Oral rimegepant for preventive treatment of migraine: a phase 2/3, randomised, double-blind, placebo-controlled trial.

BACKGROUND: Rimegepant is a calcitonin gene-related peptide receptor antagonist that has shown efficacy and safety in the acute treatment of migraine. We aimed to compare the efficacy of rimegepant with placebo for preventive treatment of migraine. METHODS: We did a multicentre, phase 2/3, randomised, double-blind, placebo-controlled trial at 92 sites in the USA. Adults with at least a 1-year history of migraine were recruited. After a 4-week observation period, eligible participants were randomised using an interactive web response system to oral rimegepant 75 mg or matching placebo every other day for 12 weeks (double-blind treatment phase). The primary efficacy endpoint was change from the 4-week observation period in the mean number of migraine days per month in the last 4 weeks of the double-blind treatment phase (weeks 9-12). Participants who received at least one dose of their assigned study medication and who had 14 days or more of data in the observation period and 14 days or more of data for at least one 4-week interval during the double-blind treatment phase were analysed for efficacy. Those who received at least one dose of study medication were analysed for safety. This study is registered with ClinicalTrials.gov, NCT03732638. FINDINGS: Between Nov 14, 2018, and Aug 30, 2019, 1591 participants were recruited and assessed for eligibility, of whom 747 were randomly allocated either rimegepant (n=373) or placebo (n=374). 695 participants were included in the analysis for efficacy, of whom 348 were assigned rimegepant and 347 were allocated placebo. Rimegepant was superior to placebo on the primary endpoint of change in the mean number of migraine days per month during weeks 9-12. The change from the observation period in mean number of migraine days per month during weeks 9-12 was -4·3 days (95% CI -4·8 to -3·9) with rimegepant and -3·5 days (-4·0 to -3·0) with placebo (least squares mean difference -0·8 days, 95% CI -1·46 to -0·20; p=0·0099). 741 participants received study medication and were included in the safety analysis. 133 (36%) of 370 patients who received rimegepant reported an adverse event, compared with 133 (36%) of 371 who received placebo. Seven (2%) participants who received rimegepant and four (1%) who received placebo discontinued the study due to an adverse event; no patients died. INTERPRETATION: Taken every other day, rimegepant was effective for preventive treatment of migraine. Tolerability was similar to that of placebo, and no unexpected or serious safety issues were noted. FUNDING: Biohaven Pharmaceuticals.

Rimegepant, an Oral Calcitonin Gene-Related Peptide Receptor Antagonist, for Migraine.

BACKGROUND: Calcitonin gene-related peptide receptor has been implicated in the pathogenesis of migraine. Rimegepant is an orally administered, small-molecule, calcitonin gene-related peptide receptor antagonist that may be effective in acute migraine treatment. METHODS: In a multicenter, double-blind, phase 3 trial, we randomly assigned adults with at least a 1-year history of migraine and two to eight migraine attacks of moderate or severe intensity per month to receive rimegepant orally at a dose of 75 mg or matching placebo for the treatment of a single migraine attack. The primary end points were freedom from pain and freedom from the most bothersome symptom (other than pain) identified by the patient, both of which were assessed 2 hours after the dose of rimegepant or placebo was administered. RESULTS: A total of 1186 patients were randomly assigned to receive rimegepant (594 patients) or placebo (592 patients); of these, 537 patients in the rimegepant group and 535 patients in the placebo group could be evaluated for efficacy. The overall mean age of the patients evaluated for efficacy was 40.6 years, and 88.7% were women. In a modified intention-to-treat analysis, the percentage of patients who were pain-free 2 hours after receiving the dose was 19.6% in the rimegepant group and 12.0% in the placebo group (absolute difference, 7.6 percentage points; 95% confidence interval [CI], 3.3 to 11.9; P<0.001). The percentage of patients who were free from their most bothersome symptom 2 hours after the dose was 37.6% in the rimegepant group and 25.2% in the placebo group (absolute difference, 12.4 percentage points; 95% CI, 6.9 to 17.9; P<0.001). The most common adverse events were nausea and urinary tract infection. CONCLUSIONS: Treatment of a migraine attack with the oral calcitonin gene-related peptide receptor antagonist rimegepant resulted in a higher percentage of patients who were free of pain and free from their most bothersome symptom than placebo. (Funded by Biohaven Pharmaceuticals; ClinicalTrials.gov number, NCT03237845.).

Zavegepant nasal spray for the acute treatment of migraine: A Phase 2/3 double-blind, randomized, placebo-controlled, dose-ranging trial.

OBJECTIVE: Evaluate the efficacy, safety, and tolerability of zavegepant nasal spray in the acute treatment of migraine. BACKGROUND: Calcitonin gene-related peptide-targeting agents are a novel class of therapeutics for migraine, but none are currently available as a nonoral option for acute treatment. Zavegepant, a high-affinity, selective, and structurally unique calcitonin gene-related peptide-receptor antagonist in late-stage development, is formulated as a nasal spray for the acute treatment of migraine. METHODS: This randomized, dose-ranging, placebo-controlled, Phase 2/3 trial in adults aged ≥18 years with migraine (NCT03872453) was conducted at US study sites. Participants were randomized by an interactive web response system and treated a single attack of moderate to severe pain intensity with zavegepant nasal spray 5, 10, 20 mg, or placebo. Coprimary efficacy endpoints were pain freedom and freedom from the most bothersome symptom at 2 h postdose. RESULTS: Of the 1673 participants aged 18 to 79 years who were randomized, 1588 were treated with study medication, and 1581 (mean age 40.8 years, 85.5% female) were analyzed for efficacy: zavegepant 5 mg (n = 387), 10 mg (n = 391), 20 mg (n = 402), and placebo (n = 401). Zavegepant 10 and 20 mg were more effective than placebo on the coprimary endpoints of pain freedom at 2 h postdose (placebo: 15.5% [98.3% confidence interval (CI), 11.1, 19.8]; 10 mg: 22.5% [98.3% CI, 17.5, 27.6; p = 0.0113]; 20 mg: 23.1% [98.3% CI, 18.1, 28.2; p = 0.0055]) and freedom from the most bothersome symptom at 2 h postdose (placebo: 33.7% [98.3% CI, 28.0, 39.3]; 10 mg: 41.9% [98.3% CI, 36.0, 47.9; p = 0.0155]; 20 mg: 42.5% [98.3% CI, 36.6, 48.4; p = 0.0094]). Findings for the 5 mg dose were not significant. The most common treatment-emergent adverse events with zavegepant 10 and 20 mg and placebo were dysgeusia (13.5% to 16.1% vs. 3.5%), nausea (2.7% to 4.1% vs. 0.5%), and nasal discomfort (1.3% to 5.2% vs. 0.2%). Most adverse events were mild or moderate and resolved without treatment. There was no signal of hepatotoxicity. CONCLUSION: Zavegepant nasal spray, in single doses of 10 or 20 mg, was effective for the acute treatment of migraine, with a favorable safety profile. Additional research is needed to confirm its potential as a nonoral medication for the acute treatment of migraine.

Efficacy, safety, and tolerability of rimegepant orally disintegrating tablet for the acute treatment of migraine: a randomised, phase 3, double-blind, placebo-controlled trial.

BACKGROUND: Rimegepant, a small molecule calcitonin gene-related peptide receptor antagonist, has shown efficacy in the acute treatment of migraine using a standard tablet formulation. The objective of this trial was to compare the efficacy, safety, and tolerability of a novel orally disintegrating tablet formulation of rimegepant at 75 mg with placebo in the acute treatment of migraine. METHODS: In this double-blind, randomised, placebo-controlled, multicentre phase 3 trial, adults aged 18 years or older with history of migraine of at least 1 year were recruited to 69 study centres in the USA. Participants were randomly assigned to receive rimegepant (75 mg orally disintegrating tablet) or placebo and instructed to treat a single migraine attack of moderate or severe pain intensity. The randomisation was stratified by the use of prophylactic medication (yes or no), and was carried out using an interactive web response system that was accessed by each clinical site. All participants, investigators, and the sponsor were masked to treatment group assignment. The coprimary endpoints were freedom from pain and freedom from the most bothersome symptom at 2 h postdose. The efficacy analyses used the modified intention-to-treat population, which included all patients who were randomly assigned, had a migraine attack with pain of moderate or severe intensity, took a dose of rimegepant or placebo, and had at least one efficacy assessment after administration of the dose. The safety analyses included all randomly assigned participants who received at least one dose of study medication. This study is registered with ClinicalTrials.gov, number NCT03461757, and is closed to accrual. FINDINGS: Between Feb 27 and Aug 28, 2018, 1811 participants were recruited and assessed for eligibility. 1466 participants were randomly assigned to the rimegepant (n=732) or placebo (n=734) groups, of whom 1375 received treatment with rimegepant (n=682) or placebo (n=693), and 1351 were evaluated for efficacy (rimegepant n=669, placebo n=682). At 2 h postdose, rimegepant orally disintegrating tablet was superior to placebo for freedom from pain (21% vs 11%, p<0·0001; risk difference 10, 95% CI 6-14) and freedom from the most bothersome symptom (35% vs 27%, p=0·0009; risk difference 8, 95% CI 3-13). The most common adverse events were nausea (rimegepant n=11 [2%]; placebo n=3 [<1%]) and urinary tract infection (rimegepant n=10 [1%]; placebo n=4 [1%]). One participant in each treatment group had a transaminase concentration of more than 3â€ˆ× the upper limit of normal; neither was related to study medication, and no elevations in bilirubin greater than 2â€ˆ× the upper limit of normal were reported. Treated participants reported no serious adverse events. INTERPRETATION: In the acute treatment of migraine, a single 75 mg dose of rimegepant in an orally disintegrating tablet formulation was more effective than placebo. Tolerability was similar to placebo, with no safety concerns. FUNDING: Biohaven Pharmaceuticals.

Safety, tolerability, and efficacy of zavegepant 10 mg nasal spray for the acute treatment of migraine in the USA: a phase 3, double-blind, randomised, placebo-controlled multicentre trial.

BACKGROUND: Intranasal formulations can provide treatment options for people with migraine in whom oral drugs are ineffective, slow-acting, or intolerable because of nausea and vomiting. Zavegepant, an intranasally administered small molecule calcitonin gene-related peptide (CGRP) receptor antagonist, was previously assessed in a phase 2/3 trial. This phase 3 trial aimed to compare the efficacy, tolerability, safety, and timecourse of response for zavegepant nasal spray with placebo in the acute treatment of migraine. METHODS: This double-blind, randomised, placebo-controlled, multicentre phase 3 trial, conducted at 90 academic medical centres, headache clinics, and independent research facilities in the USA, recruited adults (aged ≥18 years) with a history of two to eight moderate or severe migraine attacks per month. Participants were randomly assigned (1:1) to zavegepant 10 mg nasal spray or matching placebo and self-treated a single migraine attack of moderate or severe pain intensity. Randomisation was stratified by the use or non-use of preventive medication. Study centre personnel entered eligible participants into the study using an interactive web response system that was operated and managed by an independent contract research organisation. All participants, investigators, and the funder were masked to group assignment. The coprimary endpoints, freedom from pain and freedom from the most bothersome symptom at 2 h after the treatment dose, were assessed in all randomly assigned participants who took the study medication, had a migraine attack of moderate or severe pain intensity at baseline, and provided at least one evaluable post-baseline efficacy datapoint. Safety was analysed in all randomly assigned participants who received at least one dose. The study is registered with ClinicalTrials.gov, number NCT04571060, and is closed to accrual. FINDINGS: Between Oct 27, 2020, and Aug 20, 2021, 1978 participants were recruited and assessed for eligibility. 1405 participants were eligible (703 were assigned to zavegepant and 702 to placebo), and 1269 were included in the efficacy analysis set (623 in the zavegepant group and 646 in the placebo group). 2 h after the treatment dose, more participants in the zavegepant group than in the placebo group had pain freedom (147 [24%] of 623 participants vs 96 [15%] of 646 participants, risk difference 8·8 percentage points, 95% CI 4·5-13·1; p<0·0001) and freedom from their most bothersome symptom (247 [40%] vs 201 [31%], risk difference 8·7 percentage points, 3·4-13·9; p=0·0012). The most common adverse events in either treatment group (≥2%) were dysgeusia (129 [21%] of 629 in the zavegepant group vs 31 [5%] of 653 in the placebo group), nasal discomfort (23 [4%] vs five [1%]), and nausea (20 [3%] vs seven [1%]). No signal of hepatotoxicity due to zavegepant was identified. INTERPRETATION: Zavegepant 10 mg nasal spray was efficacious in the acute treatment of migraine, with favourable tolerability and safety profiles. Additional trials are needed to establish the long-term safety and consistency of effect across attacks. FUNDING: Biohaven Pharmaceuticals.

Safety and efficacy of rimegepant orally disintegrating tablet for the acute treatment of migraine in China and South Korea: a phase 3, double-blind, randomised, placebo-controlled trial.

BACKGROUND: No acute treatments targeting calcitonin gene-related peptide (CGRP) have been approved for use in China or South Korea. We aimed to compare the efficacy and safety of rimegepant-an orally administered small molecule CGRP antagonist-with placebo in the acute treatment of migraine among adults in these countries. METHODS: This double-blind, randomised, placebo-controlled, multicentre phase 3 trial was done at 86 outpatient clinics at hospitals and academic medical centres (73 in China and 13 in South Korea). Participants were adults (≥18 years) with at least a 1-year history of migraine who had two to eight moderate or severe attacks per month and fewer than 15 headache days per month within the 3 months before the screening visit. Participants were randomly assigned (1:1) to 75 mg rimegepant or placebo to treat a single migraine attack of moderate or severe pain intensity. Randomisation was stratified by the use of preventive medication and by country. The allocation sequence was generated and implemented by study personnel using an interactive web-response system accessed online from each study centre. All participants, investigators, and the sponsor were masked to treatment assignment. The coprimary endpoints of freedom from pain and freedom from the most bothersome symptom (nausea, phonophobia, or photophobia) 2 h after dosing were assessed in the modified intention-to-treat (mITT) population (randomly assigned participants who took study medication for a migraine attack of moderate or severe pain intensity, and provided at least one efficacy datapoint after treatment) using Cochran-Mantel Haenszel tests. Safety was assessed in all participants who received rimegepant or placebo. The study is registered with ClinicalTrials.gov, number NCT04574362, and is completed. FINDINGS: 1431 participants were randomly assigned (716 [50%] to rimegepant and 715 [50%] to placebo). 668 (93%) participants in the rimegepant group and 674 (94%) participants in the placebo group received treatment. 1340 participants were included in the mITT analysis (666 [93%] in the rimegepant group and 674 [94%] in the placebo group). 2 h after dosing, rimegepant was superior to placebo for pain freedom (132 [20%] of 666 vs 72 [11%] of 674, risk difference 9·2, 95% CI 5·4-13·0; p<0·0001) and freedom from the most bothersome symptom (336 [50%] of 666 participants vs 241 [36%] of 674 participants, 14·8, 9·6-20·0; p<0·0001). The most common (≥1%) adverse events were protein in urine (8 [1%] of 668 participants in the rimepegant group vs 7 [1%] of 674 participants in the placebo group), nausea (7 [1%] of 668 vs 18 [3%] of 674), and urinary tract infection (5 [1%] of 668 vs 8 [1%] of 674). There were no rimegepant-related serious adverse events. INTERPRETATION: Among adults living in China or South Korea, a single dose of 75 mg rimegepant was effective for the acute treatment of migraine. Safety and tolerability were similar to placebo. Our findings suggest that rimegepant might be a useful new addition to the range of medications for the acute treatment of migraine in China and South Korea, but further studies are needed to support long-term efficacy and safety and to compare rimegepant with other medications for the acute treatment of migraine in this population. FUNDING: BioShin Limited. TRANSLATIONS: For the Chinese and Korean translations of the abstract see Supplementary Materials section.

Application of microbial analyses to feeds and potential implications for poultry nutrition.

Poultry nutrition and feed manufacturing are interrelated for a variety of reasons. Diet formulation is essential for optimizing bird growth and feed conversion, but compositional differences and the presence of certain feed additives can alter the gastrointestinal microbial composition and functionality. Not only does dietary composition and digestibility influence poultry performance, but specific physical characteristics such as feed particle size and thermal treatments can impact the avian gastrointestinal tract (GIT) microbiota. Poultry feeds also have a characteristic microbial ecology consisting of pathogenic and nonpathogenic microorganisms. Some feed-borne pathogens such as Salmonella are well studied and linked with the colonization of birds consuming the feed. However, much less is known about the nonpathogenic feed microbiome and what impact that might have on the bird's GIT. This review discusses the potential interaction between poultry feed and the GIT microbiome, microbial ecology of feed, application of microbiome analyses to feed, and approaches for communicating these complex data sets to the poultry industry.

Human Milk and Plasma Pharmacokinetics of Single-Dose Rimegepant 75 mg in Healthy Lactating Women.

Objective: Investigate whether rimegepant-an oral small molecule calcitonin gene-related peptide receptor antagonist for the treatment of migraine-is excreted in human milk after a single 75 mg dose and characterize its concentration-time profile in the plasma and milk of healthy lactating women to determine the relative infant dose (RID). Methods: This open-label, single-center study enrolled healthy lactating women aged 18-40 years with a gestation of 37-42 weeks and uncomplicated delivery of a single healthy child ≥2 weeks (14 days) and ≤6 months before study drug administration. Plasma samples were collected 0, 1, 2, 4, and 8 hours postdose; human milk samples were collected at 0, 1, 2, 4, 8, 12, 16, 24, 32, and 36 hours. The milk:plasma drug concentration ratio was estimated as the ratio of the human milk:plasma areas under the curve. The RID (%) was calculated as 100 times the quotient of the body weight-normalized infant and maternal doses. Results: Subjects (N = 12) were enrolled between 25 January and 15 September 2020. The mean (standard deviation [SD]) age was 29.8 (3.6) years; mean (SD) body mass index was 26.8 (4.9) kg/m2. The mean (SD) RID of rimegepant was 0.51% (0.14). The mean (SD) body-weight normalized infant dose was 0.005 (0.001) mg/kg/day, the mean (SD) body-weight normalized maternal dose was 1.04 (0.18) mg/kg/day, and mean (SD) maternal body weight was 74.0 (13.3) kg. Conclusion: On a weight-adjusted basis, the mean RID of rimegepant was <1% of the maternal dose.

P-Glycoprotein and Breast Cancer Resistance Protein Transporter Inhibition by Cyclosporine and Quinidine on the Pharmacokinetics of Oral Rimegepant in Healthy Subjects.

Rimegepant (Nurtec ODT)-an orally administered, small-molecule calcitonin gene-related peptide receptor antagonist indicated for the acute and preventive treatment of migraine-is a substrate for both the P-glycoprotein and breast cancer resistance protein transporters in vitro. We evaluated the effects of concomitant administration of strong inhibitors of these transporters on the pharmacokinetics of rimegepant in healthy subjects. This single-center, open-label, randomized study was conducted in 2 parts, both of which were 2-period, 2-sequence, crossover studies. Part 1 (n = 15) evaluated the effect of a single oral dose of 200-mg cyclosporine, a strong inhibitor of the P-glycoprotein and breast cancer resistance protein transporters, on the pharmacokinetics of rimegepant 75 mg. Part 2 (n = 12) evaluated the effect of a single oral dose of 600-mg quinidine, a strong selective P-glycoprotein transporter, on the pharmacokinetics of rimegepant 75 mg. Coadministration with cyclosporine showed an increase in rimegepant area under the plasma concentration-time curve from time 0 to infinity and maximum observed concentration based on geometric mean ratios (90% confidence intervals [CIs]) of 1.6 (1.49-1.72) and 1.41 (1.27-1.57), respectively, versus rimegepant alone. Coadministration with quinidine showed an increase in rimegepant area under the plasma concentration-time curve from time 0 to infinity and maximum observed concentration geometric mean ratios (90% CIs) of 1.55 (1.40-1.72) and 1.67 (1.46-1.91), respectively, versus rimegepant alone. Strong P-glycoprotein inhibitors (cyclosporine, quinidine) increased rimegepant exposures (>50%, <2-fold). In parts 1 and 2, rimegepant coadministration was well tolerated and safe. The similar effect of cyclosporine and quinidine coadministration on rimegepant exposure suggests that inhibition of breast cancer resistance protein inhibition may have less influence on rimegepant exposure.

Best practices in compound management for preserving compound integrity and accurately providing samples for assays.

Preserving the integrity of the compound collection and providing high-quality materials for drug discovery in an efficient and cost-effective manner are 2 major challenges faced by compound management (CM) at Bristol-Myers Squibb (BMS). The demands on CM include delivering hundreds of thousands of compounds a year to a variety of operations. These operations range from single-compound requests to hit identification support and just-in-time assay plate provision for lead optimization. Support needs for these processes consist of the ability to rapidly provide compounds as solids or solutions in a variety of formats, establishing proper long- and short-term storage conditions and creating appropriate methods for handling concentrated, potent compounds for delivery to sensitive biological assays. A series of experiments evaluating the effects of processing compounds with volatile solvents, storage conditions that can induce freeze/thaw cycles, and the delivery of compounds were performed. This article presents the results of these experiments and how they affect compound integrity and the accuracy of compound management processes.

Strain-related differences in urine composition of male rats of potential relevance to urolithiasis.

In carcinogenicity studies with PPAR gamma and alpha/gamma agonists, urinary bladder tumors have been reported in Harlan Sprague-Dawley (HSD) and Charles River Sprague-Dawley (SD) but not Wistar (WI) rats, with urolithiasis purported to be the inciting event. In two 3-month studies, the authors investigated strain-related differences in urine composition by sampling urine multiple times daily. Urine pH, electrolytes, creatinine, protein, citrate and oxalate levels, and serum citrate were assessed; urine sediment was analyzed by scanning electron microscopy and energy dispersive x-ray spectroscopy. HSD rats had significantly higher urine calcium than SD or WI rats, primarily as calcium phosphate-containing precipitate. When compared to SD rats, HSD rats had lower urine volume, higher urine protein, and a comparable (week 4) to lower (week 13) burden of MgNH(4)PO(4) aggregates. Relative to WI rats, HSD rats had higher urine protein and magnesium and lower serum and urine citrate. Overall, the susceptibility to urolithiasis in male rats was HSD > SD > WI; this was likely due to strain-related differences in the amount of urine protein (a nidus for crystal formation), lithogenic ions, citrate (an inhibitor of lithogenesis), and/or volume. Strain-related differences in urine composition need to be considered when interpreting the outcome of studies with compounds that alter urine composition.

Viral Drug Resistance Through 48 Weeks, in a Phase 2b, Randomized, Controlled Trial of the HIV-1 Attachment Inhibitor Prodrug, Fostemsavir.

BACKGROUND: Fostemsavir is a prodrug of temsavir, an attachment inhibitor that binds to HIV-1 gp120, blocking viral attachment to host CD4 T-cells. The phase 2b trial AI438011 investigated the safety, efficacy, and dose-response of fostemsavir vs ritonavir-boosted atazanavir (ATV/r) in treatment-experienced, HIV-1-infected subjects. METHODS: Two hundred fifty-one treatment-experienced subjects with baseline (BL) susceptibility to study drugs [temsavir half-maximal inhibitory concentration (IC50) <100 nM, PhenoSense Entry assay] received fostemsavir or ATV/r, each with tenofovir disoproxil fumarate + raltegravir. Subjects meeting resistance-testing criteria were assessed for emergent viral drug resistance. Changes in temsavir IC50 from BL was given a conservative technical cutoff (>3-fold increase). RESULTS: 66/200 fostemsavir and 14/51 ATV/r subjects had resistance testing performed; 44/66 and 9/14 were successfully tested using the PhenoSense GT assay. No subjects had emergent tenofovir disoproxil fumarate or ATV resistance. Six fostemsavir-treated subjects developed emergent raltegravir resistance. 29/66 fostemsavir-treated subjects had an evaluable phenotype using PhenoSense Entry (which tests for viral susceptibility to temsavir) and 13/29 exhibited >3-fold increase in temsavir IC50 from BL. gp120 population sequencing was successful in 11/13 subjects and 7 had emergent substitutions in gp120 associated with reduced temsavir susceptibility (S375, M426, or M434). However, 5/13 fostemsavir-treated subjects achieved subsequent suppression to <50 copies/mL before the week 48 database lock, regardless of key gp120 substitutions. CONCLUSIONS: Response rates remained similar across study arms regardless of BL nucleoside reverse transcriptase inhibitor, nonnucleoside reverse transcriptase inhibitor, and protease inhibitor resistance-associated mutations. Emergent changes in viral susceptibility occurred more frequently with fostemsavir compared with ATV/r. However, the full impact of temsavir IC50 changes and emergent HIV-1 gp120 substitutions, and thus appropriate clinical cutoffs, requires further study. Fostemsavir is being evaluated in a phase 3 trial in heavily treatment-experienced subjects.

Safety, efficacy, and dose response of the maturation inhibitor GSK3532795 (formerly known as BMS-955176) plus tenofovir/emtricitabine once daily in treatment-naive HIV-1-infected adults: Week 24 primary analysis from a randomized Phase IIb trial.

GSK3532795 (formerly known as BMS-955176) is a second-generation maturation inhibitor targeting a specific Gag cleavage site between capsid p24 and spacer peptide 1 of HIV-1. Study 205891 (previously AI468038) investigated the efficacy, safety, and dose response of GSK3532795 in treatment-naive, HIV-1-infected participants. Study 205891 (NCT02415595) was a Phase IIb, randomized, active-controlled, double-blind, international trial. Participants were randomized 1:1:1:1 to one of three GSK3532795 arms at doses 60 mg, 120 mg or 180 mg once daily (QD), or to efavirenz (EFV) at 600 mg QD, each in combination with tenofovir disoproxil fumarate and emtricitabine (TDF/FTC) (300/200 mg QD). Primary endpoint was proportion of participants with plasma HIV-1 RNA <40 copies/mL at Week 24. Between May 2015 and May 2016, 206 participants received treatment. At Week 24, 76-83% participants receiving GSK3532795 and 77% receiving EFV achieved HIV-1 RNA <40 copies/mL. Fifteen participants receiving GSK3532795 and one receiving EFV met resistance testing criteria; 10/15 receiving GSK3532795 had emergent substitutions at reverse transcriptase positions M184, and one at position K65, while the participant receiving EFV did not have any nucleoside reverse transcriptase inhibitor (NRTI)/non-NRTI mutations. EFV, relative to GSK3532795, had more serious adverse events (9% versus 5%) and adverse events leading to discontinuation (17% versus 5%). However, 3-4-fold higher rates of gastrointestinal adverse events were observed with GSK3532795 relative to EFV. GSK3532795 combined with TDF/FTC is efficacious with 24 weeks of therapy. However, GSK3532795 showed a higher rate of gastrointestinal intolerability and treatment-emergent resistance to the NRTI backbone relative to EFV. Trial registration: ClinicalTrials.gov NCT02415595.

Safety and efficacy of the HIV-1 attachment inhibitor prodrug fostemsavir in antiretroviral-experienced subjects: week 48 analysis of AI438011, a Phase IIb, randomized controlled trial.

BACKGROUND: Fostemsavir is a prodrug of temsavir, an attachment inhibitor that binds directly to HIV-1 gp120, blocking initial viral attachment and entry into host CD4+ T-cells. Efficacy, safety and dose-response data of fostemsavir in treatment-experienced, HIV-1-infected subjects, through week 48, are reported. METHODS: AI438011 is an ongoing Phase IIb, randomized, active-controlled trial (NCT01384734). Subjects were randomized 1:1:1:1:1 into five arms: fostemsavir (400 mg twice daily, 800 mg twice daily, 600 mg once daily or 1,200 mg once daily) and a reference arm (ritonavir-boosted atazanavir [ATV/r] 300/100 mg once daily), each with a backbone of raltegravir 400 mg twice daily plus tenofovir disoproxil fumarate 300 mg once daily. RESULTS: In total, 251 subjects were treated. Through week 48, the proportion of fostemsavir subjects with HIV-1 RNA <50 copies/ml was 61-82% and 77-95% (modified intent-to-treat [mITT] and observed analysis, respectively); 71% and 88% for ATV/r subjects (mITT and observed). Observed virological response rates were 74-100% versus 96% (fostemsavir versus ATV/r) in subjects with baseline viral load <100,000 copies/ml and 60-91% versus 71% when baseline viral load was ≥100,000 copies/ml. Across fostemsavir arms, median CD4+ T-cell count increases from baseline were 145-186 cells/µl and 142 cells/µl for the ATV/r arm. Fostemsavir doses were generally well tolerated and no fostemsavir-related adverse events led to discontinuation. CONCLUSIONS: Through week 48, fostemsavir continued to be well tolerated and showed similar efficacy to ATV/r. These results support the ongoing Phase III trial in heavily treatment-experienced adults with limited therapeutic options (≤2 classes of active antiretrovirals remaining). ClinicalTrials.gov identifier: NCT01384734.

Soluble Abeta and cognitive function in aged F-344 rats and Tg2576 mice.

Recent findings suggest that Alzheimer's dementia may be mediated by soluble beta amyloid (Abeta) more than the deposits of aggregated, insoluble Abeta, and vulnerability to cognitive deficits after scopolamine challenge may help identify AD even in patients that are still pre-symptomatic. The objectives of the present experiments were to determine if vulnerability to cognitive deficits after scopolamine challenge is related to levels of soluble Abeta, and if levels of soluble Abeta are more closely related to cognitive deficits than levels of insoluble Abeta, even in aged, transgenic mice, after they have developed very high levels of insoluble Abeta. Aged F-344 rats and young mice over-expressing the Swedish mutation in the human amyloid precursor protein (APPsw; Tg2576+) had elevated levels of soluble Abeta, and were more vulnerable to scopolamine challenge in the Morris water maze (MWM), relative to young rats and Tg2576- mice; but, among individual animals, higher levels of soluble Abeta were not correlated with vulnerability to scopolamine. On the other hand, in aged Tg2576+ mice, cognitive deficits were related to levels of soluble Abeta, not insoluble Abeta, despite the fact that the levels of insoluble Abeta were thousands of times higher than the levels of soluble Abeta. The results of the present experiments suggest that vulnerability to cognitive deficits after scopolamine challenge is not related to elevated levels of soluble Abeta, but that high levels of soluble Abeta are more closely correlated with cognitive deficits than the amount insoluble Abeta, even after large amounts of aggregated, insoluble Abeta have been deposited.

Adverse effects of gabapentin and lack of anti-allodynic efficacy of amitriptyline in the streptozotocin model of painful diabetic neuropathy.

Amitriptyline and gabapentin are the primary treatments for painful diabetic neuropathy (PDN), and it is clear that they produce beneficial effects, but there are questions about these treatments that have not been adequately addressed. For example, although there is a growing consensus that the therapeutic effects of amitriptyline in pain patients are independent of its effects on mood, it is not clear that amitriptyline has specific and direct effects on pain. There is also a fairly broad consensus that gabapentin is safe and well tolerated, but the side-effect profile of gabapentin has not been adequately assessed in pain populations. The rat streptozotocin (STZ) model of PDN was used (a) to assess the effects of amitriptyline on objective, quantitative measures of tactile allodynia, a common type of pain in PDN patients, and (b) to assess the side effects of gabapentin using measures of motor/ambulatory and cognitive function. Amitriptyline did not attenuate STZ-induced mechanical allodynia, even after chronic administration of high doses. Gabapentin produced robust anti-allodynic effects but also produced deficits in tests of motor/ambulatory and cognitive functions. The present experiments suggest that the beneficial effects of amitriptyline in PDN may not be a result of anti-allodynic efficacy and that gabapentin produces robust anti-allodynic effects but may also produce significant motor and cognitive deficits even at or near the lowest effective doses. These findings challenge the consensus opinions about these primary treatments for PDN and suggest that their therapeutic and adverse effects should be explored further in pain patients.

Efficacy, safety, bone and metabolic effects of HIV nucleoside reverse transcriptase inhibitor BMS-986001 (AI467003): a phase 2b randomised, controlled, partly blinded trial.

BACKGROUND: BMS-986001 is a thymidine analogue nucleoside reverse transcriptase inhibitor (NRTI) designed to maintain in-vitro antiviral activity while minimising off-target effects. We assessed the efficacy and safety of BMS-986001 versus tenofovir disoproxil fumarate in treatment-naive patients with HIV-1. METHODS: In this phase 2b, randomised, active-controlled trial (AI467003), we recruited treatment-naive (no current or previous exposure to an antiretroviral drug for >1 week) adults (aged at least 18 years) with HIV-1 from 47 sites across Asia, Australia, Europe, North America, South Africa, and South America. Patients with plasma HIV-1 RNA greater than 5000 copies per mL and CD4 counts greater than 200 cells per µL were randomly assigned (2:2:2:3) to receive BMS-986001 100 mg, 200 mg, or 400 mg once a day or to receive tenofovir disoproxil fumarate 300 mg once a day; each allocation was given with efavirenz 600 mg once a day and lamivudine 300 mg once a day. Both patients and investigators were masked to BMS-986001 dose (achieved with similar looking placebo tablets), but not allocation up to and including week 48. The primary endpoints were the proportion of patients with plasma HIV-1 RNA less than 50 copies per mL and safety events (serious adverse events and adverse events leading to discontinuation) through week 24; the main analysis was with a modified intention-to-treat population. Resistance analysis was a secondary endpoint, and additional safety parameters were exploratory endpoints. This trial is registered with ClinicalTrials.gov, number NCT01489046, and the European Clinical Trials Database, number EudraCT 2011-003329-89. FINDINGS: Patients were recruited between Jan 25, 2012, and Oct 3, 2012; 757 patients were assessed for eligibility and 301 were randomly assigned to receive either BMS-986001 once a day (67 patients to 100 mg, 67 to 200 mg, and 66 to 400 mg) or tenofovir disoproxil fumarate (n=101). 297 patients received at least one dose of study drug. At week 24, 57 (88%) of 65 patients for whom there were data in the 100 mg group, 54 (81%) of 67 in the 200 mg group, 62 (94%) of 66 in the 400 mg group achieved HIV-1 RNA less than 50 copies per mL, compared with 88 (89%) of 99 in the tenofovir disoproxil fumarate group (modified intention-to-treat population). BMS-986001 was generally well tolerated through week 48. Two patients had BMS-986001-related serious adverse events (atypical drug eruption and thrombocytopenia) and two in the tenofovir disoproxil fumarate group had study drug-related serious adverse events (potential drug-induced liver injury and depression or lipodystrophy) that led to discontinuation. NRTI resistance-associated mutations were reported in four (2%) of 198 patients, and non-NRTI mutations in 17 (9%) of 198 patients receiving BMS-986001 versus none of 99 and one (1%) of 99 patients receiving tenofovir disoproxil fumarate, respectively. Compared with tenofovir disoproxil fumarate, individuals in the BMS-986001 groups showed a smaller decrease in lumbar spine and hip bone mineral density but greater accumulation of limb and trunk fat, subcutaneous and visceral adipose tissue, and increased total cholesterol. INTERPRETATION: BMS-986001 had similar efficacy to that of tenofovir disoproxil fumarate and was associated with a smaller decrease in bone mineral density; however, greater resistance and gains in both peripheral and central fat accumulation were recorded for the investigational drug. Bristol-Myers Squibb has discontinued its involvement in the development of BMS-986001, and future decisions on development will be made by Oncolys BioPharma. FUNDING: Bristol-Myers Squibb.

Safety and efficacy of the HIV-1 attachment inhibitor prodrug BMS-663068 in treatment-experienced individuals: 24 week results of AI438011, a phase 2b, randomised controlled trial.

BACKGROUND: BMS-663068 is an oral prodrug of BMS-626529, an attachment inhibitor that binds to HIV-1 gp120, blocking viral attachment to host CD4 cells. AI438011 is an ongoing trial investigating the efficacy, safety, and dose-response of BMS-663068 in treatment-experienced, HIV-1-infected patients. Herein we present the results of the primary analysis. METHODS: AI438011 is a phase 2b, randomised, active-controlled trial, at 53 hospitals and outpatient clinics across ten countries in North and South America, Europe, and Africa. Individuals with an HIV-1 RNA viral load of at least 1000 copies per mL and a BMS-626529 half-maximum inhibitory concentration lower than 100 nmol/L were randomly assigned (1:1:1:1:1) to receive either BMS-663068 at 400 mg twice daily, 800 mg twice daily, 600 mg once daily, or 1200 mg once daily or ritonavir-boosted atazanavir (300 mg of atazanavir and 100 mg of ritonavir once daily), each with 400 mg of raltegravir twice daily and 300 mg of tenofovir disoproxil fumarate once daily as a backbone. The sponsor, participants, and investigators were masked for BMS-663068 dose but not for allocation. Primary endpoints were the proportion of patients with an HIV-1 RNA viral load less than 50 copies per mL (response rate) at week 24 and the frequency of serious adverse events and adverse events leading to discontinuation, up to the week 24 analysis. The primary analyses included all patients who received at least one dose of study drug (modified intention-to-treat population). This study is registered at ClinicalTrials.gov, NCT01384734. FINDINGS: Between July 26, 2011, and July 16, 2012, 581 participants were assessed for eligibility. Of these, 254 patients were randomly assigned to receive either BMS-663068 (n=52 for the 400 mg twice daily group, n=50 for the 800 mg twice daily group, n=51 for the 600 mg once daily group, and n=50 for the 1200 mg once daily group) or ritonavir-boosted atazanavir (n=51). 200 patients received at least one dose of BMS-663068, and 51 patients received at least one dose of ritonavir-boosted atazanavir. At week 24, 40 (80%) of 50 patients in the BMS-663068 400 mg twice daily group, 34 (69%) of 49 patients in the 800 mg twice daily group, 39 (76%) of 51 patients in the 600 mg once daily group, and 36 (72%) of 50 patients in the 1200 mg once daily group had an HIV-1 RNA viral load less than 50 copies per mL, compared with 38 (75%) of 51 patients in the ritonavir-boosted atazanavir group. Serious adverse events were noted in 13 (7%) of 200 patients in the BMS-663068 groups and five (10%) of the 51 patients in the ritonavir-boosted atazanavir group. Four (2%) of the 200 patients in the BMS-663068 groups and two (4%) of the 51 patients in the ritonavir-boosted atazanavir group discontinued because of adverse events. No serious adverse events or adverse events leading to discontinuation were BMS-663068-related. Grade 2-4 adverse events related to study drug(s) occurred in 17 (9%) of 200 patients across the BMS-663068 groups and 14 (27%) of 51 patients in the ritonavir-boosted atazanavir group. For the BMS-663068 groups these events were mostly single instances with no dose relation and for the ritonavir-boosted atazanavir group these were mostly gastrointestinal or hepatobiliary disorders associated with hyperbilirubinaemia. INTERPRETATION: In a comparison with ritonavir-boosted atazanavir, efficacy and safety of BMS-663068 up to the week 24 analysis support continued development of BMS-663068, which is being assessed in a phase 3 trial in heavily treatment-experienced individuals. FUNDING: Bristol-Myers Squibb.