Kovaltry® (antihemophilic factor) is a recombinant, human DNA sequence-derived, full-length factor VIII (FVIII) concentrate indicated for on-demand treatment and control of bleeding episodes, perioperative bleeding management, and routine prophylaxis to decrease the frequency of bleeding episodes in adults and children with hemophilia A. Treatment of von Willebrand disease with Kovaltry is not recommended.1 The European Commission provided clearance for Bayer to market Kovaltry in Europe on February 22, 2016. On March 17, 2016, the US Food and Drug Administration (FDA) gave its approval.2 The approval is based on findings from the LEOPOLD clinical trials, which showed that Kovaltry regulated bleeds and decreased the number of bleeding episodes in children and adults with hemophilia A when taken 2 or 3 times per week.3 

Hemophilia A is a rare X-linked genetic disease marked by an FVIII deficiency. Factor VIII levels in those with severe hemophilia are less than 1% of what they should be in a healthy individual. If not treated properly, such patients would experience recurrent bleeding episodes, resulting in cumulative damage and common arthropathy. Despite the fact that Kovaltry is an unmodified full-length recombinant standard half-life FVIII product, pharmacokinetic investigations have revealed that it has a longer half-life than standard FVIII products used in adult patients with hemophilia A and a consistent terminal half-life is observed in children of all ages.4 

Mechanism of Action

Patients with hemophilia A are deficient in FVIII, a protein required for optimal blood clotting.  Kovaltry’s active ingredient, octocog alfa, operates in the body the same way that human FVIII does; it helps the blood coagulate and provides temporary bleeding control by replacing the deficient FVIII.5 Octocog alfa is a protein that has been designed to be equivalent to the full-length natural FVIII in the body. This is the same active ingredient as Bayer’s other drug, Kogenate®, although it is manufactured using a different method. Kovaltry is made with cells from a baby hamster kidney (BHK) cell line that have been given the octocog alfa gene as well as the heat shock protein 70 (HSP70). The octocog alfa protein is produced by the cells, and the HSP70 induces proper folding of the FVIII protein. Usage of HSP70 in the manufacturing process is exclusive to Kovaltry. During manufacturing, no human- or animal-derived raw materials are added, and Kovaltry is purified in a multistep technique that includes a specific step for virus removal.2 Patients with hemophilia A have a longer plasma clotting time, as evaluated by the activated partial thromboplastin time (aPTT). The aPTT is normalized after treatment with Kovaltry.6

Get full prescribing information for Kovaltry at MPR

Efficacy in Trials and Trial Results

The regulatory approvals of Kovaltry are based on the results of the LEOPOLD clinical trials, including LEOPOLD 1 (NCT01029340),7 LEOPOLD 2 (NCT01233258),8 and LEOPOLD Kids (NCT01311648).9

In the phase 3 LEOPOLD 1 trial, 62 male patients with severe hemophilia A were evaluated over 1 year to determine the safety and efficacy of Kovaltry. The patients were randomly assigned a dose of 20 to 50 IU/kg twice or thrice a week.The findings showed that Kovaltry was safe and significantly decreased the median number of bleeds per year.7 

On-demand Kovaltry was compared to Kovaltry as a prophylactic treatment in the phase 3 LEOPOLD 2 trial. The findings showed that prophylactic treatment outperformed on-demand treatment by a significant margin. When compared to on-demand treatment, prophylactic treatment lowered the median annualized bleeding rate by 97%.8 

The phase 3 LEOPOLD Kids trial was designed to assess the safety and efficacy of  prophylactic treatment with Kovaltry in children with hemophilia A. Kovaltry was well tolerated and lowered the median annualized number of bleeds considerably.9

The LEOPOLD trials also looked at the safety and efficacy of Kovaltry during surgery. Thirty-two patients (including adults and children) had surgery while on Kovaltry, and none of them experienced blood loss beyond what was expected for surgery. The findings show that Kovaltry is capable of effectively controlling bleeding during surgery.10 

Warnings, Precautions, and Adverse Reactions

Kovaltry can cause hypersensitivity reactions, including allergies and anaphylaxis. Allergic reactions can occur particularly if the patient is allergic to rodents. In the event of an allergic reaction, such as tightness in the chest and throat, dizziness, a drop in blood pressure, or nausea, Kovaltry should be discontinued and emergency treatment should be provided.2,6 

It is possible that neutralizing antibodies or inhibitors to Kovaltry could develop. An FVIII inhibitor concentration assay should be done if intended FVIII activity plasma levels are not achieved or if bleeding is not managed with an adequate dose.6 

The common adverse events noted in clinical trials included pyrexia, headaches, and pruritus.11

References

  1. Kovaltry. Prescribing information. Bayer; 2016. Accessed December 27, 2021.
  2. Kovaltry for hemophilia A. Hemophilia News Today. Accessed December 27, 2021.
  3. Bayer receives FDA approval for Kovaltry® for the treatment of children and adults with hemophilia A. News release. Bayer; March 17, 2016.
  4. O’Hara J, Hirst C, Cabre Marquez JF, Burke T. Real-world evidence on Kovaltry (81-8973) in children with moderate or severe hemophilia A in Europe: a nested cohort analysis. Orphanet J Rare Dis. 2021;16(1):33. doi:10.1186/s13023-021-01676-w
  5. EPAR summary for the public: Kovaltry. European Medicines Agency. Updated February 2016. Accessed December 27, 2021.
  6. Kovaltry. Package insert. Bayer; 2021, Accessed December 27, 2021.
  7. Saxena K, Lalezari S, Oldenburg J, et al. Efficacy and safety of BAY 81-8973, a full-length recombinant factor VIII: results from the LEOPOLD I trial. Haemophilia. 2016;22(5):706-712. doi:10.1111/hae.12952
  8. Kavakli K, Yang R, Rusen L, Beckmann H, Tseneklidou-Stoeter D, Maas Enriquez M; LEOPOLD II Study Investigators. Prophylaxis vs. on-demand treatment with BAY 81-8973, a full-length plasma protein-free recombinant factor VIII product: results from a randomized trial (LEOPOLD II). J Thromb Haemost. 2015;13(3):360-369. doi:10.1111/jth.12828
  9. Ljung R, Kenet G, Mancuso ME, et al.; Investigators of the LEOPOLD Kids Trial. BAY 81-8973 safety and efficacy for prophylaxis and treatment of bleeds in previously treated children with severe haemophilia A: results of the LEOPOLD Kids trial. Haemophilia. 2016;22(3):354-360. doi:10.1111/hae.12866
  10. Oldenburg J, Windyga J, Hampton K, et al. Safety and efficacy of BAY 81-8973 for surgery in previously treated patients with haemophilia A: results of the LEOPOLD clinical trial programme. Haemophilia. 2016;22(3):349-353. doi:10.1111/hae.12839
  11. Kovaltry (anti-haemophilic factor VII (recombinant)) for the treatment of haemophilia A. Clinical Trials Arena. Accessed December 27, 2021.

Reviewed by Kyle Habet, MD, on 12/31/2021.