ALTUVOCT Powder and solvent for solution for injection Ref.[111575] Active ingredients: Efanesoctocog alfa

Pharmacotherapeutic group: antihaemorrhagics, blood coagulation factor VIII
ATC code: B02BD02

Mechanism of action

Efanesoctocog alfa is replacement factor VIII therapy. Activated factor VIII acts as a cofactor for activated factor IX, accelerating the conversion of factor X to activated factor X. Activated factor X converts prothrombin into thrombin. Thrombin then converts fibrinogen into fibrin and a clot can be formed. Haemophilia A is an X-linked hereditary disorder of blood coagulation due to decreased levels of functional factor VIII:C and results in bleeding into joints, muscles or internal organs, either spontaneously or as a result of accidental or surgical trauma. By replacement therapy the plasma levels of factor VIII are increased, thereby enabling a temporary correction of the factor deficiency and correction of the bleeding tendencies.

Of note, annualized bleeding rate (ABR) is not comparable between different factor concentrates and between different clinical studies.

ALTUVOCT (efanesoctocog alfa) or recombinant coagulation Factor VIII Fc-Von Willebrand Factor-XTEN is a recombinant fusion protein that temporarily replaces the missing coagulation Factor VIII needed for effective haemostasis.

Efanesoctocog alfa is a FVIII protein that is designed not to bind endogenous VWF in order to overcome the half-life limit imposed by FVIII-VWF interactions. The D’D3 domain of VWF is the region that interacts with FVIII. Appending the D’D3 domain of VWF to a rFVIII-Fc fusion protein provides protection and stability to FVIII and prevents FVIII interaction with endogenous VWF, thus overcoming the limitation on FVIII half-life imposed by VWF clearance.

The Fc region of human immunoglobulin G1 (IgG1) binds to the neonatal Fc receptor (FcRn). FcRn is part of a naturally occurring pathway that delays lysosomal degradation of immunoglobulins by recycling them back into circulation and thus prolonging the plasma half-life of the fusion protein. Efanesoctocog alfa contains 2 XTEN polypeptides, which further increase its pharmacokinetics (PK). The natural FVIII B domain (except 5 amino acids) is replaced with the first XTEN polypeptide, inserted in between FVIII N745 and E1649 amino acid residues; and the second XTEN is inserted in between the D’D3 domain and Fc.

Clinical efficacy and safety

The safety, efficacy, and pharmacokinetics of ALTUVOCT have been evaluated in two multi-centre, prospective, open-label Phase 3 clinical studies (one study in adults and adolescents [XTEND-1] and one paediatric study in children < 12 years of age [XTEND-Kids, see Paediatric population]) in previously treated patients (PTPs) with severe haemophilia A (<1% endogenous FVIII activity or a documented genetic mutation consistent with severe haemophilia A). The long-term safety and efficacy of ALTUVOCT is also being evaluated in a long-term extension study.

All studies evaluated the efficacy of routine prophylaxis with a weekly dose of 50 IU/kg and determined haemostatic efficacy in the treatment of bleeding episodes and during perioperative management in subjects undergoing major or minor surgical procedures. Furthermore, the efficacy of ALTUVOCT prophylaxis compared with previous prophylactic factor VIII was also evaluated in an intra-subject comparison in subjects who had participated in a prospective observational study (OBS16221) prior to enrolment in the XTEND-1 study.

Clinical efficacy during routine prophylaxis in adults/adolescents

The completed adult and adolescent study (XTEND-1) enrolled a total of 159 PTPs (158 male and 1 female subjects) with severe haemophilia A. Subjects were aged 12 to 72 years and included 25 adolescent subjects aged 12 to 17 years. All 159 enrolled subjects received at least one dose of ALTUVOCT and were evaluable for efficacy. A total of 149 subjects (93.7%) completed the study.

The efficacy of weekly 50 IU/kg ALTUVOCT as routine prophylaxis was evaluated as estimated by the mean annualized bleeding rate (ABR) (Table 3) and by comparing the ABR during on-study prophylaxis vs. the ABR during pre-study factor VIII prophylaxis (Table 4). A total of 133 adults and adolescents, who had been receiving factor VIII prophylaxis prior to study enrolment, were assigned to receive ALTUVOCT for routine prophylaxis at a dose of 50 IU/kg once weekly (QW) for 52 weeks (Arm A). An additional 26 subjects, who were on pre-study episodic (on-demand) treatment with factor VIII, received episodic (on-demand) treatment with ALTUVOCT at doses of 50 IU/kg for 26 weeks, followed by routine prophylaxis at a dose of 50 IU/kg once weekly for 26 weeks (Arm B). Overall, 115 subjects received at least a total number of 50 exposure days in Arm A and 17 subjects completed at least 25 exposure days of routine prophylaxis in Arm B.

Table 3. Summary of Annualized bleeding rate (ABR) with ALTUVOCT prophylaxis, ALTUVOCT on-demand treatment, and after switch to ALTUVOCT prophylaxis in subjects ≥12 years of age:

¹ All analyses of bleeding endpoints are based on treated bleeds.
² Subjects assigned to receive ALTUVOCT prophylaxis for 52 weeks.
³ Subjects assigned to receive ALTUVOCT for 26 weeks.
⁴ Based on negative binomial model.
ABR = annualized bleed rate; CI = confidence interval; IQR = interquartile range, 25th percentile to 75th percentile.

An intra-subject comparison of ABRs during on-study and pre-study prophylaxis demonstrated a statistically significant reduction of 77% in ABR during routine prophylaxis with ALTUVOCT compared to pre-study factor VIII prophylaxis (see Table 4).

Table 4. Intra-Subject comparison of Annualized bleeding rate (ABR) with ALTUVOCT prophylaxis versus pre-study factor VIII prophylaxis in subjects ≥12 years of age:

¹ Based on negative binomial model.
² Prospective observational study (OBS16221).
ABR = annualized bleed rate; CI = confidence interval; IQR = interquartile range, 25th percentile to 75th percentile.

An intra-subject comparison (N=26) of ABR during the first 26 weeks of on-demand ALTUVOCT treatment versus ABR in the following 26 weeks on weekly ALTUVOCT prophylaxis (Arm B) showed a clinically important bleeding reduction of 97% for the weekly prophylactic regimen and an increase of subjects with zero bleeds from 0 to 76.9%.

Efficacy in control of bleeding

In the adult and adolescent study (XTEND-1), a total of 362 bleeding episodes were treated with ALTUVOCT, most occurring during on-demand treatment in Arm B. The majority of bleeding episodes were localized in joints. Response to the first injection was assessed by subjects at least 8 hours after treatment. A 4-point rating scale of excellent, good, moderate, and no response was used to assess response. Efficacy in control of bleeding episodes in subjects ≥12 years of age is summarized in Table 5. Control of bleeding episodes was similar across the treatment arms.

Table 5. Summary of efficacy in control of bleeding in subjects ≥12 years of age:

Perioperative management of bleeding

Perioperative haemostasis was assessed in 49 major surgeries in 41 subjects (32 adults and 9 adolescents and children) across Phase 3 studies. Of the 49 major surgeries, 48 surgeries required a single pre-operative dose to maintain haemostasis during surgery; for 1 major surgery during routine prophylaxis, no pre-operative loading dose was administered on the day of/or before surgery. The median dose per pre-operative injection was 50 IU/kg (range 12.7 – 84.7). The mean (SD) total consumption and number of injections during the perioperative period (from the day before surgery until Day 14 after surgery) were 171.85 (51.97) IU/kg and 3.9 (1.4), respectively.

The clinical evaluation of haemostatic response during major surgery was assessed using a 4-point scale of excellent, good, moderate, or poor/none. The haemostatic effect of ALTUVOCT was rated as “excellent” or “good” in 48 of 49 surgeries (98%). No surgery had an outcome rated as “poor/none” or “missing”.

Types of major surgeries assessed include major orthopaedic procedures such as joint arthroplasties (joint replacements of knee, hip, and elbow), joint revisions and ankle fusion. Other major surgeries included molar extractions, dental restoration and tooth extraction, circumcision, resection of vascular malformation, hernia repair, and rhinoplasty/mentoplasty. An additional 25 minor surgeries were evaluated; haemostasis was reported as “excellent” in all available cases.

Immunogenicity

Immunogenicity was evaluated during clinical studies with ALTUVOCT in previously treated adults and children diagnosed with severe haemophilia A. Inhibitor development to ALTUVOCT was not detected in clinical studies.

During Phase 3 clinical studies (median treatment duration 96.3 weeks), 4/276 (1.4%) of evaluable patients developed transient treatment-emergent anti-drug antibodies (ADA). No evidence of ADA impact on pharmacokinetics, efficacy or safety was observed.

Paediatric population

Routine prophylaxis

The efficacy of weekly 50 IU/kg ALTUVOCT as routine prophylaxis in children <12 years was evaluated as estimated by the mean ABR. A total of 74 children (38 children <6 years of age and 36 children 6 to <12 years of age) were enrolled to receive ALTUVOCT for routine prophylaxis at a dose of 50 IU/kg intravenously once weekly for 52 weeks. In all 74 subjects, routine prophylaxis resulted in an overall mean ABR (95% CI) of 0.9 (0.6; 1.4) and a median (Q1; Q3) ABR of 0 (0; 1.0) for treated bleeds.

A sensitivity analysis (N=73), excluding one subject who did not receive the weekly prophylaxis treatment as specified in the protocol for an extended period, showed a mean ABR (95% CI) of 0.6 (0.4; 0.9) for treated bleeds [median (Q1; Q3) 0 (0; 1.0)]. 47 children (64.4%) experienced no bleeding episode that required treatment. The mean ABR (95% CI) for treated spontaneous bleeds was 0.2 (0; 0.3) [median (Q1; Q3) 0 (0; 0)]. For treated joint bleeds, the mean ABR (95% CI) was 0.3 (0.2; 0.6) and the median (Q1; Q3) was 0 (0; 0).

Control of bleeding

The efficacy in control of bleeding in children <12 years of age was assessed in the paediatric study, excluding one subject who did not receive the weekly prophylaxis treatment as specified in the protocol for an extended period. A total of 43 bleeding episodes were treated with ALTUVOCT. Bleeding was resolved with a single 50 IU/kg injection of ALTUVOCT in 95.3% of bleeding episodes. The median (Q1; Q3) total dose to treat a bleeding episode was 52.6 IU/kg (50.0; 55.8).