Efficacy and Safety of Fitusiran Prophylaxis, an siRNA Therapeutic, in a Multicenter Phase 3 Study (ATLAS-INH) in People with Hemophilia A or B, with Inhibitors (PwHI)

Abstract Introduction Hemophilia A and B are rare bleeding disorders characterized by ineffective clot formation due to impaired thrombin generation as a result of deficiency of FVIII or FIX, respectively. Fitusiran is a subcutaneously (SC) administered investigational siRNA therapeutic targeting antithrombin to restore thrombin generation and rebalance hemostasis in people with hemophilia A or B, with or without inhibitors. Here, we present the safety and efficacy of fitusiran prophylaxis for PwHI in a phase 3 study (ATLAS-INH; NCT03417102). Methods The ATLAS-INH study is a randomized, open-label Phase 3 study designed to evaluate the efficacy and safety of fitusiran in PwHI. Eligible males ≥12 years receiving on-demand treatment with bypassing agents (BPA) were randomized in a 2:1 ratio to receive once monthly 80 mg SC fitusiran prophylaxis or continue with on-demand BPA. The primary endpoint is annualized bleeding rate (ABR) in PwHI on fitusiran prophylaxis compared to those on BPA on-demand in the efficacy period. The secondary endpoints include spontaneous ABR, joint ABR, and quality of life (QoL) measured by Haem-A-QoL. Results 57 subjects were randomized into the study. Mean (range) age of the study participants at screening was 28.4 (13-63) yrs. Statistical significance was achieved for primary and all secondary endpoints with significant reduction in ABRs of treated bleeds: all, spontaneous and joint bleeds for fitusiran vs on-demand BPA arm (Table 1). A total of 25 patients in fitusiran arm (65.8%) had zero treated bleeding events. Efficacy of fitusiran prophylaxis treatment was seen in both hemophilia A and hemophilia B patients with inhibitors. Statistical significance was also achieved for improvement in physical health domain score, with a difference (95% CI) of -28.72 (-39.07 to -18.37, p-value <0.0001) as well as overall HRQoL and between fitusiran and on-demand BPA arms. Overall, 38 patients (92.7%) in the fitusiran arm and 11 patients (57.9%) in the on-demand BPA arm experienced at least 1 treatment emergent adverse event (TEAE). A total of 13 treatment emergent serious adverse events (TESAEs) were reported in 7 patients (17.1%) in the fitusiran arm and 8 TESAEs were reported in 5 patients (26.3%) in the on-demand BPA arm. All TESAEs were reported in 1 patient each; in the fitusiran prophylaxis arm these included events of device related infection, hematuria, spinal vascular disorder, subclavian vein thrombosis, thrombosis, acute cholecystitis, chronic cholecystitis and asymptomatic COVID-19. One patient (2.4%) in the fitusiran arm experienced TEAEs that resulted in study drug discontinuation (spinal vascular disorder and thrombosis). There were no fatal TEAEs reported. Conclusions This Phase 3 study demonstrated the efficacy of the 80 mg monthly subcutaneous prophylaxis dose of fitusiran in people with hemophilia A or B with inhibitors. Specifically, fitusiran significantly reduced bleeding with a median ABR of zero and significant proportion of people with zero bleeds, resulting in a meaningful improvement in health-related quality of life. Reported TESAEs were generally consistent with what is anticipated in an adult and adolescent population with severe hemophilia A or B with inhibitors, or with the previously identified risks of fitusiran. A revised fitusiran dosing regimen with reduced dose and dose frequency is currently being evaluated in ongoing clinical studies. Figure 1 Figure 1. Disclosures Young: Genentech/Roche, Grifols, and Takeda: Research Funding; Apcintex, BioMarin, Genentech/Roche, Grifols, Novo Nordisk, Pfizer, Rani, Sanofi Genzyme, Spark, Takeda, and UniQure: Consultancy. Kavakli: Roche: Consultancy, Other: Clinical Trial Support; Novo Nordisk A/S: Consultancy, Other: Clinical Trial Support; Takeda: Consultancy, Other: Clinical Trial Support. Poloskey: Sanofi: Current Employment, Current equity holder in publicly-traded company. Qui: Sanofi: Current Employment, Current equity holder in publicly-traded company. Kichou: Sanofi: Current Employment, Current equity holder in publicly-traded company. Andersson: Sanofi: Current Employment, Current equity holder in publicly-traded company; WEST advisory committee member: Membership on an entity's Board of Directors or advisory committees. Mei: Sanofi: Current Employment, Current equity holder in publicly-traded company. Rangarajan: Sanofi: Other: Advisory Board; Pfizer: Other: Advisory Board; Reliance Life Sciences: Consultancy; Takeda: Other: Advisory Board, Conference Support, Speakers Bureau.

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The Crimson 1 Study: A Phase 3 Study to Evaluate the Efficacy and Safety of Subcutaneous Marzeptocog Alfa (activated) for on-Demand Treatment and Control of Bleeding Episodes in Subjects with Hemophilia A or Hemophilia B, with Inhibitors

Blood ◽

10.1182/blood-2020-137806 ◽

2020 ◽

Vol 136 (Supplement 1) ◽

pp. 39-40

Author(s):

Linda Neuman ◽

Shraddha Desai ◽

Tom Knudsen ◽

Frank Del Greco ◽

Howard Levy

Keyword(s):

Initial Dose ◽

Hemophilia A ◽

Factor Vii ◽

Coagulation Disorder ◽

Efficacy And Safety ◽

Publicly Traded ◽

Phase 3 ◽

On Demand ◽

History Of ◽

Bleeding Episodes

Background Hemophilia A (HA) and HB are X-linked bleeding disorders caused by a deficiency of Factor VIII (HA) or Factor IX (HB). A significant number of individuals with HA and HB develop inhibitors against the wild-type FVIII or FIX, respectively, and thereby become refractory to factor replacement treatment. Treatment of episodic bleeding in these individuals requires technical expertise to gain the requisite intravenous (IV) access and is often associated with pain. This causes delays in administration, which results in prolonged bleeding and accumulation of blood in the joint or other bleeding site. Currently approved FVIIa containing products take 6-24 hours to achieve hemostasis and maintain efficacy. Marzeptacog alfa (activated) (MarzAA), a novel variant activated recombinant Factor VII (rFVIIa), is being developed for subcutaneous (SQ) administration to address this important unmet need. Data from the Phase 1 study, MAA-102, demonstrated that SQ MarzAA is quickly absorbed and has the potential to achieve and maintain plasma levels in the desired range with an acceptable safety profile. This open-label, global, multi-center, randomized, cross-over Phase 3 study will evaluate the efficacy and safety of MarzAA for on demand treatment of spontaneous or traumatic bleeding episodes in adolescents and adults with congenital HA or HB with inhibitors. MarzAA will be compared to the Standard of Care (SOC). Approximately 60 subjects will be enrolled at 54 sites in 19 countries. Study Design and Methods Key inclusion criteria: Eligible male or female subjects ≥ 12 years of age must have: confirmed diagnosis of HA or HB unresponsive to or intolerant of standard replacement therapy; history of bleeding with annualized bleeding rate of ≥ 8; investigator-confirmed subject's ability to identify bleeding episodes and administer MarzAA SQ and infuse SOC IV at home. Key exclusion criteria: Subjects should not have had previous exposure to SQ administration of rFVIIa or exposure to any other variant rFVIIa; known positive antibody or hypersensitivity to MarzAA, FVIIa, or variants thereof; history of other coagulation disorder(s); platelet count <50,000/µL; CD4 T cell count <200 cells/mm3. Treatment: Subjects >17 years of age will be randomized in blocks to target treatment of approximately 5 bleeds with MarzAA and an additional 5 bleeds with SOC in either order, Sequence A or Sequence B, with a washout period to assess anti-drug antibodies (ADA) status between treatments. A total of 488 eligible bleeds will be treated, ~244 bleeds with each treatment, until ≥80% of patients have ≥3 bleeds treated with MarzAA and SOC. Pharmacokinetic samples will be collected during the MarzAA treatment period. Subjects 12-17 years of age will be enrolled after a positive DSMB assessment of 30 eligible bleeds treated with MarzAA. Subjects will administer 60 µg/kg SQ dose of MarzAA, at 3-hour intervals, for up to 3 doses as required to achieve hemostasis. Endpoints: Primary endpoint includes percentage of treated bleeds resulting in effective hemostasis (excellent or good) at 24 hours after the initial dose. Key secondary endpoints include time to cessation of bleeding after the initial dose; percentage of treated bleeds resulting in effective hemostasis at fixed timepoints; percentage of those that maintain hemostasis at 48 hours after the initial dose; use and amount of rescue therapy. Key safety endpoints include the incidence of adverse events; occurrence of thrombotic events and binding and/or neutralizing anti-drug antibodies. Key exploratory endpoints include assess patient satisfaction with the Treatment Satisfaction Questionnaire for Medicine- 9; assessment of pain using the Visual Analogue Scale; time required to administer treatment. Statistics: The goal is to demonstrate the true proportion of bleeds effectively treated with MarzAA is not inferior to SOC. Using a baseline efficacy of 85% for SOC, with a -12% margin of non-inferiority, treatment of 244 bleeds in each group provides 90% power with a one-sided 2.5% significance level to substantiate this result. Figure Disclosures Neuman: Catalyst Biosciences: Current Employment, Current equity holder in publicly-traded company. Desai:Catalyst Biosciences: Current Employment, Current equity holder in publicly-traded company. Knudsen:Catalyst Biosciences: Current Employment, Current equity holder in publicly-traded company. Del Greco:Catalyst Biosciences: Current Employment, Current equity holder in publicly-traded company. Levy:Catalyst Biosciences: Current Employment, Current equity holder in publicly-traded company.

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Auriculotherapy to reduce anxiety and pain in nursing professionals: a randomized clinical trial

Revista Latino-Americana de Enfermagem ◽

10.1590/1518-8345.1761.2843 ◽

2017 ◽

Vol 25 (0) ◽

Cited By ~ 4

Author(s):

Leonice Fumiko Sato Kurebayashi ◽

Ruth Natalia Teresa Turrini ◽

Talita Pavarini Borges de Souza ◽

Carolina Felicio Marques ◽

Renata Tavares Franco Rodrigues ◽

...

Keyword(s):

Quality Of Life ◽

Clinical Trial ◽

Randomized Clinical Trial ◽

Nursing Staff ◽

Repeated Measures ◽

Statistical Significance ◽

Cohen’S D ◽

Pain Visual Analog Scale ◽

Cohen's D

RESUMEN Objectives: to evaluate the effectiveness of the auricular protocol (APPA) in reducing pain and anxiety and improving the quality of life of the nursing staff of a hospital. Method: randomized clinical trial with an initial sample of 180 professionals divided into 4 groups Control (G1), Seed (G2), Needle (G3) and Tape (G4). The evaluation instruments were the State-Trait Anxiety Inventory, Pain Visual Analog Scale and Quality of Life instrument, applied at the start and after five and 10 sessions (five weeks). Descriptive statistics, analysis of variance (ANOVA) and Cohen's d Index were used in the analysis. Results: there was a statistical difference (p < 0.05) for anxiety according to the repeated measures ANOVA, with better results for the G3 in the final assessment (Cohen's d index 1.08/17% reduction). There was a reduction of pain of 36% in G3 and 24% in G2 and a 13% increase in the mental aspect of quality of life for the G3, although without statistical significance. Conclusion: the APPA protocol reduced the anxiety levels of nursing staff after 10 sessions. Further studies are, however, suggested with new populations and in different contexts so that the results can be confirmed. RBR-5pc43m.

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Impact of adding plinabulin to pegfilgrastim for the prevention of TAC chemotherapy (Chemo) induced neutropenia (CIN), on patient quality of life (QoL).

Journal of Clinical Oncology ◽

10.1200/jco.2021.39.15_suppl.e24031 ◽

2021 ◽

Vol 39 (15_suppl) ◽

pp. e24031-e24031

Author(s):

Ramon Mohanlal ◽

Yvette Lelorier ◽

Dominic Mitchell ◽

Lan Huang ◽

Douglas W. Blayney

Keyword(s):

Clinical Trial ◽

Energy Levels ◽

Breast Cancer Patients ◽

Emotional Wellbeing ◽

Phase 3 ◽

Tac Chemotherapy ◽

Physical Wellbeing ◽

The Impact ◽

Clinical Trial Information

e24031 Background: Plinabulin is a novel non-G-CSF small molecule being developed for the prevention of chemotherapy in conjunction with pegfilgrastim and is administered via 30 min IV infusion, 30 min after chemo on Day (D) 1. The QoL was analyzed using the Functional Assessment of Cancer Therapy - General questionnaire (FACT-G) as part of a phase 3 (Ph3) clinical trial comparing pegfilgrastim alone versus pegfilgrastim and plinabulin for the prevention of neutropenia in newly diagnosed breast cancer patients being treated with Docetaxel (75 mg/m2), Doxorubicin (50 mg/m2), and Cyclophosphamide (500 mg/m2) (TAC) on D1 for four 21 D cycles and study treatment. Methods: The FACT-G was administered to patients in China and Ukraine using an ePRO app downloaded onto patients' phones as part of the Phase 3 PROTECTIVE-2 trial (NCT0329457) with TAC. Patients completed the FACT-G during each chemo cycle at D-1, D1, D8 and D15. Patients received reminders 1 hour before the required completion time and all entries were time stamped. The FACT-G measured the impact of cancer on four categories: Physical wellbeing, Social wellbeing, Emotional wellbeing and Functional wellbeing. Results: Compared to pegfilgrastim alone, patients on plinabulin + pegfilgrastim performed significantly better for Physical wellbeing on D8 and D15 of Cycle 2 (p < 0.0589 and p < 0.0039 respectively) and Cycle 3 (p < 0.0360 and p < 0.0343 respectively). Further analysis of the sub questions showed that both energy levels “I have a lack of energy” and pain”(I have pain” were significantly better for the plinabulin + pegfilgrastim combination versus pegfilgrastim alone (p < 0.0377 and p < 0.0420 respectively). Overall FACT-G completion compliance for the trial was 91%. Conclusions: The Physical wellbeing (in particular, pain and for energy levels) of patients receiving plinabulin in combination with pegfilgrastim for the prevention of TAC CIN, was significantly less impacted by chemo dosing compared to the pegfilgrastim alone arm. In addition, the results suggest that patients receiving the combination therapy recovered their pre-chemo Physical wellbeing levels more rapidly. Clinical trial information: NCT03531099.

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Factor VIII Use in the Treatment of Breakthrough Bleeds in Hemophilia A Patients without Inhibitors on Emicizumab Prophylaxis: The Phase 3 HAVEN 3 Study Experience

Blood ◽

10.1182/blood-2019-123654 ◽

2019 ◽

Vol 134 (Supplement_1) ◽

pp. 2395-2395

Author(s):

Michael Callaghan ◽

Benjamin Trzaskoma ◽

Richard H. Ko ◽

Lucy Lee ◽

Anisha M. Patel ◽

...

Keyword(s):

Factor Viii ◽

Exposure Time ◽

Cumulative Dose ◽

Research Funding ◽

Hemophilia A ◽

Phase 3 ◽

Breakthrough Bleeding ◽

On Demand ◽

Equity Ownership ◽

The Individual

Introduction HAVEN 3 was a phase 3 study investigating the use of emicizumab as prophylaxis in adult and adolescent (≥12 years old) persons with hemophilia A (PwHA) without factor VIII (FVIII) inhibitors (NCT02847637; Mahlangu et al. 2018). HAVEN 3 demonstrated that emicizumab prophylaxis once weekly or every two weeks was safe and highly effective in bleed prevention. The primary analysis of HAVEN 3 included an intrapatient comparison of 48 participants who received FVIII prophylaxis in a non-interventional study (NIS) prior to enrollment in HAVEN 3. Compared with emicizumab prophylaxis during the HAVEN 3 study, emicizumab prophylaxis resulted in an annualized bleed rate that was 68% lower than the rate with previous FVIII prophylaxis (1.5 vs 4.8, p<0.001). No dosing guidance was provided regarding the use of on-demand FVIII in HAVEN 3, and investigators prescribed FVIII at their own discretion. In this subsequent analysis, we characterize the dose and frequency of replacement FVIII used for the treatment of breakthrough bleeding in these 48 participants. Methods The primary comparisons in our analyses are focused on on-demand FVIII use for breakthrough bleeding while participants were on FVIII prophylaxis during the NIS versus its use while on emicizumab prophylaxis during HAVEN 3. Any use of on demand FVIII other than to manage breakthrough bleeding (e.g. prior to activity) was not included in our analyses. Given that, collectively, the total exposure time to emicizumab during HAVEN 3 was more than twice the exposure time to FVIII prophylaxis during the NIS (75.8 vs 28.6 years respectively), any treatment comparisons are drawn on an annualized basis. Annualized on-demand FVIII use was calculated by dividing by the number of days in the efficacy period and multiplying the resulting daily consumption by 365.25 days. The number of infusions and cumulative doses of on-demand FVIII use are described at the participant level as well as at the individual bleed level and are presented descriptively for both the NIS and HAVEN 3 exposure periods. No formal statistical inferences (i.e. calculation of p-values) have been conducted. All analyses were based on an October 2018 data cutoff. Results A total of 48 participants who were treated with FVIII prophylaxis during the NIS were then treated with emicizumab prophylaxis during HAVEN 3 and thus make up the total cohort for our analyses. Annualized infusion rates of on-demand FVIII per participant and cumulative doses of on-demand FVIII (in international units [IU] per kilogram) per participant were higher during the FVIII prophylaxis period when compared with the emicizumab exposure period (mean 15.3 vs 7.2; median 3.6 vs 0.6 annual infusions per participant and mean 602.4 IU/kg vs 209.0 IU/kg; median 75.5 IU/kg vs 19.1 IU/kg, respectively). At the individual bleed level, FVIII infusions and total cumulative dose suggested that participants were administered a similar amount of medication to treat bleeds during both the NIS and HAVEN 3 study periods: median number of infusions per bleed were 1.0 (interquartile range [IQR]=1.0) versus 2.0 (IQR=3.0) and median cumulative doses were 43.5 (IQR=35.1) versus 50.0 (IQR=72.7) IU/kg, respectively (Table 1). Conclusions This analysis revealed a lower annualized infusion rate and a correspondingly lower annualized cumulative dose of FVIII for treatment of breakthrough bleeds during emicizumab prophylaxis compared with FVIII prophylaxis. At the individual bleed level, the amount of on-demand FVIII used per bleeding episode was comparable between NIS and HAVEN 3 exposure periods. Thus, based on this single analysis, it appears that patients received less on-demand FVIII during emicizumab prophylaxis compared with FVIII prophylaxis, as a result of overall reduction of bleed frequency, while the treatment of individual bleeds appeared similar regardless of the prophylaxis therapy administered. Disclosures Callaghan: Octapharma: Consultancy; Novonordisk: Consultancy, Speakers Bureau; Global Blood Therapeutics: Consultancy; Sanofi: Consultancy; Takeda: Consultancy, Research Funding; Bayer: Consultancy, Speakers Bureau; Alnylum: Equity Ownership; Biomarin, Bioverativ, Grifols, Kedrion, Pfizer, Roche/Genentech, Shire, and Spark Therapeutics: Consultancy; Roche/Genentech: Speakers Bureau; Shire/Takeda: Speakers Bureau; Pfizer: Research Funding; Roche: Research Funding. Trzaskoma:Genentech: Employment, Equity Ownership. Ko:Genentech, Inc.: Employment. Lee:Genentech, Inc.: Employment. Patel:Genentech: Employment; Roche/Genentech: Equity Ownership. Tzeng:Genentech, Inc.: Employment. Shah:Genentech: Employment. Chang:Genentech, Inc.: Employment; Genentech/Roche: Equity Ownership. Niggli:F. Hoffmann-La Roche Ltd: Employment. Dhalluin:F. Hoffmann-La Roche Ltd: Employment. Mahlangu:Sanofi: Research Funding; Pfizer: Research Funding; Novartis: Research Funding; Biomarin: Research Funding; Spark: Consultancy, Honoraria, Research Funding, Speakers Bureau; Roche: Consultancy, Honoraria, Research Funding, Speakers Bureau; Novo Nordisk: Consultancy, Honoraria, Research Funding, Speakers Bureau; Catalyst Biosciences: Consultancy, Honoraria, Research Funding, Speakers Bureau; CSL Behring: Consultancy, Honoraria, Research Funding, Speakers Bureau; Baxalta: Consultancy, Honoraria, Research Funding, Speakers Bureau; Unique: Research Funding.

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Impact of Systematic Pharmacokinetic (PK) Profiles in a Cohort of 29 Patients Treated with Conventional and Extended-Half Life (EHL) Products

Blood ◽

10.1182/blood-2019-132199 ◽

2019 ◽

Vol 134 (Supplement_1) ◽

pp. 1123-1123

Author(s):

Teresa Ceglie ◽

Berardino Pollio ◽

Irene Ricca ◽

Maria Messina ◽

Claudia Linari ◽

...

Keyword(s):

Hemophilia A ◽

Factor Ix ◽

Hemophilia B ◽

Null Mutation ◽

Severe Hemophilia ◽

Factor Level ◽

On Demand ◽

Active Life ◽

Genetic Assessment

Introduction. Prophylaxis with factor concentrates reduces bleeding events and improves quality of life for adults and children with severe hemophilia. However, the optimal dosing and infusion frequency is not yet established. Integration of PK data into decision making is gaining support, in particular at the transition between conventional and EHL products. Here we report about 29 PK data of patients affected by hemophilia treated at our centre since childhood. Improved quality of life was our first aim, supposed that decreasing frequency of infusions or increasing the target through factor level allows a more active life without increased risk of bleeding. Patients' characteristics and methods. 18 patients (62%) were ≤ 18 years of age at PK time. 16 were affected by severe hemophilia A, 5 by moderate hemophilia A, 6 by severe hemophilia B and 2 by moderate hemophilia B. At PK time, 28 patients were on prophylaxis and 1 was on demand with recombinant factor IX. Median age at onset of prophylaxis was 9 years (range 3 months-38 years). Genetic assessment was available in 24 patients. Of these, 37.5% and 62.5% were carriers of null and not null mutations respectively. 4 patients were undergone to PK with standard products (1 Octocog alfa, 1 Simoctocog alfa, 1 Octocog alfa-Kovaltry®, 1 Turoctocog alfa) in order to define timing and dosage of successive infusions, while 25 patients switched to EHL factors (15 Efmoroctocog alfa, 2 Ionoctocog alfa, 7 Albutrepenonacog alfa, 1 Eftrenonacog alfa). In 15 patients a population-based PK (popPK) according to WAPPS-Hemo program was also performed. The annualized bleeding rate (ABR) was counted from patient's home bleeding records for one year before PK until now. Results. According to PK data, 21 patients (75%) decreased infusion frequency (100% hemophilia B and 67% hemophilia A patients). The remaining 7 hemophilia A patients maintained the same timing in order to increase the through factor level. Notably, 1 hemophilia B patient switched from on demand treatment to prophylaxis with EHL product due to the more acceptable schedule. 66% of null mutation patients and 73% of not null mutation patients decreased timing. Of 28 patients available at follow-up, 32%, 50% and 18% decreased, increased and maintained the same annual average factor consumption/kg, respectively. All patients had a good adherence after switch. In particular, the on demand patient started a regular prophylaxis with optimal compliance. ABR displayed a reduction with a median of 0 (range 0-5) after PK analysis compared to 1 (range 0-12) before the switch. Full PK vs popPK data obtained using at least two individual PK sampling points were almost similar. Conclusions. Our results remark the necessity of PK study especially in children due to the inter-individual variability independent of genetic assessment. Regarding factor IX, PK allowed us to propose timing even longer than that recommended by prescribing indications resulting in a better personalized prophylaxis. Moreover, our study demonstrates that a full PK analysis is feasible also in children. However, given similar results, popPK could be more feasible in most patients. Regarding consumption, the reduction of only 32% of patients reflects our aim to maintain a high safety profile in an active pediatric population. Nevertheless, the mean annualized consumption was just 0.6-fold increased in the remaining patients. This approach led us to further reduce ABR and in some cases to obtain a persistent no-bleeding status even with a full active life. Disclosures No relevant conflicts of interest to declare.

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Fitusiran Treatment Impacts on Health-Related Quality of Life in Subjects with Hemophilia A and B with Inhibitors Assessed with the Haemophilia Quality of Life Questionnaire for Adults (Haem-A-QoL)

Blood ◽

10.1182/blood-2020-142266 ◽

2020 ◽

Vol 136 (Supplement 1) ◽

pp. 23-24

Author(s):

Sylvia Von Mackensen ◽

Pratima Chowdary ◽

Sarah Mangles ◽

Qifeng Yu ◽

Baisong Mei ◽

...

Keyword(s):

Quality Of Life ◽

Hemophilia A ◽

Phase 1 ◽

Phase 2 ◽

Publicly Traded ◽

Advisory Committees ◽

Related Quality ◽

Health Related ◽

Dose Dependent

Background: Fitusiran, an investigational RNA interference treatment for people with hemophilia A or B (PwH), with or without inhibitors, has shown dose-dependent lowering of antithrombin, increase in thrombin generation, and decrease in bleeding frequency in clinical trials. The novel mechanism of action and long pharmacodynamic effect enables once-monthly subcutaneous administration. This sustained hemostatic protection and less burdensome administration may improve patient-reported outcomes (PRO). Objective: To evaluate changes in PRO in terms of patient-relevant improvements in health-related quality of life (HRQoL) in PwH with inhibitors (PwHI) on prophylactic fitusiran treatment. Methods: Fitusiran was evaluated in a phase 1 dose-escalation study (NCT02035605) followed by a phase 2 open-label extension (OLE) study (NCT02554773) with monthly subcutaneous fixed doses of 50 mg or 80 mg. HRQoL was assessed using the Haem-A-QoL and the EuroQol 5 Dimensions (EQ-5D) questionnaires at baseline and at end of study in a cohort of 17 PwHI (Hemophilia A, n=15; Hemophilia B, n=2) from the phase 1 study. Results: Subjects previously treated on-demand or prophylactically had a mean (standard deviation [SD]) age of 34.6 (10.3) years and a mean (SD) number of bleeding episodes in the 6 months before baseline of 16.6 (10.7). Mean (SD) changes from baseline to end of study (day 84 or later) in Haem-A-QoL total (-9.2 [11.2]) and physical health (−12.3 [15.1]) domain scores suggest clinically meaningful improvement (lower scores indicate better HRQoL). Numeric reduction (i.e., improvement) in all other domains appeared to be dose-dependent (greater improvement in the 80 mg group) (Table 1). Changes in EQ-5D utility and EQ-VAS scores were not clinically meaningful. Further analyses in PwH with and without inhibitors from the phase 2 OLE will be presented. Conclusions: Fitusiran prophylaxis may improve HRQoL - particularly the Haem-A-QoL 'Physical health' domain (painful swelling, joint pain, pain with movement, difficulty walking, and time to get ready) as shown in a cohort of 17 PwHI . Additional analyses from ongoing OLE and phase 3 studies are planned to quantify the patient-relevant changes with fitusiran treatment in all hemophilia patients over time. Disclosures Von Mackensen: Sanofi, Bayer, Sobi, Chugai, Kedrion, Spark: Consultancy; Biotest, Sobi, CSL Behring: Honoraria; Novo Nordisk, Sobi: Research Funding. Chowdary:BioMarin: Honoraria; Bayer, CSL Behring, Freeline, Novo Nordisk, Pfizer and Sobi: Research Funding; Chugai, CSL Behring, Novo Nordisk, Pfizer, Roche, Sobi: Speakers Bureau; Bayer, Chugai, CSL Behring, Freeline, Novo Nordisk, Pfizer, Roche, Sanofi, Shire (Baxalta), Sobi, Spark: Membership on an entity's Board of Directors or advisory committees. Mangles:Roche, Takeda, Novo Nordisk: Consultancy, Membership on an entity's Board of Directors or advisory committees; Sobi, Octapharma, Novo Nordisk, Shire and Roche/Chugai: Other: travel funding. Yu:Sanofi: Other: was an employee and stockholder of Sanofi, at the time of study; Albireo Pharmaceuticals, Inc: Current Employment. Mei:Sanofi: Current Employment, Current equity holder in publicly-traded company. Andersson:Sanofi: Current Employment, Current equity holder in publicly-traded company. Dasmahapatra:Sanofi: Current Employment, Current equity holder in publicly-traded company.

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A Population Pharmacokinetic Model for Concizumab Based on Phase 1 and Phase 2 Trial Data

Blood ◽

10.1182/blood-2020-140255 ◽

2020 ◽

Vol 136 (Supplement 1) ◽

pp. 4-4

Author(s):

Trine Høyer Rose ◽

Christian Hollensen ◽

Henrik Agersø ◽

Rune Viig Overgaard

Keyword(s):

Rate Constant ◽

Drug Disposition ◽

Hemophilia A ◽

Phase 1 ◽

Population Pharmacokinetic ◽

Phase 2 ◽

Publicly Traded ◽

Phase 3 ◽

Target Mediated Drug Disposition ◽

Population Pk

Introduction Concizumab is a high-affinity anti-tissue factor pathway inhibitor (TFPI) monoclonal antibody in clinical investigation for the subcutaneous (SC) treatment of patients with hemophilia. The data generated from phase 1 and 2 concizumab trials have been used to develop a population pharmacokinetic (PK) model with the aim of supporting dose selection for phase 3 trials. WMethods The objective of this study was to develop a model to describe the PK of concizumab across administration routes in various groups of patients with hemophilia to generate a generally applicable population PK model of concizumab. The model was developed based on available PK data from four phase 1 trials (for both intravenous [IV] and SC concizumab administration) and two phase 2 trials (for SC concizumab administration). Trial populations in the phase 1 trials included both healthy subjects and patients with hemophilia, whilst the phase 2 trials enrolled patients with hemophilia A or B with inhibitors and patients with hemophilia A without inhibitors. A structural population PK model was first developed based on phase 1 data and the final population PK model was then estimated using data from both phase 1 and phase 2 trials. Simulations were performed for phase 3 concizumab exposure using a full parametric simulation (n=10,000), including both inter-individual and intra-individual variability for the selected population. Randomly sampled body weights from a normal distribution with mean and variance corresponding to body weight distribution from phase 2 trials were used to simulate patient profiles. WResults The population PK dataset used for the model comprised 1,504 observations from 119 subjects (89 patients and 30 healthy individuals), with a mean age of 35 years (range: 18-65 years) and mean body weight of 74.4 kg (range: 47.1-130 kg). The PK model parameters were first estimated based on phase 1 data alone, and after fixing the majority in order to ensure robustness of the model only a few parameters were re-estimated based on phase 1 and 2 data combined. The PK model (Figure 1) was evaluated by standard goodness-of-fit plots and qualification assessments. Using visual predictive checks, it was shown that the model was able to reproduce the median and the 5th and 95th percentiles of the observed concizumab concentrations from phase 1 and 2 trials, and so it was deemed suitable for simulation purposes. The PK model suggested a target-mediated drug disposition following concizumab binding to TFPI at the endothelium, and subsequent elimination of the complex to account for the non-linear elimination. WConclusions The developed model accurately described the PK of concizumab delivered at a wide dose range by either SC or IV administration to both healthy subjects and patients with hemophilia A or B with and without inhibitors. The model was used for simulations to select the dosing regimen for subsequent phase 3 studies. Figure 1. Concizumab pharmacokinetic model. Structure of the final concizumab PK model for SC and IV dosing with target-mediated drug disposition via the endothelial TFPI. CL, clearance; doseiv, intravenous dose; dosesc, subcutaneous dose; IV, intravenous; ka, absorption rate constant; kcom, elimination rate constant of the concizumab-TFPI complex; kon and koff, rate constants for binding of concizumab to the endothelial TFPI; ktr, rate constant from the transit compartment; Q, inter-compartmental clearance; Rtot, amount of endothelial TFPI available for concizumab binding; SC, subcutaneous; TFPI, tissue factor pathway inhibitor; V, volume. Figure Disclosures Høyer Rose: Novo Nordisk A/S: Current Employment, Divested equity in a private or publicly-traded company in the past 24 months. Hollensen:Novo Nordisk: Current Employment, Current equity holder in private company, Current equity holder in publicly-traded company. Agersø:Novo Nordisk A/S: Current Employment. Viig Overgaard:Novo Nordisk A/S: Current Employment, Current equity holder in publicly-traded company.

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O-135 Long term secondary efficacy of linzagolix for heavy menstrual bleeding (HMB) due to uterine fibroids (UF): 52-week results from two placebo-controlled, randomized, phase 3 trials

Human Reproduction ◽

10.1093/humrep/deab126.060 ◽

2021 ◽

Vol 36 (Supplement_1) ◽

Author(s):

H Taylor ◽

J Donnez ◽

F Petraglia ◽

K Gemzell Danielsson ◽

S Renner ◽

...

Keyword(s):

Quality Of Life ◽

Pain Score ◽

Uterine Fibroids ◽

Heavy Menstrual Bleeding ◽

Menstrual Bleeding ◽

Phase 3 ◽

Once Daily ◽

Secondary Endpoints

Abstract Study question Are symptomatic improvements in women with UF observed after 24 weeks of linzagolix treatment with or without add-back therapy (ABT) maintained over 52 weeks? Summary answer Improvements in anemia, pain and quality of life previously reported at 24 weeks were maintained at 52 weeks. What is known already We previously reported that partial or full suppression of estradiol (E2) with once daily doses of either 100 or 200 mg linzagolix for 24 weeks, with or without ABT, were effective in reducing heavy menstrual bleeding associated with uterine fibroids, improving other symptoms such as pain and anemia and improving quality of life. Here we report the maintenance of effect on secondary endpoints after 52 weeks of treatment. Study design, size, duration Linzagolix is an investigational, oral GnRH antagonist being developed to treat HMB due to UF. PRIMROSE 1 (P1, USA, NCT03070899) and PRIMROSE 2 (P2, Europe and USA, NCT03070951) are randomized, double-blind, placebo-controlled Phase 3 trials, with essentially identical design, investigating the efficacy and safety of linzagolix with and without hormonal add-back therapy (ABT: 1 mg estradiol/0.5 mg norethindrone acetate) once daily for 52 weeks. Participants/materials, setting, methods Participants had HMB due to UF (>80mL menstrual blood loss (MBL)/cycle) and were equally randomized to: placebo, linzagolix 100mg, linzagolix 100mg+ABT, linzagolix 200mg, or linzagolix 200mg+ABT. After 24 weeks, subjects originally randomized to placebo or linzagolix 200mg were switched to linzagolix 200mg+ABT except in P1 where 50% placebo subjects continued placebo until 52 weeks. Secondary efficacy assessments included hemoglobin, pain (0–10 numeric rating scale) and health related quality of life (HRQL) on the UF-QoL questionnaire. Main results and the role of chance P1 trial subjects (n = 526) had a mean age of 42 years, pain score of 6.6 and HRQL total score (0–100) of 36.4 and 63% were Black. P2 trial subjects (n = 511) had a mean age of 43 years, pain score 4.8 and HRQL total score of 46.1 and 5% were Black. Mean baseline MBL was about 200 mL per cycle in both studies. In both trials, significant improvements compared to placebo observed at week 24 for secondary endpoints, including pain, anemia and QoL in all linzagolix treatment groups were maintained at 52 weeks. Mean±SD hemoglobin levels in anemic patients (<12 g/dL) increased from baseline by 1.7±1.9, 1.9±1.7, 2.2±2.4, 2.7±1.9 in P1 and 1.2±1.9, 2.9±1.8, 2.4±2.1, 3.0±1.4 in P2 in the 100mg, 100mg+ABT, 200mg/200mg+ABT, 200mg+ABT groups, respectively, compared to 0.6±1.8 with placebo (P1). Mean±SD change from baseline in pain scores were -3.3±3.1, -2.7±3.2, -2.6±3.0, -3.9±3.2 in P1 and -2.6±3.1, -2.6±2.8, -3.0±2.6, -2.8±3.0 in P2 in the 100mg, 100mg+ABT, 200mg/200mg+ABT, 200mg+ABT groups, respectively, compared to -0.4±2.5 with placebo (P1). Mean±SD change in HRQL total scores were 25.0±26.2, 34.2±30.1, 29.7±29.2, 38.3±29.2 in P1 and 16.8±24.0, 29.6±23.2, 31.9±26.8, 30.7±26.0 in P2 in the 100mg, 100mg+ABT, 200mg/200mg+ABT, 200mg+ABT groups, respectively, compared to 14.6±23.9 with placebo (P1). Limitations, reasons for caution Here we report data in both trials up to 52 weeks of treatment. No statistical comparisons were done at 52 weeks (the primary analysis was done after 24 weeks treatment). Post-treatment follow-up will provide more information in symptom recurrence after stopping treatment. Wider implications of the findings All linzagolix treatments provided sustained benefit. Two regimens previously identified for potential long-term treatment, 200mg with ABT and 100mg without ABT, provided sustained improvements of anemia, pain and associated quality of life. These different treatment regimens could be important to address the diverse needs of women suffering from uterine fibroids. Trial registration number ClinicalTrials.gov: NCT03070899, NCT03070951

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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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