The impact of individualized prophylactic treatment based on pharmacokinetic parameters on the prognosis of patients with severe hemophilia A

When and how to start prophylaxis in boys with severe hemophilia without inhibitors: communication from the SSC of the ISTH

Age at first joint bleed and bleeding severity in boys with severe hemophilia A: Canadian Hemophilia Primary Prophylaxis Study

Tailored prophylaxis in severe hemophilia A: Real-world experience with efanesoctocog alfa

The pharmacokinetics (PK) of extended half-life factor VIII (FVIII) products might allow longer dosing intervals in prophylaxis, potentially affecting its efficacy. We used published population PK models of a recombinant full-length FVIII (rAHF-PFM) and a recombinant B-domain-deleted FVIII Fc fusion product (rFVIIIFc) to assess the time spent weekly with FVIII levels below 3IUdL(-1) or above 10IUdL(-1) . These FVIII levels were chosen based on the observation that trough levels of 1IUdL(-1) may not be sufficient in all patients. This approach was applied to a simulated population of 1000 severe haemophilia A subjects with dosing regimens included in the prescribing information or evaluated in clinical trials. FVIII levels remained ≥3IUdL(-1) in 57% of patients treated with rAHF-PFM 30IUkg(-1) every 48h compared with 41.1%, 18.3%, 0.9% and 0% of patients treated with rFVIIIFc 30IUkg(-1) every 72h, 50IUkg(-1) every 96h or 120h and 65IUkg(-1) every 168h respectively. Patients on rAHF-PFM 30IUkg(-1) every 48h spent more time weekly with FVIII levels above 10IUdL(-1) than those on rFVIIIFc 50IUkg(-1) every 96h or 120h, and 65IUkg(-1) every 168h. In conclusion, PK modelling indicates that choice and dosing intervals of standard and extended half-life FVIII products require careful evaluation of individual PK to allow more time at protective levels, especially in patients with active lifestyles.

Searching for the role of primary prophylaxis in preventing inhibitor development in hemophilia A

BackgroundHemophilia A (HA) is an established inherited bleeding condition caused by the lack of factor VIII, which causes recurrent joint hemorrhages and related adverse outcomes. Emicizumab, a bispecific monoclonal antibody, provides sustained prophylaxis, minimizing bleeding episodes and enhancing treatment adherence. This study assesses its impact on joint health, functional independence, and quality of life (QoL) in Indian patients with severe HA.MethodologyThis retrospective study, conducted at Goa Medical College, Goa, India, involved 20 patients with severe HA receiving emicizumab prophylactic therapy over a period of one year from January 2023 to January 2024. Outcomes were judged using the Hemophilia Joint Health Score (HJHS), annualized bleed rate (ABR), functional independence score in hemophilia (FISH), and the European Quality of Life 5-Dimension 5-Level (EQ-5D-5L) questionnaire for a period of one year. Ethical approval was secured for the study, and patient confidentiality was upheld.ResultsThis study comprised 20 male participants (median age: 30.15 years), of whom 90% had severe HA and 55% had inhibitors present. Most (90%) participants were on an on-demand treatment protocol. At baseline, 90% of participants had target joints (mean: 4.7±2.51), and the mean ABR was 24.6±9.02. Over 12 months, HJHS decreased from 36.00 to 6.05 (p<0.001), FISH improved from 14.00 to 25.95 (p<0.001), and ABR dropped by 99.8% (median: 0.00, p<0.001). The EQ-5D-5L score significantly improved (p<0.001), indicating better QoL. Treatment adherence was 100%, with no adverse events (AEs).ConclusionsEmicizumab demonstrated significant benefits in severe HA, including improved joint health, enhanced functional independence, and a better QoL over the course of 12 months. With 100% adherence and no AEs reported, it proves to be a feasible and well-tolerated prophylactic option. These findings support its long-term role in disease management, warranting further research in diverse patient populations.

Prophylaxis with a recombinant factor VIII Fc in hemophilia A: long-term follow-up on joint health, efficacy, and safety from phase 3 studies in children and adults

IntroductionCurrent treatment of severe haemophilia A includes prophylaxis with factor VIII (FVIII) replacement. The supply of plasma‐derived FVIII is short in China.PurposeTo evaluate the efficacy and safety of a new B‐domain deleted (BDD) recombinant FVIII (TQG202) produced by human‐derived cells for prophylaxis in severe haemophilia A patients and compare the bioequivalence with Xyntha.MethodsThis multicentre, clinical trial consisted of an open‐label, randomized, two‐period cross‐over trial assessing single‐dose pharmacokinetics (PK), and a single‐arm clinical trial evaluating the efficacy and safety of 24 weeks of TQG202 prophylaxis, and repeated PK were assessed after prophylaxis phase. The single‐dose was 50 IU/kg in PK assessment, and the initial dose was 30 ± 5 IU/kg for prophylaxis. The primary endpoints of prophylaxis were the annualized bleeding rate (ABR) and the incremental recovery rate of the first administration. Adverse events (AEs) were recorded.ResultsTwenty‐six participants were enrolled in the PK assessment and 81 participants in the prophylaxis phase. Mean age was 25.9 ± 10.8 years and all participants were male. The results of PK assessment showed TQG202 is bioequivalent to Xyntha. The total ABR was 2.0 (95% CI: 1.2–2.9) in prophylaxis phase. The mean incremental recovery rate of the first administration was .027 (95% CI: .026–.028) (IU/ml)/(IU/kg). AEs occurred in 42 participants, with an incidence of 51.9%. One severe AE not related to TQG202 occurred. No participants developed FVIII inhibitors.ConclusionTQG202 shows bioequivalence with Xyntha. The promising efficacy and tolerability in the severe haemophilia A prophylaxis support the use of TQG202in clinical practice.

With licensure of extended half-life (EHL) factor products and the changing landscape of available hemophilia products, patients and providers have options for less treatment-intense prophylaxis. The impact of these products in clinical practice to date remains understudied. We aimed to quantify the use of EHL products in prophylaxis in the US using the ATHN-dataset, a database of 145 ATHN-affiliated hemophilia treatment centers (HTCs). Further, we aimed to quantify the impact of EHL on key hemophilia indicators including annualized bleed rates (ABRs), hemophilia joint health scores (HJHS) and quality of life (QOL) metrics. The use of EHL vs standard half-life (SHL) products in severe hemophilia was compared between June 2018 and March 2019 using the ATHN-dataset. A cohort of patients was also recruited from seven participating HTCs in order to compare ABR, HJHS and QOL between product classes. By March 2019 the number of individuals with severe Hemophilia A (SHA) receiving EHLs remained relatively stable (28.4%), whereas the number of prescribed non-factor products increased to 7.1%, with a diminishing majority of patients (64.0%) continuing to receive SHLs. The majority of patients with severe hemophilia B (SHB) received treatment with EHLs including 57.5% by March 2019. There was a trend toward lower ABR with use of EHLs in SHA and SHB, although this did not result in improved HJHS nor QOL. EHL use in the United States in severe hemophilia continues to increase, although at a slower rate in SHA with the availability of non-factor therapy. The impact of the EHL therapies in clinical practice should continue to be examined prospectively.

Target of prophylaxis in severe haemophilia: more than factor levels.

Design of an Observational Study (PROVE) to Assess the Long-Term Effects of Prophylaxis with Simoctocog Alfa or Emicizumab on Joint and Bone Health in Hemophilia a Patients

Haemophilia A is a sex-linked disorder characterised chiefly by recurrent, spontaneous joint and muscle bleedings resulting from deficiency of factor VIII (FVIII). Recurrent joint bleeds result in haemophilic arthropathy. Unless treated with factor replacement therapy, many patients with severe haemophilia become disabled. The first clinical evidence favouring prophylaxis originated from the studies in Sweden and the Netherlands in the 1960s. Later on, it was shown that prophylaxis could prevent arthropathy, if started early in life, or slow its progression in adults with established arthropathy. The optimal dosing of FVIII in long-term prophylaxis has still not been determined, and there is growing evidence that the dose and frequency of FVIII should be individualised. We conducted a systematic search of PubMed to identify all relevant articles on FVIII prophylaxis in severe haemophilia A. We focused on articles with detailed information about individualisation of prophylaxis. Long-term prophylaxis in haemophilia was introduced in Sweden in the late 1950s. However, standard prophylactic regimens may not be appropriate for all patients with severe haemophilia. Factors such as age, joint status, co-morbidities and differences in pharmacokinetics lead to interindividual variation in factor requirement. Dose tailoring of FVIII by clinical outcome was first described in 1994. Since then, several dose-finding studies questioned the necessity to maintain preinfusion levels of FVIII above 1%. Individualising prophylaxis by dose tailoring is now recommended. Each country should adopt policies for individualising prophylaxis in patients with severe haemophilia. This would lead to a better distribution of the available source of factor concentrates.

Early initiation of prophylaxis in severe haemophilia is critical for effective prevention of arthropathy. However, the optimum time for starting prophylaxis has not been established yet. This study assessed long-term effects of age at starting prophylaxis and joint bleeding before prophylaxis on haemophilic arthropathy. In patients with severe haemophilia (FVIII/IX <0.01 IU mL-1 ), born between 1965 and 2000, haemophilic arthropathy was evaluated on X-rays. Patient groups were compared by multivariable regression analysis, adjusted for bleeding phenotype and lifetime intensity of prophylaxis. One hundred and twenty-four patients were evaluated at a median age of 22 years. When comparing patients according to age at starting prophylaxis, starting before age 6 years was significantly better than starting later (P < 0.01), but no additional benefit of starting before age 3 years was demonstrated. The number of joint bleeds before prophylaxis had a stronger association with arthropathy than age at starting prophylaxis. Starting prophylaxis before the onset of joint bleeding resulted in the best long-term outcome (P ≤ 0.02); starting after one joint bleed appeared to have acceptable long-term outcome. The difference between starting after 0-1 and 2-5 joint bleeds was notable, but statistical significance was not reached (P = 0.15). Future research with more patients on early prophylaxis will have to clarify whether starting prophylaxis before joint bleeding is superior.

Use of Clinical Practice Guidelines on Long-term Prophylaxis in Severe Hemophilia in France: A Retrospective Audit

Prophylaxis is the recommended treatment for children with severe haemophilia A, but whether prophylaxis should be continued in adulthood is still under debate. Previous studies with limited follow-up have suggested that some patients may be able to stop prophylaxis in adulthood, while maintaining good joint health. This single-centre observational cohort study examined patients with severe haemophilia A born 1970-1988 without inhibitor development, and assessed the long-term consequences of discontinuing prophylaxis. Patient-initiated changes in prophylaxis, including all switches to on-demand treatment lasting a minimum of two consecutive weeks, were recorded from the time self-infusion began until the last evaluation. Sixty-six patients were evaluated at a median age of 32.4 years: 26 % of patients had stopped prophylaxis for a median of 10 years, 15 % had interrupted prophylaxis and 59 % had continued prophylaxis. Annual joint bleeding rate (AJBR), Haemophilia Joint Health Score (HJHS-2.1; 0-124 points), radiological Pettersson score (0-78 points) and Haemophilia Activities List score (HAL; 100-0 points) were compared between patients who stopped and patients who continued prophylaxis. Although self-reported bleeding rates and functional limitations were similar in both groups (AJBR: 1.5 vs 1.2 and HAL: 84 vs 84 for those who stopped and continued prophylaxis, respectively), objective assessment of joint status showed increased arthropathy after 10 years of on-demand treatment in patients who stopped prophylaxis compared with those who continued (HJHS: 23 vs. 14 and Pettersson: 16 vs 5, respectively; P< 0.01). These results support continuation of long-term prophylaxis in adults and demonstrate the need for objective monitoring of joint status.