Timothy Nicholas

Disease progression model for cognitive deterioration from Alzheimer's Disease Neuroimaging Initiative database

A mathematical model was developed to describe the longitudinal response in Alzheimers Disease Assessment Scale‐cognitive (ADAS‐cog) obtained from the Alzheimers Disease Neuroimaging Initiative.

AlzheimerâÂÂs and ParkinsonâÂÂs Diseases Face Common Challenges inTherapeutic Development: Role of the Precompetitive Consortium,Coalition Against Major Diseases

Alzheimer’s disease (AD) and Parkinson’s disease (PD) pose significant challenges for successful development of new therapies, with anextremely high drug trial failure rate and yet no approved disease modifying drugs available. Given the magnitude of the challenges, it has become clear that larger collaborations and multi-partner joint efforts, pooling resources and expertise,are required for theadvancement of methods and tools that are critically needed to support drug development studies. Critical Path Institute’s Coalition against Major Diseases was formed in 2008, at a time prior to the era of public private partnerships, with the mission of streamlining and de-risking drug development for AD and PD. Since its origin, the consortium has achieved several milestones including development of consensus data standards for AD and PD, a unified clinical trial database comprised of placebo data from AD therapeutic trials and regulatory endorsement of drug development tools. In addition, the consortium is progressing strongly on other initiatives, with ongoing regulatory interactions. The coalition held its annual conference at the U.S. Food and Drug Administration, where diverse stakeholders including industry, academic experts, government agency representatives, patient advocacy organizations and regulators gathered together to share their accomplishments and focus on the needs of the future. The current landscape was emphasized with focus on the need to expand the precompetitive space and enhance data sharing globally.

Coalition Against Major Diseases Precompetitive Collaborations and Regulatory Paths to Accelerating Drug Development for Neurodegenerative Diseases

Precompetitive collaborations have been successful in several disease areas and industries. Such collaborations are critical to address the gaps and challenges in therapeutic development for chronic neurodegenerative diseases. On November 5, 2012, members of the scientific community, advocates, regulators, industry, and government officials met at the US Food and Drug Administration to develop tools to expedite drug development and maximize the potential for success in future drug trials for Alzheimer disease and Parkinson disease. The meeting established that multiple collaborative approaches are essential for accelerating drug development. Such approaches include precompetitive data sharing, regulatory qualification of biomarkers and clinical outcome assessments, implementation of data standards, and development of quantitative drug disease trial models. While challenges to collaboration among industry partners are formidable, they are not insurmountable. The Coalition Against Major Diseases (CAMD) has several positive examples to highlight. This review represents proceedings from CAMD’s annual conference and discusses the key themes that are being advanced by the Critical Path Institute.

A novel BACE inhibitor (PF-05297909): A two-part adaptive design to evaluate safety, pharmacokinetics and pharmacodynamics for modifying beta-amyloid in a first-in-human study

BackgroundThe accumulation of amyloid beta (Aβ) peptides is believed to be a central contributor to the neurodegeneration seen in the Alzheimers disease (AD) brain. Given the central role of Aβ42 in AD pathogenesis, a therapeutic strategy to lower central Aβ42 (and Aβ40) levels via inhibition of BACE was adopted in a first in human trial in a 2-part adaptive design.MethodsPart 1 evaluated PF-05297909 plasma PK and the PK/PD relationship for the reduction of plasma Aβ40, Aβ42 and AβX levels; Part 2 evaluated the exposure-response relationship between PF-05297909 and CSF levels of Aβ40, Aβ42 and AβX. Sufficient safety and tolerability, plasma exposure and reduction in plasma Aβ were necessary to initiate Part 2. Part 1 was a sequential parallel group dose escalation (25, 100, 250 and 325 mg) with n=8 (6:2, active:placebo) healthy volunteers (HV) in each cohort. Part 2 consisted of 3 cohorts of n=8 (6:2, active:placebo) HV. Doses selected for Part 2 started with the highest safe dose in Part 1 and then adapted for subsequent cohorts. The PK/PD relationship between PF-05297909 and Aβ42 was determined using a non-linear mixed effects (NLME) analysis. The doses for Part 2 - cohort 2 and 3 were to be chosen to improve the relative standard error in the estimate of the BACE IC50 as quantified by evaluating the determinant of the Fisher information matrix for the NLME model.ResultsPF-05297909 was well-tolerated. Reduction in plasma Aβ (Aβ40 and Aβ42) was exposure related with an apparent maximum at the 250 mg dose with a greater duration of activity at the 325 mg dose of PF-05297909. A 325 mg dose was selected for Part 2 - cohorts 1 and 2 without further cohorts being run, as stopping criteria for futility were met following analysis of cohort 2. A PK/PD relationship in CSF was not observed.ConclusionsThe adaptive designed PF-05297909 FIH study allowed efficient testing of safety and of the PK/PD relationship between PF-05297909 exposure and Aβ (Aβ40 and Aβ42). PF-05297909 was safe and well tolerated in HV at exposures tested. A robust effect on plasma Aβ did not translate to CSF pharmacodynamic effects.

Preliminary population pharmacokinetic modeling of PF-04360365, a humanized anti-amyloid monoclonal antibody, in patients with mild-to-moderate Alzheimer's disease

Introduction ● PF-04360365 is a humanized anti-amyloid IgG2 monoclonal antibody that recognizes amino acids 33–40 of the beta-amyloid (Aβ) 1–40 peptide, and requires a free carboxy terminus for binding. ● In transgenic mice that overexpress amyloid precursor protein, the murine analog of PF-04360365 has been observed to decrease Aβ levels in the central nervous system and to improve their performance in various models of learning and memory. ● PF-04360365 is currently undergoing clinical testing in patients with Alzheimer’s disease (AD) as a potential disease modifying agent to reduce brain Aβ burden and to improve clinical outcomes. ● A robust population pharmacokinetic (PK) model at an early stage of drug development can be critical in helping design more efficient clinical studies.

A mathematical model of multisite phosphorylation of tau protein

Abnormal tau metabolism followed by formation of tau deposits causes a number of neurodegenerative diseases called tauopathies including Alzheimer’s disease. Hyperphosphorylation of tau protein precedes tau aggregation and is a topic of interest for the development of pharmacological interventions to prevent pathology progression at early stages. The development of a mathematical model of multisite phosphorylation of tau would be helpful for searching for the targets of pharmacological interventions and candidates for biomarkers of pathology progression. In the present study, we for the first time developed a model of multisite phosphorylation of tau protein and elucidated the relative contribution of kinases to phosphorylation of distinct sites. The model describes phosphorylation of tau or PKA-prephosphorylated tau by GSK3β and CDK5 and dephosphorylation by PP2A, accurately reproducing the data for short-term kinetics of tau (de)phosphorylation. Our results suggest that kinase inhibition may more specifically prevent tau hyperphosphorylation, e.g., on PHF sites, which are key biomarkers of pathological changes in Alzheimer’s disease. The main features of our model are partial phosphorylation of tau residues and merging of random and sequential mechanisms of multisite phosphorylation within the framework of the probability-based approach assuming independent phosphorylation events.

Dopamine Transporter Neuroimaging as an Enrichment Biomarker in Early Parkinson's Disease Clinical Trials: A Disease Progression Modeling Analysis

Given the recognition that disease‐modifying therapies should focus on earlier Parkinsons disease stages, trial enrollment based purely on clinical criteria poses significant challenges. The goal herein was to determine the utility of dopamine transporter neuroimaging as an enrichment biomarker in early motor Parkinsons disease clinical trials. Patient‐level longitudinal data of 672 subjects with early‐stage Parkinsons disease in the Parkinsons Progression Markers Initiative (PPMI) observational study and the Parkinson Research Examination of CEP‐1347 Trial (PRECEPT) clinical trial were utilized in a linear mixed‐effects model analysis. The rate of worsening in the motor scores between subjects with or without a scan without evidence of dopamine transporter deficit was different both statistically and clinically. The average difference in the change from baseline of motor scores at 24 months between biomarker statuses was –3.16 (90% confidence interval [CI] = –0.96 to –5.42) points. Dopamine transporter imaging could identify subjects with a steeper worsening of the motor scores, allowing trial enrichment and 24% reduction of sample size.

A Translational Systems Pharmacology Model for Aβ Kinetics in Mouse, Monkey, and Human

A mechanistic model of amyloid beta production, degradation, and distribution was constructed for mouse, monkey, and human, calibrated and externally verified across multiple datasets. Simulations of single‐dose avagacestat treatment demonstrate that the Aβ42 brain inhibition may exceed that in cerebrospinal fluid (CSF). The dose that achieves 50% CSF Aβ40 inhibition for humans (both healthy and with Alzheimers disease (AD)) is about 1 mpk, one order of magnitude lower than for mouse (10 mpk), mainly because of differences in pharmacokinetics. The predicted maximal percent of brain Aβ42 inhibition after single‐dose avagacestat is higher for AD subjects (about 60%) than for healthy individuals (about 45%). The probability of achieving a normal physiological level for Aβ42 in brain (1 nM) during multiple avagacestat dosing can be increased by using a dosing regimen that achieves higher exposure. The proposed model allows prediction of brain pharmacodynamics for different species given differing dosing regimens.

Systems pharmacology modeling in 5HT4: Prediction and outcome of a clinical scopolamine impairment trial and further application to Alzheimer's disease pathology

then challenged orally with CWD infected brains. Tonsil and rectal biopsies plus blood, saliva, feces and urine were collected every three months post-infection until the 9 month; and every 45 days thereafter. Results: Two vaccinated animals produced low antibody titers, two intermediate titers and one high titers of IgA and IgG anti-PrP. Both groups produced high titers of IgA and IgG against Salmonella. Six months post-infection 5 out of 6 controls and 3 out of 5 vaccinated showed histologically prion structures in the tonsils. Ayear post-infection one of the vaccinated animals remained prion free, with all controls being infected. The negative animal has the highest titers of IgA in saliva and IgG systemic against PrP. Immunoglobulins purified from saliva, feces and serum of this vaccinated deer reacts to PrP. Conclusions: Oral immunization can be used to overcome tolerance to self-PrP protein and produce a mucosal IgA and systemic IgG response to normal and conformational modified PrP in large mammals. High antibody titers might be enough to prevent transmission or to retard progression of PrP infection. This approach may lead to an effective anti-prion vaccine.

An updated Aβ systems kinetic model for mouse, monkey and human

icity in Alzheimer’s disease (AD) has been focused on sensory deficit, especially impaired olfactory sensibility. AD might provide pathogenic ally significant causes of olfactory dysfunction, which designated even nonfibrillar Ab peptide deposition within olfactory bulb prior to the deposition within any region of brain. In addition, the olfactory receptor neurons (ORNs) might be affected by Ab peptides and contribute to atypical olfactory sensory dysfunction. Therefore, approaches allowing the simple, direct detection of the AD marker within the ORNs in vitro would be beneficial for the assessment of the diseases status. Methods: We suggest a new technical concept that is capable of evaluating as small as a few femtomolar Ab peptides by using a photo-sensitive field-effect transistor (p-FET) integrated with a selectively optical-transmissible filter. Selenium filter has optically adequate properties for the quantum dots for labeling Ab peptides, which reflects the unwanted range (<600 nm) of the excitation light and is only able to transmit the emitted light (>650 nm). The ORNs including Ab peptide s were lysed and placed on the sensing area of the p-FET.Results:We observed destructively decayed photo-current by the selenium-filtered p-FET compared with the bare p-FET, which confirmed that the selenium filter rarely transmit the excitation beam. Thereafter, we measured the photo-currents generated from the transmitted fluorescent beam through the selenium filter when the quantum dots conjugated with Ab on the filter w ere excited at 550 nm and emitted at 655 nm. Compared with no Ab peptide cases, t he difference of the photo-currents with Ab peptide s is as much apparent as about 10 mA. Conclusions: This study showed that with even slightly small amount of Ab peptides the selenium-filtered p-FET is simply applicable to differentiating the optically tenuous fluorescent beam. In addition, the correlation between the p-FET photo-currents and the various amounts of the quantum dots (Ab peptides) represented a linearity which showed a good conceptual agreement with the theoretically induced equation, consequently assuming that the photo-current would potentially evaluate the small quantity of Ab peptides on the p-FET sensing area.