Effects of Fremanezumab on Medication Overuse in Japanese Chronic Migraine Patients: Post Hoc Analysis of a Multicenter, Randomized, Double-Blind, Placebo-Controlled Trial.

INTRODUCTION: Chronic migraine (CM) patients commonly take acute headache medications, often resulting in medication overuse (MO). This post hoc analysis evaluated the efficacy of fremanezumab in CM patients from Japan with and without MO, which is not yet established. METHODS: A multicenter, double-blind, parallel-group, phase 2b/3 trial randomized patients (1:1:1) to monthly fremanezumab via subcutaneous injection (initial dose: 675 mg, second/third doses: 225 mg), quarterly fremanezumab (initial dose: 675 mg, second/third doses: placebo), or placebo for 3 months. This post hoc analysis analyzed data from Japanese patients with and without MO (monthly use of acute headache medication ≥ 15 days, migraine-specific acute medication ≥ 10 days, or combination medication ≥ 10 days). Outcomes included the original primary endpoint of average headache days of moderate or greater severity per month (HDs), the proportion of patients with ≥ 50% reduction in HDs and the proportion of patients changing status from with to without MO. RESULTS: Of 479 patients enrolled, 320 (66.8%) had baseline MO. Monthly average HDs were significantly reduced versus placebo with fremanezumab in both patients with MO (mean [standard error] difference vs. placebo: monthly - 2.0 [0.6], p = 0.0012; quarterly - 1.8 [0.6], p = 0.0042) and without MO (- 1.6 [0.8], p = 0.0437; - 1.5 [0.8], p = 0.0441). Significantly more fremanezumab-treated patients with MO (monthly 28/108 [25.9%], p = 0.0040 quarterly 25/99 [25.3%], p = 0.0070) or without MO (18/50 [36.0%], p = 0.0132; and 21/60 [35.0%], p = 0.0126) had ≥ 50% reduction in HDs versus placebo (12/111 [10.8%] and 7/49 [14.3%], respectively). A significantly greater proportion of fremanezumab-treated patients reverted to no MO (monthly 50/108 [46.3%], p = 0.0115; quarterly 44/99 [44.4%], p = 0.0272) vs. placebo (33/111 [29.7%]). CONCLUSION: Fremanezumab appears effective as preventive migraine treatment in Japanese CM patients with or without MO while also being beneficial in reducing MO.

Improved quality of life with fremanezumab in Japanese and Korean patients with episodic and chronic migraine: Results of two multicenter, randomized, double-blind, placebo-controlled, parallel-group clinical trials.

OBJECTIVE: To evaluate quality of life (QoL) endpoints from two 12-week trials investigating fremanezumab efficacy and safety in Japanese/Korean patients with chronic (CM) or episodic (EM) migraine. BACKGROUND: Migraine is a leading cause of disability and affects QoL considerably, interfering with work and daily activities, social and family life, and emotional wellbeing. METHODS: This planned exploratory analysis used data from two multicenter, randomized, double-blind, placebo-controlled, parallel-group studies in which Migraine-Specific QoL (MSQoL; Role Function-Restrictive [RR], Role Function-Preventive [RP], and Emotional Function [EF] domains) scores and Patient Global Impression of Change (PGIC) scores were pre-specified QoL outcomes in individuals receiving monthly or quarterly fremanezumab or placebo. In both trials, MSQoL was assessed at baseline, and MSQoL and PGIC at Weeks 4, 8, and 12. PGIC responders had a score of ≥5 points, indicating significant improvement. RESULTS: Mean baseline MSQoL scores were similar across groups in both CM (N = 565; RR, 60.3-61.5; RP, 78.5-80.0; EF, 69.0-71.4) and EM (N = 353; RR, 68.6-71.1; RP, 83.1-85.7; EF, 76.7-81.9) trials. In the CM trial, all three MSQoL domains improved in both fremanezumab groups at 12 weeks compared with placebo: least squares mean (LSM) and standard error (SE) change from baseline, p versus placebo (quarterly; monthly; placebo): RR 14.9 (1.3), p = 0.030; 15.1 (1.4), p = 0.020; 11.6 (1.3); RP 8.9 (1.1), p = 0.007; 8.6 (1.1), p = 0.013; 5.4 (1.1); EF 13.3 (1.5), p < 0.001; 12.5 (1.5), p = 0.003; 7.5 (1.5). In the EM trial, RR/EF domains improved in both fremanezumab groups compared with placebo: LSM change from baseline, p versus placebo (quarterly; monthly; placebo): RR 16.3 (1.4), p = 0.003; 16.4 (1.3), p = 0.002; 11.6 (1.4); EF 13.0 (1.3), p < 0.001; 11.5 (1.2), p = 0.004; 7.4 (1.3); RP improved in the quarterly group RP 8.6 (1.1), p = 0.010; 7.6 (1.1), p = 0.066; 5.4 (1.1). The proportion of PGIC responders at Week 12 was greater in the monthly and quarterly fremanezumab groups compared with the placebo group in the CM (96/182 [52.7%] and 98/180 [54.4%] vs. 68/179 [38.0%]; p < 0.05) and EM trial (81/118 [68.6%] and 86/113 [76.1%] vs. 38/111 [34.2%]; p < 0.001). CONCLUSION: Patients with EM/CM receiving monthly or quarterly fremanezumab, for a duration of 12 weeks, showed significant improvements in their QoL.

Fremanezumab for Episodic Migraine Prevention in Japanese Patients: Subgroup Analysis from Two International Trials.

Purpose: The monoclonal antibody fremanezumab has been shown effective and well tolerated in numerous Phase 2 and Phase 3 trials. This subgroup analysis of the international HALO episodic migraine (EM; [NCT02629861]) trial and a similarly designed phase 2b/3 trial in Japanese and Korean patients (NCT03303092) sought to evaluate the efficacy and safety of fremanezumab in Japanese patients with EM. Patients and Methods: In both trials, eligible patients were randomly assigned at baseline to receive subcutaneous monthly fremanezumab, quarterly fremanezumab, or placebo in a 1:1:1 ratio. The primary endpoint was the mean change from baseline in the monthly (28-day) average number of migraine days during the 12-week period after the first dose of fremanezumab or placebo. Secondary endpoints assessed other aspects of efficacy, including disability and medication use. Results: A total of 301 patients in the Japanese and Korean phase 2b/3 trial and 75 patients in the HALO EM trial were Japanese with baseline and treatment characteristics similar between treatment groups. According to ANCOVA analysis of the primary endpoint, both fremanezumab quarterly and monthly led to greater reductions in the monthly (28-day) average number of migraine days than placebo. This was supported by MMRM analysis of the primary endpoint over the initial 4 weeks, highlighting the rapid onset of action of fremanezumab. Results of secondary endpoint analysis supported the primary endpoint analyses. Fremanezumab was well tolerated with no new safety signals seen in this population of Japanese patients. Conclusion: Fremanezumab appears to be an effective and well-tolerated preventive medication for Japanese patients with EM.

Fremanezumab for Chronic Migraine Prevention in Japanese Patients: Subgroup Analysis from Two International Trials.

Purpose: Fremanezumab monoclonal antibody therapy has demonstrated efficacy for chronic migraine (CM) with rapid onset and good tolerability. This subgroup analysis of two clinical trials (Japanese and Korean CM Phase 2b/3 [NCT03303079] and HALO CM Phase 3 [NCT02621931]) aimed to evaluate the efficacy and safety of fremanezumab in Japanese patients. Patients and Methods: Both trials randomly assigned eligible patients at baseline (1:1:1 ratio) to subcutaneous monthly fremanezumab, quarterly fremanezumab, or placebo at 4-week intervals. The primary endpoint was the mean change from baseline in the monthly (28-day) average number of headache days of at least moderate severity during the 12-week period after the first dose of study medication (analyzed by ANCOVA over 12 weeks and MMRM over initial 4 weeks). Secondary endpoints examined other aspects of efficacy, including medication use and disability. Results: A total of 479 and 109 patients were Japanese in the Japanese and Korean CM Phase 2b/3 and HALO CM trials, respectively. Baseline and treatment characteristics were generally similar between treatment groups for both trials. Results of subgroup analyses for the primary endpoint according to ANCOVA demonstrated the superiority of fremanezumab over placebo in Japanese patients (quarterly fremanezumab, p=0.0005; monthly fremanezumab, p=0.0002 in both trials). Results using the MMRM analysis confirmed the rapid onset of action in this population. Results of the secondary endpoints further supported the efficacy of fremanezumab in Japanese patients. Fremanezumab was well tolerated with nasopharyngitis and injection-site reactions representing the most common adverse events in all treatment groups. Conclusion: Despite the limitations of subgroup analyses, these consistent results confirm the efficacy and tolerability of fremanezumab in Japanese patients with CM.

A multicenter, open-label, phase 3 study to evaluate the safety of fremanezumab for migraine, subcutaneously self-administered with an auto-injection device at institutional sites and at home.

BACKGROUND: Fremanezumab is a humanized monoclonal antibody against calcitonin gene-related peptide for subcutaneous use to suppress migraine attacks. A phase 3 study was conducted to investigate the safety of autoinjector (AI)-assisted self-injection of fremanezumab 225 mg. RESEARCH DESIGN AND METHODS: The multicenter, open-label study involving 71 patients with migraine was conducted between June 2020 and November 2020 at ten institutions in Japan. The study consisted of a 4-week (28-day) screening period and an 8-week (57-day) treatment period. According to the investigator's instructions, all patients successfully performed self-injection for 4 weeks at the institutional site and at home and maintained eDiaries of their headaches. The primary endpoint was safety of the drug based on treatment-emergent adverse events (TEAEs). RESULTS: Treatment-emergent adverse events were more frequent after at-home injection than after at-site injection, but they were mainly injection site reactions and mostly mild. The safety profile was comparable, raising no concerns compared with what has been reported in previous studies. Both migraine days and headache days were decreased considerably. CONCLUSIONS: Overall, AI-assisted, at-home self-injection of fremanezumab was found to be generally safe and well-tolerated. This injection strategy is considered clinically meaningful in view of improved utility of and adherence to the drug.

Early onset of efficacy with fremanezumab in patients with episodic and chronic migraine: subanalysis of two phase 2b/3 trials in Japanese and Korean patients.

BACKGROUND: Early onset of action has become recognized as an important efficacy feature of preventive migraine treatment, which can help overcome adherence issues commonly associated with older medications. Preventive treatments that target the calcitonin gene-related peptide (CGRP) or the CGRP receptor have been previously shown to provide early onset of action. METHODS: This subanalysis of primary endpoints of two separate phase 2b/3 studies sought to determine the onset of action of fremanezumab in Japanese and Korean patients with episodic migraine (EM) and chronic migraine (CM). RESULTS: In EM patients (n = 357), both fremanezumab quarterly and fremanezumab monthly led to greater reductions in weekly migraine days (days/week) than placebo from the first week after the initial injection and thereafter during the remainder of the study period. Similarly, CM patients (n = 571) had a greater reduction in headache days of at least moderate severity (days/week) with fremanezumab (total) than placebo. The percentage of patients with a migraine day (EM) or headache day at least moderate severity (CM) was lower in those treated with fremanezumab than placebo and this effect was apparent from as early as Day 2 (1 day after first injection). CONCLUSIONS: These results suggest that fremanezumab has an early onset of action, as noted in previous post hoc analyses of anti-CGRP monoclonal antibodies. TRIAL REGISTRATION: ClinicalTrials.gov. NCT03303092 , Registered 5 October 2017, NCT03303079 , Registered 5 October 2017.

Increased hippocampal quinone reductase 2 in Alzheimer's disease.

Quinone reductase 2 (QR2), a detoxifying cytosolic flavoenzyme, is thought to play an important role in the acquisition and loss of memory. We determined the amount of QR2 in the hippocampus, amygdala, and superior frontal gyrus of Alzheimer's disease (AD) patients with dementia by using western blot analysis. The level of QR2 was significantly higher in the hippocampus of AD patients than in that of the control subjects. The relation between QR2 and AD has not yet been determined; however, our results suggest that the increase in hippocampal QR2 might be a cause of AD or might promote the progression of AD by causing an increase in the toxic quinone levels and consequent loss of cognitive function.

[Bacterial contamination of mobile phones shared in hospital wards and the consciousness and behavior of nurses about biological cleanliness].

OBJECTIVES: The purpose of this study was to clarify the contamination of mobile phones shared in hospital wards and its relationship with the consciousness and behavior of nurses about biological cleanliness. METHODS: Samples from mobile phones were cultured to detect viable bacteria (n=110) and Staphylococcus aureus (n=54). A questionnaire survey was conducted on 110 nurses carrying mobile phones on the day of sampling. RESULTS: Viable bacteria were detected on 79.1% of the mobile phones, whereas S. aureus was detected on 68.6%. All the nurses were aware of hand washing with water or alcohol after regular work, but 33.6% of the nurses were not conscious of hand washing with water or alcohol after using a mobile phone. There was a significant positive relationship between the frequency of using mobile phones and the number of hand washings with water or alcohol. A significant negative relationship was found between the detection of viable bacteria and the number of hand washings with alcohol. The results of logistic regression analysis showed that the detection of viable bacteria was related significantly with the number of hand washings with alcohol (Odds ratio, 0.350; 95%CI, 0.143-0.857) and that the detection of S. aureus was related significantly with the frequency of using mobile phones (Odds ratio, 0.183; 95%CI, 0.036-0.933). CONCLUSIONS: It is important to be conscious of the fact that mobile phones shared in hospital wards are easily contaminated. Because hand washing with water or alcohol prevents the contamination of the mobile phones, nurses should take standard precautions after using mobile phones.

Age-related severity of dopaminergic neurodegeneration to MPTP neurotoxicity causes motor dysfunction in C57BL/6 mice.

This study investigated the influence of advancing age on dopaminergic neuronal degeneration induced by 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) intoxication from the perspective concerning the relationship between dopaminergic function and behavioral features. Young (10 weeks) and older (14-15 months) C57BL/6 mice were treated with one to four injections of MPTP (20 mg/kg at 2h intervals). Although young mice showed no mortality in either MPTP treatment, older mice exhibited mortality from only two injections of MPTP during the experimental period. An extensive dopaminergic cell loss was found in both the striatum and substantia nigra of older mice given one and two injections of MPTP with marked decrease in striatal dopamine (DA) levels, but not young mice. We also found a behavioral change in the tail suspension test associated with the extent of decrease in striatal DA levels in MPTP-treated older mice, but not in young mice. These results clearly present age-related vulnerability to MPTP neurotoxicity in C57BL/6 mice and strongly support our previous report showing that there is a critical threshold level of the decrement in striatal DA contents causing motor dysfunction in this mouse model of Parkinson's disease.

H MRS identifies lactate rise in the striatum of MPTP-treated C57BL/6 mice.

Mitochondrial dysfunction has been implicated in the death of nigrostriatal dopaminergic neurons in 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-treated experimental models of Parkinson's disease (PD). Here we utilized proton magnetic resonance spectroscopy ((1)H MRS) to identify changes in energy metabolism in the striatum of MPTP-treated C57BL/6 mice. Remarkable increases in lactate/creatine (Lac/Cr) ratio were observed at 2 h and then quickly returned to about the basal level by 7 h after injection of MPTP. Neurochemical and Western blot analyses revealed that dopamine contents and protein levels of tyrosine hydroxylase and dopamine transporter in the striatum were profoundly decreased at 3 days after MPTP treatment. Pretreatment with deprenyl, a monoamine oxidase B inhibitor, or GBR-12909, a dopamine uptake inhibitor, almost completely attenuated both the increases in striatal Lac/Cr ratio and the subsequent loss of dopaminergic nerve terminals in MPTP-treated mice. The present study indicates that (1)H MRS is a sensitive measure of biochemical alterations of the brain in a mouse model of PD, and further shows that the increases in striatal Lac/Cr ratio induced by MPTP may be associated with mitochondrial energy crisis, followed by dopaminergic neurotoxicity.

Neural mechanisms underlying motor dysfunction as detected by the tail suspension test in MPTP-treated C57BL/6 mice.

Contradictory data on behavioral changes in MPTP-treated C57BL/6 mice have been reported, even though the toxin-treated mice have been widely used for non-clinical studies as an in vivo model of Parkinson's disease (PD). We found that the duration of immobility in the tail suspension test (TST) was significantly increased in MPTP-treated C57BL/6 mice as compared with control mice without a significant change in the locomotor activity (LA). Dopamine (DA) contents and protein levels of tyrosine hydroxylase and dopamine transporter in the striatum were profoundly decreased in the toxin-treated mice. These behavioral and neurobiochemical changes were almost completely inhibited by a pretreatment with deprenyl, a monoamine oxidase-B inhibitor. The stimulation of dopaminergic neurotransmission induced by L-dopa or a dopamine D2 receptor agonist ameliorated the increase in immobility time. Threshold level of striatal DA that produced the increase in immobility time in MPTP-treated mice was estimated to be between 11 and 27% of control level. We concluded that the increase in immobility time in the TST was induced by the nigrostriatal dopaminergic degeneration and was thought to be a consequence of motor dysfunction in this mouse model of PD.

Differential effects of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine in the olfactory bulb and the striatum in mice.

The present study was undertaken to examine whether 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) causes damage of dopaminergic glomerular cells of the olfactory bulb (OB) in C57BL/6 mice. At 3 days after MPTP treatment, dopamine level in the striatum and the OB decreased to 13% and 84% of the control mice, respectively. While a small reduction of tyrosine hydroxylase protein level was observed in the OB of MPTP-treated mice, dopamine transporter (DAT) was undetectable at the protein level in this region. These results indicate that the DAT protein level could account for resistance of the OB to the Parkinsonism-inducing toxin.

Diminished catalepsy and dopamine metabolism distinguish aripiprazole from haloperidol or risperidone.

Catalepsy and changes in striatal and limbic dopamine metabolism were investigated in mice after oral administration of aripiprazole, haloperidol, and risperidone. Catalepsy duration decreased with chronic (21 day) aripiprazole compared with acute (single dose) treatment across a wide dose range, whereas catalepsy duration persisted with chronic haloperidol treatment. At the time of maximal catalepsy, acute aripiprazole did not alter neostriatal dopamine metabolite/dopamine ratios or homovanillic acid (HVA) levels, and produced small increases in dihydroxyphenylacetic acid (DOPAC). Effects were similar in the olfactory tubercle. Dopamine metabolism was essentially unchanged in both regions after chronic aripiprazole. Acute treatments with haloperidol or risperidone elevated DOPAC, HVA, and metabolite/dopamine ratios in both brain areas and these remained elevated with chronic treatment. The subtle effects of aripiprazole on striatal and limbic dopamine metabolism, and the decrease in catalepsy with chronic administration, illustrate fundamental differences in dopamine neurochemical actions and behavioral sequelae of aripiprazole compared to haloperidol or risperidone.

1-methyl-4-phenylpyridinium (MPP+) decreases mitochondrial oxidation-reduction (REDOX) activity and membrane potential (Deltapsi(m)) in rat striatum.

Mitochondrial dysfunction has long been implicated in the death of nigrostriatal dopaminergic neurons in Parkinson's disease (PD) and its experimental models. Here we further analyzed changes in the mitochondrial oxidation-reduction (REDOX) activity and membrane potential (Deltapsi(m)) of striatal synaptosomes after the infusion of 1-methyl-4-phenylpyridinium (MPP+) into rat striatum. MPP+ (40 nmol) treatment produced decreases in mitochondrial REDOX activity and Deltapsi(m) at 18 h, as measured by fluorometric analysis with both Alamar blue and JC-1 (5,5',6,6'-tetrachloro-1,1',3,3'-tetraethylbenzimidazolyl-carbocyanine iodide) dyes. At this time point, tyrosine hydroxylase (TH) and dopamine transporter (DAT) protein levels were not altered, but both decreased at 7 days after MPP+ (40 nmol) infusion. Both measures of mitochondrial dysfunction induced by MPP+ (40 nmol) at 18 h were attenuated, at least in part, by pretreatment with a selective dopamine uptake inhibitor GBR-12909 (1-(2-(bis(4-fluorophenyl)methoxy)ethyl)-4-(3-phenylpropyl) piperazine). In addition, GBR-12909 partially attenuated MPP+ (40 nmol)-caused a loss of striatal nerve terminal as indicated by decreases in TH and DAT immunoreactivities as well as dopamine and its metabolites levels. The present study indicates that decreases in mitochondrial REDOX activity and Deltapsi(m) may play a role in MPP+ -induced dopaminergic neurotoxicity, and further provides that improvement of mitochondrial dysfunction may be a better way to slow progressive dopaminergic neurodegeneration commonly associated with PD.

Attenuation of scopolamine-induced and age-associated memory impairments by the sigma and 5-hydroxytryptamine(1A) receptor agonist OPC-14523 (1-[3-[4-(3-chlorophenyl)-1-piperazinyl]propyl]-5-methoxy-3,4-dihydro-2[1H]-quinolinone monomethanesulfonate).

Sigma and 5-HT(1A) receptor stimulation can increase acetylcholine (ACh) release in the brain. Because ACh release facilitates learning and memory, we evaluated the degree to which OPC-14523 (1-[3-[4-(3-chlorophenyl)-1-piperazinyl]propyl]-5-methoxy-3,4-dihydro-2[1H]-quinolinone monomethane sulfonate), a novel sigma and 5-HT(1A) receptor agonist, can augment ACh release and improve learning impairments in rats due to cholinergic- or age-related deficits. Single oral administration of OPC-14523 improved scopolamine-induced learning impairments in the passive-avoidance task and memory impairment in the Morris water maze. The chronic oral administration of OPC-14523 attenuated age-associated impairments of learning acquisition in the water maze and in the conditioned active-avoidance response test. OPC-14523 did not alter basal locomotion or inhibit acetylcholinesterase (AChE) activity at concentrations up to 100 microM and, unlike AChE inhibitors, did not cause peripheral cholinomimetic responses. ACh release in the dorsal hippocampus of freely moving rats increased after oral delivery of OPC-14523 and after local delivery of OPC-14523 into the hippocampus. The increases in hippocampal ACh release were blocked by the sigma receptor antagonist NE-100 (N,N-dipropyl-2-[4-methoxy-3-(2-phenylethoxy)-phenyl]-ethylamine). Thus, OPC-14523 improves scopolamine-induced and age-associated learning and memory impairments by enhancing ACh release, due to a stimulation of sigma and probably 5-HT(1A) receptors. Combined sigma/5-HT(1A) receptor agonism may be a novel approach to ameliorate cognitive disorders associated with age-associated cholinergic deficits.