Sridhar Duvvuri

First-In-Human safety and long-term exposure data for AAB-003 (PF-05236812) and biomarkers after intravenous infusions of escalating doses in patients with mild to moderate Alzheimer’s disease

BackgroundIn the First-In-Human (FIH), 39-week, randomized, adaptive design study, safety, tolerability, pharmacokinetics and biomarkers were measured in patients with mild-to-moderate Alzheimer’s disease (AD) after infusion of a humanized monoclonal antibody to amyloid β, AAB-003 (NCT01193608; registered 19 August 2010). AAB-003 was developed by modifying bapineuzumab to reduce Fc-receptor-mediated effector function as a strategy to reduce the removal of amyloid from vessel walls associated with amyloid-related imaging abnormalities with edema/effusions (ARIA-E) without diminishing overall amyloid clearance.MethodsEighty-eight patients with AD received up to three infusions of AAB-003 (or placebo) 13 weeks apart at doses of 0.5, 1, 2, 4 or 8 mg/kg in the FIH trial. Dose escalation was based on safety data reviews using a Bayesian escalation algorithm. Subjects who completed the FIH study were permitted to enter a 1-year open-label extension trial with four additional intravenous infusions of AAB-003 (NCT01369225; registered 10 May 2011).ResultsDose-dependent increases in plasma amyloid β and AAB-003 were observed. No significant changes in cerebral spinal fluid biomarkers were observed. Pharmacokinetics elimination half-life (21–28 days) clearance and volume of distribution values were consistent across dose groups indicating linearity. ARIA-E was the most notable safety finding detected by magnetic resonance imaging (MRI) at 8 mg/kg in two patients. Three cases of microhemorrhage were observed. No new safety findings or MRI abnormalities were observed for the 52 subjects who received AAB-003 in the extension trial.ConclusionBased on integrated review of laboratory, electrocardiogram, adverse events, and MRI, AAB-003 was safe and well tolerated up to 8 mg/kg for up to 91 weeks (FIH and extension trials) in patients with mild to moderate AD. Asymptomatic and resolvable ARIA-E was observed after the first or second infusion of AAB-003, similar to bapineuzumab. The AAB-003 dose at which ARIA-E was observed was higher compared to bapineuzumab, supporting the hypothesis that reducing Fc-receptor effector function may reduce the ARIA associated with monoclonal antibodies targeting cerebral amyloid.

In vivo measurement of PDE10A enzyme occupancy by positron emission tomography (PET) following single oral dose administration of PF-02545920 in healthy male subjects.

&NA; Phosphodiesterase 10A (PDE10A) is an enzyme highly enriched in the striatal medium spiny neurons. It is involved in the regulation of cytoplasmic levels of cAMP and cGMP and signaling within the basal ganglia. This study with PDE10A radioligand [18F]MNI‐659 was designed to measure the enzyme occupancy of PF‐02545920 in 8 healthy male volunteers (48 ± 4 years) after a single oral dose (10 mg or 20 mg) and to evaluate safety and tolerability. Arterial blood sampling was performed to obtain a metabolite‐corrected plasma input function for the quantification of [18F]MNI‐659 binding to PDE10A. The occupancy of PF‐02545920 was calculated with two different methods: In Method 1, [18F]MNI‐659 enzyme occupancy was calculated from the estimates of binding potential, using the cerebellum as a reference region; in Method 2, occupancy was estimated from the slope of the revised Lassens plot. Serum concentrations of PF‐02545920 were measured to determine the relationship between concentration and occupancy. Based on Method 1, striatal PDE10A occupancy increased with increasing PF‐02545920 dose: 14–27% at 10 mg dose (N = 4) and 45–63% at 20 mg dose (N = 3). Comparable occupancies were observed using Lassens plot Method 2: 10 mg: 14–37%; 20 mg: 46–55%. The relationship between exposure and occupancy was best described using an Emax model. The serum concentration associated with 50% occupancy was estimated to be 93.2 ng/mL. Single oral doses of 10 mg or 20 mg of PF‐02545920 were safe and well tolerated in healthy male volunteers [NCT# 01918202]. HighlightsSingle oral doses (10 mg, 20 mg) of PF‐02545920 were safe and well tolerated in healthy male volunteers.Enzyme occupancy of PF‐02545920 obtained using [18F]MNI‐659 PET was in the expected range.Striatal PDE10A occupancy increased with increasing PF‐02545920 dose and exposure, reaching ˜50% following the 20 mg single dose.A 20 mg oral dose of PF‐02545920 provides sufficient target brain occupancy for evaluation in future PDE10 clinical trials.

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.

ESTIMATION OF CIRCULATING DRUG METABOLITE EXPOSURE IN HUMAN USING IN VITRO DATA AND PHYSIOLOGICALLY BASED PHARMACOKINETIC MODELLING: EXAMPLE OF A HIGH METABOLITE/PARENT DRUG RATIO

(R)-4-((4-(((4-((tetrahydrofuran-3-yl)oxy)benzo[d]isoxazol-3-yl)oxy)methyl)piperidin-1-yl)methyl)tetrahydro-2H-pyran-4-ol (TBPT), a serotonin-4 receptor partial agonist, is metabolized to two metabolites: an N-dealkylation product [(R)-3-(piperidin-4-ylmethoxy)-4-((tetrahydrofuran-3-yl)oxy)benzo[d]isoxazole (M1)] and a cyclized oxazolidine structure [7-(((4-(((R)-tetrahydrofuran-3-yl)oxy)benzo[d]isoxazol-3-yl)oxy)methyl)octahydro-3H (M2)]. After administration of TBPT to humans the exposure to M1 was low and the exposure to M2 was high, relative to the parent drug, despite this being the opposite in vitro. In this study, projection of the plasma metabolite/parent (M/P) ratios for M1 and M2 was attempted using in vitro metabolism, binding, and permeability data in static and dynamic physiologically based pharmacokinetic (PBPK) models. In the static model, the fraction of parent clearance yielding the metabolite (which also required taking into account secondary metabolites of M1 and M2), the clearance of the metabolites and parent, and an estimate of the availability of the metabolites from the liver were combined to yield estimated parent/metabolite ratios of 0.32 and 23 for M1 and M2, respectively. PBPK modeling that used in vitro and physicochemical data input yielded estimates of 0.26 and 20, respectively. The actual values were 0.12 for M1/TBPT and 58 for M2/TBPT. Thus, the ratio for M1 was overpredicted, albeit at values less than unity. The ratio for M2/TBPT was underpredicted, and the high ratio of 58 may exceed a limiting ceiling of the approach. Nevertheless, when considered in the context of determining whether a potential circulating metabolite may be quantitatively important prior to administration of a drug for the first time to humans, the approaches succeeded in highlighting the importance of M2 (M/P ratio >> 1) relative to M1, despite M1 being much greater than M2 in vitro.

Studying the Progression of Amyloid Pathology and Its Therapy Using Translational Longitudinal Model of Accumulation and Distribution of Amyloid Beta

Long‐term effects of amyloid targeted therapy can be studied using a mechanistic translational model of amyloid beta (Aβ) distribution and aggregation calibrated on published data in mouse and human species. Alzheimer disease (AD) pathology is modeled utilizing age‐dependent pathological evolution for rate constants and several variants of explicit functions for Aβ toxicity influencing cognitive outcomes (Adas‐cog). Preventive Aβ targeted therapies were simulated to minimize the Aβ difference from healthy physiological levels. Therapeutic targeted simulations provided similar predictions for mouse and human studies. Our model predicts that: (1) at least 1 year (2 years for preclinical AD) of treatment is needed to observe cognitive effects; (2) under the hypothesis with functional importance of Aβ, a 15% decrease in Aβ (using an imaging biomarker) is related to 15–20% cognition improvement by immunotherapy. Despite negative outcomes in clinical trials, Aβ continues to remain a prospective target demanding careful assessment of mechanistic effect and duration of trial design.

LOW PREVALENCE OF AMYLOID POSITIVITY IN HEALTHY ELDERLY PARTICIPANTS OF A METHODOLOGY STUDY EVALUATING REMOTE TABLET-BASED COGNITIVE LEARNING

Conclusions Though a gold standard of amyloid burden was not available, results indicate that a hybrid qualitative visual / quantitative method can be used to obtain greater concordance between quantitative and visual results. Clinical studies using only visual or only SUVR information for eligibility decisions must understand the implications of potential differences between the visual and quantitative methodologies.

Cross-species analysis of cerebrospinal fluid (CSF) beta-amyloid reductions by the BACE1 inhibitor PF-05297909 indicates species differences in PK/PD relationships: Relevance to clinical translation

reversed Ab oligomer-damaged long-term potentiation (LTP) at concentrations that did not interfere normal high frequency stimulation-induced LTP. Moreover, bis(heptyl)-cognitin prevented Ab oligomer-induced reduction of neurite length and synaptic quantity in mature hippocampal neurons. In contrast, tacrine could not reverse synaptic impairments in these models. Under oligomerization condition, bis(heptyl)-cognitin reduced the amount of Ab oligomer as evidenced by dot blot assay and immunoblot analysis. Finally, bis(heptyl)-cognitin was shown to alter Ab self-assembling as demonstrated by circular dichroism spectroscopy and transmission electron microscopy. Conclusions: All these results not only offer a modality as to how dimeric agents protect against Ab oligomer-induced synaptic impairments, but also offers a strong support for the beneficial therapeutic effects of bis(heptyl)-cognitin in the treatment of AD.