Effects of replacement therapies with clotting factors in patients with hemophilia: A systematic review and meta-analysis

Background Different prophylactic and episodic clotting factor treatments are used in the management of hemophilia. A summarize of the evidence is needed inform decision-making. Objective To compare the effects of factor replacement therapies in patients with hemophilia. Methods We performed a systematic search in PubMed, Central Cochrane Library, and Scopus. We included randomized controlled trials (RCTs) published up to December 2020, which compared different factor replacement therapies in patients with hemophilia. Random-effects meta-analyses were performed whenever possible. The certainty of the evidence was assessed using the Grading of Recommendations Assessment, Development, and Evaluation (GRADE) methodology. The study protocol was registered in PROSPERO (CRD42021225857). Results Nine RCTs were included in this review, of which six compared episodic with prophylactic treatment, all of them performed in patients with hemophilia A. Pooled results showed that, compared to the episodic treatment group, the annualized bleeding rate was lower in the low-dose prophylactic group (ratio of means [RM]: 0.27, 95% CI: 0.17 to 0.43), intermediate-dose prophylactic group (RM: 0.15, 95% CI: 0.07 to 0.36), and high-dose prophylactic group (RM: 0.07, 95% CI: 0.04 to 0.13). With significant difference between these subgroups (p = 0.003, I2 = 82.9%). In addition, compared to the episodic treatment group, the annualized joint bleeding rate was lower in the low-dose prophylactic group (RM: 0.17, 95% CI: 0.06 to 0.43), intermediate-dose prophylactic group (RM of 0.14, 95% CI: 0.07 to 0.27), and high-dose prophylactic group (RM of 0.08, 95% CI: 0.04 to 0.16). Without significant subgroup differences. The certainty of the evidence was very low for all outcomes according to GRADE methodology. The other studies compared different types of clotting factor concentrates (CFCs), assessed pharmacokinetic prophylaxis, or compared different frequencies of medication administration. Conclusions Our results suggest that prophylactic treatment (at either low, intermediate, or high doses) is superior to episodic treatment for bleeding prevention. In patients with hemophilia A, the bleeding rate seems to have a dose-response effect. However, no study compared different doses of prophylactic treatment, and all results had a very low certainty of the evidence. Thus, future studies are needed to confirm these results and inform decision making.

Download Full-text

Comparison of Short-Term Tertiary Prophylaxis at Low-Dose and Intermediate-Dose for Adults with Severe Hemophilia a in China

Blood ◽

10.1182/blood.v126.23.4681.4681 ◽

2015 ◽

Vol 126 (23) ◽

pp. 4681-4681 ◽

Cited By ~ 1

Author(s):

Shunhua Huang ◽

Zhitao Li ◽

Yang Liu ◽

Fangmei Qin ◽

Xiaoqin Feng ◽

...

Keyword(s):

Dose Regimen ◽

Dose Group ◽

Low Dose ◽

Hemophilia A ◽

Severe Bleeding ◽

Severe Hemophilia ◽

Joint Function ◽

Bleeding Rate ◽

Breakthrough Bleeding ◽

Intermediate Dose

Abstract Background: Some studies had indicated that the joint damage progression could not be prevented by low-dose prophylaxis regimen though it had been practiced and achieved good outcomes as well as largely reduced bleedings. we initiated a retrospective study to compare the different outcomes between low-dose and intermediate-dose regimen of tertiary prophylaxis for adults with severe hemophilia A. Methods: Data collected from the hemophilia treatment centre at Nanfang hospital from July 2010 to February 2015 ( median 2 years of follow-up), a total of 40 adult patients with severe hemophilia A (FVIII < 1%) who are receiving prophylaxis treatment≥1 year and treatment data available were eligible for enrollment in the study, including 25 patients in low-dose regimen(F‡[8-15 IU/kg 1-2times weekly or weekly<30 IU/kg), and 15 patients in intermediate-dose regimen( F‡[ 15-20 IU/kg 2-3 times weekly or weekly≥40IU/kg and <75 IU/kg). Collect the data with patients' characteristics, previous condition and treatment, treatment efficacy indexFannual bleeding rate(ABR), annual joint bleeding rate(AJBR), number of target joint, annual target joint bleeding rate, annual severe bleeding event, etc.), FVIII consumption. Use FISH scoring system to evaluate patients' joint status, use the difference between the beginning of this study and one year ago of FISH score to represent the improvement of joint function. To analyze the joint function in various subgroups(joint bleeding rate ≤5 times or >5 times) under prophylaxis treatment. Screening out patients whose dosage and frequency adherence both >75% in two groups, including 15 patients in low-dose regimen and 14 patients in intermediate-dose regimen, observed the situation that breakthrough bleeding events occurred in different time period after clotting factors' injection and calculate the proportion. Results: 1. There were no statistical differences between two groups in age, weight, age at first bleeding, age at first treatment, family history of hemophilia and history of hepatitis. (the range of p-value was 0.221-1.000). 2. Intermediate-dose prophylaxis regimen reduced ABR than the low-dose regimen (median 13 vs. 5.5, P=0.000), as well as AJBR (median 10 vs. 4, p=0.001) and the annual target joint bleeding rate (median 8 vs. 3.5, p=0.002) .Reduced median annual absent days was found in intermediate-dose regimen group (median 7.5 vs. 0, p=0.005). In terms of total annual usages of FVIII, the intermediate-dose regimen group increased 35% than low-dose regimen group(2630 IU/kg/year vs.1950 IU/kg/year,P=0.000), but decreased 63% ABR, 60% AJBR and 56% annual target joint bleeding than low-dose regimen group. There was no statistical differences between low-dose and intermediate-dose groups in terms of target joint numbers (median 1 vs.1,P=0.579) and annual severe bleeding events(median 0 vs.0, P=0.911). 3. There was statistical differences between two groups on the improvement of FISH(P=0.008). The proportion that patients' annual joint bleeding rate ≤5 in low dose and intermediate-dose group were 12% and 73.3%. When AJBR ≤5, the mean improvement of Fish score of low-dose and intermediate-dose group was 0.33 and 1.18, When AJBR>5, the mean score was -0.09 and 1.00 respectively, while the joint function still improved in intermediate-dose group.3. The low-dose group had higher proportion of breakthrough bleeding in 24-48h after FVIII injection (median 45.5% vs.27.95%, P=0.000), while intermediate-dose group got higher proportion in more than 48h after FVIII injection (median 60% vs.43.75%,P=0.001). Conclusion: 1. Compared to low-dose prophylaxis regimen, the ABR, AJBR, annual target joint bleeding rate, annual absent days and joint functionwere significantly decreased in patients treated with intermediate-dose regimen.2. It is indicated the intermediate-dose prophylaxis treatment would be better in long-term effect than low-dose regimenin improving joint function. 3. The low-dose group had higher proportion of breakthrough bleeding in 24-48h after FVIII injection, while intermediate-dose group got higher proportion in more than 48h after FVIII injection. Once every other day regimen is beneficial to further reduce bleedings in intermediate-dose prophylaxis treatment. Disclosures No relevant conflicts of interest to declare.

Download Full-text

Long Term Dose-Dependent Correction of Hemophilia A Dogs Using AAV-8 and AAV-9-Mediated FVIII Gene Transfer.

Blood ◽

10.1182/blood.v108.11.999.999 ◽

2006 ◽

Vol 108 (11) ◽

pp. 999-999

Author(s):

Denise E. Sabatino ◽

Amy M. Lange ◽

Melinda Mucci ◽

Rita Sarkar ◽

Aaron M. Dillow ◽

...

Keyword(s):

Gene Transfer ◽

Dose Group ◽

Low Dose ◽

Hemophilia A ◽

Clotting Factor ◽

High Dose ◽

Functional Assay ◽

Dependent Manner ◽

Aav Vector ◽

Dose Dependent

Abstract Hemophilia A (HA) is an X-linked bleeding disorder characterized by deficiency in clotting factor VIII (FVIII). Current treatment for hemophilia is protein replacement therapy while a gene-based therapy would provide continuous expression of even low levels of FVIII protein (>1% of normal) that is likely to improve the disease phenotype. It is challenging to utilize an AAV-mediated gene transfer approach for the FVIII cDNA (4.4kb) since the AAV vector can only efficiently accommodate a <5.3kb transgene cassette. The FVIII protein is composed of 2 chains -the heavy chain (HC) and the light chain (LC). FVIII undergoes proteolytic cleavage and processing of the 2 individual chains that form the active FVIII protein. In other studies in HA dogs (n=8), no dose-response and AAV serotype-dependent FVIII expression has been documented, which illustrates the difficulties in using a FVIII single-chain approach. We have utilized a 2-chain approach in which the 2.4kb LC cDNA is packaged in one AAV vector while the 2.5kb HC is packaged into a second AAV vector. Each construct contains a 695bp thyroxine-binding globulin gene promoter/enhancer fused to a 175bp intron along with a 263bp SV40 poly A signal. For this approach the LC and HC vectors packaged into either AAV8 or AAV9 were administered to HA dogs via the hepatic artery. Two male HA dogs received HC and LC in AAV8 and 2 male dogs received HC and LC in AAV9 at doses of 6x1012gc/vector/kg (low dose) or 1.25x1013gc/v/kg (high dose). At 150 days after vector infusion, the high dose group expressed FVIII at levels of 4.8% (AAV8) and 3% (AAV9) as detected by a functional assay (Coatest assay). FVIII remained stable for 797 days (AAV8) and >200 days (AAV9) (the longest time points to date) without any evidence of antibody formation to the transgene. In the low dose group at 150 days, FVIII levels were 1.5% (AAV8) and 0.5% (AAV9) cFVIII activity and were maintained in a follow up period of >150 days (AAV8) and >700 days (AAV9) without formation of antibodies to FVIII. Thus, no major differences between AAV8 and AAV9 vectors were observed. The transgene product is also functional based on shortening of whole blood clotting time (baseline values >50 min), in a dose-dependent manner, 10–15 min and 16–20 min for the high and low dose cohorts, respectively. Interestingly, high dose injection of AAV8 to 2 female HA dogs (1.25x1013 and 3x1013gc/v/kg) results in FVIII levels of 1–2%, which is consistent with data obtained in mice on the poor performance of AAV in mediating gene transfer to liver in female animals. Liver function tests and other blood chemistries were transiently elevated after the surgical procedure and were in normal limits within 4 days. Importantly, all dogs did not develop antibodies to FVIII. These findings suggest that FVIII chains efficiently assemble in vivo without increasing the protein immunogenicity. The 4 male dogs have remained asymptomatic with no spontaneous bleeds, whereas >20 bleeding episodes were expected for this group since untreated dogs require 5.5 plasma infusions/year. These data demonstrate for the first time, dose-dependent sustained expression of functional cFVIII in HA dogs by AAV8 and AAV9 vectors without formation of antibodies to cFVIII.

Download Full-text

Impact of Prophylaxis Usage on Bleeding Rates Among Persons with Hemophilia A: Evidence from Longitudinal Analyses in the USA

Blood ◽

10.1182/blood-2018-99-119215 ◽

2018 ◽

Vol 132 (Supplement 1) ◽

pp. 494-494

Author(s):

Michael B. Nichol ◽

Randall Curtis ◽

Yuchen Ding ◽

Elmar R. Aliyev ◽

Marion A. Koerper ◽

...

Keyword(s):

Health Insurance ◽

Health Outcomes ◽

Joint Pain ◽

Research Funding ◽

Prophylactic Treatment ◽

Hemophilia A ◽

Age Groups ◽

Clotting Factor ◽

Bleeding Rate

Abstract BACKGROUND There are limited longitudinal studies following up persons with hemophilia (PWH) in adherence to clotting factor treatment and health outcomes. The Hemophilia Utilization Group Studies part Va (HUGS Va) was a two-year observational study of persons with hemophilia A conducted from 2005-2007. Participants from HUGS Va were enrolled to the long-term follow-up study (HUGS LTS) in 2014. OBJECTIVES To compare participants' characteristics between baseline of HUGS Va and follow-up in LTS; and investigate the impacts of changes of participants' characteristics on annualized bleeding rates. METHODS We collected data on sociodemographic and clinical characteristics. Self-reported bleedings were obtained from periodic surveys for 2-years in HUGS Va, and a survey that asked bleedings in the past 6-month in HUGS LTS. Clotting factor dispensing records were collected prospectively for two years in HUGS Va, and retrospectively for six months prior to HUGS LTS enrollment. Annualized bleeding rates and factor dispensing (unit/kg body weight) were calculated. Adherence to factor treatment was determined by the ratio of dispensed clotting factor to clinical recommended factor usage. We classified age at baseline of HUGS Va into three groups: children (aged 2-11 years), adolescents (aged 12-20 years), and adults (aged ≥21 years). The characteristics of participants were compared among the three age groups using Chi-square tests for categorical variables and ANOVA for continuous variables for each study. Annualized factor dispensed and bleeding rates were compared between HUGS Va and HUGS LTS using paired T-tests. RESULTS A total of 74 persons participated in both HUGS Va and LTS with completed data to calculate annualized factor dispensed and bleeding rates were included to the analyses. The mean age was 17.8±11.4 years in HUGS Va, and 26.2±11.5 years in LTS, respectively. The sample had 43% of children, 22% adolescents, and 35% adults at baseline. All adolescents at baseline transitioned to young adults in LTS. Approximately 80% of participants were severe hemophilia. Adults (73%) were less likely to have an entire year of health insurance as compared to children (100%) or adolescents (93.8%, P<0.01) in HUGS Va. Health insurance status was not significantly different among age groups in LTS. In HUGS Va, children had the highest rate of prophylactic treatment (74%), adherence to factor treatment (62%), highest mean annualized factor dispensed (4724±4090 u/kg), lowest rate of self-reported moderate or severe joint pain (31%), and lowest mean annualized bleeding rate (4.2±4.7); while adults had the lowest rate of prophylactic treatment (31%), adherence (28%), lowest mean annualized factor dispensed (2084±1870 u/kg), highest rate of self-reported moderate or severe joint pain (73%), and highest mean annualized bleeding rate (11.9±9.3), all P<0.05 among age group comparisons for these variables. There were 18 (26%) people (22% children, 17% adolescents, and 61% adults) switching from episodic treatment to prophylactic treatment from HUGS Va to LTS; others remained on the same treatment regimens. Adolescents and adults increased in prophylactic treatment (63% to 80% for adolescents, 31% to 69% for adults, respectively), adherence (36% to 75%, 28% to 61%), and mean annualized factor dispensed (3206±2581 to 4931±2945 u/kg, 2084±1870 to 4612±2577 u/kg) from HUGS Va to LTS. Mean annualized bleeding rates were not statistically significant different between HUGS Va (7.3±8.4) and LTS (10.6±22.0, P>0.05). The bleeding rates were not significantly different among age groups in LTS (P=0.06). CONCLUSIONS Although current literature indicated that PWH in transition from childhood to adulthood maybe at high risk of adverse health outcomes due to poor management of their condition with diminishing influence from parents, adolescents showed a significant increase in prophylactic treatment, adherence to factor treatment, and annualized factor dispensed, which may be associated with unchanged annualized bleed rates after they transitioned to adulthood in this study. Adults had a larger increase in dispensed factors than adolescents. Prophylaxis and adherence to clotting factor treatment were associated with a lower bleeding rate. Our current analyses reinforce the importance of prophylaxis and adherence to factor treatment for decreasing bleedings in persons with hemophilia A. Disclosures Nichol: Bayer: Research Funding; CSL Behring: Research Funding; Bioverativ: Research Funding; Shire/Baxter: Research Funding; Pfizer: Research Funding; Novo Nordisk: Research Funding; Genentech: Research Funding. Curtis:Gilead: Honoraria; Pfizer: Research Funding; Novo Nordisk: Honoraria, Research Funding; Shire/Baxter: Research Funding; Bioverativ: Research Funding; National Hemophilia Foundation: Honoraria; CSL Behring: Research Funding; Bayer: Research Funding, Speakers Bureau; Genentech: Honoraria, Research Funding. Ding:Novo Nordisk: Employment; Bioverativ: Research Funding. Aliyev:Genentech: Research Funding. Lou:Bioverativ: Research Funding; Novo Nordisk: Research Funding; Genentech: Research Funding; Bayer: Research Funding; Pfizer: Research Funding; CSL Behring: Research Funding; Shire/Baxter: Research Funding. Ullman:Genentech: Research Funding. Tran:Bioverativ: Honoraria; Novo Nordisk: Honoraria; Bayer: Honoraria; Genentech: Research Funding. Baker:Genentech: Research Funding. Riske:Genentech: Research Funding. Wu:Pfizer: Research Funding; Genentech: Research Funding; Bioverativ: Research Funding; CSL Behring: Research Funding; Bayer: Research Funding; Shire/Baxter: Research Funding; Novo Nordisk: Research Funding.

Download Full-text

Low Dose Secondary/Tertiary Prophylaxis Is Feasible and Effective in Resource Limited Setting in South India for Children with Hemophilia

Blood ◽

10.1182/blood.v128.22.2336.2336 ◽

2016 ◽

Vol 128 (22) ◽

pp. 2336-2336 ◽

Cited By ~ 2

Author(s):

Neeraj Sidharthan ◽

Vijayakumar Narayana Pillai ◽

Sheena Mathew ◽

Remya Sudevan ◽

Dinkar Viswam ◽

...

Keyword(s):

Low Dose ◽

Prophylactic Treatment ◽

Hemophilia A ◽

Functional Independence ◽

Hemophilia B ◽

Clotting Factor ◽

School Absenteeism ◽

Severe Hemophilia ◽

On Demand ◽

Hospitalization Rates

Abstract Prophylaxis for Hemophilia is globally accepted as a treatment strategy compared to on-demand therapy in the care of persons with hemophilia (PwH) . Prophylaxis is rarely practized in low and middle income countries due to several reasons such as ill-affordability of clotting factor concentrates ( CFCs), lack of awareness, absence of comprehensive / home care infrastructure and misconcepts regarding treatment among general population. The South Indian state of Kerala had been providing CFCs free of cost for on-demand treatment. A recent initiative was started in Hemophilia Treatment Centre(HTC), Aluva , Ernakulam district to provide secondary/tertiary prophylaxis free of cost to children with severe hemophilia (Factor level <1%, aged 5-15 yrs) as a joint effort from HTC and the local government. A clinical audit was done in 11 children at this center for a period of twelve months (6 months retrospectively for on-demand treatment and 6 months prospectively for prophylactic treatment). Among all patients with severe hemophilia, eight have Hemophilia A and the remaining three have Hemophilia B. They were previously treated with CFCs/plasma/cryoprecipitate, a few of them had established joint disease and all of them had absence of inhibitors. These children were initiated on low dose prophylaxis with plasma derived CFCs. Factor VIII concentrate was given at a dose of 20-40 U/kg in 2 divided doses per week for Hemophilia A and Factor IX concentrate at 25-40 U/Kg once a week for Hemophilia B. Outcomes were measured at two time points - at the end of secondary/tertiary prophylactic treatment period and at the end of preceding six months of on-demand treatment. The variables taken as outcome measures were changes in bleed rates, Hemophilia joint health score (HJHS), Functional independence score in Hemophilia (FISH), hospitalization rates and school absenteeism. A reduction in the bleed rate was seen from the transition of on demand treatment to secondary/tertiary prophylactic treatment (14.9 vs 0.91, p 0.005). Similar reductions were seen for hospitalization rates (12.45 vs 2.36 days, p 0.005) and school absenteeism (78.55 vs 1.27 days, p 0.01) respectively(Fig 1 a). FISH and HJHS scores were either maintained or improved during the prophylaxis period.(Fig 1b, 1c). None of the children developed inhibitors during the study period. The estimated cost of CFCs for on demand treatment per patient was 1314.4 USD and 1691.8USD during prophylaxis. The factor consumption for on demand treatment for 6 months was 968.24 IU/Kg and that of secondary/tertiary prophylaxis was 1077.96 IU/Kg respectively. We conclude that low dose prophylaxis for severe Hemophilia in a developing economy is feasible and has marked clinical benefits with greater well-being when compared to on demand therapy. In countries with resource constraints low dose secondary/tertiary prophylaxis should be considered as a therapeutic option over on demand therapy for children with severe Hemophilia in the light of its potential benefits . Disclosures No relevant conflicts of interest to declare.

Download Full-text

Successful Long Term Therapeutic Expression of Factor VIII in Hemophilia A Dogs After Administration of AAV-cFVIII Using a Two-Chain or Single Chain Delivery Approach.

Blood ◽

10.1182/blood.v114.22.546.546 ◽

2009 ◽

Vol 114 (22) ◽

pp. 546-546

Author(s):

Denise E. Sabatino ◽

Ekaterina Altynova ◽

Amy M. Lange ◽

Shangzhen Zhou ◽

Elizabeth P. Merricks ◽

...

Keyword(s):

Low Dose ◽

Hemophilia A ◽

High Dose ◽

Dependent Manner ◽

Igg Antibodies ◽

Single Chain ◽

Spontaneous Bleeding ◽

Aav Vector ◽

Bleeding Episodes

Abstract Abstract 546 While adeno-associated virus (AAV) is a promising gene delivery vector, it has been challenging to deliver FVIII due to the large size of the FVIII cDNA and the high frequency of FVIII antibody formation in hemophilia A (HA) patients. We used two approaches to overcome the size limitation of AAV for FVIII: (1) two-chain delivery in which the canine FVIII (cFVIII) heavy chain (HC) is delivered in one AAV vector and the cFVIII light chain (LC) is delivered in a second AAV vector and (2) single chain delivery in which the B-domain deleted cFVIII cDNA with minimal regulatory elements is within one AAV vector. In the two-chain approach AAV-HC (4.0 Kb) and AAV-LC (3.9 Kb) with a liver specific promoter was co-injected at a dose of 6×1012 vector genomes/vector/kg or 1.25×1013vg/vector/kg using AAV8 or AAV9 via hepatic infusion. Five hemophilia A dogs treated with AAV-HC and AAV-LC expressed 0.5-11% cFVIII in a dose-dependent manner. The mean cFVIII activity based on Coatest assay for the low dose was 1.3% (>1220d)(Linus)(AAV8) and 0.6% (>1770d)(H19)(AAV9), while for the high dose it was 5.2% (800d)(F24)(AAV8) and 2.4% (>1270d)(Woodstock)(AAV9). One dog (J60) had a splenectomy due to a complication at the time of surgery and has maintained high levels of expression (mean 11.0%; >820d). The WBCT consistently remained at a mean of 17.6 min for low dose dogs and 13.7 min for high dose dogs compared to 8-12 min in normal dogs. Using novel reagents that we generated specific to cFVIII, we developed assays to detect cFVIII antigen levels and IgG antibodies. Despite receiving equal doses of each vector, at day 85 the cFVIII-LC antigen levels (71.7 ± 19.2 ng/ml) were >10-fold higher than would be predicted based on activity while the cFVIII-HC antigen levels (14.6 ± 9.2 ng/ml) were >3-fold higher than activity. Since functional FVIII synthesis relies on the co-transduction of AAV-HC and AAV-LC in the same cell, this suggests that only a portion of the vector co-transduces and expresses cFVIII in the same cell and that the light chain is secreted more efficiently than the HC. No IgG antibodies to cFVIII were detected at any time point in these dogs. Three dogs have maintained FVIII expression for >3.5 years and two dogs for >2 years with ongoing observation. No spontaneous bleeding episodes have been observed in these dogs for a cumulative observation of >16 years while >80 bleeding episodes would be expected during this time period. The second approach, the single chain delivery, overcomes the co-transduction requirement of the two-chain approach by ensuring that each transduced cell expresses functional FVIII. However, it is difficult to efficiently package the large 5.2 Kb single chain construct into an AAV vector. Since no significant differences were observed between AAV8 and AAV9 using the two-chain approach, we used AAV8 to deliver the single chain cFVIII by peripheral vein infusion at 2×1013vg/kg or 4×1013vg/kg. The mean cFVIII activity was 0.7% (>430d) for the low dose dog (L51) and 6.8% (>290d) and 2.2% (>110d) for the high dose dogs (M06, M50). cFVIII HC and LC ELISA showed that cFVIII antigen levels correlated with activity. WBCT was a mean of 19.1 min for L51, 15.3 min for M06 and 11.6 min for M50. No spontaneous bleeding episodes have been observed in these dogs. The high dose dogs had no IgG antibodies to FVIII. L51 had transient IgG antibodies to FVIII until d52 in the absence of a Bethesda titer. A rise in FVIII expression in L51 coincided with the disappearance of anti-cFVIII antibodies. Comparison of single chain and two-chain delivery of FVIII reveals that (1) long term therapeutic levels of cFVIII in a dose-dependent manner can be obtained with both delivery approaches; (2) circulating cFVIII antigen levels are >10-fold higher than activity in the two-chain delivery in contrast to single chain delivery in which antigen correlates with activity; and (3) high antigen levels may facilitate tolerance to FVIII in the setting of liver-directed gene transfer, since a transient non-inhibitory antibody was observed in only one dog with very low FVIII levels. Notably, no cellular toxicity due to continuous expression of various forms of FVIII was found in these animals based on long-term sustained FVIII expression levels and normal liver enzymes in all eight HA dogs. Further studies to characterize the immune responses to the transgene will define the optimal vector approach. These data will form the basis for clinical studies in humans with severe HA. Disclosures: No relevant conflicts of interest to declare.

Download Full-text

Human-Cl Rhfviii Effectively and Safely Prevents Bleeding Episodes in Previously Treated Adult Patients with Severe Haemophilia A

Blood ◽

10.1182/blood.v120.21.1132.1132 ◽

2012 ◽

Vol 120 (21) ◽

pp. 1132-1132

Author(s):

Sigurd Knaub ◽

Toshko Lissitchkov ◽

Kingsley Hampton ◽

Mario Von Depka ◽

Savita Rangarajan ◽

...

Keyword(s):

Gene Therapy ◽

Research Funding ◽

Prophylactic Treatment ◽

Hemophilia A ◽

Haemophilia A ◽

Severe Haemophilia ◽

Open Label ◽

Bleeding Rate ◽

Previously Treated

Abstract Abstract 1132 The main purpose of this prospective, multi-center, open-label phase 3 study was to assess the efficacy of prophylactic treatment with Human-cl rhFVIII, the first human cell-line derived recombinant FVIII, in previously treated patients (PTPs) with severe haemophilia A. Patients were to receive 30–40 international units (IU) FVIII of Human-cl rhFVIII per kg every other day for 6 months. Efficacy of preventing and treating bleeds were judged using objective criteria taking the monthly bleeding rate and the number of infusions needed to manage a break-through bleed into account. In-vivo recovery (IVR) was determined at the beginning of the study and after 3 and 6 months. FVIII:C was measured by validated chromogenic (CHR) and one-stage (OS) assays in a central laboratory, which also assigned drug potencies. Inhibitor activity was determined using the Nijmegen modification of the Bethesda assay before the first administration and at defined intervals thereafter. Thirty-two patients between 18 and 75 years of age were enrolled from 11 centres in Europe and treated prophylactically for 6.0±0.9 months (mean ± SD) with a mean prophylactic dose of 32.8 IU/kg. Sixteen patients never bled, 11 patients bled once and 5 more than once. The mean total and spontaneous monthly bleeding rate was 0.188±0.307 and 0.095±0.211, respectively. Efficacy of the prophylactic treatment was “excellent” in all patients for spontaneous BEs and “excellent” or “good” in all patients but one for all types of bleeds. All treatments of bleeds were rated as “excellent” (71.4%) or “good” (28.6%). The IVR at baseline was 2.6±0.5 % per IU/kg for the CHR and 2.2±0.5 % per IU/kg for the OS assay and remained stable during the study. A total of 2921 infusions were given in the study. Human-cl rhFVIII was well tolerated and no patient experienced a related serious adverse event. No FVIII inhibitors were detected. Conclusion: The data indicate that Human-cl rh FVIII is safe and efficacious in preventing and treating bleeds in PTPs with severe haemophlia A. Disclosures: Knaub: Octapharma AG: Employment. Lissitchkov:Octapharma AG: PI Other. Tuddenham:College London: Consultancy, Employment, Gene therapy for hemophilia A, Gene therapy for hemophilia A Patents & Royalties, Research Funding. Collins:Octapharma AG: Consultancy. Oldenburg:d and e: Baxter, Bayer, Biotest, CSL-Behring, Grifols, Inspiration, NovoNordisk, Octapharma, Pfizer e: Biogen IDec, Swedish Orphan Biovitrum: Honoraria, Research Funding. Bichler:Octapharma AG: Employment.

Download Full-text

Consumption Of FVIII Concentrate During On-Demand and Prophylactic Treatment With Human-cl rhFVIII In Prospective Clinical Studies In Adult Patients With Severe Hemophilia A

Blood ◽

10.1182/blood.v122.21.3595.3595 ◽

2013 ◽

Vol 122 (21) ◽

pp. 3595-3595 ◽

Cited By ~ 1

Author(s):

Andreas Tiede ◽

Sigurd Knaub ◽

Johannes Oldenburg ◽

Johann Bichler

Keyword(s):

Prophylactic Treatment ◽

Hemophilia A ◽

Fold Increase ◽

Human Cell Line ◽

Adult Patients ◽

Study Entry ◽

Severe Hemophilia ◽

Ample Evidence ◽

Bleeding Rate ◽

On Demand

Abstract Background There is ample evidence to support prophylactic treatment with factor VIII (FVIII) in children with severe hemophilia A (HA). Adults with severe HA are often treated on-demand and the potential benefit of regular prophylaxis is linked to a higher consumption of FVIII concentrates. During the clinical development of Human-cl rhFVIII, the first recombinant FVIII concentrate from a human cell line, its efficacy and safety was evaluated in previously treated adult patients (PTPs) during on-demand treatment only (GENA-01) and prophylaxis (GENA-08). Aims To compare post-hoc the annualized bleeding rate (ABR) and the consumption of FVIII concentrate in patients treated exclusively on-demand with those treated prophylactically. Methods Both prospective multi-centre studies were approved by the Ethics Committees of each participating institution and informed consent was obtained from the patient prior to any trial activity. In GENA-01, patients were to be treated on-demand for ≥6 months and ≥50 exposure days with protocol recommended doses ranging from 20 to 60 IU/kg, depending on the severity of the bleed. In GENA-08, patients were to be treated prophylactically with Human-cl rhFVIII every other day with 30-40 IU/kg for ≥6 months. Human-cl rhFVIII was also to be used in case of breakthrough bleeds. Results 22 PTPs with severe HA were enrolled in GENA-01, and 32 in GENA-08. The study populations were reasonably well comparable to each other (GENA-01 vs. GENA-08, mean±SD), regarding age (39.6±14.1 vs. 37.3±13.6 years), body mass index (23.9±4.8 vs. 25.8±4.9 kg/m2), hemophilia joint health score (38.4±30.3 vs. 34.6±32.2), race (>80% White in both studies) and historical bleeding sites. In GENA-08, the majority of patients (65.6%) had been treated prophylactically prior to study entry. Their historical mean±SD ABR was 6.6 ±11.3 (median: 2.0, range: 0-48.7) and their mean prophylactic dose/month was 293 IU/kg. The other 11 patients who had been treated on-demand had a mean±SD ABR of 47.4±34.6 (median: 36.5, range: 12.2-121.7). In GENA-01, all but 2 patients were treated on-demand prior to study entry. The historical mean±SD ABR of all GENA-01 patients was 49.5±35.9 (median: 44.6, range: 2.0-158.7). The ABR and FVIII consumption during the studies are shown in Table 1. Conclusion The data suggest that regular prophylactic treatment with Human-cl rhFVIII in adult PTPs with severe HA resulted in an approximately 25-fold reduction of bleeding rate, and a 3-fold increase of FVIII concentrate consumption. Disclosures: Tiede: Octapharma AG: Consultancy, Investigator Other. Knaub:Octapharma AG: Employment. Oldenburg:Octapharma AG: Consultancy, Investigator Other. Bichler:Octapharma AG: Employment.

Download Full-text

Low dose long-acting factor VIII prophylaxis in pediatric and young adult patients with hemophilia A: Short-term single-center experience from a developing country

10.25259/jhas_13_2021 ◽

2021 ◽

Vol 0 ◽

pp. 1-6

Author(s):

Shailendra Prasad Verma ◽

Anil Kumar Tripathi ◽

Geeta Suri Sharma ◽

Nidhish Kumar ◽

Rashmi Kushwaha

Keyword(s):

Young Adult ◽

Adverse Events ◽

Factor Viii ◽

Low Dose ◽

Hemophilia A ◽

Adult Patients ◽

Severe Hemophilia ◽

Emergency Visits ◽

Episodic Treatment ◽

Long Acting

Objectives: High dose factor prophylaxis in hemophilia has been proven to prevent joint bleeds in the western world effectively. We look for a cost-effective and feasible way for Indian patients to reduce the dose and frequency of factor infusion. Data on prophylaxis with a low dose, long-acting factor infusion twice a week dosing schedule is limited. The purpose was to study the efficacy and safety of long-acting factor VIII (Eloctate) for secondary/ tertiary prophylaxis in pediatric and young adult patients with moderate and severe hemophilia A. Materials and Methods: Thirty-eight patients with moderate and severe hemophilia A with an age range from 1 to 25 years were included in the study. During the initial 4 months, they received therapeutic doses of ELOCTATE (Factor VIII with Fc Fusion Protein) on an episodic basis after a clinical bleed. In the next 4 months, they received prophylactic intravenous ELOCTATE at the dose of 20 units/kg body weight twice a week. Annual bleeding rates (ABR), school absenteeism, emergency visits, joint scores, and adverse events were compared during both periods. Results: The total number of joint bleeds during the episodic treatment and prophylaxis period was 608 and 67, respectively. ABR was 47.9 during the episodic treatment period and 5.3 during prophylaxis showing an 88.9% reduction in joint bleeds. School/college absenteeism and emergency visits were significantly reduced during prophylaxis. No significant adverse events were noted during prophylaxis. Conclusion: Low dose, twice a week, and long-acting recombinant factor VIII-Fc (Eloctate) prophylaxis can be a reasonable options for patients with hemophilia A in developing countries.

Download Full-text

Individualized prophylactic treatment of patients with hemophilia A to improve effectiveness and optimize product consumption on the example of octocog alpha and rurioctocog alpha pegol. A systematic literature review

Kachestvennaya klinicheskaya praktika ◽

10.37489/2588-0519-2021-2-22-29 ◽

2021 ◽

pp. 22-29

Author(s):

A. G. Tolkushin ◽

M. E. Holownia-Voloskova ◽

N. L. Pogudina

Keyword(s):

Observational Studies ◽

Prophylactic Treatment ◽

Pediatric Patients ◽

Hemophilia A ◽

Controlled Study ◽

Bleeding Rate ◽

Risk Of Bleeding ◽

Product Consumption ◽

Annual Consumption ◽

International Data

Objective: to review the data on the efficacy and consumption of octocog alfa and rurioctoctog alfa pegol in standard prophylaxis and individualized prophylaxis in hemophilia A patients based on published international data. Material and methods: a systematic literature search and review were performed. Among 25 sources identified within the systematic search 7 relevant sources describing the comparison of treatment with octocog alfa and rurioctocog alfa pegol in adult and pediatric patients with severe and moderate hemophilia A based on personalized assessment of the pharmacokinetic curve using the interactive tool myPKFit versus the standard (non-personalized) dosage regimen were selected. Data on individual patients, as well as data from secondary subgroups defined by age, bleeding rate, risk of bleeding associated with the daily physical activity were combined and analyzed. Results. In observational studies, adjustments of the dose and administration of octocog alfa in patients with severe hemophilia based on personalized assessment of the pharmacokinetic curve using myPKFit resulted in the reduced consumption and/or increased efficacy of prophylaxis — a reduced annual bleeding rate. In an extended controlled study of rurioctocog alpha pegol a trend toward reduced bleeding rate and increased mean annual consumption of the drug was reported in patients who received myPKFit guided prophylaxis compared to a non-personalized treatment regimen. In the single-cut studies, myPKFiT use resulted in the regimen revisions in less than a quarter of patients. Summary. Personalized dosing for octocog alpha and rurioctocog alpha pegol based on pharmacokinetic curve built using pharmacokinetic population model enables reasonable dose adjustments and improves outcomes.

Download Full-text

Evaluation of anti-ulcer activity of 4-hydrooxy benzalydehide against NSAIDs induced ulcers in rats

International Journal of Research in Medical Sciences ◽

10.18203/2320-6012.ijrms20211878 ◽

2021 ◽

Vol 9 (5) ◽

pp. 1412

Author(s):

Rupali V. Jadhav ◽

V. K. Redasani ◽

Shankar B. Kalbhare ◽

Karishma Yadav ◽

Aryan Langeh ◽

...

Keyword(s):

Low Dose ◽

Positive Control ◽

Gastric Volume ◽

Control Group ◽

High Dose ◽

Antiulcer Activity ◽

Ulcer Index ◽

Pylorus Ligation ◽

The Impact ◽

Intermediate Dose

Background: The aim of this study was to evaluate antiulcer activity of 4-hydroxybenzaldehyde against NSAIDs induced ulcer in rats based differences in its morphology, distance with other external landmarks and also to sigmoid and transverse sinuses.Methods: The antiulcer activity of 4-HBD was evaluated using pylorus ligation-aspirin induced ulcer method. Animals of this models were treated with 4-HBD (50mg/kg, 100mg/kg and 150mg/kg).Results: It has been observed that 4-HBD at low dose (50mg/kg), intermediate dose (100mg/kg) and high dose (150mg/kg) showed significant increase in pH, significant decrease in gastric volume, significant decrease in ulcer index and significant decrease in total acidity.Conclusions: The impact of 4-HBD therapy with intermediate (100mg/kg, p.o.) dose was observed to be similar with the positive control group.

Download Full-text