BackgroundZervimesine (CT1812) is a first-in-class, brain-penetrant sigma-2 receptor ligand that prevents binding and displaces Aβ42 oligomers from receptors on neuronal synapses.ObjectiveThis study evaluated the safety and efficacy of zervimesine in mild to moderate Alzheimer's disease (AD).MethodsThis was a Phase 2, randomized, double-blind, placebo-controlled study. Participants were randomized to zervimesine 100 mg or 300 mg or placebo. In addition to ADAS-Cog11, outcomes were evaluated from baseline plasma p-tau217 in prespecified subgroups.ResultsOf 153 adults randomized, 150 were included in the mITT population. Adverse events occurred in 70.6% with zervimesine 100 mg, 82.4% with zervimesine 300 mg, and 78.0% with placebo. At Day 182, the ADAS-Cog 11 increased from baseline (indicating a decline in cognitive function) with the LS mean (SE) change of 2.69 (0.81) points in the placebo group versus 1.66 (0.60) points in the pooled zervimesine group [δ = -1.03 (-3.01, 0.96), p = 0.310]. For participants with baseline plasma p-tau217 levels below the median (1.0 pg/mL), the pooled zervimesine group showed greater improvement on the ADAS-Cog 11 at Day 182 relative to placebo (δ = -2.66; p = 0.080).ConclusionsThis phase 2 study indicated that zervimesine was safe and well tolerated and showed consistently favorable numerical treatment differences versus placebo. More robust treatment differences were observed in the below median baseline plasma p-tau217 group suggesting potentially greater efficacy of zervimesine in less advanced AD. These results support larger pivotal trials with zervimesine.Registered at clinicaltrials.gov: NCT03507790.

NCT03522129 https:// clini caltr ials.gov/ ct2/ show/ NCT03 522129.Investigational therapies for Alzheimer's disease (AD) target a wide range of mechanisms, yet promising disease-modifying therapies remain a huge unmet need.Much evidence indicates that the oligomeric form of amyloid-beta (Aβ) is a toxic species contributing to AD through synaptic damage and neuronal toxicity [1].In support of this, Aβ oligomer reduction in an AD mouse model leads to memory preservation [2, 3], and clinical benefit was observed in trials of lecanemab, which targets Aβ oligomers and protofibrils [4], in AD patients, encouraging the continued development of Aβ oligomertargeting therapies.CT1812 is a novel, small-molecule, brain-penetrant sigma-2 receptor (S2R) modulator that selectively prevents and displaces Aβ oligomers from binding to neuronal synapses, thereby mitigating downstream toxicity.This is thought to occur through allosteric modulation

AbstractBackgroundElayta (CT1812) is a novel allosteric antagonist of the sigma‐2 receptor complex that prevents and displaces binding of Aβ oligomers to neurons. By stopping a key initiating event in Alzheimer's disease, this first‐in–class drug candidate mitigates downstream synaptotoxicity and restores cognitive function in aged transgenic mouse models of Alzheimer's disease.MethodsA phase 1, two‐part single and multiple ascending dose study was conducted in 7 and 4 cohorts of healthy human subjects, respectively. In part A, healthy, young subjects (<65 years old) received CT1812 doses ranging from 10 to 1120 mg (6:2 active to placebo [A:P] per cohort). In part B, subjects were administered 280, 560, and 840 mg once daily for 14 days (8:2 A:P per cohort). An elderly cohort, aged 65‐75 years, was dosed at 560 mg once daily for 14 days (7:2 A:P). Serum concentrations of CT1812 in part B were measured on day 3 and 14 and cerebrospinal fluid concentrations on day 7 or 9. Cognitive testing was performed in the healthy elderly cohort at baseline and at day 14 of treatment.ResultsTreatment with CT1812 was well tolerated in all cohorts. Adverse events were mild to moderate in severity and included headache and GI tract symptoms. Plasma concentrations of drug were dose proportional across two orders of magnitude with minimal accumulation over 14 days. Cognitive scores in the healthy elderly cohort were similar before and after treatment.ConclusionsCT1812 was well tolerated with single dose administration up to 1120 mg and with multiple dose administration up to 840 mg and 560 mg in healthy young and healthy elderly subjects, respectively. CT1812 is currently being studied in early phase 2 trials in patients with Alzheimer's disease.

CT1812 is a novel, clinical stage, experimental Alzheimer's therapeutic that displaces Abeta oligomers from their receptors to protect and restore synapses. By binding to the sigma-2 receptor complex, CT1812 allosterically modulates the oligomer receptor complex, destabilizing its binding site and increasing the off-rate of oligomers from neurons. Displaced oligomers are measured in interstitial and cerebrospinal fluid. This displacement reduces the oligomer-induced toxic effects and results in normalized synapse function and improved cognitive deficits in transgenic mouse AD models. CT1812 demonstrated a favorable clinical safety profile in healthy volunteers. A 28 day, multicenter, double-blind, placebo-controlled trial was performed with once daily CT1812 (90, 280 or 560 mg) or placebo (N = 4 or 5 group) p.o.to AD patients (MMSE 18-26). Patients were followed for safety. Plasma and CSF protein, lipid and metabolite values were measured at baseline and 28 days via ELISA or tandem mass spectroscopy. CSF Abeta oligomer concentrations were increased at day 28 relative to baseline in CT1812-treated compared with placebo-treated patients. Concentrations of 30 CSF proteins and 91 plasma proteins and lipids known to be dysregulated in AD changed in a therapeutic direction in CT1812-treated vs. placebo-treated patients. Synaptic protein fragments neurogranin and synaptotagmin were decreased in CSF at day 28 relative to baseline in CT1812-treated compared to the placebo group. AEs were similar between placebo and CT1812 in the 90 and 280mg dose groups. Sporadic elevations in liver enzymes and lymphopenia were observed at 560mg. These clinical data support CT1812’s mechanism of action of displacing Abeta oligomers, and provide evidence of target engagement, reduction of synaptic damage, and disease-modification. Ongoing trials include PET assessment of synaptic density, measures of synapse damage markers, and cognitive assessments.

CT1812 is a first in class therapeutic currently in Phase 1/2 testing in AD patients (ClinicalTrials.gov Identifier: NCT02907567) that selectively displaces Aβ oligomers from synaptic receptor sites and clears them from the brain into the cerebrospinal fluid, restoring cognitive performance to normal in aged transgenic mouse models of AD. In prior clinical studies, CT1812 was safe and well tolerated with multiple doses up to 560 mg in healthy elderly volunteers. CSF concentrations observed with multiple dosing of CT1812 indicate that they exceed the expected minimum target concentrations needed to improve memory in AD patients. To further the clinical development of CT1812 a study was conducted to evaluate potential drug-drug interactions of CT1812 involving effects on cytochrome P450 (CYP) isoenzymes. A Phase 1, single-center, open-label, single-sequence drug-drug interaction study was performed to evaluate the effect CT1812 on the pharmacokinetics of 4 CYP probe drugs (tolbutamide, midazolam, dextromethorphan and omeprazole) given before and following administration of 6 consecutive daily oral doses of 560 mg CT1812 (steady state). Small increases (<2 fold) in dextromethorphan and dextrorphan exposure were observed after co-administration of dextromethorphan with steady-state CT1812, consistent with a weak inhibitory interaction of CT1812 on the CYP2D6 enzyme. Small decreases (<50%) in midazolam exposure were observed after co-administration of midazolam with steady-state CT1812, consistent with weak induction of the CYP3A4 enzyme by CT1812. There were no clinically meaningful interactions between CT1812 and omeprazole (CYP2C19) or tolbutamide (CYP2C9). Based on the weak drug-drug interactions observed in this study between steady-state CT1812 and standard CYP probe drugs, clinically meaningful implications are unlikely. These results permit fewer medication exclusions in AD current and future clinical trials including the planned Phase 2 trial in mild to moderate AD.

CT1812 is a novel Aβ oligomer receptor antagonist and the only therapeutic demonstrated to prevent and displace binding of Abeta oligomers to receptors on neurons. By stopping the initiating event in the oligomer cascade, this first-in–class drug candidate blocks downstream synaptotoxicity and restores memory to normal in aged transgenic mouse models of AD (Izzo et al., 2014a, b). CT1812 was administered to healthy volunteers to assess its safety, tolerability and pharmacokinetics. In the single ascending dose part, six cohorts of 6 CT1812-treated and 2 placebo-treated volunteers aged 18-50 were administered doses ranging from 10-1120 mg. In the multiple ascending dose part, three cohorts of eight CT1812-treated and two placebo-treated volunteers were dosed at 280, 560 and 840 mg once daily for 14 days. CSF trough levels of CT1812 were measured prior to dosing in the 280 and 560 mg dose groups after subjects were dosed on multiple days. An older cohort, aged 65-75, was also dosed at 560 mg once daily for 14 days. Adverse events were mild to moderate in severity and mainly included headache and GI tract symptoms. Plasma concentrations of drug were dose proportional across two orders of magnitude with no evidence of accumulation over 14 days. At the 560 mg dose, CSF levels of CT1812 correspond to estimated brain concentrations equivalent to 95% receptor occupancy. In healthy volunteers, CT1812 was well tolerated with single doses up to 1120 mg and with multiple doses up to 840 mg in healthy young volunteers and 560 mg in healthy elderly volunteers. Multiple dose exposure of CT1812 corresponded to more than 20x the expected minimum therapeutic dose while CSF analysis indicated that brain concentrations exceeded the minimum target expected to improve memory (>80% receptor occupancy). CT1812 is designed to directly test the oligomer hypothesis of AD treatment. Further development will test the ability of CT1812 to improve cognitive ability in AD patients.

The treatment of hyperlipidaemia in human immunodeficiency virus (HIV)-infected patients has become increasingly important. However, treatment options are limited because of the drug–drug interaction between certain statins and HIV medications metabolized by cytochrome P450 (CYP) enzymes.

Dr. Sponseller is an employee of Kowa Pharmaceuticals America, Inc.

Purpose: Results from a Phase III, European, non-inferiority trial in elderly (age >= 65 years) patients with primary hyperlipidemia or mixed (combined) dyslipidemia demonstrated significantly greater reductions in LDL-C for pitavastatin versus pravastatin across 3 pair-wise dose comparisons (1 mg vs 10 mg, 2 mg vs 20 mg, and 4 mg vs 40 mg, respectively). The present study investigated whether pitavastatin 4 mg is superior to pravastatin 40 mg in LDL-C reduction in adults (18-80 years old) with primary hyperlipidemia or mixed (combined) dyslipidemia.Methods: This was a Phase IV, multicenter, randomized, double-blind, double-dummy, active-control superiority study conducted in the United States. Patients with baseline LDL-C levels of 130 to 220 mg/dL (inclusive) and triglyceride levels <= 400 mg/dL after a 6-week washout/dietary stabilization period were randomized to 12 weeks of once-daily treatment with either pitavastatin 4 mg or pravastatin 40 mg.Findings: A total of 328 subjects (164 per treatment arm) were randomized (mean age, 57.9 years [76% were aged <65 years]; 49.4% women; mean body mass index, 30.2 kg/m(2)) to treatment. The median percent change in LDL-C from baseline to the week 12 endpoint was -38.1% for pitavastatin 4 mg and -26.4% for pravastatin 40 mg; the difference in median percent change between treatments was -12.5% (P < 0.001). Differences between treatments in median percent reductions from baseline for apolipoprotein B, total cholesterol, and non-HDL-C were also significant in favor of pitavastatin (P < 0.001). Both treatments significantly (P < 0.001) increased HDL-C and decreased triglycerides, but the differences between treatments were not statistically significant. The overall rate of treatment-emergent adverse events was 47.6% (78 of 164) for pitavastatin and 44.5% (73 of 164) for pravastatin. Myalgia was reported by 3 patients (1.8%) in the pitavastatin group and by 4 patients (2.4%) in the pravastatin group. There were no reports of myositis or rhabdomyolysis.Implications: Pitavastatin 4 mg demonstrated superior LDL-C reductions compared with pravastatin 40 mg after 12 weeks of therapy in adults with primary hyperlipidemia or mixed (combined) dyslipidemia. There were no new safety findings in the trial. Clinical Trials.gov identifier: NCT01256476. (C) 2014 Published by Elsevier HS Journals, Inc.

Dr. Sponseller is an employee of Kowa Pharmaceuticals America.

Abstract Objective: Statins have been shown to impact international normalized ratio (INR) when coadministered with warfarin. The aim of this study was to assess the effect of pitavastatin compared with rosuvastatin on steady-state pharmacodynamics (PD) of warfarin by measuring INR in healthy adult subjects. Methods: Subjects received oral doses of warfarin 5 mg once daily on days 1 through 3. The dose was titrated on days 4 through 9 to reach a steady-state INR of 1.5 to 2.2. Warfarin was continued on days 10 through 21 and pitavastatin 4 mg or rosuvastatin 40 mg was administered once daily on days 14 through 22. After a 14-day washout period, the process was repeated with the alternate statin. Study number: NK-104-4.03US. Results: For pitavastatin, mean INR changed from 1.73 ± 0.18 (n = 42) on day 14 before starting statin dosing, to 1.78 ± 0.29 (n = 42) on day 22 at treatment end; the difference in INR was not significant (p = 0.219). For rosuvastatin, mean INR increased significantly from 1.74 ± 0.20 (n = 43) at baseline to 1.90 ± 0.30 (n = 43) at treatment end (p < 0.001). Rosuvastatin caused a significantly greater increase in INR than pitavastatin (p < 0.001). Conclusion: Steady-state INR during warfarin treatment did not change significantly when pitavastatin 4 mg was added to the regimen, while a significant increase was observed when rosuvastatin 40 mg was added. The effect of rosuvastatin on INR was significantly larger than the effect of pitavastatin. This study is limited because it was done in healthy volunteers. Further studies in patient populations are needed to better understand the clinical significance of the results.

Pitavastatin (2 mg and 4 mg) has demonstrated significantly greater reduction of low-density lipoprotein cholesterol (LDL-C) versus pravastatin (20 mg and 40 mg) and comparable reductions versus atorvastatin (10 mg and 20 mg) and simvastatin (20 mg and 40 mg) in Phase III, noninferiority trials. However, with respect to effect on lipoprotein particles, limited data exist to date on pitavastatin.

OBJECTIVES:Pitavastatin, a statin recently approved in the United States, has a potential benefit of reduced risk of cytochrome P450 (CYP)-mediated drug-drug interaction due to minimal metabolism by the CYP system. The primary objective was to investigate pharmacokinetic (PK) effects of lopinavir/ritonavir 400 mg/100 mg twice daily on pitavastatin 4 mg when coadministered. DESIGN:This was an open-label one-arm study. METHOD:Pitavastatin 4 mg was administered once daily (days 1-5 and days 20-24). Lopinavir/ritonavir 400 mg/100 mg was administered twice daily (days 9-24). Plasma samples for PK assessments were collected on days 5, 19, and 24. Plasma concentrations of analytes were determined by liquid chromatography with tandem mass spectrometric detection methods. RESULTS:PK data were available for 23 of 24 subjects enrolled. For pitavastatin, area under the concentration time curve (AUC0-τ) and maximum concentration (C(max)) were 136.8 ± 52.9 ng·h(-1)·mL(-1) and 58.6 ± 30.4 ng/mL, respectively, when given alone, versus 113.9 ± 53.8 ng·h(-1)·mL(-1) and 58.2 ± 32.7 ng/mL when combined with lopinavir/ritonavir. The geometric mean ratio for AUC(0-τ) for pitavastatin with lopinavir/ritonavir versus pitavastatin alone was 80.0 (90% confidence interval: 73.4 to 87.3) and C(max) was 96.1 (90% confidence interval: 83.6 to 110.4). Median T(max) of pitavastatin was approximately 0.5 hours for both treatments. The PK effect of pitavastatin on lopinavir/ritonavir was minimal. No significant safety issues were reported. CONCLUSIONS:The effect on exposures when pitavastatin and lopinavir/ritonavir are coadministered was minimal. Concomitant use of pitavastatin and lopinavir/ritonavir was safe and well tolerated in healthy adult volunteers.

Recent studies showed that some statins may impair glucose metabolism. In a reanalysis of WOSCOPS, individual risk of diabetes with pravastatin was reported as null. Limited information is available on the glycemic effect of a recently approved statin, pitavastatin. The objective of this

Pitavastatin is a novel statin recently approved in the United States as an adjunctive therapy with diet to reduce elevated total cholesterol, low-density lipoprotein cholesterol, apolipoprotein B, and triglycerides and to increase high-density lipoprotein cholesterol. This open-label study enrolled 16 subjects as follows: group A: 8 adult subjects with severe renal impairment who were not on hemodialysis (estimated glomerular filtration rate of 15-29 mL/min/1.73 m2) and group B: 8 healthy adult subjects (estimated glomerular filtration rate ≥80 mL/min/1.73 m2). On day 1, the subjects received a single oral dose of pitavastatin 4 mg and remained in the clinic on days 1-3 for safety and pharmacokinetic assessments. Comparing group A with group B, the geometric mean ratio of AUC(0-inf) for pitavastatin was 1.36 (90% confidence interval, 0.88-2.11). For Cmax, the corresponding ratio was 1.18 (90% confidence interval, 0.68-2.02). There were no severe treatment-emergent adverse events (AEs), serious AEs, deaths, or treatment-emergent AEs leading to study drug discontinuation. A single dose of pitavastatin 4 mg was safe and well tolerated by the subjects in this study with severe renal impairment, who were not on hemodialysis.

In a Phase III, non-inferiority trial in elderly subjects (at least 65 years) with primary hyperlipidemia or mixed dyslipidemia, pitavastatin demonstrated significantly greater reductions in low-density lipoprotein cholesterol (LDL-C) compared with pravastatin across 3 pair-wise dose comparisons (1 mg vs. 10 mg, 2 mg vs. 20 mg, and 4 mg vs. 40 mg, respectively).

Background: Phosphodiesterase inhibitors have been shown to improve claudication-limited exercise performance in patients with peripheral artery disease. K-134, a novel phosphodiesterase inhibitor, was evaluated in a phase II trial incorporating an adaptive design to assess its safety, tolerability, and effect on treadmill walking time.Design: Patients with peripheral artery disease were randomized to receive placebo (n = 87), K-134 at a dose of 25 mg (n = 42), 50 mg (n = 85), or 100 mg (n = 84), or cilostazol at a dose of 100 mg (n = 89), each twice daily for 26 weeks. Peak walking time (PWT) was assessed using a graded treadmill protocol at baseline and after 14 and 26 weeks of treatment. A Data and Safety Monitoring Board-implemented adaptive design was used that allowed early discontinuation of unsafe or minimally informative K-134 arms.Results: As determined by the prospectively defined adaptive criteria, the 25-mg K-134 arm was discontinued after 42 individuals had been randomized to the arm. During the 26-week treatment period, PWT increased by 23%, 33%, 37%, and 46% in the placebo, 50-mg K-134, 100-mg K-134, and cilostazol arms, respectively (primary analysis placebo vs 100-mg K-134 arm not statistically significant, P = .089). Secondary analyses showed that cilostazol significantly increased PWT after 14 weeks of treatment and that the 100-mg K-134 dose and cilostazol both increased PWT vs placebo after 14 and 26 weeks in those individuals who completed the 26-week trial and were compliant with the study drug, or when the data were analyzed using a mixed-effects model incorporating all time points. K-134 had tolerability and adverse effect profiles similar to that of cilostazol. Both drugs were associated with an increase in withdrawals before study completion due to adverse events compared with placebo.Conclusions: K-134 was generally well tolerated. K-134 at a dose of 100 mg twice daily did not affect PWT according to the primary analysis, but K-134 and cilostazol both increased PWT when analyzed using a mixed-effects model and in the per-protocol population. (J Vase Surg 2012;55:381-9.)

Background: In peripheral artery disease (PAD), claudication limits exercise performance, functional status and quality of life. Phosphodiesterase III inhibitors improve claudication-limited exercise performance in patients with PAD. K-134, a novel phosphodiesterase III inhibitor, was evaluated in a phase II trial incorporating an adaptive design to assess safety, quality of life and peak walking time (PWT) on a graded treadmill with cilostazol as an active comparator. Design: Patients with PAD were randomized to receive placebo (N = 87), K-134 at a dose of 25 mg (N = 42), 50 mg (N = 85) or 100 mg (N = 84), or cilostazol at a dose of 100 mg (N = 89), each given twice daily for 26 weeks. A Data Safety Monitoring Board (DSMB) implemented adaptive design was used to allow early discontinuation of unsafe or minimally informative K-134 arms. Interim safety assessments at 2 weeks included dosing of study medication at the study site followed by measurements of postural vital signs and symptoms, and at 4 weeks with a treadmill test at peak drug concentration to evaluate for ischemia or arrhythmias. Results: Based on prospectively defined adaptive criteria, the 25 mg K-134 arm was discontinued as the 50 mg and 100 mg doses were adequately tolerated, had no unanticipated safety signals, and were thus most likely to be informative concerning K-134 in the target population. In the intention-to-treat cohorts at 26 weeks PWT increased by 37% in the 100 mg K-134 arm and 23% on placebo (primary analysis p = 0.089). Using a mixed effects analysis in the entire population, 100 mg K-134 and cilostazol were each superior to placebo in improving PWT. In the per protocol population both K-134 100 mg and cilostazol 100 mg increased PWT as compared with placebo at 14 and 26 weeks. K-134 had tolerability and adverse effect profiles similar to that of cilostazol, with gastrointestinal adverse events, headache and dizziness the most common. Both drugs were associated with an increase in withdrawals prior to study completion due to adverse events as compared with placebo. Conclusions: K-134 was generally well tolerated, and at a dose of 100 mg twice daily had a safety profile and effect on treadmill walking performance that was similar to that of cilostazol.