Background:
Factor VIII (FVIII) pharmacokinetic (PK) parameters and other patient characteristics may play a role in effectiveness of FVIII prophylaxis. Objective: A post-hoc analysis was conducted to assess the association between PK parameters and BAY 81-8973 (Kovaltry® ) prophylaxis regimen in patients with severe hemophilia A.
Methods:
LEOPOLD I was a randomized, open-label, phase 2/3 trial to investigate use of BAY 81-8973 routine prophylaxis for treatment of bleeds in adolescents and adults with severe hemophilia A. In the efficacy part of the trial (part B), patients received BAY 81-8973 at a dose of 20‒50 IU/kg 2x/week (n=18) or 3x/week (n=44) for 12 months. Prophylaxis regimens were determined by study investigators, independent of BAY 81-8973 PK data. A subset of 20 patients (2x/week, n=7; 3x/week, n=13) had data from an earlier PK study (part A), in which patients received a single 50-IU/kg injection of BAY 81-8973 and had blood samples collected over 48 hours to assess PK parameters, including area under the curve (AUC), half-life (t½), and clearance (CL). Estimates of PK parameters were also derived using a population PK model based on data from all patients. This analysis compared model-based PK parameters, baseline characteristics, total annual dosing, and bleed outcomes between 2x/week and 3x/week prophylaxis groups. A similar analysis was done among the subset of patients in part A who had PK data. Differences between 2x/week and 3x/week dosing were assessed using Wilcoxon rank sum tests for continuous variables, and chi-square or Fisher’s exact tests for categorical variables.
Results:
In the full trial population, model-based AUC [mean (SD): 1957.1 (648.3) vs 2139.1 (875.7), 2x/week and 3x/week, respectively], t½ [15.0 (3.7) vs 15.9 (6.6)], and CL [0.028 (0.009) vs 0.027 (0.011)] were comparable between groups. The proportion of patients with ≥3 bleeds at 12 months was 33% for 2x/week and 48% for 3x/week. The 3x/week group had more bleeds in the past 12 months, higher baseline Gilbert bleeding scores, were more likely to have target joints at baseline, and received higher doses of BAY 81-8973 during the 12- month treatment period. In the part A subset analysis, observed and model-based AUC, t½, and CL were similar in both groups. The proportion of patients with ≥3 bleeds at 12 months was 0% for 2x/week and 46.2% for 3x/week (P=0.052).
Conclusions:
The similarity of PK parameters in patients successfully treated with 2x/week and 3x/week regimens suggests that clinical factors other than t½, AUC, and CL are important in predicting success of prophylaxis with BAY 81-8973. Physician decisions, taking into consideration clinical factors to identify appropriate patients for specific prophylaxis regimens, appear to be an important factor for 2x/week or 3x/week dosing with BAY 81-8973. These factors should be considered when individualizing BAY 81-8973 prophylaxis frequency.
Objective:
The B-HERO-S study assessed the impact of hemophilia on US adults with hemophilia B, including affected females. Here we describe the symptoms, management, and impact on education, employment, and engagement in recreational activities in women.
Methods:
Adults aged ≥18 years with hemophilia B (factor IX <40%) completed a survey including questions about bleeding, treatment, and psychosocial impact.
Summary:
Of 299 respondents, 86 were women (median age, 29 years; 6% were aged >45 years) with mild (29%), moderate (65%), or severe (6%) hemophilia. The majority reported arthritis (66%) and anxiety/depression (57%); 19% reported acute and/or chronic pain. Most (86%) were treated with some form of “routine infusions to prevent bleeding”; 16% reported self-infusing, 31%/17% by partners/family. Self-infusion was initiated at median age of 18, and learned from HTCs (86%), camps (71%), or parents (57%). Most reported difficulty with access to factor due to affordability/availability in the past 5 years (72%) or expected in the next 5 years (85%). Women reported a median (mean) of 4 (3.86) bleeds in prior year; 83% bled within the last 4 weeks with most recent bleeding in joints (73%) or muscles (21%). Twenty-five percent reported one specific “bad” joint, most commonly the knee (69%). Nearly all were seen in HTCs (85%) with a median (mean) of 3 (3.5) HTC visits per year. Most (88%) went past high school with 55% completing 4-year college and 24% graduate degrees. Most (94%) reported some negative impact on completing their education (7% very large/69% moderate/19% small impact), most commonly due to difficulties concentrating at school due to bleeds or pain (81%). Most were employed full-time (71%) or part-time (10%), commonly in office work (71%). Most (94%) reported a negative impact on their working life (3% very large/71% moderate/20% small impact); 36% reported leaving a job because of their hemophilia. Nearly all (99%) indicated some negative impact on their ability to engage in recreational activities (3% large/83% moderate/13% small impact). From a list of predetermined activities, dancing (50%) and walking (48%) were the most common current activities; bicycling (20%), dancing (17%), and swimming (16%) were the most common discontinued activities. Most reported treatment changes around activities (21% started prophylaxis, 52% revised time of doses, 38% added doses, 34% changed amount of doses); 8% reported no change and 3% no moderate/vigorous activities.
Conclusion:
Clinical presentation and treatment in women mirrored that reported by men except for greater anxiety/depression and more issues with access to treatment. Nearly all affected women reported a negative impact on their education, employment, and activities. While these results may be limited by bias in recruitment selecting those most symptomatic, the data reveal opportunities to improve awareness of and guidance around management and counselling of affected women.
Background:
Gene transfer for hemophilia offers the potential to convert the disease from a severe to mild phenotype with a single treatment. AMT-060 consists of an AAV5 vector containing a codon-optimized wildtype hFIX gene under control of a liver-specific promoter.
Objective:
This phase 1/2 study investigates the safety and efficacy of AMT-060 at 2 dose levels in adults with moderate-severe or severe hemophilia B.
Methods:
Multi-national, open-label, dose-escalating study in patients with factor IX (FIX) activity ≤2% of normal, and a severe bleeding phenotype (prophylactic exogenous FIX; or ondemand exogenous FIX, plus ≥4 bleeds/year or hemophilic arthropathy). Patients received either 5x1012 gc/kg (n=5) or 2×1013 gc/kg (n=5) of AMT-060 iv. Efficacy assessments include endogenous FIX activity (measured ≥10 days after use of exogenous FIX); reduction of exogenous FIX use; and annualized spontaneous bleeding rates. Safety assessments include treatment related adverse events, immunological and inflammatory biomarkers.
Summary:
There were no screening failures due to AAV5 neutralizing antibodies. Mean FIX activity in the lower dose cohort was 5.2% (min-max, 3.0-6.8%; n=4; 1 patient remaining on prophylaxis excluded) during 1 year of follow-up, and 6.9% (min-max, 3.1-12.7%; n=5) in the higher dose cohort during 26 weeks follow-up. Eight of 9 patients on FIX prophylaxis discontinued use after AMT-060 infusion. Follow-up to up to 1.5 years will be presented, with annualized reduction of exogenous FIX use and spontaneous bleeding rates. Mild, temporary elevations in ALT were observed in 3 patients with higher mean FIX activity (6.3-12.7%; 1 in the lower and 2 in the higher dose cohort). Each received a tapering course of prednisolone. ALT elevations were not associated with changes in FIX activity or a capsid-specific T-cell response.
Conclusions:
Patients continue to show sustained clinical benefit and endogenous FIX activity with no T-cell activation ≥1 year after a single infusion of AMT-060.
Objective:
Functional impairment from recurrent joint bleeding in people with hemophilia results in joint pain and reduces quality of life. The P-FiQ study formally evaluated patient- and site-reported functional assessment including responses to generic and hemophilia-specific patient-reported outcomes (PROs) tools. Psychometric analyses were used to evaluate reliability, validity, and consistency of responses.
Methods:
Adult males with hemophilia and a history of joint pain or bleeding completed a hemophilia history and 5 PROs assessing function: EQ-5D-5L, Brief Pain Inventory v2 Short Form (BPI), International Physical Activity Questionnaire (IPAQ), Short Form-36 v2 (SF-36v2), and Hemophilia Activities List (HAL). PROs were assessed for reliability, consistency, and correlation, with factors including patient-reported characteristics.
Summary:
A total of 381 adults (median age, 34 years; range, 18-86 years) were enrolled in P-FiQ. Most participants (66%) and sites (59%) reported functional disability in the past 6 months (CDC-UDC scale). Patients self-reported arthritis/bone/joint problems (65%) and history of joint procedures or surgeries (50%). On EQ-5D-5L, most reported problems “today” with mobility (61%) and usual activities (53%) but fewer with self-care (19%). On BPI, similar median pain interference scores (0- 10 scale, 10 is complete interference) were reported with general activity (3.0), walking ability (3.0), and normal work (3.0). On IPAQ, physical activity was reported by 49% of respondents over the prior week, with more reporting walking (35%) than moderate (16%) or vigorous (16%) activities. On SF-36v2, activities in the past 4 weeks that were most frequently limited were vigorous activities (80%), bending, kneeling, or stooping (67%), walking more than a mile (61%), and climbing several flights of stairs (59%). Physical problems caused participants to limit kinds of work/activities (69%), accomplish less than they would like (66%), have difficulty in performing work/activities (65%), and reduce time spent on work/activities (62%). On HAL, greater difficulties were seen for lower vs upper extremity functions/activities; within the lying/sitting/kneeling/standing domain, the most frequent problems in the previous month were squatting for a long time (74%), kneeling (73%) or standing (72%), and kneeling/squatting (70%). Similar items across different PROs were correlated with one another. Self- reported functional impairment was significantly differentiated by BPI pain interference, IPAQ total activity, SF-36v2 physical functioning, and all HAL domains and summary scores.
Conclusion:
PRO instruments assessing functional status range from simple/generic (EQ-5D-5L) to complex/disease-specific (HAL) and provide varying levels of detail. Greater use of formal PRO instruments in the clinical setting may improve dialogue between health care professionals and patients/caregivers and inform proactive approaches to specifically target patient identified functional limitations (eg, HAL) and identify areas for further targeted management strategies.
Dr. Laura Sommerville graduated cum laude from Messiah College and then obtained her MS and PhD degrees in cellular and molecular biology from Temple University. Her graduate work and doctoral dissertation produced several awards and publications in peer reviewed publications. She has been a postdoctoral fellow in the laboratory of Dr. Maureane Hoffman at Duke University since July 2014. Dr. Sommerville's 2015 JGP research fellowship award project is on understanding the loss of perivascular tissue factor during angiogenesis in hemophilia.
