Aβ43 is a frequent constituent of plaques (6.0% immunostained area), similar to Aβ42 (3.9% immunostained area). Aβ43 immunostained area was significantly higher than that of Aβ40 (2.3%, p = 0.006). In addition, we show that Aβ43 is only a minor component of CAA in both parenchymal vessels (1.5 Aβ43-positive vessels per cm2 cortex vs. 5.3 Aβ42-positive vessels, p = 0.03, and 6.2 Aβ40-positive vessels, p = 0.045) and leptomeningeal vessels (5.6% Aβ43-positive vessels vs. 17.3% Aβ42-positive vessels, p = 0.007, and 27.4% Aβ40-positive vessels, p = 0.003). Furthermore, we have shown that Aβ43 is cleared from plaques after Aβ immunotherapy, similar to Aβ42 and Aβ40. Cerebrovascular Aβ43 levels did not change after immunotherapy.

Persistent neuropathological effects 14 years following amyloid-β immunization in Alzheimer's disease.

We performed a 15-year post-mortem neuropathological follow-up of patients in the first trial of amyloid-β immunotherapy for Alzheimer's disease. Twenty-two participants of a clinical trial of active amyloid-β42 immunization (AN1792, Elan Pharmaceuticals) or placebo were studied. Comprehensive post-mortem neuropathological assessments were performed from 4 months to 15 years after the trial. We analysed the relationships between the topographical distribution of amyloid-β removal from the cerebral cortex and tau pathology, cerebrovascular territories, plasma anti-AN1792 antibody titres and late cognitive status. Seventeen of 22 (77%) participants had Alzheimer's neuropathological change, whereas 5 of 22 (23%) had alternative causes for dementia (progressive supranuclear palsy = 1, Lewy body disease = 1, vascular brain injury = 1, and frontotemporal lobar degeneration = 2). Nineteen of the 22 participants had received the active agent, three the placebo. Fourteen of 16 (88%) patients with Alzheimer's disease receiving the active agent had evidence of plaque removal (very extensive removal = 5, intermediate = 4, very limited = 5, no removal = 2). Of particular note, two Alzheimer's patients who died 14 years after immunization had only very sparse or no detectable plaques in all regions examined. There was a significant inverse correlation between post-vaccination peripheral blood anti-AN1792 antibody titres and post-mortem plaque scores (ρ = - 0.664, P = 0.005). Cortical foci cleared of plaques contained less tau than did cortex with remaining plaques, but the overall distribution of tangles was extensive (Braak V/VI). In conclusion, patients with Alzheimer's disease actively immunized against amyloid-β can remain virtually plaque-free for 14 years. The extent of plaque removal is related to the immune response. This long duration of efficacy is important in support of active immunization protocols as therapy for, or potentially prevention of, neurodegeneration-associated protein accumulations. Inclusion of patients without Alzheimer's disease in Alzheimer's therapy trials is a problem for assessing the efficacy of treatment. Despite modification of Alzheimer's pathology, most patients had progressed to severe dementia, notably including the five with very extensive plaque removal, possibly due to continued tau propagation. Neuropathology follow-up of patients in therapeutic trials provides valuable information on the causes of dementia and effects of treatment.

The TOUCH program and natalizumab: Fundamental flaw in patient protection.

Many drugs have been approved by the Food and Drug Administration (FDA) since 1993 for treatment of relapsing forms of multiple sclerosis (MS). One such drug is natalizumab (Tysabri, Biogen Idec and Elan pharmaceuticals) which has enjoyed great success in the management of MS since its re-introduction in 2006. One of the complications of using natalizumab is the risk of development of progressive multifocal leukoencephalopathy (PML). To mitigate the risk of PML development, Biogen Idec initiated the TOUCH program - this strategy helps monitor the disease. Clinical vigilance remains key in the early diagnosis of PML but serological testing for the John Cunningham Virus Antibody (JCV) helps with risk stratification of PML. However, some physicians do not test for the JCV Ab and since they are not required to send such data to the company or inform the patient, one red flag for suspicion of PML is lost particularly if the patient is asymptomatic. This undercuts the premise of the TOUCH program. In an ideal world, reporting JCV Ab status should be made mandatory since that ensures a basic tenet of the program is met - to identify patients at increased risk of developing PML and make appropriate recommendations based on that finding. Lack of requirement of reporting of this vital finding opens the door for uncertainty in assessment of risk PML development and everyone remains in the dark till it may be too late. This is unacceptable when the company created the TOUCH program specifically with intent to track PML risk in patients on natalizumab. It makes no scientific sense to let the drug be used without setting stringent criteria given the possibility of PML development.

The TOUCH program and natalizumab: Fundamental flaw in patient protection

Many drugs have been approved by the Food and Drug Administration (FDA) since 1993 for treatment of relapsing forms of multiple sclerosis (MS). One such drug is natalizumab (Tysabri, Biogen Idec and Elan pharmaceuticals) which has enjoyed great success in the management of MS since its re-introduction in 2006. One of the complications of using natalizumab is the risk of development of progressive multifocal leukoencephalopathy (PML). To mitigate the risk of PML development, Biogen Idec initiated the TOUCH program – this strategy helps monitor the disease. Clinical vigilance remains key in the early diagnosis of PML but serological testing for the John Cunningham Virus Antibody (JCV) helps with risk stratification of PML. However, some physicians do not test for the JCV Ab and since they are not required to send such data to the company or inform the patient, one red flag for suspicion of PML is lost particularly if the patient is asymptomatic. This undercuts the premise of the TOUCH program. In an ideal world, reporting JCV Ab status should be made mandatory since that ensures a basic tenet of the program is met – to identify patients at increased risk of developing PML and make appropriate recommendations based on that finding. Lack of requirement of reporting of this vital finding opens the door for uncertainty in assessment of risk PML development and everyone remains in the dark till it may be too late. This is unacceptable when the company created the TOUCH program specifically with intent to track PML risk in patients on natalizumab. It makes no scientific sense to let the drug be used without setting stringent criteria given the possibility of PML development.

The TOUCH program and natalizumab: Fundamental flaw in patient protection

Many drugs have been approved by the Food and Drug Administration (FDA) since 1993 for treatment of relapsing forms of multiple sclerosis (MS). One such drug is natalizumab (Tysabri, Biogen Idec and Elan pharmaceuticals) which has enjoyed great success in the management of MS since its re-introduction in 2006. One of the complications of using natalizumab is the risk of development of progressive multifocal leukoencephalopathy (PML). To mitigate the risk of PML development, Biogen Idec initiated the TOUCH program – this strategy helps monitor the disease. Clinical vigilance remains key in the early diagnosis of PML but serological testing for the John Cunningham Virus Antibody (JCV) helps with risk stratification of PML. However, some physicians do not test for the JCV Ab and since they are not required to send such data to the company or inform the patient, one red flag for suspicion of PML is lost particularly if the patient is asymptomatic. This undercuts the premise of the TOUCH program. In an ideal world, reporting JCV Ab status should be made mandatory since that ensures a basic tenet of the program is met – to identify patients at increased risk of developing PML and make appropriate recommendations based on that finding. Lack of requirement of reporting of this vital finding opens the door for uncertainty in assessment of risk PML development and everyone remains in the dark till it may be too late. This is unacceptable when the company created the TOUCH program specifically with intent to track PML risk in patients on natalizumab. It makes no scientific sense to let the drug be used without setting stringent criteria given the possibility of PML development.

The TOUCH program and natalizumab: Fundamental flaw in patient protection

Many drugs have been approved by the Food and Drug Administration (FDA) since 1993 for treatment of relapsing forms of multiple sclerosis (MS). One such drug is natalizumab (Tysabri, Biogen Idec and Elan pharmaceuticals) which has enjoyed great success in the management of MS since its re-introduction in 2006. One of the complications of using natalizumab is the risk of development of progressive multifocal leukoencephalopathy (PML). To mitigate the risk of PML development, Biogen Idec initiated the TOUCH program - this strategy helps monitor the disease. Clinical vigilance is remains key in the early diagnosis of PML but serological testing for the John Cunningham Virus Antibody (JCV) helps with risk stratification of PML. However, some physicians do not test for the JCV Ab and since they are not required to send such data to the company or inform the patient, one red flag for suspicion of PML is lost particularly if the patient is asymptomatic. This undercuts the premise of the TOUCH program. In an ideal world, reporting JCV Ab status should be made mandatory since that ensures a basic tenet of the program is met - to identify patients at increased risk of developing PML and make appropriate recommendations based on that finding. Lack of requirement of reporting of this vital finding opens the door for uncertainty in assessment of risk PML development and everyone remains in the dark till it may be too late. This is unacceptable when the company created the TOUCH program specifically with intent to track PML risk in patients on natalizumab. It makes no scientific sense to let the drug be used without setting stringent criteria given the possibility of PML development.

Effect of active Aβ immunotherapy on neurons in human Alzheimer's disease.

Amyloid β peptide (Aβ) immunization of Alzheimer's disease (AD) patients has been reported to induce amyloid plaque removal, but with little impact on cognitive decline. We have explored the consequences of Aβ immunotherapy on neurons in post mortem brain tissue. Eleven immunized (AN1792, Elan Pharmaceuticals) AD patients were compared to 28 non-immunized AD cases. Immunohistochemistry on sections of neocortex was performed for neuron-specific nuclear antigen (NeuN), neurofilament protein (NFP) and phosphorylated-(p)PKR (pro-apoptotic kinase detected in degenerating neurons). Quantification was performed for pPKR and status spongiosis (neuropil degeneration), NeuN-positive neurons/field, curvature of the neuronal processes and interneuronal distance. Data were corrected for age, gender, duration of dementia and APOE genotype and also assessed in relation to Aβ42 and tau pathology and key features of AD. In non-immunized patients, the degree of neuritic curvature correlated with spongiosis and pPKR, and overall the neurodegenerative markers correlated better with tau pathology than Aβ42 load. Following immunization, spongiosis increased, interneuronal distance increased, while the number of NeuN-positive neurons decreased, consistent with enhanced neuronal loss. However, neuritic curvature was reduced and pPKR was associated with Aβ removal in immunized patients. In AD, associations of spongiosis status, curvature ratio and pPKR load with microglial markers Iba1, CD68 and CD32 suggest a role for microglia in neurodegeneration. After immunization, correlations were detected between the number of NeuN-positive neurons and pPKR with Iba1, CD68 and CD64, suggesting that microglia are involved in the neuronal loss. Our findings suggest that in established AD this form of active Aβ immunization may predominantly accelerate loss of damaged degenerating neurons. This interpretation is consistent with in vivo imaging indicating an increased rate of cerebral atrophy in immunized AD patients.

Clinical Benefit of Adalimumab Dose Adjustment for Patients With Moderately to Severely Active Crohn’s Disease in EXTEND

Clinical Benefit of Adalimumab Dose Adjustment for Patients With Moderately to Severely Active Crohn’s Disease in EXTEND

Aβ immunotherapy for Alzheimer’s disease: effects on apoE and cerebral vasculopathy

Aβ immunotherapy for Alzheimer's disease (AD) results in the removal of Aβ plaques and increased cerebral amyloid angiopathy (CAA). In current clinical trials, amyloid-related imaging abnormalities (ARIAs), putatively due to exacerbation of CAA, are concerning side effects. We aimed to assess the role of the Aβ transporter apolipoprotein E (apoE) in the exacerbation of CAA and development of CAA-associated vasculopathy after Aβ immunotherapy. 12 Aβ42-immunized AD (iAD; AN1792, Elan Pharmaceuticals) cases were compared with 28 unimmunized AD (cAD) cases. Immunohistochemistry was quantified for Aβ42, apoE, apoE E4 and smooth muscle actin, and CAA-associated vasculopathy was analyzed. Aβ immunotherapy was associated with redistribution of apoE from cortical plaques to cerebral vessel walls, mirroring the altered distribution of Aβ42. Concentric vessel wall splitting was increased threefold in leptomeningeal vessels after immunotherapy (cAD 6.3 vs iAD 20.6%, P<0.001), but smooth muscle cell abnormalities did not differ. The findings suggest that apoE is involved in the removal of plaques and transport of Aβ to the cerebral vasculature induced by Aβ immunotherapy. Immunotherapy was not associated with CAA-related vascular smooth muscle damage, but was accompanied by increased splitting of the vessel wall, perhaps reflecting enhanced deposition and subsequent removal of Aβ. ARIA occurring in some current trials of Aβ immunotherapy may reflect an extreme form of these vascular changes.

THE PROSPECTS FOR A VACCINE FOR ALZHEIMER'S DISEASE

Alzheimer's disease (AD) neuropathology is characterised by abnormal aggregation in the brain of amyloid-β (Ab) and hyperphosphorylated tau, associated with inflammation and loss of neurons and synapses. The amyloid cascade...

The Potential Biomedical Application of Cyclopeptides from Marine Natural Products

The largely unexplored marine would represent a unique and excellent resource of new natural products. The chemical and biological diversity of the marine environment formed a practically unlimited resource of new bioactive substances. Marine natural products captured the attention of natural products chemists because they exhibit significant and extremely potent biological activities. With the development of technologies and methodologies for structure elucidation, organic synthesis and biological assay, more and more marine natural products are isolated and investigated, ranging from simple peptides to macrocyclicpolyethers. Due to its bioactive property, marine natural products have yielded a considerable number of drug candidates. Some are already on the market or will be approved soon, such as Ziconotide (Prialt; Elan Pharmaceuticals), the first marine-derived compound approved in the United States for the treatment of pain. This compound is a peptide originally discovered in a tropical cone snail, while most of them are still in preclinical development. Naturally occurring cyclopeptides, in particular, exhibit a wide variety of potent biological activities. Some exhibit potent insecticidal activity and antimicrobial activity, while others have strong antifungal and antiproliferative activity. Hence, cyclopepiptides can be potential drug candidates. This review highlights the potential biomedical application of cyclopeptides from marine nature products. Keywords: Biomedical application, cyclopeptide, marine natural product.

PTU-055 Long-Term Efficacy of Adalimumab for Treatment of Moderately to Severely Active Ulcerative Colitis

PTU-055 Long-Term Efficacy of Adalimumab for Treatment of Moderately to Severely Active Ulcerative Colitis

Cost–effectiveness of natalizumab in multiple sclerosis: an updated systematic review

As natalizumab (Tysabri®; Elan Pharmaceuticals, Inc., Dublin, Ireland) and other disease-modifying drugs are entering the market for multiple sclerosis, the treatment repertoire is expanding beyond the established first-line treatments. This is creating new opportunities but also increasing the uncertainty in the appropriate management of this condition with its considerable societal burden. As a result, economic evaluations are increasingly influential in healthcare decision making. Seven evaluations that included natalizumab have been published to date. They largely report favorable results for this treatment compared with other drugs. However, the models used to reach these conclusions have been subjected to significant debate, owing to limited data availability as well as the methodological complexities and uncertainties in the pharmacoeconomics of multiple sclerosis. This review critically discusses the available evidence based on the cost–effectiveness of natalizumab and uses the data to explain more general issues in the evaluation of similar drugs. The review also suggests how shortcomings in current studies may potentially be addressed in the future.

S.13.02 Immunotherapy in tauopathies

Immunotherapy targeting Ab is currently in clinical trials for Alzheimer’s disease (AD). Two complications have been identified, leucoencephalopathy and cortical microhaemorrhages, both likely mediated by increased severity of cerebral amyloid angiopathy, accompanied by inflammation, as Ab plaques are cleared from the cortex. We have performed a long term neuropathological follow up of patients with a clinical diagnosis of mild to moderate AD (MMSE 15−25) who were actively immunised with Ab42 (Elan Pharmaceuticals). Of 80 patients in the study, 64 received Ab42 peptide and 16 the placebo. Post-mortem neuropathology confirmed the clinical diagnosis of AD in 12/16 (75%; 11 immunised, 1 placebo) and 4/16 (25%) had alternative neuropathological substrates for dementia: progressive supranuclear palsy, dementia with Lewy bodies, vascular dementia and frontotemporal dementia. All AD immunised patients showed variable histopathological evidence of mobilization and clearance of Ab plaques via microglia and/or the cerebral vasculature, implying an effect of the immunotherapy extending over many years [1,2]. 10/11 immunised AD patients had progressed to severe dementia (MMSE 10), by 6 years after immunization; one had died at 4 months [3]. The inclusion in a therapeutic trial for AD of patients with dementia due to other causes inevitably hampered the statistical power of the study. Many of the current clinical trials of immunotherapy include brain amyloid imaging (e.g. PIB-PET) and CSF Ab42 and phospho-tau to increase diagnostic accuracy, nevertheless post-mortem neuropathology follow up would provide additional valuable information.

Nuclear Factor-κB Regulates βAPP and β- and γ-Secretases Differently at Physiological and Supraphysiological Aβ Concentrations

Anatomical lesions in Alzheimer disease-affected brains mainly consist of senile plaques, inflammation stigmata, and oxidative stress. The nuclear factor-κB (NF-κB) is a stress-activated transcription factor that is activated around senile plaques. We have assessed whether NF-κB could be differentially regulated at physiological or supraphysiological levels of amyloid β (Aβ) peptides. Under these experimental conditions, we delineated the putative NF-κB-dependent modulation of all cellular participants in Aβ production, namely its precursor βAPP (β-amyloid precursor protein) and the β- and γ-secretases, the two enzymatic machines involved in Aβ genesis. Under physiological conditions, NF-κB lowers the transcriptional activity of the promoters of βAPP, β-secretase (β-site APP-cleaving enzyme 1, BACE1), and of the four protein components (Aph-1, Pen-2, nicastrin, presenilin-1, or presenilin-2) of the γ-secretase in HEK293 cells. This was accompanied by a reduction of both protein levels and enzymatic activities, thereby ultimately yielding lower amounts of Aβ and AICD (APP intracellular domain). In stably transfected Swedish βAPP-expressing HEK293 cells triggering supraphysiological concentrations of Aβ peptides, NF-κB activates the transcription of βAPP, BACE1, and some of the γ-secretase members and increases protein expression and enzymatic activities, resulting in enhanced Aβ production. Our pharmacological approach using distinct NF-κB kinase modulators indicates that both NF-κB canonical and alternative pathways are involved in the control of Aβ production. Overall, our data demonstrate that under physiological conditions, NF-κB triggers a repressive effect on Aβ production that contributes to maintaining its homeostasis, while NF-κB participates in a degenerative cycle where Aβ would feed its own production under pathological conditions.

Conotoxins that Confer Therapeutic Possibilities

Cone snails produce a distinctive repertoire of venom peptides that are used both as a defense mechanism and also to facilitate the immobilization and digestion of prey. These peptides target a wide variety of voltage- and ligand-gated ion channels, which make them an invaluable resource for studying the properties of these ion channels in normal and diseased states, as well as being a collection of compounds of potential pharmacological use in their own right. Examples include the United States Food and Drug Administration (FDA) approved pharmaceutical drug, Ziconotide (Prialt®; Elan Pharmaceuticals, Inc.) that is the synthetic equivalent of the naturally occurring ω-conotoxin MVIIA, whilst several other conotoxins are currently being used as standard research tools and screened as potential therapeutic drugs in pre-clinical or clinical trials. These developments highlight the importance of driving conotoxin-related research. A PubMed query from 1 January 2007 to 31 August 2011 combined with hand-curation of the retrieved articles allowed for the collation of 98 recently identified conotoxins with therapeutic potential which are selectively discussed in this review. Protein sequence similarity analysis tentatively assigned uncharacterized conotoxins to predicted functional classes. Furthermore, conotoxin therapeutic potential for neurodegenerative disorders (NDD) was also inferred.

Antibody Shows Promise As Alzheimer’s Treatment

Back to table of contents Previous article Next article Clinical & Research NewsFull AccessAntibody Shows Promise As Alzheimer’s TreatmentLeslie SinclairLeslie SinclairSearch for more papers by this authorPublished Online:1 Jun 2012https://doi.org/10.1176/pn.47.11.psychnews_47_11_23-aAbstractIt’s too soon to say if the monoclonal antibody bapineuzumab can cure or even prevent Alzheimer’s disease, but new information about its ability to affect Alzheimer’s biomarkers makes it a promising candidate.As reported in the online April 2 Archives of Neurology, research teams based at the University of Gothenburg in Mölndal, Sweden, and at Brown University in Providence, R.I., have completed two 12-month trials—one in the United States and one in England and Finland—to evaluate the effects of bapineuzumab on 46 patients with mild to moderate Alzheimer’s disease.Their intention was to determine whether immunotherapy with bapineuzumab would result in decreases in cerebrospinal fluid (CSF) biomarkers, which might in turn indicate downstream effects on the degenerative processes associated with Alzheimer’s.“We evaluated whether bapineuzumab impacted the CSF levels of the downstream biomarkers total tau (T-tau) and phosphorylated tau (P-tau), and the primary biomarker beta-amyloid in these trials,” wrote lead author Kaj Blennow, M.D., Ph.D., who is associated with the Clinical Neurochemistry Laboratory of the Sahlgrenska Academy at the University of Gothenburg, and colleagues.Blennow’s work has focused on the development of laboratory measures for clinical diagnosis and therapy monitoring in Alzheimer’s disease, with significant implications for both drug development and patient care. The European College of Neuropsychopharmacology (ECNP) awarded Blennow the 2010 ECNP Neuropsychopharmacology Award in recognition of his original and influential contributions to Alzheimer’s disease research.Blennow’s previous work includes a 2009 JAMA publication that reported the results of a multicenter study that verified that CSF levels of beta-amyloid, T-tau, and P-tau can identify incipient Alzheimer’s with good accuracy.In this latest report, Blennow and colleagues make the case for the use of these same biomarkers for assessing the efficacy of disease-modifying therapies, particularly those aimed at the treatment of Alzheimer’s. Historically, the identification of a beneficial clinical effect of Alzheimer’s treatments required very large and extended clinical trials.Their results? In a pooled analysis of CSF data from the two trials of passive immunotherapy with bapineuzumab in patients with mild to moderate Alzheimer’s, a decrease in both P-tau and T-tau at the end of the study compared with baseline within the bapineuzumab group was observed. For CSF P-tau, a statistically significant treatment difference was observed between the bapineuzumab and placebo groups.“These findings may indicate downstream effects of bapineuzumab treatment on the degenerative process,” explained Blennow and colleagues, who acknowledged that the important question is whether such changes in CSF biomarkers correlate with clinical benefit. They intend to address that question in the ongoing bapineuzumab phase 3 trials.The study was funded by Elan (acquired by Janssen Alzheimer Immunotherapy in 2009) and Wyeth Pharmaceuticals (acquired by Pfizer in 2009). Employees of both sponsor companies were involved in the study design, collection, analysis, and interpretation of data, as well as in the development and submission of the scientific report. An abstract of “Effect of Immunotherapy with Bapineuzumab on Cerebrospinal Fluid Biomarker Levels in Patients With Mild to Moderate Alzheimer Disease” is posted at http://archneur.jamanetwork.com/article.aspx?articleid=1151841#Abstract. ISSUES NewArchived