Jivi (damoctocog alfa pegol) for hemophilia

 

What is Jivi for hemophilia?

Jivi (damoctocog alfa pegol) is an approved therapy used to prevent and treat bleeds, including those occurring during surgery, in previously treated adults and adolescents, ages 12 and older, with hemophilia A.

Developed by Bayer, the therapy is administered via an into-the-vein (intravenous) infusion.

Therapy snapshot

Brand name:	Jivi
Chemical name:	Damoctocog alfa pegol
Usage:	Used for preventive or on-demand treatment of bleeds, including those occurring during surgery, in hemophilia A patients
Administration:	Intravenous infusion

 

How does Jivi work?

Hemophilia is a rare genetic condition in which the blood does not clot properly, which can cause spontaneous bleeds and excessive bleeding after an injury or surgery. It most commonly affects males.

Hemophilia A is caused by mutations in the F8 gene that lead to a deficient production of a clotting protein called factor VIII (FVIII) or to the generation of faulty FVIII, ultimately resulting in blood clotting abnormalities.

The mainstay treatment for hemophilia A is regular, lifelong infusions of FVIII replacement therapy to restore the levels of the missing clotting protein and prevent bleeds.

Jivi is one of such therapies. It’s designed to deliver a lab-made version of FVIII that’s been engineered to have a nontoxic molecule called polyethylene glycol (PEG) attached to it.

This modification, called PEGylation, increases FVIII’s stability, taking longer for the body to break it down, meaning that the therapy works for longer periods of time after being infused into the bloodstream. This allows for less frequent dosing.

As such, Jivi is called an extended half-life product. A therapy’s half-life refers to the time it takes for the levels of a molecule to drop by half in the blood.

PEGylation also reduces FVIII’s ability to trigger undesirable immune responses.

The medication is made in a laboratory via lab-grown hamster cells, and therefore may contain traces of hamster and mouse proteins.

Who can take Jivi?

Jivi was approved by the U.S. Food and Drug Administration (FDA) in August 2018 to treat hemophilia A patients, ages 12 and older, who have received previous lines of treatment.

The therapy is specifically indicated to be used as a routine prophylactic or preventive therapy to lower the frequency of bleeding episodes, as well as an on-demand treatment to control active bleeds. Jivi also can be used to manage bleeds occurring during surgery.

Jivi is approved for the same indication in Europe, Canada, and Japan.

Who should not take Jivi?

Jivi is contraindicated, or not recommended, to anyone with a known allergy to the medication or any of its ingredients, including PEG, and mouse or hamster proteins.

Children younger than 12 should not be treated with Jivi due to a higher risk of allergic reactions. The therapy is also not indicated for hemophilia A patients who have not received prior treatment, and for people with von Willebrand disease, another inherited bleeding disorder.

How is Jivi administered?

Jivi is given through an infusion directly into the bloodstream and may be self-administered after proper training.

It is available as a white to slightly yellow powder that comes in single-use glass vials containing 500, 1,000, 2,000, or 3,000 international units (IU) of FVIII per vial. The powder must be reconstituted, or diluted, in 2.5 milliliter (mL) of a supplied diluent and infused within three hours of it being reconstituted.

The therapy is given through an infusion that lasts one to 15 minutes. The rate of administration should be adapted to the response of each patient, up to a maximum infusion rate of 2.5 mL/minute.

Treatment dosage and duration depend on the severity of FVIII deficiency, the location and extent of the bleed, and the patient’s clinical condition. It should also be adjusted based on a patient’s clinical response. The recommended maximum dose per infusion is about 6,000 IU.

For routine prophylaxis, Jivi should be initiated at a dose of 30-40 IU/kg twice weekly. This can be adjusted to 45-60 IU/kg given every five days, and to less or more frequent dosing based on bleeding episodes.

For on-demand treatment, the recommended dose depends on the bleed’s severity.

• For minor bleeds, such as early joint, muscle, or oral bleeds, Jivi should be given at a dose of 10-20 IU/kg every 24 to 48 hours until the bleed is resolved.
• For moderate bleeds, such as more extensive joint, muscle bleeds, or hematomas, the recommended dose is 15-30 IU/kg every 24 to 48 hours until resolved.
• Major bleeds, including those in the brain, gastrointestinal tract, and abdomen, and those threatening life or a limb, should be treated with 30-50 IU/kg every eight to 24 hours until bleeding is resolved.

Patients undergoing minor surgery, such as a tooth extraction, should receive 15-30 IU/kg every 24 hours, for at least one day, until healing is achieved. For major surgeries — those involving the head, abdomen, and chest, as well as for joint replacement surgery — Jivi should be given at a dose of 40-50 IU/kg every 12 to 24 hours until adequate wound healing is complete, and for at least another seven days to maintain FVIII activity levels at 30% to 60%. FVIII activity levels should be closely monitored during major surgery.

Jivi can be self-administered by patients, but only after they have been trained by their healthcare provider or a hemophilia center in how to perform infusions. Additional instructions for preparing and administering Jivi can be found on the treatment’s website.

Jivi in clinical trials

Approvals of Jivi were mainly supported by data from a global, two-part Phase 2/3 clinical trial called PROTECT VIII (NCT01580293).

PROTECT VIII Part A

The global PROTECT VIII study enrolled more than 140 boys and men, ages 12 to 65, with severe hemophilia A (FVIII activity of less than 1% of normal), at sites across 19 countries. All patients had previously received FVIII therapy for at least 150 days (or nearly five months), and none had a history of FVIII inhibitors, or neutralizing antibodies against FVIII.

The trial’s part A, which included 134 patients, evaluated Jivi’s safety and efficacy as prophylaxis (114 patients) and as an on-demand treatment (20 patients) over 36 weeks (about eight months).

The prophylaxis group comprised patients who previously had used either on-demand or prophylactic treatment. In the trial, they received 25 IU/kg of Jivi twice weekly for the first 10 weeks to see whether they could benefit from a less frequent dosing regimen.

Based on their bleeding rates in that initial 10-week period, patients were switched to: 30–40 IU/kg, twice weekly; a starting dose of 45 IU/kg, every five days; or a fixed dose of 60 IU/kg, every seven days.

Those in the on-demand group, who previously only were treated on-demand for bleeds, received Jivi at an individual dose and frequency based on bleed location and severity.

Results showed that Jivi prophylaxis prevented bleeds in each of the dosing regimens. Particularly, patients who increased their twice-weekly prophylactic dose in the trial’s remaining 26 weeks experienced a reduction in their median annualized bleeding rate (ABR), which dropped from 17.4 to 4.1.

Less frequent dosing regimens also provided protection against bleeds, with more than 35% of these patients remaining bleed-free. Median ABR was 1.93 for those who remained in the once-every-five-days dosing schedule, and 0.96 for those maintaining the once-every-seven-days regimen.

A total of 705 bleeds occurred in both the on-demand (388) and prophylaxis groups (317). Approximately 90% of bleeds were treated with one to two infusions, with more than 70% of the patients reporting “good” or “excellent” response to treatment.

Extension part

Participants completing the trial’s part A could enter its extension phase, in which all continued treatment — 107 as prophylaxis and 14 as on-demand — for at least 100 days of Jivi infusions. Prophylaxis regimens could vary based on individual patients’ needs.

At the last visit of the extension phase, 67.3% of patients were on less frequent regimens, and up to seven years of Jivi treatment showed that those on prophylaxis had a lower ABR than those receiving on-demand treatment (1.49 vs. 34.09).

In addition, 20.6% of prophylaxis patients were bleed-free during the entire extension portion (a median of 3.2 years), and 50% were bleed-free during its final six months.

Those who were treated with prophylaxis before PROTECT VIII experienced a gradual reduction in ABR over time, from 3.5 before the trial to 2.1 in the study’s main part and 1.6 in its extension portion. Also, eight in 10 patients reduced their prophylaxis dosing frequency relative to that used before the trial with standard half-life FVIII products.

The therapy was generally safe and well tolerated during the trial’s main and extension portions, and no patient developed FVIII inhibitors.

PROTECT VIII Part B

PROTECT VIII’s part B assessed whether Jivi could prevent bleeds occurring during major surgery. It involved a total of 20 patients, who either were already receiving Jivi on-demand or as prophylaxis in the trial or who were enrolled in the trial due to major surgery.

Results demonstrated the therapy effectively controlled bleeds during all 26 major surgeries. Hemostasis, the natural process of slowing blood flow and forming clots at sites of injury to prevent blood loss, was rated by the surgeon as “good” or “excellent” for all surgeries. No bleeding complications occurred during surgery, and no patient developed FVIII inhibitors following surgery.

PROTECT VIII Kids trial

The Phase 3 PROTECT VIII Kids study (NCT01775618) was designed to assess the safety and efficacy of Jivi prophylaxis in previously treated children with hemophilia A. The trial enrolled a total of 73 boys younger than age 12 with severe hemophilia A. All had previously received FVIII therapy for at least 150 days (nearly five months).

In the main study, 61 children received 25 IU/kg of Jivi twice weekly, 45 IU/kg every five days, or 60 IU/kg every seven days, for a minimum of six months. Doses and dosing schedules could be changed at any time at a physician’s discretion.

The study also involved an expansion group that included additional children, all younger than age 6, to obtain more safety data. Children in this expansion group received Jivi twice weekly at a dose of 25-60 IU/kg for 12 weeks.

Children completing either the main study or the 12-week expansion could opt to enter an optional extension phase and continue treatment with Jivi at the same dosing schedule they were given in the main or expansion study.

A total of 12 children, most of younger than age 6, discontinued treatment due to an apparent loss of efficacy or allergic reactions. The median ABR was 2.9 for children who participated in the main study, and 2.4 for those who were in the expansion group; these values were similar in children younger than 6 years old and those ages 6-12.

More than 90% of the bleeds reported during the main study were successfully treated with one or two Jivi infusions. Treatment response was rated as “good” or “excellent” by more than 80% of the patients or caregivers.

Of the 73 children who enrolled in the main or expansion study, 59 entered the optional extension phase and 39 completed at least five years of treatment. The median ABR was low (1.6) and identical in younger and older children. None of the children developed FVIII inhibitors in any of these studies.

Ongoing trials

A Phase 3 trial, called Alfa-PROTECT (NCT05147662), is assessing the safety and efficacy of Jivi prophylaxis in up to 33 previously treated boys, ages 7–11, with hemophilia A. Participants will receive Jivi twice a week for six months, after which they can enter the trial’s extension part, in which dosing frequency can be reduced to every five days for up to 1.5 years.

Its main goal is to determine the rate of two side effects previously reported in this younger patient population, including allergic reactions and loss of efficacy due to the development of antibodies against the therapy or its ingredients.

Common side effects of Jivi

The most common side effects of Jivi reported in clinical trials include:

• headache
• cough
• nausea
• fever.

Allergic reactions

Allergic reactions, including severe reactions, have been reported in patients treated with Jivi. Patients should be monitored for signs of allergic reactions, which can progress to a severe form called anaphylaxis, including chest or throat tightness, dizziness, mild low blood pressure, and nausea.

If an allergic reaction occurs, Jivi should be stopped immediately and patients should be given appropriate treatment.

Development of inhibitors

Patients treated with Jivi may develop neutralizing antibodies, or inhibitors against the therapy, which may lower its effectiveness, and potentially render it useless.

As such, patients on Jivi should be monitored for signs of FVIII inhibitor development. These may include an inability to reach expected FVIII activity levels and/or control bleeds. If patients present any of these signs, levels of FVIII inhibitors should be measured with an appropriate assay.

Immune response to PEG

Jivi may lead to the production of antibodies against PEG. These immune responses, associated with symptoms of allergic reactions and/or the loss of therapy effectiveness, mainly have been reported in children younger than age 6 who participated in Jivi clinical trials.

Symptoms of this immune response were temporary, and the levels of anti-PEG antibodies dropped over time to undetectable levels.

Patients showing signs that are suggestive of a loss of Jivi’s effect should be tested for the presence of FVIII inhibitors and for FVIII level recovery. If no FVIII inhibitors are detected and FVIII levels remain low after Jivi infusion, antibodies against PEG are likely the cause of such loss. In this case, patients should discontinue Jivi and be given a previously effective FVIII replacement therapy.

Use in pregnancy and breastfeeding

The use of Jivi has not been thoroughly studied in patients who are pregnant. In addition, no animal studies have evaluated the therapy’s effects on reproduction or during pregnancy, so it is unclear whether Jivi can affect reproductive capacity or cause harm to a developing fetus.

It also is not known if Jivi can be found in breast milk, and whether it has any impact on nursing infants or on milk production.

Patients and their care teams should work together to evaluate the potential risks and benefits of Jivi’s use by women who are pregnant or breastfeeding.

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