Pharmacokinetics, Safety, and Efficacy of Maraviroc in Treatment-Experienced Pediatric Patients Infected With CCR5-Tropic HIV-1

Maraviroc is a CCR5 antagonist approved to treat adults infected with CCR5-tropic (R5) HIV-1. Study A4001031 was conducted to evaluate the pharmacokinetics, safety, and efficacy of maraviroc in combination with optimized background therapy (OBT) in treatment-experienced pediatric patients infected with R5 HIV-1 and support registration of maraviroc for pediatric use

Global Seroprevalence of Pre-existing Immunity Against AAV5 and Other AAV Serotypes in People with Hemophilia A.

Adeno-associated virus (AAV)-mediated gene therapy may provide durable protection from bleeding events and reduce treatment burden for people with hemophilia A (HA). However, pre-existing immunity against AAV may limit transduction efficiency and hence treatment success. Global data on the prevalence of AAV serotypes are limited. In this global, prospective, noninterventional study, we determined the prevalence of pre-existing immunity against AAV2, AAV5, AAV6, AAV8, and AAVrh10 among people ≥12 years of age with HA and residual FVIII levels ≤2 IU/dL. Antibodies against each serotype were detected using validated, electrochemiluminescent-based enzyme-linked immunosorbent assays. To evaluate changes in antibody titers over time, 20% of participants were retested at 3 and 6 months. In total, 546 participants with HA were enrolled at 19 sites in 9 countries. Mean (standard deviation) age at enrollment was 36.0 (14.87) years, including 12.5% younger than 18 years, and 20.0% 50 years of age and older. On day 1, global seroprevalence was 58.5% for AAV2, 34.8% for AAV5, 48.7% for AAV6, 45.6% for AAV8, and 46.0% for AAVrh10. Considerable geographic variability was observed in the prevalence of pre-existing antibodies against each serotype, but AAV5 consistently had the lowest seroprevalence across the countries studied. AAV5 seropositivity rates were 51.8% in South Africa (n = 56), 46.2% in Russia (n = 91), 40% in Italy (n = 20), 37.2% in France (n = 86), 26.8% in the United States (n = 71), 26.9% in Brazil (n = 26), 28.1% in Germany (n = 89), 29.8% in Japan (n = 84), and 5.9% in the United Kingdom (n = 17). For all serotypes, seropositivity tended to increase with age. Serostatus and antibody titer were generally stable over the 6-month sampling period. As clinical trials of AAV-mediated gene therapies progress, data on the natural prevalence of antibodies against various AAV serotypes may become increasingly important

PERSEPT 3: A phase 3 clinical trial to evaluate the haemostatic efficacy of eptacog beta (recombinant human FVIIa) in perioperative care in subjects with haemophilia A or B with inhibitors.

INTRODUCTION: Surgical procedures in persons with haemophilia A or B with inhibitors (PwHABI) require the use of bypassing agents (BPA) and carry a high risk of complications. Historically, only two BPAs have been available; these are reported to have variable responses. AIM: To prospectively evaluate the efficacy and safety of a new bypassing agent, human recombinant factor VIIa (eptacog beta) in elective surgical procedures in PwHABI in a phase 3 clinical trial, PERSEPT 3. METHODS: Subjects were administered 200 µg/kg (major procedures) or 75 µg/kg eptacog beta (minor procedures) immediately prior to the initial surgical incision; subsequent 75 µg/kg doses were administered to achieve postoperative haemostasis and wound healing. Efficacy was assessed on a 4-point haemostatic scale during the intra- and postoperative periods. Anti-drug antibodies, thrombotic events and changes in clinical/laboratory parameters were monitored throughout the perioperative period. RESULTS: Twelve subjects underwent six major and six minor procedures. The primary efficacy endpoint success proportion was 100% (95% CI: 47.8%-100%) for minor procedures and 66.7% (95% CI: 22.3%-95.7%) for major procedures; 81.8% (95% CI: 48.2%-97.7%) of the procedures were considered successful using eptacog beta. There was one death due to bleeding from a nonsurgical site; this was assessed as unlikely related to eptacog beta. No thrombotic events or anti-eptacog beta antibodies were reported. CONCLUSION: Two eptacog beta dosing regimens in PwHABI undergoing major and minor surgical procedures were well-tolerated, and the majority of procedures were successful based on surgeon/investigator assessments. Eptacog beta offers clinicians a new potential therapeutic option for procedures in PwHABI

Eptacog beta efficacy and safety in the treatment and control of bleeding in paediatric subjects (<12 years) with haemophilia A or B with inhibitors.

INTRODUCTION: Eptacog beta is a new recombinant activated human factor VII bypassing agent approved in the United States for the treatment and control of bleeding in patients with haemophilia A or B with inhibitors 12 years of age or older. AIM: To prospectively assess in a phase 3 clinical trial (PERSEPT 2) eptacog beta efficacy and safety for treatment of bleeding in children <12 years of age with haemophilia A or B with inhibitors. METHODS: Using a randomised crossover design, subjects received initial doses of 75 or 225 μg/kg eptacog beta followed by 75 μg/kg dosing at predefined intervals (as determined by clinical response) to treat bleeding episodes (BEs). Treatment success criteria included a haemostasis evaluation of 'excellent' or 'good' without use of additional eptacog beta, alternative haemostatic agent or blood product, and no increase in pain following the first 'excellent' or 'good' assessment. RESULTS: Treatment success proportions in 25 subjects (1-11 years) who experienced 546 mild or moderate BEs were 65% in the 75 μg/kg initial dose regimen (IDR) and 60% in the 225 μg/kg IDR 12 h following initial eptacog beta infusion. By 24 h, the treatment success proportions were 97% for the 75 μg/kg IDR and 98% for the 225 μg/kg IDR. No thrombotic events, allergic reactions, neutralising antibodies or treatment-related adverse events were reported. CONCLUSION: Both 75 and 225 μg/kg eptacog beta IDRs provided safe and effective treatment and control of bleeding in children <12 years of age

The safety of activated eptacog beta in the management of bleeding episodes and perioperative haemostasis in adult and paediatric haemophilia patients with inhibitors.

INTRODUCTION: Haemophilia patients with inhibitors often require a bypassing agent (BPA) for bleeding episode management. Eptacog beta (EB) is a new FDA-approved recombinant activated human factor VII BPA for the treatment and control of bleeding in haemophilia A or B patients with inhibitors (≥12 years of age). We describe here the EB safety profile from the three prospective Phase 3 clinical trials performed to date. AIM: To assess EB safety, immunogenicity and thrombotic potential in children and adults who received EB for treatment of bleeding and perioperative care. METHODS: Using a randomized crossover design, 27 subjects in PERSEPT 1 (12-54 years) and 25 subjects in PERSEPT 2 (1-11 years) treated bleeding episodes with 75 or 225 μg/kg EB initially followed by 75 μg/kg dosing at predefined intervals as determined by clinical response. Twelve PERSEPT 3 subjects (2-56 years) received an initial preoperative infusion of 75 μg/kg (minor procedures) or 200 μg/kg EB (major surgeries) with subsequent 75 μg/kg doses administered intraoperatively and post-operatively as indicated. Descriptive statistics were used for data analyses. RESULTS: Sixty subjects who received 3388 EB doses in three trials were evaluated. EB was well tolerated, with no allergic, hypersensitivity, anaphylactic or thrombotic events reported and no neutralizing anti-EB antibodies detected. A death occurred during PERSEPT 3 and was determined to be unlikely related to EB treatment by the data monitoring committee. CONCLUSION: Results from all three Phase 3 trials establish an excellent safety profile of EB in haemophilia A or B patients with inhibitors for treatment of bleeding and perioperative use

Eptacog Beta Efficacy in Children and Adolescents with Hemophilia A or B and Inhibitors: Subset Analysis Suggests Improved Caregiver Capacity to Assess Bleeding Episode Resolution with Subject Age

Abstract Introduction Following treatment with a bypassing agent, parents or caregivers often face difficulties in determining bleeding episode (BE) resolution in children with hemophilia A or B and inhibitors (CwHABI), potentially contributing to a longer treatment duration in children as compared to adults (Valentino et al, Haemophilia 2012; 18:554-60. Gruppo et al, Haemophilia 2013; 19:524-32). Eptacog beta is a new recombinant activated human factor VII proven to be safe and effective for the treatment and control of BEs in patients with hemophilia A or B with inhibitors (≥12 years of age). The pivotal phase 3 trial (PERSEPT 1; NCT02020369) included subjects from ages 12 to <18 years, in addition to adult subjects. A subsequent phase 3 trial (PERSEPT 2; NCT02448680) further examined the safety and efficacy of eptacog beta for bleed treatment in CwHABI <12 years of age. Within this population, we hypothesized that caregivers could better ascertain treatment success in older children, which would manifest as increasing eptacog beta efficacy measurements and tighter 95% confidence intervals (CIs) with increasing subject age. We explored this question by analyzing BE treatment success in three age subgroups within PERSEPT 1 and PERSEPT 2. Aims The study objective is to evaluate and compare the clinical response to eptacog beta for BEs in CwHABI at 12 and 24 hours after initial dose of eptacog beta in 3 pediatric age subgroups (<6 years, 6 to <12 years, and 12 to <18 years). Methods PERSEPT 1 and PERSEPT 2 were prospective, global, open-label trials of eptacog beta using two initial dose regimens (IDRs) of 75 and 225 µg/kg in a randomized, non-blinded, crossover design. Subjects received initial doses of 75 or 225 µg/kg eptacog beta followed by 75 µg/kg dosing at predefined intervals (determined by clinical response) to treat BEs (Figure 1). Treatment success for mild or moderate BEs was defined as obtaining a hemostasis evaluation of "excellent" or "good" with no use of additional eptacog beta, alternative hemostatic agents or blood products, and no increase in pain following the first "excellent" or "good" assessment. Evaluations were provided by the parent/caregiver in conjunction with the study participant when possible, depending upon subject age and verbal capacity. Written informed consent from the participants' parents/legal guardians were obtained at enrollment. Results Thirty subjects were assessed (25 from PERSEPT 2 [13 subjects, 0 to <6 years; 12 subjects, 6 to <12 years] and 5 from PERSEPT 1 [ages 12 to <18 years]). These subjects experienced 628 mild/moderate BEs. No subject was receiving emicizumab prophylaxis. Nearly all BEs in every pediatric age subgroup were successfully treated by 24 hours after initial eptacog beta infusion (Figure 2). At 12 hours, BE treatment success proportions in the 0 to <6 year, 6 to <12 year, and 12 to <18 year subgroups for the 75 µg/kg IDR were 58%, 72%, and 93%, respectively. Corresponding treatment success proportions for the 225 µg/kg IDR in the 0 to <6 year, 6 to <12 year, and 12 to <18 year subgroups were 58%, 63%, and 89%, respectively. The increased treatment success proportions seen for the 12 to <18 year subgroup over those seen for the 0 to <6 year and 6 to <12 year subgroups were statistically significant for both IDRs (p < 0.05; Figure 2). Differences in treatment success between the 0 to <6 year and 6 to <12-year subgroups were not statistically significant for either IDR. Treatment success point estimates at 12 hours in the 0 to <6 years age group showed the widest CIs among the various subgroups (Figure 2). Conclusions Eptacog beta treatment of BEs in this pediatric population yielded remarkable (>95%) treatment success proportions in both IDRs by 24 hours after initial eptacog beta infusion of 75 or 225 µg/kg. Differing age group pharmacokinetics could contribute to the observed increase in treatment efficacy at 12 hours with increasing subject age. In addition, when taken together with the wide CIs associated with treatment success point estimates at 12 hours for the 0 to <6 year subgroup, these results are consistent with well-known challenges that drive pediatric dosing of bypassing agents: chiefly, that of caregivers experiencing uncertainty with regard to BE resolution in young children. The high efficacy and narrow 95% CIs seen at 24 hours further indicate that caregivers had achieved clarity regarding BE resolution by the 24-hour timepoint. Figure 1 Figure 1. Disclosures Young: Apcintex, BioMarin, Genentech/Roche, Grifols, Novo Nordisk, Pfizer, Rani, Sanofi Genzyme, Spark, Takeda, and UniQure: Consultancy; Genentech/Roche, Grifols, and Takeda: Research Funding. Pipe: Catalyst Biosciences: Consultancy; CSL Behring: Consultancy; HEMA Biologics: Consultancy; Freeline: Consultancy, Other: Clinical trial investigator; Novo Nordisk: Consultancy; Pfizer: Consultancy; Roche/Genentech: Consultancy, Other; Sangamo Therapeutics: Consultancy; Sanofi: Consultancy, Other; Takeda: Consultancy; Spark Therapeutics: Consultancy; uniQure: Consultancy, Other; Regeneron/ Intellia: Consultancy; Genventiv: Consultancy; Grifols: Consultancy; Biomarin: Consultancy, Other: Clinical trial investigator; Bayer: Consultancy; ASC Therapeutics: Consultancy; Apcintex: Consultancy; Octapharma: Consultancy; Shire: Consultancy. Carcao: Bayer, Bioverativ/Sanofi, CSL Behring, Novo Nordisk, Octapharma, Pfizer, Roche, and Shire/Takeda: Research Funding; Bayer, Bioverativ/Sanofi, CSL Behring, Grifols, LFB, Novo Nordisk, Pfizer, Roche, and Shire/Takeda: Honoraria, Membership on an entity's Board of Directors or advisory committees. Castaman: Uniqure: Honoraria; Bayer: Honoraria; Sobi: Honoraria; CSL Behring: Honoraria; Novo Nordisk: Honoraria; Kedrion: Honoraria; LFB: Honoraria; Grifols: Honoraria; Werfen: Honoraria; Biomarin: Honoraria; Sanofi: Honoraria; F Hoffmann-La Roche Ltd: Honoraria. Davis: Genentech, Spark Therapeutics, BioMarin, Bayer: Consultancy; Takeda, Sanofi: Honoraria; Genentech, Sanofi, Novo Nordisk: Membership on an entity's Board of Directors or advisory committees. Ducore: Octapharma: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; HEMA Biologics: Consultancy, Honoraria; Bayer: Consultancy, Honoraria, Speakers Bureau; Shire: Consultancy, Honoraria. Dunn: Sanofi, Takeda, Freeline, BioMarin, ATHN, Novo Nordisk: Research Funding; Genentech, Kedrion, CSL Behring, BioMarin: Consultancy; UniQure, CSL Behring, World Federation of Hemophilia USA: Membership on an entity's Board of Directors or advisory committees; Roche/Genentech: Honoraria. Journeycake: HEMA Biologics: Honoraria; LFB: Honoraria. Khan: Genentech, Octapharma, BioMarin, CSL Behring, HEMA Biologics, Kedrion, and Takeda: Consultancy, Membership on an entity's Board of Directors or advisory committees. Mahlangu: Bayer, Biogen, BioMarin, CSL, Novo Nordisk, Sobi, Roche, and UniQure: Research Funding; Amgen, Bayer, Biotest, Biogen, Baxalta, CSL Behring, Catalyst Biosciences, Novo Nordisk, Roche, and Spark: Membership on an entity's Board of Directors or advisory committees; Alnylam, Bayer, Biotest, Biogen, Novo Nordisk, Pfizer, Sobi, Shire, Roche, ISTH, and WFH: Speakers Bureau. Meeks: Sangamo Therapeutics: Consultancy; Spark Therapeutics: Consultancy; National Hemophilia Foundation: Research Funding; Pfizer: Consultancy; Sanofi: Consultancy; CSL Behring: Consultancy; Genentech: Consultancy; Takeda: Consultancy; Hemophilia of Georgia: Research Funding; National Institutes of Health: Research Funding. Négrier: UniQure: Membership on an entity's Board of Directors or advisory committees; CSL Behring: Membership on an entity's Board of Directors or advisory committees; Biomarin: Consultancy, Membership on an entity's Board of Directors or advisory committees; Novo Nordisk: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Roche-Chugai: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Sanofi-Sobi: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Takeda: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Pfizer: Honoraria, Membership on an entity's Board of Directors or advisory committees; Spark: Honoraria, Membership on an entity's Board of Directors or advisory committees; Bayer: Honoraria, Membership on an entity's Board of Directors or advisory committees. Recht: Foundation for Women and Girls with Blood Disorders, Partners in Bleeding Disorders: Speakers Bureau; uniQure: Consultancy; Takeda: Consultancy; Sanofi: Consultancy; Pfizer: Consultancy; Octapharma: Consultancy; Novo Nordisk: Consultancy; Kedrion: Consultancy; Hema Biologics: Consultancy; Genentech: Consultancy; CSL Behring: Consultancy; Catalyst Biosciences: Consultancy; American Thrombosis and Hemostasis Network: Current Employment; Oregon Health & Science University: Current Employment. Chrisentery-Singleton: Biomarin: Speakers Bureau; Spark: Consultancy, Research Funding; Takeda: Consultancy, Speakers Bureau; Kedrion: Consultancy; Octapharma: Consultancy; Pfizer: Consultancy, Research Funding, Speakers Bureau; Sanofi: Consultancy; Hema Biologics: Consultancy; Grifols: Consultancy; CSL Behring: Consultancy, Speakers Bureau; Genentech: Consultancy, Speakers Bureau; Novo Nordisk: Consultancy, Speakers Bureau. Stasyshyn: CSL Behring: Consultancy, Research Funding; Novo Nordisk: Consultancy, Research Funding, Speakers Bureau; Octapharma: Consultancy, Research Funding, Speakers Bureau; Pfizer: Consultancy, Research Funding, Speakers Bureau; Takeda: Consultancy, Research Funding, Speakers Bureau; Grifols: Consultancy, Speakers Bureau; Shire: Consultancy. Wang: Octapharma: Other; Pfizer/Spark: Other: clinical trial investigator; uniQure: Consultancy, Other: Clinical trial investigator; Hem