Kimberley Jackson

Activation of mGlu2/3 receptors as a new approach to treat schizophrenia: a randomized Phase 2 clinical trial

Schizophrenia is a chronic, complex and heterogeneous mental disorder, with pathological features of disrupted neuronal excitability and plasticity within limbic structures of the brain. These pathological features manifest behaviorally as positive symptoms (including hallucinations, delusions and thought disorder), negative symptoms (such as social withdrawal, apathy and emotional blunting) and other psychopathological symptoms (such as psychomotor retardation, lack of insight, poor attention and impulse control). Altered glutamate neurotransmission has for decades been linked to schizophrenia, but all commonly prescribed antipsychotics act on dopamine receptors. LY404039 is a selective agonist for metabotropic glutamate 2/3 (mGlu2/3) receptors and has shown antipsychotic potential in animal studies. With data from rodents, we provide new evidence that mGlu2/3 receptor agonists work by a distinct mechanism different from that of olanzapine. To clinically test this mechanism, an oral prodrug of LY404039 (LY2140023) was evaluated in schizophrenic patients with olanzapine as an active control in a randomized, three-armed, double-blind, placebo-controlled study. Treatment with LY2140023, like treatment with olanzapine, was safe and well-tolerated; treated patients showed statistically significant improvements in both positive and negative symptoms of schizophrenia compared to placebo (P < 0.001 at week 4). Notably, patients treated with LY2140023 did not differ from placebo-treated patients with respect to prolactin elevation, extrapyramidal symptoms or weight gain. These data suggest that mGlu2/3 receptor agonists have antipsychotic properties and may provide a new alternative for the treatment of schizophrenia.

A multicenter, inpatient, phase 2, double-blind, placebo-controlled dose-ranging study of LY2140023 monohydrate in patients with DSM-IV schizophrenia

The primary objective of this study was to test the hypothesis that 1 or more dose levels of LY2140023 monohydrate, an oral prodrug of the potent metabotropic glutamate (mGlu) 2/3 receptor agonist LY404039, given to patients with schizophrenia for 4 weeks would demonstrate significantly greater efficacy than placebo. The HBBI study was a multicenter, randomized, double-blind, parallel, placebo- and active-controlled trial. Male and female patients aged 18 to 65 years who met the Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition (DSM-IV) criteria for schizophrenia were randomized in a 2:2:2:2:2:1 ratio to receive 5-, 20-, 40-, or 80-mg LY2140023 monohydrate twice daily, placebo twice daily, or placebo (am) and 15 mg of olanzapine (pm) daily. Efficacy was defined as the change from baseline on the Positive and Negative Syndrome Scale (PANSS) total score assessed at 4 weeks. The primary analysis did not show that any of the 4 LY2140023 monohydrate doses were more efficacious than placebo as measured by the PANSS total score. Similarly, olanzapine did not significantly separate from placebo. A higher-than-anticipated treatment effect (14.6-point improvement) in the placebo group was observed on PANSS total score. LY2140023 monohydrate was generally well tolerated, although 4 patients reported the serious adverse event of convulsion. LY2140023 monohydrate-treated patients showed little change in dopamine-related adverse events and weight. The results of the HBBI study are considered to be inconclusive because LY2140023 monohydrate and the active control olanzapine did not separate from placebo in the treatment of patients with acutely exacerbated schizophrenia. Additional efficacy, safety, and tolerability testing are needed.

N-(4-((2-(trifluoromethyl)-3-hydroxy-4-(isobutyryl)phenoxy)methyl)benzyl)-1-methyl-1H-imidazole-4-carboxamide (THIIC), a Novel Metabotropic Glutamate 2 Potentiator with Potential Anxiolytic/Antidepressant Properties: In Vivo Profiling Suggests a Link between Behavioral and Central Nervous System Neurochemical Changes

The normalization of excessive glutamatergic neurotransmission through the activation of metabotropic glutamate 2 (mGlu2) receptors may have therapeutic potential in a variety of psychiatric disorders, including anxiety/depression and schizophrenia. Here, we characterize the pharmacological properties of N-(4-((2-(trifluoromethyl)-3-hydroxy-4-(isobutyryl)phenoxy)methyl)benzyl)-1-methyl-1H-imidazole-4-carboxamide (THIIC), a structurally novel, potent, and selective allosteric potentiator of human and rat mGlu2 receptors (EC50 = 23 and 13 nM, respectively). THIIC produced anxiolytic-like efficacy in the rat stress-induced hyperthermia assay and the mouse stress-induced elevation of cerebellar cGMP and marble-burying assays. THIIC also produced robust activity in three assays that detect antidepressant-like activity, including the mouse forced-swim test, the rat differential reinforcement of low rate 72-s assay, and the rat dominant-submissive test, with a maximal response similar to that of imipramine. Effects of THIIC in the forced-swim test and marble burying were deleted in mGlu2 receptor null mice. Analysis of sleep electroencephalogram (EEG) showed that THIIC had a sleep-promoting profile with increased non-rapid eye movement (REM) and decreased REM sleep. THIIC also decreased the dark phase increase in extracellular histamine in the medial prefrontal cortex and decreased levels of the histamine metabolite tele-methylhistamine (t-MeHA) in rat cerebrospinal fluid. Collectively, these results indicate that the novel mGlu2-positive allosteric modulator THIIC has robust activity in models used to predict anxiolytic/antidepressant efficacy, substantiating, at least with this molecule, differentiation in the biological impact of mGlu2 potentiation versus mGlu2/3 orthosteric agonism. In addition, we provide evidence that sleep EEG and CSF t-MeHA might function as viable biomarker approaches to facilitate the translational development of THIIC and other mGlu2 potentiators.

Pharmacokinetics, Metabolism, and Excretion of the Glycogen Synthase Kinase-3 Inhibitor LY2090314 in Rats, Dogs, and Humans: A Case Study in Rapid Clearance by Extensive Metabolism with Low Circulating Metabolite Exposure

LY2090314 (3-[9-fluoro-2-(piperidin-1-ylcarbonyl)-1,2,3,4-tetrahydro[1,4]diazepino[6,7,1-hi]indol-7-yl]-4-imidazo[1,2-a]pyridin-3-yl-1H-pyrrole-2,5-dione) is an intravenous glycogen synthase kinase-3 inhibitor in oncology trials. Drug disposition was characterized after intravenous infusion of [14C]LY2090314 to rats and dogs, and was related to available clinical data. LY2090314 exhibited high clearance (approximating hepatic blood flow) and a moderate volume of distribution (∼1–2 l/kg) resulting in rapid elimination (half-life ∼0.4, 0.7, and 1.8–3.4 hours in rats, dogs, and humans, respectively). Scaled clearance from liver microsomes accurately predicted perfusion-limited clearance across species. LY2090314 was cleared by extensive metabolism, and the numerous metabolites were rapidly excreted into feces via bile (69–97% of dose; 62–93% within 0–24 hours); urinary recovery of drug-related material was low (≤3% of dose). Despite extensive metabolism, in rats and humans the parent compound was the sole identifiable drug-related moiety in plasma. Even in Mdr1a-, Bcrp-, and Mrp2-knockout rats, LY2090314 metabolites did not appear in circulation, and their urinary excretion was not enhanced, because the hypothesized impaired biliary excretion of metabolites in the absence of these canalicular transporters was not observed. Canine metabolite disposition was generally similar, with the notable exception of dog-unique LY2090314 glucuronide. This conjugate was formed in the dog liver and was preferentially excreted into the blood, where it accounted for the majority of circulating radioactivity at later times, and was predominantly recovered in urine (16% of dose). In conclusion, LY2090314 was rapidly cleared by extensive metabolism with negligible circulating metabolite exposures due to biliary excretion of metabolites into feces with no apparent intestinal reabsorption.

An open-label phase 2 study of glycogen synthase kinase-3 inhibitor LY2090314 in patients with acute leukemia

Abstract This open-label, Phase-2 study investigated the safety of LY2090314 (GSK-3 inhibitor) in AML patients. Twenty patients received 40-mg LY2090314 (50-mg ranitidine pretreatment) as follows: Cohort 1 – days 1, 8, and 15 of a 28-d cycle (n = 7); Cohort 2 – days 1, 5, and 9 of a 21-d cycle (n = 6); Cohort 3 – days 1, 5, 9, and 12 of a 21-d cycle (n = 7). Decreased appetite (n = 7) and nausea (n = 4) were the most frequently reported possibly drug-related non-hematologic treatment-emergent adverse events (TEAEs). Hematologic TEAEs included febrile neutropenia (n = 2), thrombocytopenia (n = 1), and anemia (n = 1). Atrial flutter (n = 1), QT interval prolongation (n = 3), and visual disturbances (n = 2) were observed, but were not clinically significant (investigator assessed). Although β-catenin levels indicated an on-target effect, no complete or partial remissions were observed. Pharmacokinetics were consistent with a previous Phase 1 study. These data suggest that single-agent LY2090314 has acceptable safety but limited clinical benefit in AML patients at the dose/frequencies investigated.

Desipramine, substrate for CYP2D6 activity: population pharmacokinetic model and design elements of drug-drug interaction trials

AIMS To develop a population pharmacokinetic model to describe the pharmacokinetics of desipramine in healthy subjects, after oral administration of a 50mg dose. Additional objectives were to develop a semi-mechanistic population pharmacokinetic model for desipramine, which allowed simulation of CYP2D6-mediated inhibition, when using desipramine as a probe substrate, and to evaluate certain study design elements, such as duration of desipramine pharmacokinetic sampling, required sample size and optimal pharmacokinetic sampling schedule for intermediate, extensive and ultrarapid metabolizers of CYP2D6 substrates. RESULTS The mean population estimates of the first order absorption rate constant (k(a) ), apparent clearance (CL/F) and apparent volume of distribution at steady state (V(ss) /F) were 0.15h(-1) , 111 lh(-1) and 2950 l, respectively. Further, using the proposed semi-mechanistic hepatic intrinsic clearance model with Bayesian inference, mean population desipramine hepatic intrinsic clearance was estimated to be 262 lh(-1) with between-subject variability of 84%. d-optimal PK sampling times for intermediate metabolizers were calculated to be approximately 0.25, 24, 75 and 200h. Similar sampling times were found for ultrarapid and extensive metabolizers except that the second d-optimal sample was earlier at 14 and 19h, respectively, compared with 24h for intermediate metabolizers. This difference in sampling times between the three genotypes can be attributed to the different intrinsic clearances and elimination rates. CONCLUSIONS A two compartment population pharmacokinetic model best described desipramine disposition. The semi-mechanistic population model developed is suitable to describe the pharmacokinetic behaviour of desipramine for the dose routinely used in drug-drug interaction (DDI) studies. Based on this meta-analysis of seven trials, a sample size of 21 subjects in cross-over design is appropriate for assessing CYP2D6 interaction with novel compounds.

Exposure‐Response Modeling to Characterize the Relationship Between Ixekizumab Serum Drug Concentrations and Efficacy Responses at Week 12 in Patients With Moderate to Severe Plaque Psoriasis

Ixekizumab, a high‐affinity monoclonal antibody, selectively targets interleukin‐17A and has been shown to be efficacious in the treatment of moderate to severe psoriasis. The objective was to describe the relationship between ixekizumab concentrations and efficacy response (static Physician Global Assessment [sPGA] and the Psoriasis Activity and Severity Index [PASI) scores] after 12 weeks of ixekizumab treatment in psoriasis patients from 3 phase 3 studies. Data from 2888 psoriasis patients randomized to receive placebo or 80 mg ixekizumab every 2 weeks or every 4 weeks were analyzed. Separate logistic regression models describing the relationship between ixekizumab concentrations and sPGA or PASI scores at week 12 were used to determine the probability of patients achieving a response and to investigate the impact of various patient factors other than drug concentrations on response rates. Both dosing regimens were efficacious, with higher rates of response achieved with the higher range of observed ixekizumab concentrations after every‐2‐week dosing. Although higher bodyweight, palmoplantar involvement, lower baseline disease state, or high baseline C‐reactive protein were associated with slightly lower response rates, the magnitude of effect of these factors on sPGA(0,1) response was small, with all subgroups able to achieve high levels of response. Other factors tested had no effect including age, sex, and antidrug antibody status. Logistic regression modeling of ixekizumab concentration and efficacy data accurately identified the proportion of responders using sPGA or PASI end points. The higher concentration ranges achieved with 80 mg every 2 weeks versus every 4 weeks were associated with higher response levels.

Abstract C211: Therapeutic utility of GSK‐3 inhibitors for the treatment of cancer

Glycogen synthase kinase‐3 (GSK‐3) is a constitutively active protein kinase that plays a role in diverse signaling pathways. Initially described as a regulator of glycogen synthesis and metabolism, GSK‐3 is now known to play a central role in a variety of cellular functions ranging from maintenance of stem cell function to regulation of cell cycle and apoptosis. In mammals, there are two highly homologous isoforms of GSK‐3 (GSK‐3α and GSK‐3β) which share substrate specificity and functional properties. GSK3β is one of the key components of the β‐catenin destruction complex and phosphorylation of β‐catenin by GSK‐3 targets the substrate protein for ubiquitylation and proteosomal destruction ‐ conversely, inhibition of GSK‐3β activity results in loss of phosphorylation sites and stabilization of β‐catenin in the cellular cytoplasm and nucleus. GSK‐3 expression and/or activity have been reported to be elevated in multiple tumor types, including pancreatic, gastric and colorectal carcinomas. Equally important, inhibition of GSK‐3 expression in colorectal tumor cell lines via specific siRNAs induced apoptosis and attenuated the proliferation of tumor cells. Together, these findings suggest that GSK‐3 inhibitors may represent a new class of therapeutic agents against colorectal cancer. LY‐GSK‐3i is a novel, potent and selective ATP competitive inhibitor of both isoforms of GSK‐3. In vitro, LY potently inhibits the enzymatic activity of GSK‐3α and GSK‐3β with IC50s of 1.5 nM and 0.9 nM, respectively. Pharmacologic activity of other GSK‐3 inhibitors in the literature against cancer is not clear. LY‐GSK‐3i did not evidence useful antitumor activity in its own right against colorectal, ovarian or non‐small cell lung (NSCL) tumor lines. However, when combined with different chemotherapeutic agents, LY was found to potentiate their pro‐apoptotic activity. LY‐GSK‐3i was shown to significantly potentiate caspase‐3 activation when combined cisplatin in HCT‐116 and Colo‐205 colorectal carcinoma lines. Enhancement of caspase‐3 activity was also observed when LY‐GSK‐3i was combined with 5‐fluorouracyl (5‐FU) in HCT‐116 cells. In order to explore the potential of LY‐GSK‐3i in other tumor types, we assessed the pro‐apoptotic activity of the LY/cisplatin combination against ovarian (A2780) and lung (A549 and NCI‐H460) cell lines. In all cases, LY‐GSK‐3i was shown to significantly elevate caspase‐3 activity when compared to cisplatin alone. In vivo, administration of a single dose of LY‐GSK‐3i to xenograft‐bearing mice lead to a time‐and dose‐dependent accumulation of the substrate protein ‐catenin in tumor tissues. In vivo xenograft growth studies revealed that administration of 5 mg/kg LY‐GSK‐3i in combination with cisplatin, given every 7 or 14 days, was sufficient to significantly improve the efficacy as compared to cisplatin alone given at the same intervals. Together, our findings provide evidence for the potential therapeutic utility of GSK‐3 inhibitors for the treatment of cancer. Citation Information: Mol Cancer Ther 2009;8(12 Suppl):C211.