Research Studies

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.

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.

Objectives:

Von Willebrand disease (VWD) is a common inherited bleeding disorder, but awareness among healthcare professionals is low. Timely and proper diagnosis integral for reducing VWD burden, access to proper therapies, and avoidance of improper medication. Hence, we sought to estimate the prevalence of undiagnosed VWD among commercially insured patients in the United States with a recent history of bleeding events.

Methods:

Patients with a VWD diagnosis who were users of or candidates for von Willebrand factor were identified from the IMS PharMetrics Plus Database (2006─2015). We constructed a unary patient-finding model based on 12 prediagnosis variables that best defined this population, and applied to a set of undiagnosed patients with recent bleeding events from the same database. ‘Best fit’ (confidence level 5/6) and ‘good fit’ (confidence level 3/4) patients were identified. Prevalence of symptomatic undiagnosed VWD in the commercially insured population was estimated from the best-fit and good-fit population size (projection factor 10.4).

Summary:

Overall, 507 668 undiagnosed patients with recent bleeding events were identified (86% female, 14% male). Application of the VWD model identified 3318 best-fit and 37 163 good-fit patients; 91% of best-fit patients were females aged <46 years, with heavy menstrual bleeding the most common claim. Projection to the full commercially insured US population provided an estimate of 35 000 - 387 000 symptomatic, undiagnosed patients with VWD.

Conclusion:

There is a high prevalence of symptomatic, undiagnosed VWD (undiagnosed bleeding disorder patients that likely have VWD) in the commercially insured population. This data underscores the importance of improved disease education to both patients and the first line treaters, including OBGYN, emergency room, and pediatricians. Enhanced awareness of VWD symptoms and their impact, and of screening and testing procedures, may improve diagnosis of VWD and reduce the disease burden.

Objectives:

Emicizumab, a bispecific humanized monoclonal antibody in development to address unmet medical needs in persons with hemophilia A with inhibitors (PwHAwI), bridges FIXa and FX to replace the function of missing FVIIIa, needed for effective hemostasis. This study assessed efficacy, safety and PK of emicizumab prophylaxis in PwHAwI.

Methods:

Study NCT02622321 was conducted at 43 centers/sites, and enrolled PwHAwI ≥12 y.o. Participants (pts) receiving prior episodic bypassing agents (BPAs) were randomized (2:1) to emicizumab prophylaxis vs no prophylaxis (Arm A vs B). Primary endpoint compared treated bleed rates in Arm A vs B. PwHAwI receiving prior prophylactic BPA received emicizumab prophylaxis in Arm C. Emicizumab was injected subcutaneously at 3 mg/kg/wk for 4 wks, and 1.5 mg/kg/wk thereafter.

Summary:

109 male PwHAwI were enrolled; median age 28 (range 12–75) yrs. Median (range) emicizumab treatment exposure was 24.0 (3.0–47.9) wk overall and 29.5 (3.3–47.9) wk in Arm A. Statistically significant, clinically meaningful reductions (87%) in treated bleed rates were observed between emicizumab prophylaxis vs no prophylaxis (Arm A vs B) (annualized bleeding rate [95% confidence interval] 2.9 [1.69 to 5.02] versus 23.3 [12.33 to 43.89], P<0.0001), and in all secondary bleed-related endpoints (spontaneous, joint, target joint, and all bleeds). Of note, a 79% reduction in treated bleed rate was seen with emicizumab prophylaxis (Arm C) vs BPA prophylaxis prior to study entry in a non-interventional study (NCT02476942; intra-individual comparison, P=0.0003). Overall, 67.3% of PwHAwI on emicizumab prophylaxis had zero treated bleeds. Statistically significant, clinically meaningful improvements in health-related quality of life (HRQoL) and health status were seen for Arm A vs B. Emicizumab was well tolerated. Total of 198 adverse events (AEs) were reported in 103 pts; most common AEs were injection-site reactions (15%), and 12 serious AEs were reported in 9 (8.7%) pts. Thrombotic microangiopathy and thrombosis (2 pts each in primary analysis) were reported and associated with high cumulative aPCC doses averaging >100 U/kg daily for >24 hr prior to event onset. No events occurred with emicizumab prophylaxis alone. Both TMA events resolved once aPCC treatment was stopped, and the thrombotic events did not require anticoagulation; 2 pts resumed emicizumab without sequelae (1 with TMA, 1 with thrombosis). No antidrug antibodies were detected. Mean trough emicizumab concentrations >50 μg/mL were achieved after 4 loading doses (3 mg/kg/wk) and sustained with maintenance doses of 1.5 mg/kg/wk.

Conclusion:

Emicizumab prophylaxis prevented or substantially reduced bleeds in PwHAwI and meaningfully improved HRQoL. Emicizumab had acceptable safety without excess thrombotic risk in the absence of concomitant aPCC. PK levels were sustained with once- weekly maintenance doses. These promising data could support a paradigm shift in the management and lives of PwHAwI.

Bleeding disorders are a group of conditions that result when the blood cannot clot properly (American Society of Hematology, 2017). The most frequently occurring bleeding disorders include von Willebrand Disease (VWD), Hemophilia A, and Hemophilia B (FDA ́s, 2016).Some studies shows that is important to considered the depression in the psychological approach of patients with a bleeding disorder (Recht, Batt, Witkop, Gut, Cooper, Kempton, 2016 and Osorio, Bazán, Izquierdo, 2016). Beck ́s theory defined depression in cognitive terms. He saw the essential elements of the disorder as the “cognitive triad”: (a) negative view of self, (b) a negative view of the world, and (c) a negative view of the future. The depressed person views the world through an organized set of depressive schemata that distort experience about self, the world, and the future in a negative direction (Beck, A. 1972 in Lynn, P. 2015).

Objective:

Compare depression levels in groups of patients with haemophilia, Von Willebrand (VWD) and apparently healthy people.

Methods:

The study design was quantitative, non-experimental, transactional and correlational in which the difference between three groups of participants was analyzed: 41 patients with hemophilia A or B, 10 patients with VW and 20 apparently healthy people. The sample was obtained from Tabasqueña de Hemofilia A.C. through a non - random sampling of subjects - type. Depression symptoms were obtained by Beck ́s inventory and for control variables a questionnaire was applied. All of the findings were assessed by SPSS 21 for Windows program. Data were analysed using descriptive statistics, comparisons between groups were evaluated with Games-Howell coefficient and post hoc test.

Summary:

71 participants with a mean age of 28.24. Considering the patients who have a bleeding disorder, 74.50% of the sample was deficient of factor VIII, 11.76% of factor von Willebrand, 11.76% of factor VII and 1.96% of factor IX; 82.35% of them have access to treatment while 17.64 have not access. Statistically significant differences were found only in apparently healthy people compared to haemophilia patients (p=0.031). A marginal difference was detected between the group of apparently healthy people and von Willebrand patients (p=0.081).

Conclusions:

The presence of a coagulation disease increase the levels of depression and the severity of the symptoms.

Key Words: Hemophilia, Von Willebrand, Depression.

Camping programs for individuals with chronic illness are increasingly common. Unfortunately, few studies have been conducted to empirically evaluate whether camping programs are meeting their intended goals or having the positive outcomes that are expected of them. The current study was conducted as an evaluation of a bleeding disorder camp for patients with bleeding disorders and their siblings.

Participants in the current study included 77 participants, ages 7-20 (mean 11.58, SD = 3.21). The sample was 62.3% male and 63.6% patients (36.4% siblings). Most of the patients (52.6%) had severe bleeding disorders. Participants were administered the Children’s Hope Scale (CHS; Snyder et al., 1991), which evaluates two dimensions of hope (1. Agency, the ability to identify positive goals and 2. Pathways, the ability to find ways to meet identified goals) and overall hope. Participants demonstrated a significant improvement on the agency subscale of the CHS, t(35) = -2.16, p < .05. Participants reported qualitative aspects of living with bleeding disorders, including differences in their lives, aspects of their lives that are better, aspects about bleeding disorders that are often misunderstood, and advice for others with bleeding disorders. Responses to qualitative were analysed across groups (patients and siblings; severe and mild patients) and were found to be very consistent across these groups. This information has helped to provide information about experiences of youth affected by bleeding disorders and will be used to help inform upcoming camp programming. These findings have also demonstrated positive psychosocial outcomes associated with camp attendance.

Background:

A high-purity plasma-derived FX concentrate (pdFX) has been developed for treatment of hereditary FX deficiency, an autosomal recessive disorder.

Aim:

This post hoc analysis describes the pharmacokinetics, safety, and efficacy of pdFX in 10 women and girls with hereditary FX deficiency.

Methods:

In this open-label study, subjects (10 women/girls, 6 men/boys) aged ≥12 years with moderate or severe FX deficiency (basal plasma FX activity ≤5 IU/dL) were enrolled and received 25 IU/kg pdFX for on-demand treatment of bleeding episodes or preventative use for up to 2 years. All subjects provided informed consent and the protocol was approved by appropriate independent ethics committees.

Results:

Nine women and girls had severe and 1 had moderate FX deficiency, were aged 25.5 (median; range 14–58) y, and received a total of 267 pdFX infusions (178 for on-demand and 89 for preventative treatment). Men and boys (5 severe and 1 moderate FX deficiency) received a total of 159 pdFX infusions (64 on-demand; 95 preventative). The mean number of infusions per subject per month was higher among women and girls (2.48) than males (1.62). The mean pdFX incremental recovery was similar between women/girls and men/boys (2.05 vs 1.91 IU/dL per IU/kg, respectively), as was mean half-life (29.3 and 29.5 h, respectively). Among women and girls, 132 assessable bleeding episodes (61 heavy menstrual bleeding, 47 joint, 15 muscle, and 9 other) were treated with pdFX. Women and girls reported a treatment success rate (ie, subject rating of “excellent” or “good” response to pdFX) of 98%, comparable to the 100% treatment success rate among men and boys. After study completion, 2 subjects received pdFX for hemostatic cover during obstetric delivery. Additional infusion, bleed, and safety data will be presented.

Conclusion:

These results show that, in women and girls with moderate or severe hereditary FX deficiency, who experience reproductive tract and other bleeding events, pdFX was safe and effective. The pharmacokinetic profile of pdFX in women and girls was similar to that of men and boys.

Funding: Bio Products Laboratory

Objectives:

Contemporary real-world data on units dispensed and expenditures associated with use of standard half-life (SHL) and extended half-life (EHL) factor VIII replacement products in U.S. patients with hemophilia A are limited. This exploratory analysis of real-world administrative data was conducted to determine units dispensed and factor replacement product-related direct expenditures associated with currently marketed recombinant SHL and EHL FVIII products, and to examine inter-product switches.

Methods:

De-identified claims data from the commercially available Truven Health MarketScan® Research US claims database were used to identify direct expenditures and number of international units (IUs) dispensed for all patients with a diagnosis code of ICD-9 286.0/ICD-10 D66 who used SHL (SHL group) and/or EHL (EHL group) during the study period from Aug 1, 2014 to Jan 31, 2017. Data on switching from an SHL to an EHL factor VIII replacement product were captured in patients with continuous pharmacy enrollment for whom claims data were available for at least 1 calendar quarter and up to 1 year before and after the index date of a product switch. Descriptive statistics were used to analyze results.

Summary:

Cross-sectional analysis.
The SHL group comprised 415 patients, among whom six distinct SHL FVIII products had been dispensed, and the EHL group included 91 patients, among whom two EHL FVIII products had been dispensed. The age distribution of the two groups was similar (p =0.57), although the proportion of patients under 18 years of age was somewhat higher in the SHL group than in the EHL group (46.9% vs 36.2%). The median FVIII product dispensation per calendar quarter was 46,409 IU (IQR, 12,760-87,670 IU) (SHL) versus 67,375 IU (IQR, 50,524-98,264 IU) (EHL). Median expenditures per calendar quarter were substantially higher for EHL ($135,519; IQR, $100,320-186,557) than for SHL ($61,152; IQR, $18,593-115,845).

Switching analysis.
Of the patients in the EHL group, 29 had switched from one of three SHL FVIII products to one of two EHL FVIII products during the study period. The total median IU dispensation per calendar quarter increased following the switch from 58,598 IU (pre-switch, SHL) to 68,036 IU (post-switch, EHL; 16% increase), as did the factor-related expenditure ($76,553, SHL, versus $141,101, EHL; 84% increase).

Conclusion:

Real-world data derived from a large claims database, unadjusted for treatment regimen or hemophilia severity, reveal marked differences in metric units and expenditures among hemophilia A patients to whom SHL and/or EHL products were dispensed. Switching from an SHL to an EHL FVIII replacement product was associated with a substantial increase in units dispensed and factor expenditures. Further analyses, incorporating essential clinical characteristics, should be explored.

Objective:

People with hemophilia frequently experience joint bleeds, resulting in pain and functional impairment. The P-FiQ study formally evaluated patient-reported pain descriptions, responses to standardized patient-reported outcomes (PROs) related to pain, and pain management strategies.

Methods:

Participants completed a pain/hemophilia history and 5 PRO instruments. Pain was assessed via 3 PRO instruments: EQ-5D-5L, Brief Pain Inventory v2 Short Form (BPI), and Short Form-36 v2 (SF- 36v2), and these instruments were assessed for reliability, consistency, and correlation with factors including patient-reported characteristics.

Summary:

P-FiQ enrolled 381 adult males with mild-severe hemophilia and a history of pain and/or joint bleeding. Most (65%) self-reported having arthritis/bone/joint problems. Thirty-two percent of participants reported experiencing both acute and chronic pain, 35% chronic pain only, 20% acute pain only, and 15% no pain. Of those reporting acute pain, most described the sensation as “sharp” (77%) or “aching” (65%); for those reporting chronic pain, most described the pain as “aching” (80%) or “nagging” (50%). Ankles (37%) and knees (24%) were commonly reported as the most painful joints. Many participants with acute/chronic pain reported using acetaminophen (62%/55%) or nonsteroidal anti-inflammatory drugs (34%/49%) to treat their pain in the past 6 months. Some participants indicated having moderate/severe/extreme (28%/12%/2%) pain/discomfort “today” as measured by the EQ-5D-5L pain/discomfort domain. For BPI (scale 0-10, 10 is most severe pain), median pain severity scores were 6.0 for worst pain, 3.0 for average pain, 2.0 for current pain, and 1.0 for least pain. Median BPI pain interference scores indicated interference with general activity (3.0), mood (3.0), walking ability (3.0), normal work (3.0), and enjoyment of life (2.0). On SF-36, most participants (90%) reported experiencing bodily pain, and 75% indicated that pain interfered with normal work in the last 4 weeks. Assessments of pain on PROs were highly correlated with one another. The following formal PRO assessments were associated with self-reported pain: pain/discomfort domain of EQ-5D-5L, BPI worst pain, least pain, average pain, and current pain, and SF-36 bodily pain. Greater extent of lifetime routine infusions was also associated with EQ-5D-5L pain/discomfort and SF-36 bodily pain.

Conclusion:

Pain severity and interference in people with hemophilia were identified consistently across several PROs, and correlated with patient-reported pain. In the comprehensive care setting, greater use of formalized assessment tools over time would improve dialogue and pain assessment between healthcare professionals and patients, document and validate the presence and extent of pain, establish and monitor individual goals for pain management interventions, and encourage the exploration of various pain management strategies and the evaluation of their overall quality and effectiveness.