Medication insights: marstacimab-hncq (Hympavzi)

The U.S. Food and Drug Administration (FDA) approved marstacimab-hncq (Hympavzi) in October 2024 for routine prophylaxis to prevent or reduce the frequency of bleeding episodes in adult and pediatric patients 12 years of age and older with hemophilia A (congenital factor VIII [FVIII] deficiency) without FVIII inhibitors or hemophilia B (congenital factor IX [FIX] deficiency) without FIX inhibitors. Marstacimab-hncq, also referred to as marstacimab, is a tissue factor pathway inhibitor. It marks the first non-factor treatment option for hemophilia B that is dosed as a once-weekly subcutaneous (SC) injection.¹ Prime Therapeutics sought insight from key opinion leader(s) (KOLs) within our Expert Clinical Network (ECN) who specialize in hemophilia. This month’s newsletter summarizes KOL feedback on this once-weekly product for hemophilia prophylaxis.

Efficacy, safety, and patient experience
Marstacimab is a monoclonal antibody targeted to the tissue factor pathway inhibitor (TFPI) protein. TFPI is an anticoagulant that inhibits tissue factor (TF)-factor VIIa (FVIIa) complex and factor Xa (FXa). Marstacimab decreases TFPI levels in circulation, thereby increasing thrombin generation. It is not limited to specific factor deficiency patients and is therefore suitable for treatment of both hemophilia A and B patients and has potential for the treatment of other bleeding disorders. Of note, concizumab is another anti-TFPI agent that has been approved in some countries but has not been approved for use in the U.S. As such, the anti-TFPI mechanism of action is novel, with marstacimab being the first drug in this class on the market in the U.S. This mechanism is complicated as TFPI is an intricate molecule with multiple isoforms. As a result, this mechanism of action results in more complicated pharmacokinetics than other non-factor products.

Marstacimab is considered safe and effective in patients 12 years of age and older with hemophilia A and B without inhibitors. No head-to-head trials between marstacimab and other non-factor agents currently exist. However, when evaluating the safety and efficacy data of marstacimab from the phase III BASIS trial, a few main factors stand out: first, the drug appears to be less effective than other recently published non-factor medications, such as emicizumab, concizumab, and fitusiran. When compared to routine factor-based prophylaxis, the Annualized Bleeding Rate (ABR) in the pivotal trial for marstacimab was 5.1, ²˒³ which is higher than what was seen with the other products. The second factor is regarding safety: although trials with marstacimab have not identified significant thromboembolic risk, it is a warning and precaution in the prescribing information.³ More data and longer-term follow-up will be necessary to make conclusions on this risk. Additionally, although the rate of neutralizing antibody development to marstacimab did not have clinical significance, these antibodies are of concern. Taking these factors into consideration, though there are no head-to-head comparisons, the data seems to show that marstacimab is not as potent of a hemostatic agent as the others, resulting in improved safety but lower efficacy. It should also be noted that patient groups across studies are likely different, which can impact outcomes.

Marstacimab is the first and only SC therapy for the hemophilia B population. It offers a flat dosing regimen through a prefilled syringe or pen, which makes the dosing more simplistic and eliminates the need to calculate a weight-based dose. The intravenous (IV) route is challenging for most patients, so the SC route of administration of marstacimab is advantageous. Marstacimab may be a desirable treatment option especially for patients with hemophilia B who are having difficulties with IV factor infusions or who desire a simpler, more convenient treatment option.

When it comes to monitoring the efficacy of marstacimab, factor levels are not an effective tool to assess treatment response, and thus, are not required in the prescribing information. While emicizumab also does not require any laboratory monitoring of factor levels, FVIII levels can be measured to assess efficacy of that product while patients are on therapy. In the real world, it can be difficult to monitor and rely on bleed rates alone, so some providers may see the lack of laboratory monitoring to assess marstacimab efficacy as a disadvantage.

Hemophilia treatment landscape: pipeline
Looking ahead at the pipeline, the other anti-TFPI agent, concizumab, has a more frequent SC daily dosing interval. Of note, the concizumab trials showed an increased risk of thromboembolic events and anti-drug antibodies developing in 26% of patients with no effect on bleeding patterns. Concizumab levels were noted to correlate with D-dimer levels and levels of prothrombin fragments 1 and 2. On the other hand, the pipeline agent fitusiran offers even less frequent dosing than marstacimab and has a different mechanism of action; fitusiran is a small interference RNA (siRNA) therapeutic targeting antithrombin. Its once monthly dosing regimen has been shown to be very effective while a modified every two-month dosing regimen is also being studied. Of note, fitusiran efficacy can be monitored through antithrombin activity to reach a desired target goal. If fitusiran and concizumab enter the market and join marstacimab, the hemophilia treatment landscape could experience significant transformation. The future of this dynamic market is one that is surely worth close monitoring.
 

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