MarzAA Reduced Bleed Frequency in Certain Male Patients
Preventive treatment with marzeptacog alfa activated (MarzAA) can reduce bleed frequency substantially in men with hemophilia A or B who developed inhibitors to conventional replacement therapies, according to data from a Phase 2 clinical trial.
The findings were reported in the study, “Subcutaneous engineered factor VIIa marzeptacog alfa (activated) in hemophilia with inhibitors: Phase 2 trial of pharmacokinetics, pharmacodynamics, efficacy, and safety,” published in the journal Research and Practice in Thrombosis and Haemostasis.
Hemophilia is caused by mutations that lead to a deficiency in certain blood clotting proteins: factor VIII in the case of hemophilia A and factor IX in hemophilia B.
Replacement therapy, which involves administering a version of the missing protein, is a standard treatment for both forms of hemophilia. However, some patients treated with replacement therapies will develop inhibitors, or neutralizing antibodies that bind to the provided clotting factor, blocking its activity.
Developed by Catalyst Biosciences, MarzAA is a lab-made version of another clotting protein, called factor VIIa. Catalyst is developing MarzAA to act as a bypassing agent — a type of therapy given to people with inhibitors that promotes blood clotting by methods other than delivering a replacement version of a defective clotting protein.
Notably, while most available bypassing agents are administered intravenously, or by an injection directly into the bloodstream, MarzAA is designed to be given subcutaneously, or via an under-the-skin injection. This subcutaneous route of administration is less burdensome for patients and associated with fewer health care costs.
The new study details results from a Catalyst-sponsored Phase 2 trial (NCT03407651), which assessed the safety, efficacy, and pharmacological properties of MarzAA in a small group of hemophilia patients with inhibitors. The trial enrolled 11 men — 10 with hemophilia A and one with hemophilia B — at sites in Armenia, Georgia, Poland, South Africa, and Russia. All participants were white; their average age was 31 years.
In the first part of the study, participants were given a single intravenous injection of MarzAA and then monitored to assess the medication’s pharmacokinetics and pharmacodynamics, that is, how the compound moves through and is processed, as well as the effects it has on the body. Participants were then given a single subcutaneous injection of the experimental medication, and similarly monitored.
Results from this part of the trial were generally consistent with what was found in an earlier Phase 1 trial (NCT04072237), with data indicating that MarzAA has a longer effect in the body when administered subcutaneously.
In the next part of the study, participants were given daily subcutaneous injections of MarzAA, starting at a dose of 30 micrograms per kilogram (mcg/kg), with dose escalations up to 120 mcg/kg, which were allowed if participants experienced bleeds.
Over the course of the study, two patients escalated to 60 mcg/kg, while the rest remained at 30 mcg/kg. Participants were treated for at least 50 days per dose.
At the trial’s start, the average annual bleeding rate (ABR) was 19.8 bleeds per year, and the mean proportion of bleeding days was 12.3%. By the end, ABR dropped to 1.6 bleeds per year, and significant bleeds occurred only on 0.8% of days.
Additionally, seven participants who completed the trial were free of bleeds at the final dose level.
“The data demonstrated that an individualized dose of daily SC [subcutaneous] MarzAA can significantly decrease the frequency of bleeding and provide effective prophylaxis in people with hemophilia with inhibitors,” the researchers wrote.
They also noted the investigational therapy “demonstrated an acceptable safety profile when dosed daily for 50 days.”
Three participants reported side effects that were deemed related to treatment with MarzAA, namely anemia, hematoma, or injection site reactions. Of the 517 subcutaneous MarzAA injections given, only six injection site reactions, such as swelling or redness, were observed in two participants.
One participant died in the course of the trial due to intracerebral hemorrhage (bleeding in the brain). Study investigators determined this likely was not related to MarzAA treatment. This patient had a history of high blood pressure and had been prescribed medication for it, but was not taking it at the time of study entry. This was deemed the more likely cause.
Catalyst is currently conducting a Phase 3 clinical trial called Crimson-1 (NCT04489537) to further test the safety and effectiveness of MarzAA as an on-demand treatment for hemophilia A and B patients with inhibitors. The trial is actively recruiting patients at multiple locations around the globe and dosing already started earlier this year.
The company also is sponsoring a Phase 1/2 trial (NCT04548791) testing MarzAA in hemophilia A patients with inhibitors who are being treated with Hemlibra (emicizumab), and in indiviuals with factor VII deficiency or Glanzmann thrombasthenia. Participants started being dosed earlier this year, and the study is expected to conclude in March 2022.