RARE DISEASE
Severe hemophilia A
Severe hemophilia A
Severe hemophilia A
Synonyms: Severe congenital F8 deficiency, Severe congenital factor VIII deficiency
Synonyms: Severe congenital F8 deficiency, Severe congenital factor VIII deficiency
Synonyms: Severe congenital F8 deficiency, Severe congenital factor VIII deficiency
Drug discovery
1
drug
With orphan designation
Overview
Severe Hemophilia A is an X-linked bleeding disorder characterized by factor VIII levels <1% of normal, resulting in spontaneous bleeding into joints, muscles, and soft tissues. Lifelong management focuses on preventing/treating bleeds through factor replacement or non-factor therapies. Complications include chronic arthropathy, inhibitor development, and substantial quality-of-life impairments [1][6][11][12].
Therapies
Prophylaxis: Regular FVIII infusions (plasma-derived or recombinant) to maintain levels ≥1% [1][18].
Non-factor therapies: Subcutaneous emicizumab (bispecific antibody mimicking FVIII) reduces bleed frequency [3][6].
Immune tolerance induction: High-dose FVIII regimens for inhibitor eradication [8].
Categories: rare genetic diseases, rare hematological diseases
Research Papers
3,185 drug discovery papers about Severe hemophilia A, with 4 first-in-class and 7 next-in-class emerging drug candidates forecasted to outperform the average preclinical success rate. Recent publications:
3,185 drug discovery papers about Severe hemophilia A, with 4 first-in-class and 7 next-in-class emerging drug candidates forecasted to outperform the average preclinical success rate. Recent publications:
2026-08-14 | Treatment satisfaction and patient preference for efanesoctocog alfa over previous hemophilia A treatment: Results from the XTEND-1 phase 3 clinical trial.
Treatments for Hemophilia A include prophylaxis with factor VIII (FVIII) replacement therapy. With standard and extended half-life therapies, patients still experience bleeds, and administration 2-4 times a week is needed, which affects adherence. Efanesoctocog alfa is a once-weekly FVIII replacement therapy approved to treat and prevent bleeding in patients with hemophilia A for all age groups. To analyze patient treatment preferences and satisfaction comparing once-weekly efanesoctocog alfa with pre-study prophylaxis in adults and adolescents with severe hemophilia A in the pivotal Phase 3 XTEND-1 study (NCT04161495). Exploratory post-hoc patient-reported outcomes were assessed by treatment preference at Week 52 (via a treatment preference survey) and patient satisfaction at baseline and up to Week 52 (via the 9-item Treatment Satisfaction Questionnaire for Medication [TSQM-9], covering: global satisfaction, effectiveness and convenience domains). Relationships between treatment satisfaction and preference versus bleeding and region were also explored. Of 130 patients who completed the preference survey, 90.0% preferred efanesoctocog alfa versus their previous prophylaxis regimen. Similar trends were observed by region. The most common reasons were 'less frequent treatment', 'bleeds and bleed-related complications reduction', and 'feel better protected'. Of 115 patients who completed the TSQM-9 at Week 52, there was a statistically significant improvement from baseline in all three domains. By study end, an increase in the proportion of patients selecting the "best response" for all TSQM-9 items was observed. There were no strong correlations with treatment satisfaction improvements at Week 52 and improvement in quality of life or bleeding episodes. Prophylactic efanesoctocog alfa was preferred to prior prophylactic regimens by most patients and improved patient satisfaction at 52 weeks.
2026-08-13 | Post Hoc Analyses of A-SURE and PREVENT Confirm the Effectiveness of rFVIIIFc Prophylaxis Across All Ages, BMIs, Severities, and Inhibitor Histories.
Objective To assess the effectiveness of recombinant factor VIII Fc fusion protein (efmoroctocog alfa; referred to herein as rFVIIIFc) prophylaxis in people with hemophilia A (PwHA) stratified by age, body mass index (BMI), disease severity, and inhibitor history included in the A-SURE (NCT02976753) and PREVENT (NCT03055611) real-world studies. Methods PwHA receiving at least one prescription of rFVIIIFc and ≥3 months of follow-up during the prospective periods were included. Post hoc analyses were performed for the overall analysis population and subgroups based on age, BMI, disease severity, and those with and without previous inhibitors. Effectiveness endpoints were annualized bleeding rate (ABR), annualized joint bleeding rate (AjBR), injection frequency, and factor consumption in the prospective period. Results Overall, 333 PwHA were analyzed. ABRs and AjBRs, generally, were low across the different subgroups (range of medians, 0.0-0.6 for both ABRs and AjBRs, except for ABRs in PwHA aged ≥65 years). Injection frequencies ( n injections/week) were comparable across subgroups (range of medians, 2.0-2.3), and factor consumption was generally similar (range of medians, 68.3-100.0 international units/kg/week), although with slightly higher factor consumption in pediatric PwHA and lower consumption in the overweight or obese BMI groups. Conclusion These post hoc analyses support the effectiveness and, therefore, use of rFVIIIFc prophylaxis in PwHA across all ages, BMI categories, severities, and for those with a history of inhibitors.
2026-08-08 | Long-term risk factors for hemophilic arthropathy in patients with severe hemophilia A: a 36-year retrospective cohort study
Hemophilic arthropathy (HA) is a major cause of disability in patients with severe hemophilia A. However, long-term data describing progression to advanced radiographic HA across major joint sites remain limited. We investigated risk factors for progression to advanced HA over extended follow-up. We conducted a retrospective cohort study of inhibitor-negative patients with severe hemophilia A followed at our institute between 1984 and 2020. Bilateral elbows, knees, and ankles were evaluated (six joints per patient). HA progression was defined as reaching Arnold–Hilgartner stage ≥ IV. Time to progression was analyzed using Cox proportional hazards models with cluster-robust standard errors, with participant as the clustering variable, to account for within-participant correlation across joints. Covariates included joint site, Arnold–Hilgartner stage at initiation of regular prophylaxis, age at first visit to our institute, prophylaxis status at the first visit, and laterality. The cohort included 109 patients (mean age at first visit to our institute, 14.3 years). At the first visit, Arnold–Hilgartner stage ≥ I changes were present in 15% of elbows (29/200), 8% of knees (16/200), and 27% of ankles (51/186). Across 583 joints and 8,634 joint-years of follow-up, 94 joints progressed to stage ≥ IV (10.9 per 1,000 joint-years of follow-up). In multivariable analysis, baseline radiographic status at the start of regular prophylaxis was strongly associated with progression (vs stage 0: stage I HR 14.95; stage II HR 11.84; stage III HR 34.47). Patients already receiving regular prophylaxis at the first visit had a lower risk of progression (HR 0.54). After adjustment, joint-site differences were not evident, and the independent association of age at first visit to our institute with progression was not estimated with sufficient precision. Baseline radiographic status at initiation of regular prophylaxis was strongly associated with long-term progression to advanced radiographic HA. These findings support initiating regular prophylaxis before radiographic joint changes become established.
2026-08-07 | Quality of Life in People With Haemophilia: Results in the Framework of a Nationwide Registry in Colombia.
Real-world data on health-related quality of life (HRQoL) and its predictors in people with haemophilia (PWH) are crucial to evaluate the effect of comprehensive management. It may be useful for clinicians and interdisciplinary teams to better target their interventions. We aimed to characterise global HRQoL and its associated factors in PWH within the Colombian health system. A cross-sectional study on PWH included in the Colombian Registry of Haemophilia and other Coagulopathies (CRHOC) from November 2021 to April 2022. Global HRQoL was measured using culturally validated versions of HemoLatin-QoL (adults) and CHO-KLAT 2.0 in children and their parents. A descriptive analysis and simple and multiple linear regressions were used to identify the factors associated with global HRQoL. Five hundred and eighty-three participants were analysed (452 adults and 131 children). A total of 93% were men with a median age of 36 years (IQR: 27-51) in adults and 12 years (IQR: 9-15) in children. Most people were affiliated with the contributory insurance scheme, 98% of children were students, and 63% of adults were employed. A total of 79% had haemophilia A, 44% of adults and 63% of children had a severe form, and prophylaxis was the most used treatment. Median HRQoL was 83 points (IQR: 65-95) in adults and 72 points (IQR: 63-81) in children. In both subpopulations, experiencing pain, haemarthrosis and belonging to the subsidised insurance scheme worsened HRQoL. In adults, higher education, being employed or a student, physical activity, and being treated with Emicizumab significantly improved HRQoL. Prophylaxis had a significant protective effect in adults with severe disease. Pain, haemarthrosis and being affiliated with the subsidised scheme negatively modified HRQoL in adults and children. Prophylaxis improved HRQoL in severe cases. These findings help clinicians to better focus interdisciplinary management according to patient self-reported outcomes.
2026-08-01 | Subcutaneous MG1113 in severe hemophilia A&B: Phase 1b study for safety, pharmacokinetics, and pharmacodynamics
Background MG1113 is an IgG4 monoclonal antibody targeting the Kunitz-2 domain of tissue factor pathway inhibitor (TFPI), developed as a hemostatic rebalancing agent for hemophilia A or B. Objectives We aimed to investigate the safety, pharmacokinetics (PK), pharmacodynamics (PD), and preliminary hemostatic effects of MG1113. Methods This phase 1b clinical trial was constructed in a multicenter, prospective, stepwise dose-escalating (2.0, 3.0, and 3.3 mg/kg) design. MG1113 was administered subcutaneously once weekly for 8 weeks. Results Fifteen male patients (n=5/cohort) diagnosed with severe hemophilia A (n=14) or B (n=1) without inhibitors were enrolled. MG1113 was well tolerated, with an adverse event rate of 40.0% (6/15). No serious adverse events, early withdrawals, or dose interruptions occurred. PK analysis demonstrated a non-linear profile, with the peak plasma concentration at 33-48 hours post-dose. Free TFPI and diluted prothrombin time decreased from baseline, while thrombin generation markers increased. Exploratory analysis showed a notable numerical reduction in annualized total bleeding rates at higher doses: 91.7% at 3.0 mg/kg and 76.2% at 3.3 mg/kg. Zero bleeding rate was 20.0%, 60.0%, and 40.0% at doses of 2.0, 3.0, and 3.3 mg/kg, respectively. Conclusion MG1113, administered subcutaneously as a prophylaxis in severe hemophilia A or B without inhibitors for 8 weeks, demonstrated an acceptable safety profile with a PK profile suitable for once-a-week dosing. The PD marker changes were consistent with TFPI inhibition, which was associated with reductions in bleeding events.
2026-08-14 | Treatment satisfaction and patient preference for efanesoctocog alfa over previous hemophilia A treatment: Results from the XTEND-1 phase 3 clinical trial.
Treatments for Hemophilia A include prophylaxis with factor VIII (FVIII) replacement therapy. With standard and extended half-life therapies, patients still experience bleeds, and administration 2-4 times a week is needed, which affects adherence. Efanesoctocog alfa is a once-weekly FVIII replacement therapy approved to treat and prevent bleeding in patients with hemophilia A for all age groups. To analyze patient treatment preferences and satisfaction comparing once-weekly efanesoctocog alfa with pre-study prophylaxis in adults and adolescents with severe hemophilia A in the pivotal Phase 3 XTEND-1 study (NCT04161495). Exploratory post-hoc patient-reported outcomes were assessed by treatment preference at Week 52 (via a treatment preference survey) and patient satisfaction at baseline and up to Week 52 (via the 9-item Treatment Satisfaction Questionnaire for Medication [TSQM-9], covering: global satisfaction, effectiveness and convenience domains). Relationships between treatment satisfaction and preference versus bleeding and region were also explored. Of 130 patients who completed the preference survey, 90.0% preferred efanesoctocog alfa versus their previous prophylaxis regimen. Similar trends were observed by region. The most common reasons were 'less frequent treatment', 'bleeds and bleed-related complications reduction', and 'feel better protected'. Of 115 patients who completed the TSQM-9 at Week 52, there was a statistically significant improvement from baseline in all three domains. By study end, an increase in the proportion of patients selecting the "best response" for all TSQM-9 items was observed. There were no strong correlations with treatment satisfaction improvements at Week 52 and improvement in quality of life or bleeding episodes. Prophylactic efanesoctocog alfa was preferred to prior prophylactic regimens by most patients and improved patient satisfaction at 52 weeks.
2026-08-13 | Post Hoc Analyses of A-SURE and PREVENT Confirm the Effectiveness of rFVIIIFc Prophylaxis Across All Ages, BMIs, Severities, and Inhibitor Histories.
Objective To assess the effectiveness of recombinant factor VIII Fc fusion protein (efmoroctocog alfa; referred to herein as rFVIIIFc) prophylaxis in people with hemophilia A (PwHA) stratified by age, body mass index (BMI), disease severity, and inhibitor history included in the A-SURE (NCT02976753) and PREVENT (NCT03055611) real-world studies. Methods PwHA receiving at least one prescription of rFVIIIFc and ≥3 months of follow-up during the prospective periods were included. Post hoc analyses were performed for the overall analysis population and subgroups based on age, BMI, disease severity, and those with and without previous inhibitors. Effectiveness endpoints were annualized bleeding rate (ABR), annualized joint bleeding rate (AjBR), injection frequency, and factor consumption in the prospective period. Results Overall, 333 PwHA were analyzed. ABRs and AjBRs, generally, were low across the different subgroups (range of medians, 0.0-0.6 for both ABRs and AjBRs, except for ABRs in PwHA aged ≥65 years). Injection frequencies ( n injections/week) were comparable across subgroups (range of medians, 2.0-2.3), and factor consumption was generally similar (range of medians, 68.3-100.0 international units/kg/week), although with slightly higher factor consumption in pediatric PwHA and lower consumption in the overweight or obese BMI groups. Conclusion These post hoc analyses support the effectiveness and, therefore, use of rFVIIIFc prophylaxis in PwHA across all ages, BMI categories, severities, and for those with a history of inhibitors.
2026-08-08 | Long-term risk factors for hemophilic arthropathy in patients with severe hemophilia A: a 36-year retrospective cohort study
Hemophilic arthropathy (HA) is a major cause of disability in patients with severe hemophilia A. However, long-term data describing progression to advanced radiographic HA across major joint sites remain limited. We investigated risk factors for progression to advanced HA over extended follow-up. We conducted a retrospective cohort study of inhibitor-negative patients with severe hemophilia A followed at our institute between 1984 and 2020. Bilateral elbows, knees, and ankles were evaluated (six joints per patient). HA progression was defined as reaching Arnold–Hilgartner stage ≥ IV. Time to progression was analyzed using Cox proportional hazards models with cluster-robust standard errors, with participant as the clustering variable, to account for within-participant correlation across joints. Covariates included joint site, Arnold–Hilgartner stage at initiation of regular prophylaxis, age at first visit to our institute, prophylaxis status at the first visit, and laterality. The cohort included 109 patients (mean age at first visit to our institute, 14.3 years). At the first visit, Arnold–Hilgartner stage ≥ I changes were present in 15% of elbows (29/200), 8% of knees (16/200), and 27% of ankles (51/186). Across 583 joints and 8,634 joint-years of follow-up, 94 joints progressed to stage ≥ IV (10.9 per 1,000 joint-years of follow-up). In multivariable analysis, baseline radiographic status at the start of regular prophylaxis was strongly associated with progression (vs stage 0: stage I HR 14.95; stage II HR 11.84; stage III HR 34.47). Patients already receiving regular prophylaxis at the first visit had a lower risk of progression (HR 0.54). After adjustment, joint-site differences were not evident, and the independent association of age at first visit to our institute with progression was not estimated with sufficient precision. Baseline radiographic status at initiation of regular prophylaxis was strongly associated with long-term progression to advanced radiographic HA. These findings support initiating regular prophylaxis before radiographic joint changes become established.
2026-08-07 | Quality of Life in People With Haemophilia: Results in the Framework of a Nationwide Registry in Colombia.
Real-world data on health-related quality of life (HRQoL) and its predictors in people with haemophilia (PWH) are crucial to evaluate the effect of comprehensive management. It may be useful for clinicians and interdisciplinary teams to better target their interventions. We aimed to characterise global HRQoL and its associated factors in PWH within the Colombian health system. A cross-sectional study on PWH included in the Colombian Registry of Haemophilia and other Coagulopathies (CRHOC) from November 2021 to April 2022. Global HRQoL was measured using culturally validated versions of HemoLatin-QoL (adults) and CHO-KLAT 2.0 in children and their parents. A descriptive analysis and simple and multiple linear regressions were used to identify the factors associated with global HRQoL. Five hundred and eighty-three participants were analysed (452 adults and 131 children). A total of 93% were men with a median age of 36 years (IQR: 27-51) in adults and 12 years (IQR: 9-15) in children. Most people were affiliated with the contributory insurance scheme, 98% of children were students, and 63% of adults were employed. A total of 79% had haemophilia A, 44% of adults and 63% of children had a severe form, and prophylaxis was the most used treatment. Median HRQoL was 83 points (IQR: 65-95) in adults and 72 points (IQR: 63-81) in children. In both subpopulations, experiencing pain, haemarthrosis and belonging to the subsidised insurance scheme worsened HRQoL. In adults, higher education, being employed or a student, physical activity, and being treated with Emicizumab significantly improved HRQoL. Prophylaxis had a significant protective effect in adults with severe disease. Pain, haemarthrosis and being affiliated with the subsidised scheme negatively modified HRQoL in adults and children. Prophylaxis improved HRQoL in severe cases. These findings help clinicians to better focus interdisciplinary management according to patient self-reported outcomes.
2026-08-01 | Subcutaneous MG1113 in severe hemophilia A&B: Phase 1b study for safety, pharmacokinetics, and pharmacodynamics
Background MG1113 is an IgG4 monoclonal antibody targeting the Kunitz-2 domain of tissue factor pathway inhibitor (TFPI), developed as a hemostatic rebalancing agent for hemophilia A or B. Objectives We aimed to investigate the safety, pharmacokinetics (PK), pharmacodynamics (PD), and preliminary hemostatic effects of MG1113. Methods This phase 1b clinical trial was constructed in a multicenter, prospective, stepwise dose-escalating (2.0, 3.0, and 3.3 mg/kg) design. MG1113 was administered subcutaneously once weekly for 8 weeks. Results Fifteen male patients (n=5/cohort) diagnosed with severe hemophilia A (n=14) or B (n=1) without inhibitors were enrolled. MG1113 was well tolerated, with an adverse event rate of 40.0% (6/15). No serious adverse events, early withdrawals, or dose interruptions occurred. PK analysis demonstrated a non-linear profile, with the peak plasma concentration at 33-48 hours post-dose. Free TFPI and diluted prothrombin time decreased from baseline, while thrombin generation markers increased. Exploratory analysis showed a notable numerical reduction in annualized total bleeding rates at higher doses: 91.7% at 3.0 mg/kg and 76.2% at 3.3 mg/kg. Zero bleeding rate was 20.0%, 60.0%, and 40.0% at doses of 2.0, 3.0, and 3.3 mg/kg, respectively. Conclusion MG1113, administered subcutaneously as a prophylaxis in severe hemophilia A or B without inhibitors for 8 weeks, demonstrated an acceptable safety profile with a PK profile suitable for once-a-week dosing. The PD marker changes were consistent with TFPI inhibition, which was associated with reductions in bleeding events.
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Drug Discovery Landscape
1 orphan drug designation for Severe hemophilia A.
1 orphan drug designation for Severe hemophilia A.
Drug | Therapy type | Regulator | Orphan designation | Approval | Sponsor |
|---|---|---|---|---|---|
an autologous gene therapy consisting of CD34+ hematopoietic stem and progenitor cells transduced ex-vivo with the CD68-ET3-LV lentiviral vector | gene therapies | FDA | 2026-04-12 | — | Expression Therapeutics LLC |
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