Member Of Data Safety Monitoring Board Research Articles

Children deserve simple, short, safe, and effective treatment for rifampicin-resistant tuberculosis

Children deserve simple, short, safe, and effective treatment for rifampicin-resistant tuberculosis

LB1528C. Ivermectin for Treatment of Mild-to-Moderate COVID-19 in the Outpatient Setting A Decentralized, Placebo-controlled, Randomized, Platform Clinical Trial

Abstract Background The effectiveness of ivermectin to shorten symptom duration or prevent hospitalization among outpatients in the United States with mild-to-moderate symptomatic coronavirus disease 2019 (COVID-19) is unknown. We evaluated the efficacy of ivermectin 400 µg/kg daily for 3 days compared with placebo for the treatment of early mild-to-moderate COVID-19. Methods ACTIV-6 is an ongoing, decentralized, double-blind, randomized, placebo-controlled platform trial to evaluate repurposed therapies in outpatients with mild-to-moderate COVID-19. Non-hospitalized adults age ≥ 30 years with confirmed COVID-19, experiencing ≥ 2 symptoms of acute infection for ≤ 7 days were randomized to receive ivermectin 400 µg/kg daily for 3 days or placebo. The main outcome measure was time to sustained recovery, defined as achieving at least 3 consecutive days without symptoms. Secondary outcomes included a composite of hospitalization or death by day 28. Results Of the 3457 participants who consented to be evaluated for inclusion in the ivermectin arm, 1591 were eligible for this study arm, randomized to receive ivermectin 400 µg/kg (n=817) or placebo (n=774), and received study drug. Of those enrolled, 47% reported receiving at least 2 doses of SARS-CoV-2 vaccination. The posterior probability for any improvement in time to recovery was 0.91 (hazard ratio 1.07, 95% credible interval 0.96–1.17). The posterior probability of this benefit exceeding 24 hours was less than 0.01, as measured by the difference in mean time unwell. Hospitalizations or deaths were uncommon (ivermectin [n=10]; placebo [n=9]). Ivermectin at 400 µg/kg was safe and without serious adverse events as compared with placebo (ivermectin [n=10]; placebo [n=9]). Conclusion Ivermectin dosed at 400 µg/kg daily for 3 days resulted in less than one day of shortening of symptoms and did not lower incidence of hospitalization or death among outpatients with COVID-19 in the United States during the delta and omicron variant time periods. Disclosures Susanna Naggie, MD/MHS, AbbVie: Grant/Research Support|BMS/PRA: Event adjudication|Gilead Sciences: Grant/Research Support|Pardes Biosciences: Advisor/Consultant|Personal Health Insights, Inc: Data Safety Monitoring Board Member|Silverback Therapeutics: Advisor/Consultant|Vir Biotechnology: Advisor/Consultant|Vir Biotechnology: Stocks/Bonds.

Final Analysis of the Phase 1a/b Study of Chimeric Fibril-Reactive Monoclonal Antibody 11-1F4 in Patients with Relapsed or Refractory AL Amyloidosis

Background: AL amyloidosis has a very poor prognosis with a variable median survival of 12 to 18 months depending largely on the severity of organ involvement. Current treatment focusing on eliminating the plasma cell clone that produces amyloidogenic light chains have improved overall survival in these patients [ Kumar 2011]. However, the risk of early mortality remains high due to multi-organ dysfunction caused by persistent, insoluble amyloid fibril deposits. To address this, amyloid fibril-reactive monoclonal antibody (mAb) 11-1F4 was designed to target amyloid deposits by directly binding to a conformational epitope present on human light-chain amyloid fibrils. The mAb was tested in a murine (Mu) and later a chimeric (Ch) form in mice with induced human AL amyloidomas; to which there was rapid destruction of amyloid fibrils without any evidence of toxicity in the animals [ Hrncic 2000; Solomon 2003 ]. Confirmation of the mAb's specificity for amyloid fibrils was further demonstrated when the I-124 labeled Mu mAb was visualized in amyloid-laden organs on PET/CT imaging in human subjects [ Wall 2010 ]. These promising results led to the development of GMP-grade amyloid fibril-reactive chimeric IgG1 mAb 11-1F4 by NCI's Biological Resource Branch. Here we report the final data from the open-label, dose-escalation phase 1a/b study of Ch IgG1 mAb 11-1F4 (NCT02245867).Methods: Relapsed or refractory AL Amyloidosis patients who received prior anti-plasma cell treatment were enrolled. Patients received Ch mAb 11-1F4 as a single intravenous infusion (phase 1a) or a series of weekly infusions for 4 weeks (phase 1b). A dose-escalation “up and down” design was used for both phase 1a and 1b where successive doses of 0.5, 5, 10, 50, 100, 250 and 500 mg/m2 were administered. The primary objective was to determine the maximum tolerated dose and to evaluate safety and tolerability of the antibody. Secondary objectives included determining pharmacokinetics and organ response based on the International Society of Amyloidosis' consensus criteria [ Pallidini 2012 ] and the renal staging and response criteria [ Pallidini 2014 ].Results: Twenty-seven patients were treated with mAb 11-1F4. Eight patients completed phase 1a and 19 patients completed treatment in phase 1b. Twenty-six patients were evaluable for response. Median age for Phase 1a and 1b was 68. All patients tolerated the given dose of mAb 11-1F4 up to the highest dose level of 500mg/m2 for both phase 1a and 1b. There were no drug-related grade 4 or 5 adverse events (AEs) or dose-limiting toxicities. Two patients developed a grade 2 rash 3-4 days after infusion. One patient developed the skin rash in phase 1a (dose level 4) and when he was retreated in phase 1b. A skin biopsy with immunohistochemical staining showed 11-1F4 mAb binding to amyloid fibrils with a concomitant neutrophilic infiltrate. Another patient developed a similar rash in phase 1b which further provides clinical evidence that 11-1F4 mAb directly binds to light-chain amyloid fibrils.Overall, 63% (5 of 8) of evaluable patients demonstrated organ response after one infusion of mAb 11-1F4 in phase 1a and 61% (11 of 18) of evaluable patients showed organ response in Phase 1b. The median time to response was 2 weeks after the start of treatment with the tendency of faster response in higher dosages. We observed organ response independent of the free light chain type.Conclusions: We found that mAb 11-1F4 is well tolerated and safe without grade 4 or 5 AEs nor dose limiting toxicity (MTD of 500mg/m2). Moreover, we postulate that in patients with persistent organ dysfunction after plasma-cell directed therapy; mAb 11-1F4 leads to fast, early and sustained organ response. Overall, amyloid fibril targeted therapy with mAb 11-1F4 represents both a promising and innovative approach to the management of patients with AL Amyloidosis. The rapid destruction of amyloid fibrils by mAb 11-1F4 can improve organ function and, potentially improve mortality in patients with this uniformly fatal disease. Larger randomized trials to evaluate the efficacy of this mAb are planned. DisclosuresMaurer:FoldRx Pharmaceuticals: Research Funding; Prothena: Membership on an entity's Board of Directors or advisory committees, Other: Data Safety Monitoring Board Member; Ionis: Consultancy; National Institutes of Health: Research Funding; GlaxoSmithKline: Consultancy; Pfizer: Research Funding. Wall:University of Tennessee Research Foundation: Patents & Royalties. Lentzsch:Amgen: Consultancy; Caelum Biosciences: Other: leadership position and stock; BMS: Consultancy.

Renal Clearance of FGF23 and its Fragments in Humans

Background: Relative abundance of fibroblast growth factor-23 (FGF23) measured by the C-terminal (cFGF23, which measures both intact FGF23 & c-terminal fragments) vs intact (iFGF23, measures only intact hormone) assays varies by kidney function in humans. Differential kidney clearance may explain this. Methods: We measured cFGF23 and iFGF23 in the aorta and bilateral renal veins of 162 patients with essential hypertension undergoing renal angiography. Using multivariable linear regression models, we examined factors associated with aorta to renal vein reduction of FGF23 using both assays. Similar, parameters and urine concentrations were measured in 6 Wistar rats. Results: Mean age was 54±12 years, 54% percent were women, and mean creatinine clearance was 72±48 ml/min/100g. The human kidney reduces the concentrations of both cFGF23 (16±12%) and iFGF23 (21±16%) compared to aorta, but reduction was higher for iFGF23. Greater kidney creatinine and PTH reduction were each independently associated with greater reductions of both cFGF23 and iFGF23. The relative kidney reduction of iFGF23 and cFGF23 appeared stable and consistent across the range of creatinine clearance. Kidney clearance was similar, and urine concentrations of both assays were low in the rat models, suggesting kidney metabolism of both cFGF23 and iFGF23. Conclusions: Renal reduction of iFGF23 is higher than that of creatinine and cFGF23.FGF23 is likely metabolized and cleared through the human kidney tubules, above and beyond glomerular filtration. Kidney clearance of FGF23 does not explain differences in C-terminal and intact moieties across the range of kidney function. Funding: This work was supported by National Institute of Diabetes and Digestive Kidney Diseases (NIDDK) Grants R01DK119528 and K24DK110427 (J.H.I). P30 DK079328, R01 DK091392, R01 DK092461 and R01 DK119528 (O.W.M). Veterans Health Administration IK2-CX002195 (SS). Declaration of Interest: Dr. Ix is principal investigator of an investigator-initiated research grant from Baxter International, serves as a data safety monitoring board member for Sanifit International, and has served on advisory boards for Alpha Young, AstraZeneca, Ardelyx Inc., and Jnana Inc. Dr. Moe has served on advisory boards and received compensations in the last 5 years for Allena, Alnylam, Ardelyx, Applied Therapeutics, Dicerna, Janssen, Genzyme-Sanofi, and Tricida. Remaining authors have declared no conflicts of interest. Ethical Approval: The human renal angiography studies were approved by the medical ethical committee of the Maastricht University Hospital. Animal studies were performed in accordance with the National Institutes for Health’s Guide for Care and Use of Laboratory Animals, and the experimental protocols had gained approval by the VA San Diego Health Care Systems and conducted under their guidelines.

LBA29 - Immune activation with a novel immune switch anti-macrophage antibody (anti-Clever-1 mAb; FP-1305) in phase I/II first-in-human MATINS trial in patients with advanced solid tumours

BackgroundCLEVER-1 is a scavenger receptor that is highly expressed on tumor associated macrophages (TAMs) and mediates the clearance of “unwanted” self-components. Pre-clinical studies demonstrate that CLEVER-1 inhibition switches TAMs to a pro-inflammatory phenotype and reactivates CD8+ T-cell responses with a robust anti-tumour activity (Viitala et al. Clin Cancer Res 2019). Targeting CLEVER-1 could overcome the immunosuppressive tumour microenvironment and has led to the development of FP-1305, a humanized anti-CLEVER-1 IgG4-antibody. MethodsMATINS (Macrophage Antibody To INhibit immune Suppression) trial is a multicenter first-in-human phase I/II study (NCT03733990) to assess the tolerability, safety and preliminary efficacy of FP-1305 in patients (pts) with advanced, IO-refractory melanoma, cholangiocarcinoma, hepatocellular, colorectal, and pancreatic ductal adenocarcinoma (PDAC) Results11 pts (median age 57) were enrolled in four cohorts (0.3, 1.0, 3.0 or 10mg/kg) and received 1-8 cycles (median 3) of FP-1305 every three weeks. FP-1305 has been well tolerated without dose-limiting toxicities. Most frequent treatment-emergent adverse events (AEs; ≥20%) were fatigue and raised ALT and AST levels. Initial FP-1305 dosing led to an increase in blood NK cells (median 154 %), CD8+/CD4+ T cell ratio (median 121 %), B cells (median 143 %) and a decrease in regulatory T cells (median 65 % from baseline). Clinical benefits have been observed in two colorectal cancer pts. One with an ongoing partial response (-52%) and another with disease stabilization along with a decline in Carcinoembryonic antigen (CEA). The updated safety and efficacy results will be reported. ConclusionsFP-1305 is the first macrophage checkpoint candidate promoting immune switch with promising tolerability and clinical anti-tumor activity. Analysis of circulating immune cells after administration of FP-1305 demonstrates Th1 activation as well as mobilization of NK cells and B cells. Clinical trial identificationEudraCT: 2018-002732-24 (obtained 09 Jul 2018). Legal entity responsible for the studyFaron Pharmaceuticals Ltd. FundingFaron Pharmaceuticals Ltd. DisclosureP. Bono: Full / Part-time employment, Employment: Terveystalo; Advisory / Consultancy, Shareholder / Stockholder / Stock options, Stock owenership and Scientific Board member: TILT Biotherapeutics; Spouse / Financial dependant, Family member’s stock ownereship: Faron pharmaceuticals; Advisory / Consultancy: Faron pharmaceuticals; Advisory / Consultancy, Scientific Board member: Oncorena; Advisory / Consultancy: Pfizer; Advisory / Consultancy: BMS; Advisory / Consultancy: MSD; Advisory / Consultancy: Orion Pharma; Advisory / Consultancy: Ipsen ; Honoraria (self), Data safety monitoring Board member: Herantis Pharma. M. Hollmen: Advisory / Consultancy, Shareholder / Stockholder / Stock options, patent holder: faron pharmaceuticals. P. Jaakkola: Advisory / Consultancy: Faron Pharmaceuticals. S. Shetty: Advisory / Consultancy: Faron Pharmaceuticals. A. Thibault: Full / Part-time employment: Simbec-Orion. M.J.A. de Jonge: Advisory / Consultancy: Faron Pharmaceuticals. A.R. Minchom: Advisory / Consultancy: Faron Pharmaceuticals. Y.T. Ma: Advisory / Consultancy: Faron Pharmaceuticals. C. Yap: Advisory / Consultancy: Faron Pharmaceuticals. D. Robbrecht: Advisory / Consultancy: Faron Pharmaceuticals. S. Jalkanen: Shareholder / Stockholder / Stock options: Faron Pharmaceuticals. M.K. Karvonen: Shareholder / Stockholder / Stock options, Full / Part-time employment: Faron Pharmaceuticals. J. Mandelin: Shareholder / Stockholder / Stock options, Full / Part-time employment: Faron Pharmaceuticals. J. Koivunen: Advisory / Consultancy: Novartis; Advisory / Consultancy: Pfizer; Advisory / Consultancy: AstraZeneza; Advisory / Consultancy: Boehringer Ingelheim; Advisory / Consultancy: KaikuHealth; Research grant / Funding (self): Roche. All other authors have declared no conflicts of interest.

Developing training for Data Safety Monitoring Board members: A National Institute of Allergy and Infectious Diseases case study.

Data Safety Monitoring Boards primarily review accumulating data on clinical trials and provide recommendations to sponsors on whether a protocol should continue as planned, be modified, or be terminated. Data Safety Monitoring Boards often provide their recommendations based upon accumulating data to which only their members are given access. Despite the substantial responsibilities assumed by Data Safety Monitoring Board members, there is limited information in the literature about the unique knowledge they must possess and, consequently, the training content needs that are required in order for them to fulfill their obligations. This article describes how the National Institute of Allergy and Infectious Diseases identified the knowledge that Data Safety Monitoring Board members should acquire and the computer-based training they developed to address the learning needs of the National Institute of Allergy and Infectious Diseases assembled Data Safety Monitoring Board members. The National Institute of Allergy and Infectious Diseases conducted a comprehensive literature search and interviewed Data Safety Monitoring Board subject matter experts, including Data Safety Monitoring Board members and chairs from academic institutions, pharmaceutical companies, and the National Institutes of Health to (1) assess whether Data Safety Monitoring Board training is an identified need, (2) evaluate whether Data Safety Monitoring Board training has been developed, and (3) formulate suitable learning objectives. Data Safety Monitoring Board training modules were developed based on the identified learning objectives identified from the interviews. Three Data Safety Monitoring Board training modules were developed and formatted for web-based access, which is free of charge to the public at https://dsmblearningcenter.niaid.nih.gov. The modules include the following: an introduction to the objectives and purpose of Data Safety Monitoring Boards, the organization and responsibilities of Data Safety Monitoring Boards, and a review of statistical topics. The complex concepts that Data Safety Monitoring Board members must apply to their deliberations and decisions require practice and application that come through hands-on experience. To build competency in the Data Safety Monitoring Board member role, not only does a member need to understand these complex concepts but also the member must have the opportunity to practice and apply this knowledge to real-life situations. Additional resources to facilitate practice and application of the complex issues that Data Safety Monitoring Boards deal with should be considered. The computer-based training is targeted to new and inexperienced Data Safety Monitoring Board members. Ongoing learning opportunities should be developed for experienced Data Safety Monitoring Board members. Non-English training must also be considered. The National Institute of Allergy and Infectious Diseases identified that training is not widely available for Data Safety Monitoring Board members to build the unique knowledge and skills necessary to serve on Data Safety Monitoring Boards. Consequently, National Institute of Allergy and Infectious Diseases developed publicly available web-based Data Safety Monitoring Board training modules for new or inexperienced members. Additional tools and resources are needed to help Data Safety Monitoring Board members acquire the knowledge and skills to serve their critical function in clinical research and to maximize research participant protections.

LBA27_PR - Phase II Three-Arm Randomised Study of the Braf Inhibitor (BRAFI) Dabrafenib Alone vs Combination with Mek1/2 Inhibitor (MEKI) Trametinib in Pts with Braf V600 Mutation-Positive Metastatic Melanoma (MM)

ABSTRACT Introduction Dabrafenib (D) combined with trametinib (T) shows enhanced activity in BRAF V600-mutated cancer cell lines and xenograft models compared with either drug alone. Preclinically, D + T delays resistance and prevents BRAFi-induced proliferative skin lesions. Safety and efficacy of D + T, were evaluated in a four-part Phase 1–2 study. Safety and efficacy from Part C, the randomised study of D + T vs D are presented. Methods BRAFV600E/K mutation-positive, MM, BRAFi and MEKi treatment-naive pts (≥ 18 yrs; ECOG PS Results Pt (n = 162) baseline characteristics were balanced across the three arms. Investigator assessed median PFS for 150/2 was 9.4 mo v 5.8 for D mono (HR 0.39, 95% CI 0.25–0.62; p Conclusions D + T provided a statistically significant and clinically meaningful improvement in PFS, RR and DoR compared to D mono in pts with BRAF V600 mutation-positive MM. The data is consistent to Part B reported with D + T. Increased incidence and severity of pyrexia and lower incidence of hyperproliferative skin lesions are observed with D + T compared to D mono. Phase 3 studies are ongoing. Disclosure G.V. Long: Has participated in advisory boards for GlaxoSmithKline, Bristol Myers Squibb and Roche. Has received research funding and honoraria from Roche. J.A. Sosman: Has received research funding from GlaxoSmithKline. J.S. Weber: Has participated in advisory boards for, and has received honoraria from, GlaxoSmithKline. K.T. Flaherty: Has acted as a data safety monitoring board member and consultant (compensated) for, and has received research funding from GlaxoSmithKline. J.R. Infante: Has participated in an advisory board for GlaxoSmithKline. O. Hamid: Has acted as a consultant (uncompensated) for GlaxoSmithKline. Has received research funding from Bristol Myers Squibb. L. Schuchter: Has participated in advisory boards for Merck and has received research funding from GlaxoSmithKline, Merck and Genentech. J.S. Cebon: Has participated in GlaxoSmithKline advisory boards, and has received research funding and honoraria from GlaxoSmithKline. I. Puzanov: Has acted as a paid consultant to GlaxoSmithKline. A.P. Algazi: Has received research funding from GlaxoSmithKline. K. Lewis: Has received research funding from GlaxoSmithKline. W. Hwu: Has acted as a compensated consultant for Merck. Has received research funding from Bristol Myers Squibb. R.F. Kefford: Has participated in an advisory board for GlaxoSmithKline. P. Sun: Is a GlaxoSmithKline employee (Statistician) and owns GlaxoSmithKline stocks and shares. S.M. Little: Is a GlaxoSmithKline employee (Clinical Development Manager) and owns GlaxoSmithKline stocks and shares. R. Gonzalez: Has acted as a consultant to, and has received research funding from, GlaxoSmithKline. K. Patel: Is a GlaxoSmithKline employee (Director, Oncology Clinical Development) and owns GlaxoSmithKline stocks and shares. K.B. Kim: Has received research funding from GlaxoSmithKline. All other authors have declared no conflicts of interest.

Clinical Characteristics of Parkinsonism in Frontotemporal Dementia Syndromes Associated with Mutations in MAPT, PGRN, C9ORF72 (P06.075)

Objective: To compare and contrast the features of parkinsonism in cases with different genetic mutations associated with frontotemporal lobar degeneration (FTLD). Background FTLD has been associated with mutations in the microtubule associated protein tau ( MAPT) , progranulin (PGRN) and the GGGGCC hexanucleotide repeat expansion in the open reading frame 72 on chromosome 9 ( C9ORF72 ). Several of affected individuals with an FTLD syndrome exhibited parkinsonism. The specific features of parkinsonism associated with these mutations have not been well-characterized. Design/Methods: Using data collected prospectively on the UPDRS during the course of yearly visits, we analyzed all the parkinsonian features of the patients affected by one of the three mutations. Results: We compared 14 cases with C90RF72 , 12 with PGRN and 12 with MAPT that had parkinsonism. A symmetric akinetic-rigid parkinsonism phenotype was present in the majority of the cases. Hypomimia and bradykinesia were the most common features. Tremor was present in 5% of the cases with C90RF72 , 18% with MAPT , and absent in all cases with PGRN . None in whom levodopa therapy was administered benefited from treatment. Conclusions: Although some variability exists, among those with familial FTLD associated with mutations in C90RF72, PGRN and MAPT mutations, the parkinsonian features are typically akinetic rigid and symmetric without a significant presence of tremor. Supported by: Grants AG016574, AG006786, the ALS Association, and the Robert H. and Clarice Smith and Abigail Van Buren Alzheimer s Disease Research Program of the Mayo Foundation. Disclosure: Dr. Savica has nothing to disclose. Dr. Graff-Radford has received personal compensation for activities with Codman as a participant on a scientific advisory board. Dr. Graff-Radford has received personal compensation in an editorial capacity for the Neurologist. Dr. Graff-Radford has received research support from Janssen Pharmaceuticals, Inc., Pfizer Inc, Medivation, Inc., Forrest Laboratories and Allon Therapeutics Inc. Dr. DeJesus-Hernandez has nothing to disclose. Dr. Knopman has received personal compensation for activities with Lilly Pharmaceuticals as a data safety monitoring board member. Dr. Knopman has received personal compensation in an editorial capacity for Neurology. Dr. Knopman has received research support from Elan, Forest, and Baxter. Dr. Adeli has nothing to disclose. Dr. Boot has nothing to disclose. Dr. Kuntz has received research support from Cephalon, Inc. Dr. Petersen has received personal compensation for activities with Pfizer, Inc., Janssen Alzheimer9s Immunotherapy, Elan Pharmaceuticals, and GE Healthcare. Dr. Rutherford has nothing to disclose. Dr. Baker has nothing to disclose. Dr. Rademakers has nothing to disclose. Dr. Boeve has nothing to disclose.

Risk Factors for Dementia with Lewy Bodies (S24.005)

Objective: To determine the risk factors associated with Dementia with Lewy Bodies (DLB) in a population-based case-control study. Background DLB is the second most common form of dementia and shares features with Alzheimer9s Disease (AD) and Parkinson9s disease with dementia (PDD). No prior studies have comprehensively assessed risk factors for DLB. Design/Methods: We identified 147 subjects with incident DLB and without a concomitant diagnosis of AD. Each DLB subject was matched for sex and age (+/- 5 years) with two cognitively-normal control (NC) subjects, and compared to 221 subjects with AD. We asked subjects and carers about known AD and PDD risk factors during enrollment and follow-up. We also reviewed their complete medical records to verify exposure information. Results: For DLB compared to NCs, the nominal odds ratio (OR) for a history of depression was 11.9 (p Conclusions: Like PD, DLB was associated with male preponderance, pre-existing anxiety and depression and early oophorectomy in females. Like AD it was associated with shorter life-span, stroke and the APOEe4 allele. It differed from AD in regard to gender and education. Supported by: Grants P50 AG16574 and P01 AG07216 from the National Institute on Aging, by the Robert H. and Clarice Smith and Abigail Van Buren Alzheimer9s Disease Research Program and R01 AG15866. Disclosure: Dr. Boot has nothing to disclose. Dr. Orr has nothing to disclose. Dr. Ferman has nothing to disclose. Dr. Roberts has received research support from Abbott Laboratories. Dr. Pankratz has received research support from Abbott Laboratories, Inc. Dr. Dickson has nothing to disclose. Dr. Ahlskog has nothing to disclose. Dr. Knopman has received personal compensation for activities with Lilly Pharmaceuticals as a data safety monitoring board member. Dr. Knopman has received personal compensation in an editorial capacity for Neurology. Dr. Knopman has received research support from Elan, Forest, and Baxter. Dr. Petersen has received personal compensation for activities with Pfizer, Inc., Janssen Alzheimer9s Immunotherapy, Elan Pharmaceuticals, and GE Healthcare. Dr. Boeve has nothing to disclose.

Cognitive Endophenotype Associated with the C9ORF72 GGGGCC Expansion in FTD/ALS (P05.063)

Objective: To investigate the cognitive endophenotype associated with the GGGGCC repeat in C9ORF72 in subjects with frontotemporal dementia (FTD) and/or amyotrophic lateral sclerosis (ALS) compared to FTD subjects with no known mutations in C9ORF72, MAPT, or PGRN . Background We have previously shown that the cognitive profile in subjects with the GGGGCC expansion in C9ORF72 is characterized by slowed processing speed, executive dysfunction, and impairment in phonemic word fluency. However, this phenotype is not unique to C9ORF72 and resembles the well-known phenotypic characteristics of FTD. Thus, it remains unclear how the cognitive deficits associated with C9ORF72 may differ from the FTD phenotype in subjects without any known mutation. Design/Methods: Subjects were enrolled in Mayo Clinic Alzheimer9s Disease Research Center (ADRC) or Alzheimer9s Disease Patient Registry (ADPR). FTD/ALS subjects with the C9ORF72 mutation (“ C9ORF72 subjects,” n=25) and FTD subjects without any known mutations in C9ORF72, MAPT , and PGRN (n=65) who had neuropsychological data were identified. The neuropsychological battery included tests of attention/executive functions (Digit Span, Trailmaking-B, Stroop), processing speed (Trailmaking-A), language (phonemic and semantic word fluency, Boston Naming), and memory (Logical Memory and Auditory Verbal Learning Test, AVLT). All test scores were converted into age-corrected z-scores. Results: C9ORF72 subjects were younger (57.2 ± 9.1) than FTD subjects without any mutation (66.9 ± 9.8) (p C9ORF72 subjects showed marked deficits in executive functions, speed, and phonemic fluency, but not delayed recall. Compared to those without any known mutations, C9ORF72 subjects performed worse on Trailmaking-B (p = .002), Stroop (p = .04), and phonemic fluency (p = .05), yet significantly better on Logical Memory (p Conclusions: Although a common phenotype exists characterized by impairment in speed, executive functions, and phonemic fluency, subjects with the C9ORF72 mutation demonstrate significantly worse cognitive impairment compared to FTD subjects without any known mutations. Disclosure: Dr. Pedraza has nothing to disclose. Dr. Boeve has nothing to disclose. Dr. DeJesus-Hernandez has nothing to disclose. Dr. Rush has nothing to disclose. Dr. Lucas has nothing to disclose. Dr. Fields has received personal compensation for activities with Medtronic, Inc., as a consultant. Dr. Machulda has nothing to disclose. Dr. Graff-Radford has received personal compensation for activities with Codman as a participant on a scientific advisory board. Dr. Graff-Radford has received personal compensation in an editorial capacity for the Neurologist. Dr. Graff-Radford has received research support from Janssen Pharmaceuticals, Inc., Pfizer Inc, Medivation, Inc., Forrest Laboratories and Allon Therapeutics Inc. Dr. Knopman has received personal compensation for activities with Lilly Pharmaceuticals as a data safety monitoring board member. Dr. Knopman has received personal compensation in an editorial capacity for Neurology. Dr. Knopman has received research support from Elan, Forest, and Baxter. Dr. Josephs has nothing to disclose. Dr. Rutherford has nothing to disclose. Dr. Baker has nothing to disclose. Dr. Ferman has nothing to disclose. Dr. Smith has nothing to disclose. Dr. Ivnik has nothing to disclose. Dr. Wszolek has received personal compensation in an editorial capacity for Parkinsonism and Realted Disorders and European Journal of Neurology. Dr. Boylan has nothing to disclose. Dr. Petersen has received personal compensation for activities with Pfizer, Inc., Janssen Alzheimer9s Immunotherapy, Elan Pharmaceuticals, and GE Healthcare. Dr. Rademakers has nothing to disclose.

Cholinergic Agonists as Novel Treatments for Schizophrenia: The Promise of Rational Drug Development for Psychiatry

Cholinergic Agonists as Novel Treatments for Schizophrenia: The Promise of Rational Drug Development for Psychiatry