Direct comparison of two extended half-life PEGylated recombinant FVIII products: a randomized, crossover pharmacokinetic study in patients with severe hemophilia A

An open-label, crossover randomized study was performed to compare the pharmacokinetics (PK) of damoctocog alfa pegol and rurioctocog alfa pegol, two recombinant factor VIII (FVIII) products indicated in patients with hemophilia A, both conjugated to polyethylene glycol to reduce clearance and extend time in circulation. Adult patients (N = 18) with severe hemophilia A (FVIII < 1 IU/dL), previously treated with any FVIII product for ≥ 150 exposure days, were randomized to receive a single 50 IU/kg infusion of damoctocog alfa pegol followed by rurioctocog alfa pegol, or vice versa, with ≥ 7-day washout between doses. FVIII activity was measured using the one-stage clotting assay. PK parameters, including area under the curve from time 0 to the last data point (AUC0–tlast, primary parameter), dose-normalized AUC (AUCnorm), and time to threshold, were calculated based on 11 time points between 0.25 and 120 h post-dose and evaluated using a noncompartmental model. Due to differences in batch-specific vial content used for the study, actual administered median doses were 54.3 IU/kg for damoctocog alfa pegol and 61.4 IU/kg for rurioctocog alfa pegol. Based on actual dosing, a significantly higher geometric mean (coefficient of variation [%CV]) AUCnorm was observed for damoctocog alfa pegol (43.8 h kg/dL [44.0]) versus rurioctocog alfa pegol (36.0 h kg/dL [40.1, P < 0.001]). Based on population PK modeling, median time to reach 1 IU/dL was 16 h longer for damoctocog alfa pegol compared with rurioctocog alfa pegol. No adverse events or any immunogenicity signals were observed. Overall, damoctocog alfa pegol had a superior PK profile versus rurioctocog alfa pegol. Trial registration number: NCT04015492 (ClinicalTrials.gov identifier). Date of registration: July 9, 2019 Electronic supplementary material The online version of this article (10.1007/s00277-020-04280-3) contains supplementary material, which is available to authorized users.

1 What is this study about? This is a summary of a clinical study of a medicine called Jivi ® (also known as damoctocog alfa pegol) and a medicine called Adynovi ® (also known as rurioctocog alfa pegol; Adynovate ® in some countries) in people with severe hemophilia A. It is written for the general reader and uses language that is easy to understand. It includes information about how researchers did the study and what the results were.

2
Who sponsored the study and how can I contact them?
The sponsor of this study was Bayer who would like to thank everyone who took part. 4 Why was this study done?
Researchers are looking for a better way to treat people with hemophilia A.
Hemophilia A is a form of hemophilia that is due to deficiency of one of the proteins the body produces to clot the blood. This protein is called Factor Eight (FVIII). A deficiency of FVIII can lead to frequent, spontaneous bleeding, often into joints and muscles, in addition to abnormal bleeding following an injury, surgery, or tooth extraction.
Uncontrolled, frequent bleeding could develop into further complications such as joint disease or disability. Therefore, people with hemophilia A are given medicines to prevent bleeding. These medicines replace the FVIII that is missing in these people.
In this study, the main question the researchers wanted to answer was: Is there a difference between the concentration of FVIII in the blood after treatment with Jivi ® compared with Adynovi ® , over a certain period of time? The answer to this question was important to better understand how Jivi ® can improve the health of people with hemophilia A.

Who took part in this study?
People who participated in this study had severe hemophilia A and could take part if they were: ▪ 18-65 years old ▪ Had a body mass index of 18-29.9 kg/m 2 Overall, 18 people took part in the study and all of them were men. The average age of all the participants was 33.5 years.
All 18 participants completed the study.

Notes & questions
A comparison of two similar treatments in people with severe hemophilia A 2 NCT04015492 6 What treatments did the participants in this study receive?
The researchers compared two medicines called Jivi ® and Adynovi ® . Both of these medicines are 'extended-half-life' medicines. This means that they are designed to work for longer than a medicine that isn't designed to have an 'extended-half-life'.
In this study, each participant received both medicines once, one followed by the other.
Adynovi ® was chosen as the comparator because it is similar to Jivi ® and the two have not been directly compared before.
7 What happened during the study?
▪ The 18 participants in this study were put into two groups by chance (randomized) ▪ One group received a single injection of Jivi ® first, followed by a single injection of Adynovi ® , as described below ▪ The second group received a single injection of Adynovi ® first, followed by a single injection of Jivi ® , as described below ▪ As soon as a participant received their first treatment, samples of blood were taken repeatedly over 5 days to measure the concentration of FVIII in their blood ▪ After these 5 days, each participant waited a short time before they received their second treatment ▪ As soon as a participant received their second treatment, samples of blood were taken repeatedly over 5 days to measure the concentration of the FVIII in their blood ▪ Everyone who took part in the study was also closely monitored for any medical problems ▪ The participants and the researchers both knew the order in which the medicines were taken ▪ Except for the difference in the order the medicines were taken, all participants followed the same procedures.

Notes & questions
A comparison of two similar treatments in people with severe hemophilia A 3 NCT04015492 The following diagram shows how the study was done: The first treatment this group of 9 participants received was Jivi ® The first treatment this group of 9 participants received was Adynovi Overall, this study showed that there are differences in the concentration of FVIII in the blood after treatment with Jivi ® compared with Adynovi ® .
In this study, the concentration of FVIII over 5 days after treatment with each medicine was evaluated in different ways.

Notes & questions
1. The researchers measured the amount (exposure) of FVIII protein in the blood over a period of time for each medicine (this is called 'area under the curve'). Generally, it is better for the exposure of a medicine to be higher for it to be available for clotting over time.
the amount of Jivi ® was higher than the amount of Adynovi ® In 16 of the 18 participants 2. The researchers also measured the speed at which each medicine was removed from the body (this is called 'clearance'). Generally, it is better for a medicine to be removed slowly so the medicine can act longer within the body.
In 16 of the 18 participants Jivi ® was removed from the body more slowly than Adynovi ® 3. The researchers also measured the time taken for the concentration of each medicine to be reduced by half in the blood (this is called 'half-life'). This also helps in assessing how long each medicine remains active in the body. Generally, it is better for a medicine to remain active for a long period for it to be available for clotting.

Notes & questions
What medical problems did the people who took part in the study have?
Researchers keep track of all health problems that participants have during a study. Some of these health problems might be caused by the study medicines and some by other medicines taken by the participant. These health problems are called side-effects. Other health problems might be caused by the disease, and some could have a yet different cause.
The researchers monitored the safety of Jivi ® and Adynovi ® in those who took part in this study. To do this, the researchers performed laboratory tests and made notes of any side-effects during the study: 11 Are further studies planned?
No further studies on this topic are planned.

Notes & questions
12 Where can I learn more about this study?
Bayer has committed to make research results available to the public. This summary has been provided as part of that commitment and should not be used for any other purpose. It should not be considered to make a claim for any product or to guide treatment decisions.
If you participated in this study and have questions about the study results, the doctor or staff at the study center you attended may be able to answer them.

Important notice
This summary shows only the results from one study and does not represent all of the knowledge about the medicines studied. Usually, more than one study is done to find out how well a medicine works and discover the side-effects of the medicine. Other studies may have different results.
You should consult the prescribing information for your country to get more information on the medicines studied or ask your physician about these. You should not change your therapy based on the results of this study without first talking to your physician. Always consult your physician about your specific therapy.