• Hemlibra is indicated for the treatment of PwcHA with or without inihibitors. Hemlibra is not indicated for PwAHA outside of Japan.
• Several clinical trials and real-world studies have investigated and are currently investigating the use of Hemlibra in PwAHA.
• Phase 3 AGEHA study
• This is a prospective, non-randomized, multicenter, open-label, Phase 3 study that evaluated the efficacy, safety, and pharmacokinetics of Hemlibra in PwAHA.1 This is a descriptive study with no primary or secondary endpoints.
• 14 patients aged ≥18 years with FVIII activity <50 IU/dL and an FVIII inhibitor titer ≥0.6 BU/mL were recruited. Patients were undergoing, scheduled to start, or ineligible for immunosuppressive therapy at the time of enrolment.
• Patients received Hemlibra 6 mg/kg on day 1, 3 mg/kg on day 2, and then 1.5 mg/kg once weekly from day 8 thereafter. Treatment was continued until FVIII activity was >50 IU/dL.
• For treated bleeds, major bleeds, and all bleeds, decreased mean calculated annualized bleeding rates were observed during the Hemlibra treatment period when compared to the pre-treatment period.
• There were no new clinically relevant safety findings.
• Phase 2 GTH-AHA-EMI study
• This is a single arm, non-randomized, open label, Phase 2 study that evaluated the efficacy and safety of Hemlibra in PwAHA .
• 47 patients aged ≥18 years with FVIII activity <50 IU/dL, and presence of FVIII inhibitors were recruited. Patients were not receiving immunosuppressive therapy.
• Patients received Hemlibra 6 mg/kg on day 1, 3 mg/kg on day 2, and 1.5 mg/kg once weekly until week 12.
• The primary endpoint was met, as the mean rate of bleeds per-patient week of 0.04 was significantly below the predefined threshold rate of 0.15 bleeds per-patient week from a study of patients who received immunosuppressive therapy but not Hemlibra (p<0.01).
• Two thromboembolic events were reported; both patients fully recovered. Four deaths were reported none of which were related to Hemlibra.
• Retrospective studies & case series
• Several retrospective studies and case series have reported outcome and safety data on the use of Hemlibra in AHA. Hemlibra doses and treatment schedules varied between the studies. If interested, please refer to the full publications for further details.

ADA(s)=anti-drug antibody(ies)

AE=adverse event

AHA=acquired hemophilia A

aPCC=activated prothrombin complex concentrate

aPTT=activated partial thromboplastin time

AU=arbitrary units

BPA(s)=bypassing agent(s)

BU=Bethesda unit

Ctrough,SS=steady state trough concentration

DVT=deep vein thrombosis

FVIII=factor VIII

FVIII:C=chromogenic FVIII activity

HA=hemophilia A

PwAHA=patients with acquired hemophilia A

PwcHA=patients with congenital hemophilia A 

Hemlibra is indicated for the treatment of PwcHA with or without inihibitors.[2] Hemlibra is not indicated for PwAHA outside of Japan.[3]

Several clinical trials and real-world studies have investigated and are currently investigating the use of Hemlibra in PwAHA.

AGEHA is a prospective, non-randomized, multicenter, open-label, Phase 3 study that evaluated the efficacy, safety, and pharmacokinetics of Hemlibra in PwAHA.[1] The study was designed to be descriptive with no primary or secondary endpoints.

Patient population

Patients aged ≥18 years with FVIII activity <50 IU/dL and an FVIII inhibitor titer ≥0.6 BU/mL measured within 7 days prior to enrollment. 

Patients were divided into 2 cohorts:

• Cohort 1 — Patients undergoing or scheduled to start immunosuppressive therapy at the time of enrolment (n=12)
• Cohort 2 — Patients ineligible for immunosuppressive therapy at the time of enrolment (n=2)

Documented history of bleeding episodes and treatment with coagulation factor products within 24 weeks before enrollment had to be available.

Hemlibra treatment 

Patients received Hemlibra 

• 6 mg/kg on day 1
• 3 mg/kg on day 2, and then
• 1.5 mg/kg once weekly from day 8 thereafter.

Treatment was continued until FVIII activity was >50 IU/dL and there was no use of coagulation factor product for bleeds within 72 hours.[1]

Main efficacy outcomes

In the final analysis, 9 of 12 participants (75%) in cohort 1 and 2 of 2 participants in cohort 2 (100%) did not experience bleeds that required treatment during the Hemlibra treatment period.[4] Annual bleeding rates are described in Table 1.

Table 1. Annualized bleed rates in AGEHA study [4] 

Notes: * Data cutoff August 9, 2022. † Calculated ABRs were derived for each bleed type by: (number of bleeds/total number of days during the evaluation period)×365.25. ‡ Major bleed was defined as a life-threatening bleed; symptomatic bleed in an important region or major organ; or bleed associated with a decrease of ≥2 g/dL in hemoglobin or necessitating transfusion of ≥2 units of whole blood or packed red cells.

Abbreviations: ABR=annualized bleeding rate; NA=not applicable.

Main safety outcomes

Adverse events related to Hemlibra were observed in 

• 3 out of 12 participants (25%) in cohort 1, and
• 2 out of 2 participants (100%) in cohort 2.[4]

Among them, asymptomatic DVT was observed in one patient in the primary analysis, it was considered related to Hemlibra; prednisolone use and bed rest were also considered to be associated factors.[4]

DVT was not considered related to the coexistence of emicizumab and restored endogenous FVIII activity as

• FVIII activity 1 day before DVT discovery was 1.7 IU/dL, and
• Predicted plasma emicizumab concentration at DVT discovery in this patient was lower than mean Ctrough,ss in this study population.[4]

No new thromboembolic events or thrombotic microangiopathies were reported after the primary analysis.

Overall safety outcomes are described in Table 2.

Table 2. Adverse events during AGEHA study [4]

Notes: * Data cutoff August 9, 2022. † 1 death from exacerbation of chronic kidney disease was reported and considered not related to Hemlibra. ‡ Across both cohorts, the serious AEs were acute cholangitis and chronic cholangitis in 1 patient; cholelithiasis and hemorrhagic shock in 1 patient; and pneumonia, chronic kidney disease, orthostatic hypotension, and Basedow's disease in 1 patient each. § Across both cohorts, the Hemlibra-related AEs were thrombocytopenia, increased prothrombin fragment 1+2, DVT, Basedow’s disease, and rash in 1 patient each. ¶ 1 patient had decreased emicizumab exposure.

GTA-AHA-EMI is an single arm, non-randomized, open label, Phase II study that assessed the efficacy and safety of Hemlibra in PwAHA who were not receiving immunosuppressive therapy.[5,6]

Primary and secondary endpoints

The primary endpoint was the rate of clinically relevant bleeds, defined as those that required intervention by healthcare professionals or caused pain or any other kind of harm, until Week 12.[5,6] Hemlibra was considered to have a prophylactic effect if the mean bleed rate per patient-week was significantly below the corresponding rate (0.15 bleeds per patient-week) from the GTH-AH 01/2010 study of patients who received immunosuppressive therapy but not Hemlibra.

The secondary endpoints of adverse events and mortality were evaluated until Week 24.[5,6]

Patient population

The criteria for enrollment in the study were

• patients aged ≥18 years
• FVIII activity <50 IU/dL,
• presence of FVIII inhibitors, and
• active bleeding at screening.[5]

In total, 47 patients were enrolled, of which

• 51% were men
• 30% had underlying disorders (autoimmunity, 15%; malignancy, 13%; postpartum, 2%), and
• 70% had received factor concentrate for bleeding prior to Hemlibra.[5]

At baseline, the median age was 76 (21 to 93) years, the median FVIII activity was 1.4 IU/dL, and the median FVIII inhibitor titer was 12.2 (1 to 1,951) BU/mL.[5]

Treatment

Patients received Hemlibra

• 6 mg/kg on day 1
• 3 mg/kg on day 2, and
• 1.5 mg/kg once weekly until week 12.

Immunosuppressive therapy was permitted at the investigator’s discretion from weeks 13 to 24.[5] 

Clinical outcomes

A summary of efficacy and safety endpoint outcomes are presented in Table 3.

Table 3. Summary of main efficacy and safety outcomes in GTH-AHA-EMI [5]

Several retrospective studies and case series have reported outcome and safety data on the use of Hemlibra in AHA. Hemlibra doses and treatment schedules varied between the studies. If interested, please check References 7 to 12 for the full publications.[7-12]

1. Roche Internal Regulatory Report, accessed on 24-Aug-23.
2. Chugai Obtains Regulatory Approval for Hemlibra for Additional Indication of Acquired Hemophilia A [press release]. June 21, 2022. Accessed August 24, 2023, from https://www.chugai-pharm.co.jp/english/news/detail/20220620170002_928.html
3. Shima M, Amano K, Ogawa Y, et al. A prospective, multicenter, open-label phase III study of emicizumab prophylaxis in patients with acquired hemophilia A. J Thromb Haemost 2023;21:534-545. https://www.ncbi.nlm.nih.gov/pubmed/36696195
4. Shima M, Suzuki N, Nishikii H, et al. Final analysis results from a phase III study of emicizumab prophylaxis for acquired hemophilia A (AGEHA). Presented at the International Society on Thrombosis and Haemostasis Congress in Montreal, CA; June 24-28, 2023. ISTH Oral presentation #OC 06.3. https://www.isth.org
5. Tiede A, Hart C, Knoebl P, et al. Emicizumab prophylaxis instead of immunosuppressive therapy in patients with acquired hemophilia A (AHA). Presented at the International Society on Thrombosis and Haemostasis Congress in Montreal, CA; June 24-28, 2023. ISTH Abstract #LB 01.2. https://www.isth.org
6. Tiede A, Hart C, Knoebl P, et al. Emicizumab prophylaxis instead of immunosuppressive therapy in patients with acquired hemophilia A (AHA). Presented at the International Society on Thrombosis and Haemostasis Congress in Montreal, CA; June 24-28, 2023. ISTH Oral presentation #LB 01.2. https://www.isth.org
7. Chen S, Ellsworth P, Kasthuri R, et al. Emicizumab reduces re-hospitalization for bleeding in acquired haemophilia A. Haemophilia 2021;27:e585-e588. https://www.ncbi.nlm.nih.gov/pubmed/34050698
8. Poston J, Al-Banaa K, vonDrygalski A, et al. Emicizumab for the Treatment of Acquired Hemophilia a: A Multicenter US Case Series. Presented at the American Society of Hematology in Atlanta, GA; December 11-14, 2021. ASH Oral presentation #496. https://www.sciencedirect.com/science/article/pii/S0006497121024897#!
9. Knöebl P, Thaler J, Jilma P, et al. Emicizumab for the treatment of acquired hemophilia A: an update of the Vienna experience. Presented at the International Society on Thrombosis and Haemostasis Congress in London, UK; July 9-13, 2022. ISTH Poster #PB0002. https://abstracts.isth.org/abstract/emicizumab-for-the-treatment-of-acquired-hemophilia-a-an-update-of-the-vienna-experience/
10. Engelen M, Vandesande J, De Bent J, et al. Emicizumab for acquired haemophilia A: a case series. Haemophilia 2023;https://www.ncbi.nlm.nih.gov/pubmed/37276345
11. Chen E, Gibson W, Temoczko P, et al. Emicizumab for the treatment of acquired hemophilia A: Retrospective review of a single-institution experience. Haemophilia 2023;29:84-89. https://www.ncbi.nlm.nih.gov/pubmed/36163651
12. Sridharan M, Padrnos L, Wysokinska E, et al. Emicizumab for the management of acquired hemophilia A. Presented at the European Hematology Association in Frankfurt, Germany; June 8-15, 2023. EHA Abstract #P1616. https://journals.lww.com/hemasphere/fulltext/2023/08003/p1616__emicizumab_for_the_management_of_acquired.1509.aspx