Abstract 212: Andexanet Alfa, a Universal Antidote for Reversal of Anticoagulation of Factor Xa Inhibitors in Healthy Human Volunteers

Introduction: Andexanet alfa (AnXa) is a recombinant modified fXa molecule that acts as a specific antidote for fXa inhibitors. We report clinical results in healthy subjects anticoagulated with apixaban (apix), rivaroxaban (riva), edoxaban (edox), or enoxaparin (enox), demonstrating rapid and sustained reversal of anticoagulation following administration of AnXa. Methods: These were Phase 2/3 randomized, double-blind, placebo-controlled studies in healthy subjects. In Phase 2, about153 subjects age18 - 45 were given one of the fXa inhibitors (apix 5 mg BID, riva 20 mg QD, edox 60 mg QD or enox 40 mg QD) for 6 days. AnXa or placebo (3:1 randomization) was given IV on Day 6, 3hrs after the last inhibitor dose (∼inhibitor Cmax). Safety was followed through Day 48. A range of AnXa doses (bolus or bolus+infusion) was evaluated by correction of biomarkers (anti-fXa activity, free inhibitor concentrations and thrombin generation (TG)). In Phase 3 (ANNEXA™), older subjects age 50 to 75 were dosed with apix (5 mg BID) or riva (20 mg QD) for 4 days. ANNEXA™-A had 63 subjects treated with apix. AnXa (400 mg bolus; 400 mg bolus plus 4 mg/min x 2hr infusion) or placebo (3:1 randomization) was given on Day 4, 3 hrs after the last apix dose. ANNEXA™-R had 82 subjects treated with riva. AnXa (800 mg bolus; 800 mg bolus plus 8 mg/min x 2hr infusion) or placebo (2:1) was given on Day 4, 4 hrs after the last riva dose. Safety was followed through Day 43. Results: About 298 healthy subjects were enrolled in the studies. AnXa demonstrated rapid and sustained reversal of both direct and indirect fXa inhibitors as measured by correction of biomarkers. The ANNEXA™ studies confirmed findings from Phase 2, and met all primary (reversal of anti-fXa) and secondary endpoints (reduction of free inhibitor concentration and restoration of TG) with high statistical significance. AnXa was well-tolerated with no serious adverse events, thrombotic events, or antibodies to fX or fXa reported. Conclusion: AnXa treatment results in rapid and sustained reversal of anticoagulation of fXa inhibitors. A Phase 3b/4 confirmatory study (ANNEXA-4) in patients with acute major bleeds is ongoing.

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A phase 2 PK/PD study of andexanet alfa for reversal of rivaroxaban and edoxaban anticoagulation in healthy volunteers

Blood Advances ◽

10.1182/bloodadvances.2019000885 ◽

2020 ◽

Vol 4 (4) ◽

pp. 728-739 ◽

Cited By ~ 3

Author(s):

Genmin Lu ◽

Pamela B. Conley ◽

Janet M. Leeds ◽

Mark J. Karbarz ◽

Gallia G. Levy ◽

...

Keyword(s):

Healthy Volunteers ◽

Factor Xa ◽

The United States ◽

Phase 2 ◽

Two Phase ◽

Serious Adverse Events ◽

Double Blind ◽

Therapeutic Anticoagulation ◽

Life Threatening ◽

Andexanet Alfa

Abstract As with any anticoagulant, factor Xa (FXa) inhibitors are associated with a risk of major bleeding. Andexanet alfa is a recombinant modified human FXa lacking enzymatic activity, developed for reversal of FXa inhibitor–induced anticoagulation. In two phase 2, randomized, double-blind, placebo-controlled, single-center studies, different regimens of andexanet alfa were administered to healthy volunteers after therapeutic anticoagulation with rivaroxaban or edoxaban, and multiple anticoagulation reversal and safety end points were evaluated. Andexanet alfa rapidly and effectively reversed anticoagulation with both rivaroxaban and edoxaban. Within 2 minutes after bolus, anti-FXa activity decreased significantly, with maximum decreases of ≈93% (P < .05) and ≈82% (P < .05), respectively, compared with placebo. The stoichiometric ratios of andexanet alfa:total anticoagulant at maximum reversal of anti-FXa activity ranged from 1:1 to 1.3:1 for rivaroxaban and 1.41:1 to 2.58:1 for edoxaban. Sustained normalization of thrombin generation for ≈2 hours and sustained decrease in unbound anticoagulant (maximum ≈80%) for up to ≈4 hours following completion of andexanet alfa administration, compared with placebo, were observed when andexanet was administered as a bolus or as a bolus followed by continuous infusion. Andexanet alfa was well tolerated, and there were no serious adverse events or thrombotic events. Andexanet alfa has been approved in the United States and Europe for reversal of anticoagulation in patients treated with rivaroxaban or apixaban who experience life-threatening or uncontrolled bleeding. These studies were registered with clinicaltrials.gov (#NCT03578146 and #NCT03551743).

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A Phase 2 Randomized, Double-Blind, Placebo-Controlled Trial Demonstrating Reversal Of Rivaroxaban-Induced Anticoagulation In Healthy Subjects By Andexanet Alfa (PRT064445), An Antidote For Fxa Inhibitors

Blood ◽

10.1182/blood.v122.21.3636.3636 ◽

2013 ◽

Vol 122 (21) ◽

pp. 3636-3636 ◽

Cited By ~ 40

Author(s):

Crowther Mark ◽

Mathur Vandana ◽

Kitt Michael ◽

Lu Genmin ◽

Pamela B. Conley ◽

...

Keyword(s):

Adverse Events ◽

Healthy Subjects ◽

Controlled Study ◽

Pharmacokinetic Data ◽

Phase 2 ◽

Employment Equity ◽

Double Blind ◽

Double Blind Placebo ◽

Equity Ownership ◽

Andexanet Alfa

Abstract Background Direct factor Xa inhibitors have demonstrated compelling anticoagulant efficacy and/or safety profiles across multiple diverse patient populations. A specific antidote to reverse anticoagulation during episodes of serious uncontrolled bleeding or before urgent/emergent surgery is lacking. Andexanet alfa (proposed INN)(AnXa, PRT064445) is a modified, recombinant human fXa molecule that is catalytically inactive but retains high-affinity binding to direct fXa inhibitors. It thus acts as a decoy to reverse fXa inhibitor-mediated anticoagulation in preclinical and early clinical studies. Methods This ongoing Phase 2, double-blind, placebo-controlled study is examining the reversal by AnXa of the anticoagulant activity of rivaroxaban (riva), as well as the pharmacokinetics and safety in healthy subjects. Reversal of riva anticoagulation will be studied with up to 6 different dose cohorts/ regimens of AnXa or placebo in a 6:3 ratio (i.e., 9 subjects per cohort). Riva is administered at an oral dose of 20 mg qd for 6 days and AnXa administered intravenously on Day 6, 3 hours after the last riva dose – the approximate time of maximum riva concentration (mean ± SD: 0.64 ± 0.22 mM, n=18). Pharmacodynamic and safety data are collected through Day 48 with pharmacokinetic data through Day 10. Results We report here available data from the first 2 AnXa dose cohorts (210 mg and 420 mg, n =18). Immediately after completion of the 210 mg and 420 mg doses, anti-fXa activity decreased dose-dependently by 20% and 53%, respectively, from the pre-AnXa level and returned to placebo levels by approximately 2 hours after treatment (Figure). In parallel, the plasma concentrations of unbound riva were decreased by 32% and 51%, respectively, relative to pre-AnXa values. In addition, riva-induced inhibition of thrombin generation and prolongation of both prothrombin time and activated clotting time were also rapidly partially reversed by AnXa in a dose-dependent manner. At 2 minutes after AnXa administration, the molar ratio of AnXa to total plasma riva was 0.8 for the 210 mg dose (1.2 µM/1.6 µM, respectively) and 1.2 for the 420 mg dose (2.6 µM/2.1 µM, respectively). AnXa infusion was not associated with increases in prothrombin fragments F1+2, thrombin-antithrombin, or D-dimer (all values were within normal ranges). As expected, tissue factor pathway inhibitor activity decreased due to its binding to AnXa. AnXa was well tolerated and there were no thrombotic events, serious, or severe adverse events. Adverse events occurring in 1 or more AnXa or placebo recipients included infusion-related reactions (n = 3, all mild in severity) and post-procedural hematoma, headache, or postural dizziness (n = 2 each). Summary/Conclusions Results from this ongoing clinical trial demonstrate that AnXa is able to dose-dependently partially reverse the anticoagulant effects of rivaroxaban, as assessed by pharmacodynamic markers, in healthy subjects. These data are consistent with previously reported results with apixaban in that AnXa sequesters rivaroxaban and apixaban in a similar stoichiometric manner. Additional data with higher doses of AnXa will also be presented. AnXa is well-tolerated and a potentially promising, universal antidote for fXa inhibitors. Disclosures: Mark: Portola Pharmaceuticals: Consultancy. Off Label Use: The use of PRT064445 as an antidote for reversal of anticoagulation from direct and indirect fXa inhibitors is investigational. Vandana:Portola Pharmaceuticals: Consultancy. Michael:Portola Pharmaceuticals: Employment, Equity Ownership. Genmin:Portola Pharmaceuticals: Employment, Equity Ownership. Conley:Portola Pharmaceuticals: Employment, Equity Ownership. Stanley:Portola Pharmaceuticals: Employment, Equity Ownership. Castillo:Portola Pharmaceuticals: Employment, Equity Ownership. Hutchaleelaha:Portola Pharmaceuticals: Consultancy. Karbarz:Portola Pharmaceuticals: Employment. Lin:Portola Pharmaceuticals: Employment. Barron:Portola Pharmaceuticals: Employment. Russell:Portola Pharmaceuticals: Employment. Levy:Portola Pharmaceuticals: Employment. Connolly:Portola Pharmaceuticals: Consultancy. Curnutte:Portola Pharmaceuticals: Employment, Equity Ownership.

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A Phase 2 Randomized, Double-Blind, Placebo-Controlled Trial Demonstrating Reversal of Edoxaban-Induced Anticoagulation in Healthy Subjects By Andexanet Alfa (PRT064445), a Universal Antidote for Factor Xa (fXa) Inhibitors

Blood ◽

10.1182/blood.v124.21.4269.4269 ◽

2014 ◽

Vol 124 (21) ◽

pp. 4269-4269 ◽

Cited By ~ 66

Author(s):

Mark Crowther ◽

Gallia G. Levy ◽

Genmin Lu ◽

Janet Leeds ◽

Joyce Lin ◽

...

Keyword(s):

Healthy Subjects ◽

Thrombin Generation ◽

Controlled Study ◽

Dependent Manner ◽

Phase 2 ◽

Double Blind ◽

Double Blind Placebo ◽

Equity Ownership ◽

Andexanet Alfa ◽

Inhibition Of Thrombin

Abstract Background: Direct fXa inhibitors appear to have similar or superior anticoagulant efficacy and safety relative to warfarin (and in some cases low molecular weight heparin) in the management of venous thromboembolism and stroke prevention in atrial fibrillation. However, they are limited by the lack of a specific antidote to reverse anticoagulation in cases of major bleeding episodes or prior to urgent/emergency surgery. Andexanet alfa (AnXa, PRT064445) is a modified, recombinant human fXa molecule that is catalytically inactive but retains high-affinity binding to direct and indirect fXa inhibitors, therefore acting as a decoy to bind and sequester fXa inhibitors. We previously reported Phase 2 data with apixaban, rivaroxaban and enoxaparin in healthy subjects and demonstrated that AnXa was able to rapidly and extensively reverse pharmacodynamic (PD) markers of anticoagulation. Here we report new clinical data demonstrating that AnXa rapidly reverses the PD markers of edoxaban-mediated anticoagulation – anti-fXa activity and inhibition of thrombin generation. Methods: This ongoing Phase 2, double-blind, placebo-controlled study is examining the reversal by AnXa of the anticoagulant activity of edoxaban (edox, the most recent fXa inhibitor for which an NDA/MAA was submitted) as well as its pharmacokinetics (PK) and safety profile in healthy subjects. Reversal of edox anticoagulation is being studied with up to 3 different dose cohorts/regimens of AnXa or placebo in a 6:3 ratio (i.e., 9 subjects per cohort). Edox is administered at an oral dose of 60 mg qd for 6 days and AnXa administered intravenously on Day 6, 3 hours after the last edox dose. PD and safety data are collected through Day 48 with PK data through Day 10. Results and Conclusions: We report here available data from the first 2 AnXa dose cohorts (600 mg bolus, n=9; 800 mg bolus followed by 8 mg/min infusion for 1 hr, n=9). Immediately after completion of the 600 mg or 800 mg bolus, anti-fXa activity decreased dose-dependently by 52% and 73%, respectively, from the pre-AnXa level, remained constant during the infusion, and returned to placebo levels by approximately 2 hours after treatment. In addition, edox-induced inhibition of thrombin generation and prolongation of clotting times were also reversed by AnXa in a dose-dependent manner. AnXa was well tolerated and there were no thrombotic events, serious, or severe adverse events. One subject was discontinued on Day 5 prior to AnXa dosing due to a vasovagal reaction. These data are consistent with previously reported results for other fXa inhibitors in that AnXa rapidly reverses PD markers of anticoagulation, restores normal thrombin generation, and is well tolerated. Disclosures Crowther: CSL Behring: Honoraria; Shire: Honoraria; Celgene: Honoraria; Bayer: Honoraria; AKP America: Consultancy; Leo Pharma: Consultancy, Honoraria, Research Funding; Janssen: Consultancy; Portola Pharmaceuticals, Inc.: Consultancy; The Heart and Stroke Foundation of Ontario: Career Investigator Award, Career Investigator Award Other. Levy:Portola Pharmaceuticals: Employment; University of Michigan: Patents & Royalties. Lu:Portola Pharmaceuticals Inc: Employment. Leeds:Portola Pharmaceuticals, Inc: Employment. Lin:Portola Pharmaceuticals, Inc.: Employment. Pratikhya:Portola Pharmaceuticals, Inc.: Employment. Conley:Portola Pharmaceuticals Inc: Employment; Portola Pharmaceuticals Inc: Equity Ownership. Connolly:Portola Pharmaceuticals Inc: Consultancy. Curnutte:Portola Pharmaceuticals, Inc.: Employment, Equity Ownership; Sea Lane Biotechnologies: Consultancy; 3-V Biosciences: Equity Ownership.

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314 Reversal of Betrixaban-Induced Anticoagulation in Healthy Volunteers by Andexanet Alfa

Neurosurgery ◽

10.1093/neuros/nyx417.314 ◽

2017 ◽

Vol 64 (CN_suppl_1) ◽

pp. 267-267 ◽

Cited By ~ 3

Author(s):

Mark Crowther ◽

Genmin Lu ◽

Janet Leeds ◽

Joyce Lin ◽

Alex Gold ◽

...

Keyword(s):

Healthy Subjects ◽

Anticoagulant Activity ◽

Safety Information ◽

Factor Xa ◽

Double Blind Study ◽

Double Blind ◽

Matching Placebo ◽

Medically Ill ◽

Fxa Inhibitor ◽

Andexanet Alfa

Abstract INTRODUCTION Andexanet alfa (andexanet) is a modified, recombinant human factor Xa (FXa) that acts as a decoy to bind and sequester FXa inhibitors, thus reversing their anticoagulation effects. Here, we report the efficacy of andexanet in reversing the anticoagulant activity of betrixaban, a direct FXa inhibitor which has recently completed a large Phase 3 clinical trial in acute medically ill patients (APEX). METHODS In this Phase 2, randomized, double-blind study, healthy subjects were dosed with 80 mg qd po betrixaban to steady state (7 days). In Cohort 1, subjects (n = 6) received 800-mg andexanet bolus 3 hours after the last dose of betrixaban, or matching placebo (n = 3). In Cohort 2, subjects (n = 6) received 800-mg andexanet bolus 4 hours after the last betrixaban dose, followed immediately by a 2-hour andexanet infusion (8 mg/min), or matching placebo (n = 3). Study endpoints included assessments of safety and pharmacodynamic markers of anticoagulation reversal. RESULTS >Following dosing with betrixaban, andexanet rapidly (2 minutes after the bolus) decreased anti-FXa activity by ∼80% in both cohorts (P < 0.001 vs. placebo) and decreased unbound betrixaban plasma concentration by 73% and 83% in Cohorts 1 and 2, respectively (P < 0.001 vs. placebo). The effects were maintained during the 2-hour infusion of andexanet. Thrombin generation was restored in 11/12 (91.7%) subjects administered andexanet vs. 2/6 (33.3%) placebo subjects. Andexanet was well-tolerated; there were no thrombotic events or other serious/severe adverse events. CONCLUSION Andexanet was well-tolerated and rapidly reversed anticoagulation effects of betrixaban in healthy subjects. The results of this and previous studies in healthy subjects indicate the potential of andexanet as a universal antidote for FXa inhibitors. An ongoing Phase 3b/4 study (ANNEXA-4) in patients receiving a FXa inhibitor who present with acute major bleeding and require urgent reversal of anticoagulation will provide efficacy and safety information on andexanet in this target patient population.

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P.010 Efficacy, safety, and tolerability of ubrogepant for the acute treatment of migraine: a single-attack phase 3 study, ACHIEVE II

Canadian Journal of Neurological Sciences / Journal Canadien des Sciences Neurologiques ◽

10.1017/cjn.2019.111 ◽

2019 ◽

Vol 46 (s1) ◽

pp. S16 ◽

Cited By ~ 1

Author(s):

RB Lipton ◽

DW Dodick ◽

J Ailani ◽

K Lu ◽

H Lakkis ◽

...

Keyword(s):

Pain Relief ◽

Acute Treatment ◽

Statistical Significance ◽

Phase 3 ◽

Double Blind ◽

Primary Endpoints ◽

Safety Population ◽

Secondary Endpoints ◽

Attack Phase ◽

Headache Pain

Background: To evaluate efficacy, safety, and tolerability of ubrogepant for acute treatment of migraine attacks. Methods: Multicenter, double-blind, phase 3 study (NCT02867709). Randomized patients (1:1:1, placebo or ubrogepant 25mg or 50mg) had 60 days to treat one migraine attack (moderate/severe pain intensity). Co-primary efficacy endpoints (2 hours post initial dose): headache pain freedom and absence of most bothersome migraine-associated symptom (MBS). Secondary endpoints: pain relief, sustained pain relief, sustained pain freedom, and absence of migraine-associated symptoms. Results: 1686 patients were randomized (safety population: n=1465; mITT population: n=1355). Mean age: 41 years; white: 81%; female: 89%. Significantly greater proportions of ubrogepant- than placebo-treated patients achieved 2-hour pain freedom (placebo: 14.3%; 25mg: 20.7%, adjusted P=0.0285; 50mg: 21.8%, adjusted P=0.0129) and absence of MBS for 50mg (placebo: 27.4%; 50mg: 38.9%, adjusted P=0.0129). Secondary endpoints (except absence of nausea at 2h) met statistical significance versus placebo for ubrogepant 50mg. Absence of MBS and secondary outcomes were not significant for 25mg after multiplicity adjustment. Ubrogepant’s and placebo’s AE profiles were similar. Conclusions: Co-primary endpoints were met for ubrogepant 50mg. Ubrogepant 25mg was significantly superior to placebo for 2h pain freedom. Ubrogepant was well tolerated. Results support the efficacy, tolerability, and safety of ubrogepant for acute treatment of migraine attacks.

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Rezafungin versus Caspofungin in a Phase 2, Randomized, Double-Blind Study for the Treatment of Candidemia and Invasive Candidiasis- The STRIVE Trial

Clinical Infectious Diseases ◽

10.1093/cid/ciaa1380 ◽

2020 ◽

Author(s):

George R Thompson ◽

Alex Soriano ◽

Athanasios Skoutelis ◽

Jose A Vazquez ◽

Patrick M Honore ◽

...

Keyword(s):

Invasive Candidiasis ◽

Double Blind Study ◽

Phase 2 ◽

Double Blind ◽

Once Daily ◽

Secondary Endpoints ◽

Intent To Treat ◽

Cure Rates ◽

Treat Population

Abstract Background Rezafungin (RZF) is a novel echinocandin exhibiting distinctive pharmacokinetics/pharmacodynamics. STRIVE was a phase 2, double-blind, randomized trial designed to compare the safety and efficacy of RZF once weekly (QWk) to caspofungin (CAS) once daily for treatment of candidemia and/or invasive candidiasis (IC). Methods Adults with systemic signs and mycological confirmation of candidemia and/or IC were randomized to RZF 400 mg QWk (400 mg), RZF 400 mg on week 1 then 200 mg QWk (400/200 mg), or CAS 70 mg as a loading dose followed by 50 mg daily for ≤ 4 weeks. Efficacy assessments included overall cure (resolution of signs of candidemia/IC + mycological eradication) at day 14 (primary endpoint), investigator-assessed clinical response at day 14, and 30-day all-cause mortality (ACM) (secondary endpoints), and time to negative blood culture. Safety was evaluated by adverse events and ACM through follow-up. Results Of 207 patients enrolled, 183 were in the microbiological intent-to-treat population (~21% IC). Overall cure rates were 60.5% (46/76) for RZF 400 mg, 76.1% (35/46) for RZF 400/200 mg, and 67.2% (41/61) for CAS; investigator-assessed clinical cure rates were 69.7% (53/76), 80.4% (37/46), and 70.5% (43/61), respectively. 30-day ACM was 15.8% for RZF 400 mg, 4.4% for RZF 400/200 mg, and 13.1% for CAS. Candidemia was cleared in 19.5 and 22.8 hours in RZF and CAS patients, respectively. No concerning safety trends were observed; ACM through follow-up was 15.2% (21/138) for RZF and 18.8% (13/69) for CAS. Conclusions RZF was safe and efficacious in the treatment of candidemia and/or IC.

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Topline Results of the CARE-PWS Phase 3 Study: Intranasal Carbetocin Improves Hyperphagia and Anxiety and Distress Symptoms in Prader-Willi Syndrome (PWS)

Journal of the Endocrine Society ◽

10.1210/jendso/bvab048.1403 ◽

2021 ◽

Vol 5 (Supplement_1) ◽

pp. A689-A689

Author(s):

Davis Ryman ◽

Cheri L Deal

Keyword(s):

Genetic Disorder ◽

Statistical Significance ◽

Prader Willi Syndrome ◽

Obsessive Compulsive ◽

Primary Analysis ◽

Phase 3 ◽

Double Blind ◽

Multiple Endpoints ◽

Behavioral Issues ◽

Secondary Endpoints

Abstract Prader-Willi syndrome (PWS) is a complex genetic disorder associated with multiple neuroendocrine abnormalities including significantly decreased hypothalamic oxytocin levels, resulting in symptoms of severe hyperphagia (an unrelenting false sense of starvation) and multiple severe neuropsychiatric and behavioral issues. CARE-PWS, a multi-center, randomized, double-blind, placebo-controlled phase 3 study, has evaluated the efficacy, safety, and tolerability of intranasal carbetocin, a selective oxytocin receptor agonist, in participants with PWS. Eligible participants aged 7 through 18 with genetically confirmed PWS were randomized in equal proportions to three treatment arms for the 8-week placebo-controlled period of the study: carbetocin 9.6 mg, carbetocin 3.2 mg, or a matching placebo, administered by nasal spray three times a day with meals. The primary endpoint assessed changes from baseline to week 8 in Hyperphagia Questionnaire for Clinical Trials (HQ-CT) or Children’s Yale-Brown Obsessive Compulsive Scale (CY-BOCS) scores for the carbetocin 9.6 mg arm vs placebo, and the first secondary endpoint assessed changes from baseline to week 8 in HQ-CT or CY-BOCS scores for the carbetocin 3.2 mg arm vs placebo. Additional secondary endpoints included changes from baseline to week 8 in PWS Anxiety and Distress Questionnaire (PADQ) scores, and Clinical Global Impression of Change (CGI-C) scores evaluating the overall change in severity of PWS symptoms at week 8. Due to COVID-19, enrollment was closed early with 119 evaluable participants for the primary analysis. In the carbetocin 9.6 mg arm, trends toward numerically greater improvements in HQ-CT and CGI-C scores relative to placebo were observed but did not reach statistical significance; however, the carbetocin 3.2 mg arm demonstrated a significant improvement in HQ-CT scores (LS mean improvement vs placebo -3.14 points, p=0.016). In the 3.2 mg arm, additional consistent evidence of improvements versus placebo was seen in multiple secondary endpoints, including CGI-C (p=0.027) and PADQ (p=0.027). Numeric trends toward improvement in CY-BOCS scores were observed in each dose arm, but did not reach statistical significance versus placebo. During the subsequent long-term follow-up period of the study, both carbetocin arms have experienced continued numeric improvements from baseline across multiple endpoints. Intranasal carbetocin was generally well-tolerated; the most frequently reported adverse event was flushing, which was generally mild and transient. In conclusion, results of the CARE-PWS study support that intranasal carbetocin appears to be safe and well tolerated, and reduces hyperphagia and anxiety and distress behaviors in PWS.

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Immunogenicity and safety of a third dose, and immune persistence of CoronaVac vaccine in healthy adults aged 18-59 years: interim results from a double-blind, randomized, placebo-controlled phase 2 clinical trial

10.1101/2021.07.23.21261026 ◽

2021 ◽

Author(s):

Hongxing Pan ◽

Qianhui Wu ◽

Gang Zeng ◽

Juan Yang ◽

Deyu Jiang ◽

...

Keyword(s):

Large Scale ◽

Dose Group ◽

Geometric Mean ◽

Development Program ◽

Neutralizing Antibody ◽

Immune Memory ◽

High Dose ◽

Phase 2 ◽

Serious Adverse Events ◽

Double Blind

Background Large-scale vaccination is being implemented globally with CoronaVac, an inactivated vaccine against coronavirus disease 2019 (COVID-19). Immunogenicity and safety profiles of homologous two-dose schedules have been published. We report interim results of immune persistence, and the immunogenicity and safety of a third dose of CoronaVac. Methods In this ongoing, placebo-controlled, double-blind phase 2 trial in 18-to-59-year-olds, we randomly assigned subjects, 1:1:1:1, to one of four schedules to receive a third dose, 28 days or 6 months after two two-dose regimens (14-day or 28-day apart): schedule 1: days 0, 14, 42; schedule 2: days 0, 14, 194; schedule 3: days 0, 28, 56; schedule 4: days 0, 28, 208. For each schedule, participants were randomly assigned to either a medium-dose group (3 μg per 0.5 mL of aluminum hydroxide diluent per dose), a high-dose group (6 μg), or a placebo group (2:2:1). The primary outcome was geometric mean titers (GMTs) of neutralizing antibody to live SARS-CoV-2. Results Overall, 540 participants received a third dose. In the 3 μg group, neutralizing antibody titers induced by the first two doses declined after 6-8 months to below the seropositive cutoff (GMT: 4.1 [95%CI 3.3-5.2] for Schedule 2 and 6.7 [95%CI 5.2-8.6] for Schedule 4). When a third dose was given 6-8 months after a second dose, GMTs assessed 14 days later increased to 137.9 [95%CI 99.9-190.4] for Schedule 2, and 143.1 [95%CI 110.8-184.7] for Schedule 4, approximately 3-fold above Schedule 1 and Schedule 3 GMTs after third doses. Similar patterns were observed for the 6 μg group. The severity of solicited local and systemic adverse reactions reported within 28 days after the third dose were grade 1 to grade 2 in all vaccination cohorts. None of the fourteen serious adverse events were considered to be related to vaccination. Conclusions A third dose of CoronaVac administered 6 or more months after a second dose effectively recalled specific immune response to SARS-CoV-2, resulting in a remarkable increase in antibody levels, and indicating that a two-dose schedule generates good immune memory. Optimizing the timing of a booster dose should take into account immunogenicity, vaccine efficacy/effectiveness, local epidemic situation, infection risk, and vaccine supply. (Funded by the National Key Research and Development Program, Beijing Science and Technology Program and National Science Fund for Distinguished Young Scholars; ClinicalTrials.gov number, NCT04352608.)

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0739 Efficacy and Safety of AXS-12 in the Treatment of Narcolepsy: Results from a Phase 2, Double-Blind, Placebo-Controlled, Crossover Trial

SLEEP ◽

10.1093/sleep/zsaa056.735 ◽

2020 ◽

Vol 43 (Supplement_1) ◽

pp. A281-A281

Author(s):

C O’Gorman ◽

A Jones ◽

M J Thorpy ◽

H Tabuteau

Keyword(s):

Cognitive Function ◽

Adverse Events ◽

Sleep Quality ◽

Primary Endpoint ◽

Crossover Trial ◽

Severe Illness ◽

Phase 2 ◽

Serious Adverse Events ◽

Double Blind ◽

Novel Approach

Abstract Introduction Narcolepsy is a chronic, debilitating, neurological disease characterized by excessive daytime sleepiness (EDS), cataplexy, and sleep-wake dysregulation. Existing treatments are limited, provide variable efficacy, and have significant tolerability issues. AXS-12 (reboxetine) is a potent, and highly selective norepinephrine reuptake inhibitor with potential for therapeutic differentiation in narcolepsy. Methods The CONCERT study was a Phase 2, double-blind, randomized, placebo-controlled, crossover trial of AXS-12 in narcolepsy subjects exhibiting moderate and severe symptoms of cataplexy and EDS. Subjects were randomized (1:1) to treatment with AXS-12 followed by placebo, or placebo followed by AXS-12. AXS-12 dosing was 8mg/day for week 1, escalated to 10mg/day for week 2. Crossover occurred after a one-week down-titration/washout. The primary endpoint was the change in weekly cataplexy attacks from baseline, averaged over the 2-week treatment period for overall treatment effect. Secondary endpoints included improvements in EDS, cognitive function, sleep quality and sleep-related symptoms. Results Twenty-one subjects were randomized. The baseline mean weekly number of cataplexy attacks was 30.0 and mean ESS score was 18.1, reflecting moderate and severe illness on both core symptoms. AXS-12 met the prespecified primary endpoint, demonstrating a statistically significantly greater reduction in the mean number of weekly cataplexy attacks (-13.0 with AXS-12 vs -0.3 with placebo; p<0.001) over 2 weeks of treatment. Statistically significant reductions in EDS were observed for AXS-12 compared to placebo, assessed by changes in the Epworth Sleepiness Scale (-6.0 vs -3.1; p=0.003), number of weekly inadvertent naps (-5.88 vs -0.98; p<0.001). AXS-12 was associated with improved cognitive function (p<0.002) and sleep quality (p<0.007), and reduced night awakenings (p<0.05). Rapidity of effect was observed with significant symptomatic improvements occurring as early as week 1 starting at the lower 8mg dose. AXS-12 was safe and well-tolerated with no serious adverse events or discontinuations due to adverse events. Conclusion AXS-12 is a novel approach for the treatment of narcolepsy with the potential for comprehensive clinical symptom management compared to current treatments. In this Phase 2 study, AXS-12 resulted in statistically significant improvements in cataplexy, excessive sleepiness, cognitive function and night awakenings in patients with narcolepsy with a favorable safety profile. Support Axsome Therapeutics.

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0146 Efficacy and Safety of Single Dose of TS-142, a Novel and Potent Dual Orexin Receptor Antagonist, in Insomnia Patients

SLEEP ◽

10.1093/sleep/zsaa056.144 ◽

2020 ◽

Vol 43 (Supplement_1) ◽

pp. A58-A58

Author(s):

M Uchiyama ◽

D Kambe ◽

Y Imadera ◽

H Sunaga ◽

S Hasegawa ◽

...

Keyword(s):

Receptor Antagonist ◽

Healthy Subjects ◽

Phase 1 ◽

Sleep Onset ◽

Pharmacokinetic Profile ◽

Residual Effects ◽

Digit Symbol Substitution Test ◽

Efficacy And Safety ◽

Serious Adverse Events ◽

Double Blind

Abstract Introduction TS-142 is a novel dual orexin receptor antagonist (DORA) developed for the treatment of insomnia. Here we report its pharmacokinetic profile in the healthy subjects and its efficacy and safety in patients with insomnia. Methods A phase1 study was conducted to clarify pharmacokinetic profile, in which various doses of TS-142 (1–30 mg) were orally administered once to thirty two healthy subjects. Subsequently, a phase 2a study utilizing polysomnography (PSG) was carried out in patients with primary insomnia, in which 5, 10, or 30 mg of TS-142, or placebo was randomly administered in a double-blind manner. Karolinska Sleepiness Scale (KSS) and Digit Symbol Substitution Test (DSST) were also examined in the morning after PSG. Results Following single administration of TS-142, plasma concentration of unchanged compound reached maximum within 2.50 h (median), and then eliminated rapidly, giving mean elimination half-life between 1.32 and 3.25 h. Twenty-three patients with insomnia completed the Phase2a study. Both latency to persistent sleep (LPS) and wake after sleep onset (WASO) were significantly improved with TS-142 at all doses, in comparison with placebo (-42, -42 and -45 for LPS [min] and -28, -35 and -55 for WASO [min] in 5, 10, 30 mg, respectively). KSS and DSST administered in the morning indicated no serious hangover effects. No serious adverse events were observed in these trials. Conclusion The phase 1 trial showed favorable pharmacokinetic profiles. The phase 2a trial demonstrated that TS-142 was efficacious in objective sleep onset and maintenance with minimal next-day residual effects. TS-142 was generally well tolerated in both studies. Support Taisho Pharmaceutical. Co., Ltd.

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