1st Patient Dosed in Phase 3 Trial of Injectable MarzAA

The first participant has been dosed in a Phase 3 clinical trial testing marzeptacog alfa activated (MarzAA), an experimental under-the-skin therapy for hemophilia A and B patients with inhibitors.

The study, called Crimson-1 (NCT04489537) and sponsored by the therapy’s developer, Catalyst Biosciences, is currently recruiting patients at sites in Spain, Ukraine, Poland, Russia, Georgia, India, and Turkey. Additional sites are expected to open in the U.S., U.K., and other countries around the world.

“Dosing the first patient in our pivotal Phase 3 study of MarzAA is an important milestone for Catalyst given the significant challenges encountered in conducting clinical trials during the ongoing global Covid-19 pandemic,” Nassim Usman, PhD, Catalyst’s president and CEO, said in a press release.

“MarzAA is the only [under-the-skin] therapy in development for the episodic treatment of bleeding events and if successful, could fundamentally change patients’ lives,” Usman added.

People with hemophilia have a deficiency in specific blood-clotting factors — factor VIII in hemophilia A and factor IX in hemophilia B — that impair their ability to create blood clots needed to prevent excessive bleeding.

Replacement therapy, a standard prophylactic or preventive treatment for both types of hemophilia, consists of regularly administering the missing clotting factors to patients to avoid spontaneous bleeds.

However, many patients end up developing inhibitors, or neutralizing antibodies, against the delivered clotting factors, reducing the therapy’s effectiveness.

To control bleeds, these inhibitor-positive patients are often treated with bypassing agents, which promote blood clotting through alternative mechanisms that do not involve the administration of conventional clotting factors. These treatments, given directly into the bloodstream, require technical expertise to administer and are often associated with pain and prolonged bleeding.

MarzAA is a lab-made, next-generation version of the blood-clotting factor VIIa (FVIIa). According to Catalyst, the experimental therapy stands out from other approved bypassing agents for combining higher clot-generating activity and longer activity at the site of bleeding with a subcutaneous, or under-the-skin, route of administration.

As such, MarzAA is expected to be an effective and more convenient approach to prevent or treat bleeds in hemophilia patients with inhibitors.

Preclinical studies have shown that the therapy was as effective at reducing bleeds as Novo Nordisk’s NovoSeven RT (recombinant FVIIa), an approved bypassing agent, in a mouse model of hemophilia A. It was also successful at controlling spontaneous bleeds in a dog model of hemophilia A.

Moreover, results from a previous Phase 2/3 trial (NCT03407651) showed that daily preventive treatment with MarzAA safely lowered the number of annual bleeding episodes and the proportion of days with bleeds in hemophilia A and B patients.

These promising data prompted the launch of the pivotal, global, Phase 3 Crimson-1 trial, which is evaluating the safety and effectiveness of MarzAA against standard of care for on-demand treatment of spontaneous or traumatic bleeds in hemophilia A and B patients with inhibitors.

The study seeks to recruit 60 patients, 12 and older, across multiple sites in several countries. To be eligible, participants must have experienced at least eight bleeds in the previous year and be unresponsive or intolerant to standard replacement therapy.

Adults will be randomly assigned to receive MarzAA for treating about five bleeds and standard care for the following five bleeds, in either order, for a total of 244 bleeds for each treatment regimen. In turn, younger patients will be enrolled after a positive safety assessment of 30 MarzAA-treated bleeds in adult participants.

MarzAA will be self-administered under the skin at 60 micrograms per kilogram for up to three doses per bleed episode.

The study’s main goal is to assess the proportion of effectively controlled bleeds at 24 hours after initial dosing. Secondary goals include assessing the time it takes for a bleeding episode to stop after a dose of MarzAA, the proportion of effectively controlled bleeds at certain fixed time-points and of treated bleeds that remain controlled at 48 hours post-dosing, and rescue therapy use.

Pain severity, the presence of antibodies against MarzAA, the time taken to self-administer treatment, and overall satisfaction will also be assessed.

Catalyst anticipates the submission of its first report to the Data and Safety Monitoring Board overseeing the trial in 2021 and the final report by mid-2022.

The company also launched a Phase 1/2 trial called MAA-202 (NCT04548791) to evaluate the safety, pharmacokinetics, pharmacodynamics, and effectiveness of MarzAA at treating episodic bleeds in up to 24 teenagers and adults with inherited bleeding disorders. These include FVII deficiency, Glanzmann thrombasthenia, and hemophilia A with inhibitors. Pharmacokinetics refers to the therapy’s movement into, through, and out of the body, while pharmacodynamics studies its effects on the body.

Participants are currently being recruited at the Children’s Hospital of Michigan, in the U.S., and in Bengaluru and Pune, India, with sites in other U.S. states and other countries anticipated to open soon.

Crimson-1 and MAA-202 are expected to conclude by March 2022.

“We look forward to providing further updates on the [Crimson-1] study, the associated Phase 1/2 study (MAA-202) in other rare bleeding disorders, and in our growing complement pipeline later this year,” Usman said.

The U.S. Food and Drug Administration has granted the therapy fast-track designation, which provides Catalyst access to more frequent communication with the agency during MarzAA’s development. Additionally, if other criteria are met, the therapy may be eligible for accelerated approval and/or priority review.