Anaphylaxis
Risk of severe allergic reaction. Seek urgent medical help if serious symptoms occur.
Leaflet HYMPAVZI 150mg 150mg / ml solution for injection in pre-filled syringe
- Product code:
- W72164001
- Quantity:
- 1
- Indicated for:
- prevention of bleeding episodes in severe haemophilia A or B
- Route of administration:
- injectable
- Substance:
- marstacimab (anti-TFPI monoclonal antibody)
- ATC
- B02BX11 — Blood and blood forming organs | Vitamin k and other hemostatics | Other systemic hemostatics
Marstacimab is a medicine used to prevent or reduce bleeding episodes in people with haemophilia A or B, generally adults and adolescents without inhibitors to factor VIII or IX. Its purpose is routine prophylaxis, not rapid treatment of an active serious bleed.
The medicine works by blocking tissue factor pathway inhibitor, which helps the body form clots more effectively. It does not replace every haemophilia treatment. A plan for injuries, dental work, surgery and emergency bleeding should be agreed in advance with the haemophilia care team.
Marstacimab is given as a subcutaneous injection, usually once weekly, after proper training. The patient or caregiver should know how to store the medicine, prepare the injection and record doses. Do not change the schedule without advice from your haemophilia centre.
Common side effects include injection site reactions, headache and itching. Rare but important risks include allergic reactions and blood clots. Report chest pain, shortness of breath, sudden swelling of a limb, severe headache, weakness on one side of the body, or widespread hives immediately.
The medicine works by blocking tissue factor pathway inhibitor, which helps the body form clots more effectively. It does not replace every haemophilia treatment. A plan for injuries, dental work, surgery and emergency bleeding should be agreed in advance with the haemophilia care team.
Marstacimab is given as a subcutaneous injection, usually once weekly, after proper training. The patient or caregiver should know how to store the medicine, prepare the injection and record doses. Do not change the schedule without advice from your haemophilia centre.
Common side effects include injection site reactions, headache and itching. Rare but important risks include allergic reactions and blood clots. Report chest pain, shortness of breath, sudden swelling of a limb, severe headache, weakness on one side of the body, or widespread hives immediately.
General data about HYMPAVZI 150mg 150mg / ml
- Substance:
- marstacimab
- Date of latest medicines list:
- 01-09-2026
- Product code:
- W72164001
- Concentration:
- 150mg / ml
- Pharmaceutical form:
- solution for injection in pre-filled syringe
- Quantity:
- 1
- Product type:
- Original
- Prescription status:
- P-RF — Medicines dispensed with a medical prescription that is retained by the pharmacy and cannot be renewed.
Pharmaceutical forms available for marstacimab
Official documents
- Added to database:
- 18/12/2024
- Source record updated:
- 16/07/2026
Precautions:
Additional monitoring
This medicine is subject to additional monitoring.
Breastfeeding warning
Use during breastfeeding only on medical advice.
Pregnancy warning
Use during pregnancy only on medical advice.
Contents of the package leaflet for the medicine HYMPAVZI 150mg 150mg / ml solution for injection in pre-filled syringe
Find in leaflet
Leaflet HYMPAVZI 150mg 150mg/ml
1. NAME OF THE MEDICINAL PRODUCT
Hympavzi 150 mg solution for injection in pre-filled syringe
Hympavzi 150 mg solution for injection in pre-filled pen
2. QUALITATIVE AND QUANTITATIVE COMPOSITION
Hympavzi 150 mg solution for injection in pre-filled syringe
Each pre-filled syringe contains 150 mg marstacimab in 1 mL of solution.
Hympavzi 150 mg solution for injection in pre-filled pen
Each pre-filled pen contains 150 mg marstacimab in 1 mL of solution.
Marstacimab is a human monoclonal immunoglobulin G Type 1 (IgG1) antibody produced in Chinesehamster ovary (CHO) cells by recombinant DNA technology.
Excipients with known effectHympavzi contains 0.2 mg polysorbate 80 in each mL of solution.
For the full list of excipients, see section 6.1.
3. PHARMACEUTICAL FORM
Solution for injection (injection).
Clear, colourless to light yellow solution with pH of 5.8, and osmolarity of approximately324 mOsm/L.
4. CLINICAL PARTICULARS
4.1 Therapeutic indications
Hympavzi is indicated for routine prophylaxis of bleeding episodes in patients 12 years of age andolder, weighing at least 35 kg, with:
- Haemophilia A (congenital factor VIII deficiency):
o Without factor VIII inhibitors who have severe disease (FVIII < 1%)o With factor VIII inhibitors
- Haemophilia B (congenital factor IX deficiency):o Without factor IX inhibitors who have severe disease (FIX < 1%)o With factor IX inhibitors
4.2 Posology and method of administration
Treatment should be initiated under the supervision of a healthcare professional experienced in thetreatment of haemophilia. Treatment should be initiated in a non-bleeding state.
PosologyThe recommended dose for patients 12 years of age and older, weighing at least 35 kg, is an initialloading dose of 300 mg by subcutaneous injection followed thereafter by 150 mg by subcutaneousinjection once weekly, at any time of day.
Duration of treatmentHympavzi is intended for long-term prophylactic treatment.
Dose adjustments during treatmentA dose adjustment to 300 mg subcutaneous injection weekly can be considered in patients weighing≥ 50 kg when control of bleeding events is judged to be inadequate by the healthcare professional. Themaximum weekly dose of 300 mg should not be exceeded.
Guidance on treating breakthrough bleeds
Additional doses of Hympavzi should not be used to treat breakthrough bleeding events. For guidanceon treatment in the event of breakthrough bleeds, see section 4.4.
Management in patients with acute severe illness
In acute severe illnesses with increased tissue factor expression, such as serious infection, sepsis,trauma, crush injuries, and cancer, potentiation of the inflammatory response via concomitant tissuefactor pathway inhibitor (TFPI) inhibition could pose a risk of adverse reactions, especially thrombosis(see section 4.4).
Treatment of acute severe illness should be managed per local standard of care, and continuedtreatment with Hympavzi in this situation should be weighed against the potential risks involved.
Additional monitoring for adverse reactions and the development of thromboembolism may bewarranted in these patients when marstacimab is administered. Hympavzi should be temporarilyinterrupted if clinical symptoms, imaging, and/or laboratory findings consistent with thromboticevents occur, and managed as clinically indicated. Hympavzi therapy may be resumed once the patienthas clinically recovered at the clinical judgement of the healthcare provider (see Missed dose sectionbelow).
Missed doseFor patients on a maintenance dose of 150 mg
If a dose is missed, the missed dose should be administered as soon as possible before the day of thenext scheduled dose, and then usual 150 mg subcutaneous weekly dosing schedule (same schedule asprior to the missed dose or new schedule based on date of administration of missed dose) should beresumed.
If the missed dose is more than 13 days after the last dose, then a loading dose of 300 mg bysubcutaneous injection should be administered followed thereafter by a resumption of 150 mg bysubcutaneous injection once weekly.
For patients on a maintenance dose of 300 mg
If one or more doses are missed, the missed dose should be administered as soon as possible, and thenthe usual 300 mg subcutaneous weekly dosing schedule (same schedule as prior to the missed dose ornew schedule based on date of administration of missed dose) should be resumed.
Switching to Hympavzi
Switching from prophylactic factor replacement therapy or bypassing agents to Hympavzi: Prior toinitiation of Hympavzi, patients should discontinue treatment with clotting factor concentrates(factor VIII or factor IX concentrates) or bypassing agents (e.g. recombinant FVIIa [rFVIIa] oractivated prothrombin complex concentrate [aPCC]). Patients can initiate Hympavzi at any time afterdiscontinuing clotting factor concentrates or bypassing agents.
Switching from non-factor-based haemophilia medicinal products to Hympavzi: No clinical study dataare available to guide converting patients from other non-factor-based medicinal products tomarstacimab. Although a washout period has not been studied, one approach is to allow an adequatewashout period (at least 5 half-lives) of the prior agent based on labelled half-life before initiatingtreatment with Hympavzi. Haemostatic support with clotting factor concentrates or bypassing agentsmay be needed during the switch from other non-factor-based haemophilia medicinal products to
Hympavzi.
Special populationsHepatic impairment
No dose adjustments are recommended in patients with mild hepatic impairment (see section 5.2).
Marstacimab has not been studied in patients with moderate or severe hepatic impairment.
Renal impairmentNo dose adjustments are recommended in patients with mild renal impairment (see section 5.2).
Marstacimab has not been studied in patients with moderate or severe renal impairment.
ElderlyNo dose adjustments are recommended in patients over 65 years of age (see section 5.2).
Paediatric populationHympavzi should not be used in children less than 1 year of age because of potential safety issues. Thesafety and efficacy of marstacimab in paediatric patients < 12 years of age have not yet beenestablished. The safety and efficacy of marstacimab in adolescents with a body weight < 35 kg havenot been established. No data are available.
Management in the perioperative setting
The safety and efficacy of marstacimab have not been formally evaluated in the surgical setting.
Patients have had minor surgical procedures without discontinuing Hympavzi prophylaxis in clinicalstudies.
For major surgery, it is recommended to pause Hympavzi at least 7 days prior and initiatemanagement per local standard of care with clotting factor concentrate or bypassing agent andmeasures to manage the risk of venous thrombosis which can be elevated in the perioperative period.
The product information for the clotting factor concentrate or bypassing agent should be consulted fordosing guidelines in patients with haemophilia undergoing major surgery. Resumption of Hympavzitherapy should take into account the overall clinical status of the patient, including the presence ofpost-surgical thromboembolic risk factors, use of other haemostatic products and other concomitantmedicinal products (see Missed dose section above).
Immune tolerance induction (ITI)
The safety and efficacy of marstacimab in patients receiving ongoing ITI have not been established,and no data are available.
Method of administrationHympavzi is for subcutaneous use only.
Hympavzi is intended for use under the guidance of a healthcare professional. After proper training insubcutaneous injection technique, a patient or caregiver may inject with the medicinal product if ahealthcare professional determines that it is appropriate.
Prior to subcutaneous administration, Hympavzi may be removed from the refrigerator and allowed towarm at room temperature in the carton for about 15 to 30 minutes away from direct sunlight (seesections 6.4 and 6.6). The medicinal product should not be warmed by using a heat source such as hotwater or a microwave.
The recommended injection sites are the abdomen (at least 5 cm away from the navel) and thigh.
Other locations are acceptable if required. Administration of Hympavzi in the upper arm (pre-filledsyringe only) and buttocks (pre-filled pen only) should be performed by a caregiver or healthcareprofessional only. The medicinal product should not be administered into bony areas or areas wherethe skin is bruised, red, tender or hard, or areas where there are scars or stretch marks.
For the 300 mg loading dose, each of the two Hympavzi 150 mg injections should be administered atdifferent injection sites.
It is recommended to rotate the injection site with each injection.
Hympavzi should not be injected into a vein or muscle.
During treatment with Hympavzi, other medicinal products for subcutaneous administration should,preferably, be injected at different anatomical sites.
For comprehensive instructions on the administration of the medicinal product, see section 6.6 and the‘Instructions for Use’ provided at the end of the package leaflet.
4.3 Contraindications
Hypersensitivity to the active substance or to any of the excipients listed in section 6.1.
4.4 Special warnings and precautions for use
Traceability
In order to improve the traceability of biological medicinal products, the name and the batch numberof the administered product should be clearly recorded.
Thromboembolic eventsRemoval of TFPI inhibition may increase a patient’s coagulation potential and contribute to a patient’sindividual, multifactorial risk for thromboembolic events. Arterial and venous thrombotic events,including embolism, were reported in clinical studies with marstacimab (see section 4.8). These eventsoccurred in individuals with multiple risk factors for thromboembolism. The following patients maybe at an increased risk of thromboembolic events with use of this medicinal product:
- patients with a history of coronary artery disease, venous or arterial thrombosis or ischaemicdisease,
- patients with known risk factors for thromboembolism, including but not limited to geneticprothrombotic conditions (e.g. Factor V Leiden), patients with prolonged periods ofimmobilisation, obesity, and smoking,
- patients currently experiencing an acute severe illness with increased tissue factor expression(such as serious infection, sepsis, trauma, crush injuries, cancer).
- patients managed in perioperative setting and/or undergoing surgery (see section 4.2). In theperioperative setting, concomitant use of Hympavzi with other haemostatic agents canpotentially increase the risk of thrombosis.
Marstacimab has not been studied in patients with a history of previous thromboembolic events (seesection 5.1) and there is limited experience in patients with acute severe illness.
The benefits and risks of using Hympavzi in patients with a history of thromboembolic events, withknown risk factors for thromboembolism, or currently experiencing an acute severe illness should beconsidered. Patients at risk should be monitored for early signs of thrombosis, and prophylacticmeasures against thromboembolism should be instituted according to current recommendations andstandard of care. Hympavzi prophylaxis should be interrupted if diagnostic findings consistent withthromboembolism occur and patients should be managed as clinically indicated.
The use of anti-tissue factor pathway inhibitor (anti-TFPI) products, including marstacimab, has beenassociated with the development of thromboembolic complications in patients exposed to additionalhaemostatic agents (i.e. bypassing agents) in close proximity. Factor VIII and factor IX products andbypassing agents have been safely administered for the treatment of breakthrough bleeds in patientsreceiving marstacimab. If factor VIII or factor IX products or bypassing agents are indicated in apatient receiving Hympavzi prophylaxis, the minimum effective dose according to the product label isrecommended. Patients should be informed of and monitored for the occurrence of signs andsymptoms of thromboembolic events. In case of suspicion of thromboembolic events, Hympavzishould be discontinued and appropriate medical treatment should be initiated.
Guidance on treating breakthrough bleeds
Factor VIII and factor IX products or bypassing agents (e.g. rFVIIa or aPCC) can be administered forthe treatment of breakthrough bleeds in patients receiving Hympavzi. Additional doses of Hympavzishould not be used to treat breakthrough bleeding events. Healthcare professionals should discuss withall patients and/or caregivers about the dose and schedule of the clotting factor concentrates orbypassing agents to use, if required, while receiving Hympavzi prophylaxis.
When treating breakthrough bleeds with factor VIII or factor IX products or with bypassing agents, thelowest effective dose according to the product prescribing information is recommended. Healthcareprofessionals should refer to the product information for the clotting factor concentrate or bypassingagent being used. For rFVIIa, a maximum dose of 90 μg/kg body weight per dose and a maximumdosing frequency of every 2 hours is recommended. For aPCC, a maximum dose of 100 units/kg bodyweight within 24 hours is recommended.
Hypersensitivity reactionsCutaneous reactions of rash and pruritus that may reflect drug hypersensitivity have occurred inmarstacimab-treated patients (see section 4.8). If Hympavzi-treated patients develop a severehypersensitivity reaction, advise patients to discontinue Hympavzi and seek immediate emergencytreatment.
Effects of marstacimab on coagulation tests
Marstacimab therapy does not produce clinically meaningful changes in standard measures ofcoagulation including activated Partial Thromboplastin Time (aPTT) and Prothrombin Time (PT).
ExcipientsPolysorbate content
This medicinal product contains polysorbate 80. Polysorbate 80 may cause hypersensitivity reactions.
Sodium contentThis medicinal product contains less than 1 mmol sodium (23 mg) per 1 mL, that is to say essentially‘sodium-free’.
4.5 Interaction with other medicinal products and other forms of interaction
No clinical drug interaction studies with marstacimab have been conducted.
Nonclinical in vitro pharmacodynamic drug interaction studies were conducted and support theconcomitant use of marstacimab with bypassing agents (e.g. rFVIIa or aPCC) for treatment ofbreakthrough bleeds. Combination of marstacimab with rFVIIa or aPCC (in haemophilia A and Bplasma with inhibitors) resulted in increased thrombin generation compared to marstacimab treatmentalone without exceeding peak thrombin levels achieved in non-haemophilic plasma treated withmarstacimab alone; in some cases thrombin levels were within the range reported for non-haemophilicnormal plasma.
Nonclinical in vivo pharmacodynamic drug interaction studies conducted in rats with normal FVIIIand FIX levels also support the concomitant use of marstacimab with rFVIIa at a maximum clinicaldose of ≤ 90 μg/kg or with aPCC at a maximum clinical dose of 100 units/kg for treatment ofbreakthrough bleeds. Increased incidence and/or severity of acute thrombi/emboli in the lung andinjection site were observed in haemostatically normal rats at higher doses of rFVIIa (see section 5.3).
For guidance on the use of clotting factor concentrates or bypassing agents for treatment ofbreakthrough bleeds in patients receiving marstacimab prophylaxis, see section 4.4.
As a monoclonal antibody (mAb), marstacimab is expected to be cleared through catabolic pathways.
Thus an impact on its clearance via an interaction with concomitant medicinal products cleared vianon-catabolic pathways is unlikely. Indirect effect of a biologic such as marstacimab on the expressionof cytochrome P450 enzymes is also not expected.
4.6 Fertility, pregnancy and lactation
Women of childbearing potential
Women of childbearing potential receiving Hympavzi should use effective contraception during, andfor at least 1 month after cessation of Hympavzi treatment.
PregnancyThere are no clinical studies of marstacimab use in pregnant women. Animal reproduction studieshave not been conducted with marstacimab. It is not known whether Hympavzi can cause foetal harmwhen administered to a pregnant woman or can affect reproduction capacity. Hympavzi should beused during pregnancy only if the potential benefit for the mother outweighs the risk to the foetustaking into account that, during pregnancy and after parturition, the risk for thrombosis is increasedand that several pregnancy complications are linked to an increased risk for disseminated intravascularcoagulation (DIC).
Breast-feedingIt is not known whether marstacimab is excreted in human milk. No studies have been conducted toassess the impact of marstacimab on milk production or its presence in breast milk. Human IgG isknown to be excreted in breast milk during the first few days after birth, which is decreasing to lowconcentrations soon afterwards; consequently, a risk to the breast-fed infant cannot be excluded duringthis short period. Afterwards, marstacimab could be used during breast-feeding if clinically needed.
FertilityAnimal studies do not indicate direct or indirect harmful effects with respect to fertility (seesection 5.3). No fertility data are available in humans. Thus, the effect of marstacimab on male andfemale fertility is unknown.
4.7 Effects on ability to drive and use machines
Hympavzi has no or negligible influence on the ability to drive and use machines.
4.8 Undesirable effects
Summary of the safety profile
Injection site reactions
The overall safety profile of marstacimab is based on pooled data from clinical studies. The mostserious adverse drug reaction reported from the clinical studies with marstacimab was thrombosis(0.6%) (see section 4.4).
The most frequently reported adverse reactions after treatment with marstacimab were injection sitereactions (ISRs) (11.4%).
Tabulated list of adverse reactionsSafety data in Table 1 are based on pooled data from the Phase 3 safety and efficacy study (BASIS)and from the patients who rolled over from the BASIS study into the open-label extension (OLE)study (see section 5.1). The data from the pivotal Phase 3 study 12-month Active Treatment Phasereflects exposure of 167 male patients with haemophilia A or B with inhibitors (30.5%) or withoutinhibitors (69.5%) to marstacimab administered once weekly. Of the 167 patients, 135 (80.8%) wereadults (18 years of age and older) and 32 (19.2%) were adolescents (12 years up to < 18 years). A totalof 154 of the 159 patients completing the 12-month treatment period subsequently enrolled in theongoing OLE study. The median total duration of exposure was 1 225 days (range 28 to 1 659 days).
Table 1 summarises the adverse reactions reported in patients who received marstacimab prophylaxis.
The adverse reactions listed in the table below are presented by system organ class (SOC) andfrequency categories, defined using the following convention: very common (≥ 1/10); common(≥ 1/100 to < 1/10), uncommon (≥ 1/1 000 to < 1/100), rare (≥ 1/10 000 to < 1/1 000), very rare(< 1/10 000) or frequency not known (cannot be estimated from the available data). Within eachfrequency grouping, adverse reactions are presented in the order of decreasing seriousness.
Table 1. Adverse reactions
System organ class Adverse reaction Frequency
Nervous system disorders Headachea Common
Vascular disorders Hypertension Common
Thromboembolic events (thrombosisb) Uncommon
Skin and subcutaneous tissue Rashc Commondisorders Pruritus Common
General disorders and administrations Injection site reactionsc Very commonsite conditions
a. Headache includes both headache and migraine.
b. ADR reported in the open-label extension study.
c. see ‘Description of selected adverse reactions’
Description of selected adverse reactionsInjection site reactions
In total, 19 (11.4%) patients treated with marstacimab reported ISRs. The majority of ISRs observed inmarstacimab clinical studies were transient and reported as mild to moderate in severity. Nooccurrences of injection site reaction led to a dose adjustment or drug discontinuation. ISRs includeinjection site bruising, injection site erythema, injection site haematoma, injection site haemorrhage,injection site induration, injection site oedema, injection site pain, injection site pruritus, and injectionsite swelling.
RashIn total, 6 (3.6%) patients treated with marstacimab reported rash.
One patient with severe haemophilia B with inhibitors and a history of allergic reaction to exogenousfactor IX experienced severe rash with onset at approximately 9 months. The patient required aprolonged course of oral corticosteroids for resolution and treatment with marstacimab wasdiscontinued.
Paediatric populationThe paediatric population studied comprises a total of 32 adolescent patients (from 12 to < 18 years ofage). The safety profile of marstacimab was overall consistent between adolescents and adults.
Reporting of suspected adverse reactionsReporting suspected adverse reactions after authorisation of the medicinal product is important. Itallows continued monitoring of the benefit/risk balance of the medicinal product. Healthcareprofessionals are asked to report any suspected adverse reactions via the national reporting systemlisted in Appendix V.
4.9 Overdose
There is limited experience with overdose of marstacimab.
No serious adverse events occurred in a small number of adult patients weighing ≥ 50 kg who had upto 3 months of exposure to marstacimab at 450 mg administered subcutaneously weekly during earlyphase studies. However, this was a small group, and the effect of longer-term high exposures isunknown. Receiving higher doses than recommended may result in hypercoagulability.
Patients who receive an accidental overdose should immediately contact their healthcare provider andbe monitored closely. In the event of overdose, it is recommended that the patient be monitored forany signs or symptoms of adverse reactions and/or hypercoagulability and appropriate symptomatictreatment be instituted immediately.
Paediatric populationDoses in excess of 150 mg per week for adolescents aged 12 to 17 years weighing < 50 kg have notbeen studied. No case of overdose has been reported in the paediatric population. The principlesdescribed above apply to the management of overdose in the paediatric population.
5. PHARMACOLOGICAL PROPERTIES
5.1 Pharmacodynamic properties
Pharmacotherapeutic group: antihemorrhagics, other systemic hemostatics, ATC code: B02BX11
Mechanism of actionMarstacimab is a human monoclonal IgG1 antibody directed against the Kunitz domain 2 (K2) oftissue factor pathway inhibitor (TFPI), the primary inhibitor of the extrinsic coagulation cascade. TFPIinitially binds to and inhibits the factor Xa active site via its second Kunitz inhibitor domain (K2). Theaction of marstacimab to neutralise the inhibitory activity of TFPI may serve to enhance the extrinsicpathway and bypass deficiencies in the intrinsic pathway of coagulation by increasing free factor Xaavailable to increase thrombin generation and promote haemostasis.
Pharmacodynamic effectsConsistent with its anti-TFPI mechanism, marstacimab administration to haemophilia patients withand without inhibitors causes an increase in total TFPI and downstream biomarkers of thrombingeneration such as prothrombin fragments 1+2, peak thrombin, and D-dimer. These changes werereversible after treatment discontinuation. Sporadic or transient increases in D-dimer and prothrombinfragments 1+2 above physiological values were reported in the Phase 3 study with no associated safetyconcerns.
There were no clinically relevant differences in pharmacodynamic effects between haemophiliaparticipants with and without inhibitors following weekly subcutaneous administration ofmarstacimab.
Clinical efficacy and safetyClinical studies in adult and adolescent patients with haemophilia A without FVIII inhibitors orhaemophilia B without FIX inhibitors
Patients (aged ≥ 12 years old and ≥ 35 kg) with haemophilia A without inhibitors and haemophilia Bwithout inhibitors (Study B7841005)
The pivotal Phase 3 study was a one-way, cross-over, open-label, multi-centre study which included anon-inhibitor cohort of 116 adult and adolescent males (aged 12 years and older and ≥ 35 kg) withsevere haemophilia A without FVIII inhibitors or severe haemophilia B without FIX inhibitors whopreviously received on-demand (N = 33) or prophylactic (N = 83) treatment with FVIII or FIX.
Patients with previous or current treatment for or history of coronary artery disease, venous or arterialthrombosis or ischaemic disease were excluded from the study.
The non-inhibitor cohort population was characterised by a severe bleeding phenotype. The meanannualised bleeding rates (ABRs) were 39.86 and 7.90 in a 6-month Observational Phase for theon-demand and prophylaxis cohorts, respectively, prior to crossing over to weekly marstacimabprophylaxis. All (100%) patients in the on-demand cohort had one or more target joints at study entryand 36.4% had 3 or more target joints at study entry. In the routine prophylaxis cohort, 55.4% of thepatients had one or more target joints at study entry and 15.7% had 3 or more target joints at studyentry.
After the 6-month Observational Phase in which patients received either on-demand or routineprophylactic factor-based replacement therapy, patients received an initial 300 mg loading dose ofmarstacimab followed by maintenance doses of 150 mg of marstacimab once weekly for 12 months.
Dose escalation to 300 mg of marstacimab once weekly was allowed after 6 months for patientsweighing ≥ 50 kg experiencing 2 or more breakthrough bleeds. Fourteen (12.1%) out of 116 patientswho received marstacimab for at least 6 months underwent dose escalation of their maintenance dose.
The mean age across the treatment groups was 32.4 years (min 13, max 66); 16.4% of patients were12 to < 18 years, and 83.6% were ≥ 18 years, 100% were male. In this non-inhibitor cohort 48.3% ofpatients were White, 50.0% were Asian, 0.9% were Black or African American, and 0.9% raceinformation missing; 10.3% of patients identified as Hispanic or Latino. All patients werenon-inhibitors (78.4% haemophilia A, 21.6% haemophilia B).
The primary efficacy objective of the study was to compare marstacimab prophylaxis during the
Active Treatment Phase versus routine prophylactic factor-based therapy in the Observational Phase asmeasured by the ABR of treated bleeds. Other key efficacy objectives of the study included evaluationof marstacimab prophylaxis in comparison with routine prophylactic factor-based therapy as measuredby the incidences of spontaneous bleeds, joint bleeds, target joint bleeds and total bleeds, as well asassessing patients’ health-related quality of life (HRQoL).
Table 2 shows the efficacy results of marstacimab prophylaxis compared with routine prophylacticfactor-based therapy. Marstacimab showed non-inferiority and statistical superiority over routineprophylactic factor-based therapy as measured by ABR of treated bleeds.
Table 2. Comparison of ABR with Hympavzi prophylaxis versus previous routine factor-basedprophylaxis in patients ≥ 12 years of age without factor VIII or factor IX inhibitors
Routine factor-based
Endpoints in the order of testing prophylaxis during Hympavzi prophylaxishierarchy 6-month OP during 12-month ATP(N = 83) (N = 83)
Treated bleeds (Primary)
ABR, model-based (95% CI) 7.90 (5.14, 10.66) 5.09 (3.40, 6.78)
- 2.81 (-5.42, -0.20)
Difference vs. RP (95% CI)p-value = 0.0349*
Patients with 0 bleeds, n (%) 33 (39.8) 29 (34.9)
Spontaneous bleeds, treated
ABR, model-based (95% CI) 5.89 (3.57, 8.22) 3.78 (2.25, 5.31)
- 2.11 (-4.26, 0.03)
Difference vs. RP (95% CI)
Non-inferiority*
Joint bleeds, treated
ABR, model-based (95% CI) 5.69 (3.36, 8.02) 4.13 (2.59, 5.67)
- 1.55 (-3.73, 0.62)
Difference vs. RP (95% CI)
Non-inferiority*
Total bleeds, treated and untreated
ABR, model-based (95% CI) 8.90 (6.02, 11.77) 5.98 (4.14, 7.82)
- 2.91 (-5.66, -0.17)
Difference vs. RP (95% CI)
Non-inferiority*
Target joint bleeds, treated
ABR, model-based (95% CI) 3.37 (1.60, 5.15) 2.51 (1.26, 3.76)
- 0.87 (-2.42, 0.69)
Difference vs. RP (95% CI)
Non-inferiority*
*Criterion Met (Non-inferiority/p-value if met superiority)
- The protocol specified non-inferiority criterion (upper bound of the 95% CI for the difference) was 2.5 fortreated bleeds, spontaneous bleeds, joint bleeds; 1.2 for target joint bleeds; 2.9 for total bleeds. If thenon-inferiority criterion was met, superiority was subsequently tested and established if the confidenceinterval excluded zero.
- p-value is for the superiority testing.
- The estimated mean, difference, and confidence intervals (CIs) for the ABR come from negative binomialregression model.
- Bleed definitions adapted based on International Society on Thrombosis and Haemostasis (ISTH) criteria.
- Treated bleeds = bleeds treated with FVIII or FIX
- Total bleeds = bleeds treated and not treated with FVIII or FIX
- ABR = Annualised Bleeding Rate; CI = Confidence Interval; OP = Observational Phase; ATP = Active
Treatment Phase; RP = Routine Prophylaxis
Study B7841007 interim analysis (Non-inhibitor cohort)
In the OLE of the pivotal Phase 3 study, 107 patients received marstacimab at the doses establishedduring participation in the B7841005 study (i.e. 150 mg or 300 mg subcutaneously once weekly) forup to an additional 43 months (mean 31 months) where marstacimab was shown to maintain long-termefficacy.
Descriptive analyses were conducted to assess marstacimab prophylaxis over time. The model-basedmean and other descriptive summaries for the ABR of treated bleeds are shown in Table 3.
Table 3. ABR with Hympavzi prophylaxis over time in patients ≥ 12 years of age withoutfactor VIII or factor IX inhibitors
Time interval during OLE Study B7841007*
Endpoint Year 1 Year 2 ≥ Year 3 Overall(N = 107) (N = 103) (N = 96) (N = 107)
Treated bleeds
Mean ABR 3.17 2.53 1.81 2.95(95% CI) (2.32, pct. 4.32) (1.87, 3.43) (1.31, 2.52) (2.21, 3.94)
Median ABR 1.00 1.00 0.00 0.94(IQR) (0.00, 5.00) (0.00, 3.00) (0.00, 2.66) (0.35, pct. 4.40)
*Patients received marstacimab for up to an additional 43 months (mean 31 months) during B7841007.
Year 1: Day 1 to Day 365; Year 2: Day 366 to Day 730; ≥ Year 3: Day 731 to the 43-month data cut-off
- The estimated mean and confidence intervals (CIs) for the ABR come from negative binomial regressionmodel.
- The median and the interquartile range (IQR), 25th percentile to 75th percentile, for the ABR come from thedescriptive summary.
- ABR = Annualised Bleeding Rate; CI = Confidence Interval; IQR = Interquartile Range; N = number ofpatients who contributed data for analyses at each time interval
Clinical studies in adult and adolescent patients with haemophilia A with FVIII inhibitors orhaemophilia B with FIX inhibitors
Patients (aged ≥ 12 years old and ≥ 35 kg) with haemophilia A with inhibitors and haemophilia B withinhibitors (Study B7841005)
The pivotal Phase 3 study was a one-way, cross-over, open-label, multi-centre study which includedan inhibitor cohort of 51 adult and adolescent males (aged 12 years and older and ≥ 35 kg) with severehaemophilia A with FVIII inhibitors or severe haemophilia B with FIX inhibitors who previouslyreceived on-demand (N = 48) or prophylactic (N = 3) treatment with bypassing agents (rFVIIa oraPCC). All patients had a documented history of inhibitors. Patients with previous or current treatmentfor or history of coronary artery disease, venous or arterial thrombosis or ischaemic disease wereexcluded from the study.
After the 6-month Observational Phase, patients received an initial 300 mg loading dose ofmarstacimab followed by maintenance doses of 150 mg of marstacimab once weekly for 12 months.
Dose escalation to 300 mg of marstacimab once weekly was allowed after 6 months for patientsweighing ≥ 50 kg experiencing 2 or more breakthrough bleeds. Four (7.8%) out of 51 patients whoreceived marstacimab for at least 6 months underwent dose escalation of their maintenance dose.
The primary efficacy objective of the study was to compare marstacimab prophylaxis during the
Active Treatment Phase versus on-demand bypassing agent therapy in the Observational Phase asmeasured by the ABR of treated bleeds. Other key efficacy objectives of the study included evaluationof marstacimab prophylaxis in comparison with on-demand bypassing agent therapy as measured bythe incidences of spontaneous bleeds, joint bleeds, target joint bleeds and total bleeds, as well asassessing patients’ health-related quality of life (HRQoL).
Among the 51 patients treated with marstacimab (78.4% haemophilia A, 21.6% haemophilia B), themean age was 27.7 years (min 12, max 75); 25.5% of patients were 12 to < 18 years, 74.5% were ≥ 18years, 100% were male. In this inhibitor cohort, 29.4% of patients were White, 54.9% were Asian,15.7% were Black or African American, and 2.0% of patients identified as Hispanic or Latino.
Of the 51 patients dosed, 48 patients previously received on-demand bypassing agents before crossingover to marstacimab treatment and the data from these 48 patients were used for the primary efficacyanalysis. This population was characterised by a severe bleeding phenotype. The mean ABRs fortreated bleeds were 19.78 in the Observational Phase, prior to crossing over to weekly marstacimabprophylaxis. Of the 48 patients, 70.8% patients had one or more target joints at study entry and 25.0%had 3 or more target joints at study entry.
Table 4 shows the efficacy results of marstacimab prophylaxis compared with on-demand bypassingagent therapy. Marstacimab prophylaxis demonstrated superiority over on-demand bypassing agenttherapy in incidences of treated bleeds, spontaneous bleeds, joint bleeds, total bleeds and target jointbleeds.
Table 4. Comparison of ABR with Hympavzi prophylaxis versus on-demand bypassing agenttherapy in patients ≥ 12 years of age with factor VIII or factor IX inhibitors
On-demand bypassing
Endpoints in the order of testing agent therapy during Hympavzi prophylaxishierarchy 6-month OP during 12-month ATP(N = 48) (N = 48)
Treated bleeds (Primary)
ABR, model-based (95% CI) 19.78 (16.12, 24.27) 1.39 (0.85, 2.29)
Ratio vs. OD (95% CI) 0.070 (0.042, 0.118)p-value < 0.0001
Participants with 0 bleeds, n (%) 1 (2.1) 26 (54.2)
Spontaneous bleeds, treated
ABR, model-based (95% CI) 15.27 (12.07, 19.31) 0.87 (0.53, 1.43)
Ratio vs. OD (95% CI) 0.057 (0.035, 0.092)p-value < 0.0001
Joint bleeds, treated
ABR, model-based (95% CI) 15.15 (11.87, 19.34) 1.10 (0.59, 2.04)
Ratio vs. OD (95% CI) 0.072 (0.038, 0.138)p-value < 0.0001
Total bleeds, treated and untreated
ABR, model-based (95% CI) 27.29 (22.54, 33.03) 4.36 (2.65, 7.18)
Ratio vs. OD (95% CI) 0.160 (0.102, 0.249)p-value < 0.0001
Target joint bleeds, treated
ABR, model-based (95% CI) 6.30 (4.32, 9.20) 0.79 (0.36, 1.74)
Ratio vs. OD (95% CI) 0.126 (0.062, 0.256)p-value 0.0001
- 2-sided p-value for the null hypothesis that the ratio = 0.5.
- The estimated mean, ratio, and confidence intervals (CIs) for the ABR come from negative binomialregression model.
- Bleed definitions adapted based on ISTH criteria.
- Treated bleeds = bleeds treated with bypassing agent
- Total bleeds = bleeds treated and not treated with bypassing agent
- ABR = Annualised Bleeding Rate; CI = Confidence Interval; OD = On-Demand; OP = Observational Phase;
ATP = Active Treatment Phase
Study B7841007 interim analysis (Inhibitor cohort)
In the OLE of the pivotal Phase 3 study, 47 patients received marstacimab at the doses establishedduring participation in the B7841005 study (i.e. 150 mg or 300 mg subcutaneously once weekly) forup to an additional 41 months (mean 19 months) where marstacimab was shown to maintain long-termefficacy.
Descriptive analyses were conducted to assess marstacimab prophylaxis over time. The model-basedmean and other descriptive summaries for the ABR of treated bleeds are shown in Table 5.
Table 5. ABR with Hympavzi prophylaxis over time in patients ≥ 12 years of age withfactor VIII or factor IX inhibitors
Time interval during OLE Study B7841007*
Endpoint
Year 1 Year 2 ≥ Year 3 Overall(N = 47) (N = 32) (N = 14) (N = 47)
Treated bleeds
Mean ABR 1.20 1.16 0.42 1.19(95% CI) (0.72, 2.02) (0.49, 2.76) (0.16, 1.13) (0.72, 1.95)
Median ABR 0.00 0.00 0.00 0.00(IQR) (0.00, 2.00) (0.00, 1.21) (0.00, 0.94) (0.00, 1.18)
*Patients received marstacimab for up to an additional 41 months (mean 19 months) during B7841007.
Year 1: Day 1 to Day 365; Year 2: Day 366 to Day 730; ≥ Year 3: Day 731 to the 41-month data cut-off
- The estimated mean and confidence intervals (CIs) for the ABR come from negative binomial regressionmodel.
- The median and the interquartile range (IQR), 25th percentile to 75th percentile, for the ABR come from thedescriptive summary.
- ABR = Annualised Bleeding Rate; CI = Confidence Interval; IQR = Interquartile Range; N = number ofpatients who contributed data for analyses at each time interval
ImmunogenicityFollowing at least 1 year of subcutaneous weekly marstacimab dosing in haemophilia patients withand without inhibitors in the pooled Studies B7841005/B7841007, 39 of the 167 (23.4%) anti-drugantibody (ADA)-evaluable marstacimab-treated patients developed ADAs. Incidences were 25.2%(34/135) in adults, 15.6% (5/32) in adolescents, 23.5% (12/51) in patients with inhibitors and 23.3%(27/116) in patients without inhibitors. ADAs were transient in 67% (26/39) and persistent in 31%(12/39) of the ADA-positive patients. ADA titres resolved in 38/39 (97%) patients by the end of thestudy. Neutralising antibodies (NAbs) developed in 8/167 (4.8%; 6/116 patients without inhibitors and2/51 patients with inhibitors) ADA-evaluable marstacimab-treated patients during the study. The
NAbs were transient in the majority (87.5%) of patients and no patients were NAb positive at the endof the study. Although slightly lower mean marstacimab concentrations (approximately 10%-36%lower) were reported in ADA-positive patients compared to ADA-negative patients, concentrationslargely overlapped between these 2 groups and there was no identified clinically significant effect of
ADAs, including NAbs, on safety or efficacy of marstacimab over the treatment duration of12 months. Overall, the safety profile of marstacimab was similar between patients with ADAs(including NAbs) and those without.
Paediatric populationThe European Medicines Agency has deferred the obligation to submit the results of studies with
Hympavzi in one or more subsets of the paediatric population in the treatment of congenitalhaemophilia A and congenital haemophilia B.
5.2 Pharmacokinetic properties
The pharmacokinetics of marstacimab were determined via non-compartmental analysis in healthyparticipants and haemophilia A and B patients with and without inhibitors as well as using apopulation pharmacokinetic analysis on a database composed of 287 participants (224 haemophiliapatients with and without inhibitors and 63 healthy participants) who received once weeklysubcutaneous (30 mg to 450 mg) or intravenous (150 mg and 440 mg) doses of marstacimab.
Marstacimab exhibited non-linear pharmacokinetics with systemic exposure to marstacimab, asmeasured by AUC and Cmax, increasing in a greater than dose-proportional manner. This non-linearpharmacokinetic behaviour is caused by target-mediated drug disposition (TMDD) and concentrationdependent non-linear elimination of marstacimab which occurs when marstacimab binds to endothelial
TFPI.
No clinically meaningful differences were seen in marstacimab exposures between haemophiliaparticipants with and without inhibitors.
Mean steady-state accumulation ratio for marstacimab was approximately 4 to 5, relative to the firstdose exposure following weekly subcutaneous dosing of 150 mg and 300 mg. Steady-stateconcentrations of marstacimab are expected to be achieved by approximately 60 days, i.e. by the 8th or9th subcutaneous dose when administered once weekly. For marstacimab 150 mg subcutaneous onceweekly, population estimates of mean Cmax,ss, Cmin,ss, and Cavg,ss for adults and adolescents are shown in
Table 6.
Table 6. Steady-state marstacimab plasma concentrations in haemophilia A and B patientswith and without inhibitors following once-weekly subcutaneous administration of150 mg marstacimab (with a loading dose of 300 mg subcutaneous)
Adults Adults Adolescents Adolescents
Parameterwithout inhibitors with inhibitors without inhibitors with inhibitors
Cmin,ss (ng/mL) 13 200 (95.5%) 16 100 (77.9%) 30 100 (74.5%) 35 500 (69.0%)
Cmax,ss (ng/mL) 17 700 (79.6%) 21 900 (67.7%) 37 300 (65.9%) 44 700 (63.5%)
Cavg,ss (ng/mL) 16 100 (84.3%) 19 800 (70.3%) 34 800 (68.7%) 41 400 (65.2%)
- Data are presented as arithmetic mean (%CV).
- Cmin,ss = minimum plasma concentration at steady state; Cmax,ss = maximum plasma concentration at steadystate; Cavg,ss = average plasma concentration at steady state
AbsorptionFollowing multiple subcutaneous administrations of marstacimab to haemophilia patients, median Tmaxranged from 23 to 59 hours. Bioavailability of marstacimab following subcutaneous administrationwas estimated to be about 71% by population pharmacokinetic modelling. No clinically relevantdifferences were seen in marstacimab bioavailability between arm, thigh and abdomen.
DistributionMarstacimab steady-state volume of distribution in haemophilia patients was 6.0 L based on apopulation pharmacokinetic analysis. This limited extravascular distribution suggests that marstacimabis restricted to the intravascular space.
BiotransformationMetabolism studies were not conducted with marstacimab. Similar to other therapeutic proteins withmolecular weights above the glomerular filtration cut-off, marstacimab is expected to undergoproteolytic catabolism and receptor-mediated clearance. In addition, based on the TMDD,marstacimab is expected to be also cleared by target-mediated clearance as formation ofmarstacimab/TFPI complex.
EliminationExcretion studies were not conducted with marstacimab. Based on the molecular weight, marstacimabis expected to undergo catabolic degradation and is not expected to be renally cleared. Marstacimab iscleared via linear and non-linear mechanisms. Following multiple subcutaneous doses and based on apopulation PK analysis, marstacimab linear clearance was approximately 0.017 L/hr. Based onpopulation pharmacokinetic analysis, 90% of marstacimab is expected to be eliminated by the end ofapproximately 1 month after the last dose (median time for 50% of drug to be eliminated isapproximately 7 to 11 days).
Special populationsBody weight, age group, race, and haemophilia type
Although weight was an important covariate to describe the pharmacokinetics of marstacimab, noalteration in dosing is required based on weight in patients weighing ≥ 35 kg. Marstacimab exposures(geometric mean steady state AUC, Cmax and Cmin) were 2.6 to 3.2-fold higher in adolescentscompared to adult haemophilia patients; however body weight accounts for most of these differencesin exposures. These differences in PK did not translate to a clinically relevant difference in levels ofthe downstream pharmacodynamic marker peak thrombin between the 2 groups.
The impact of haemophilia type on the pharmacokinetics of marstacimab was not found to beclinically relevant in the patient population.
Race (Asian vs. non-Asian) was not identified as a covariate influencing marstacimabpharmacokinetics after adjusting for body weight. Marstacimab weight-adjusted linear clearance was26% higher in Asian participants as compared to non-Asian participants. This difference is notconsidered clinically relevant. There are insufficient data to evaluate potential differences in theexposure of marstacimab in other races or ethnicity.
Clinical studies of marstacimab did not include a sufficient number of patients aged 65 years and olderto determine whether there are differences in exposure compared with younger patients.
Renal impairmentRenal clearance is not considered important for elimination of mAbs due to their large size andinefficient filtration through the glomerulus. Clinical studies have not been conducted to evaluate theeffect of renal impairment on the PK of marstacimab.
All patients with haemophilia A and B in the population pharmacokinetic analysis had normal renalfunction (N = 198; eGFR ≥ 90 mL/min/1.73 m2) or mild renal impairment (N = 25; eGFR of 60 to89 mL/min/1.73 m2). Mild renal impairment did not affect the pharmacokinetics of marstacimab.
There are no data available on the use of marstacimab in patients with moderate or severe renalimpairment.
Marstacimab is a monoclonal antibody and is cleared via catabolism rather than renal excretion and achange in dose is not expected to be required for patients with renal impairment.
Hepatic impairmentClinical studies have not been conducted to evaluate the effect of hepatic impairment on the PK ofmarstacimab, as it is generally not considered clinically relevant for mAbs.
All patients with haemophilia A and B in the clinical studies had normal hepatic function (N = 204;total bilirubin and AST ≤ ULN) or mild hepatic impairment (N = 20; total bilirubin > 1× to≤ 1.5× ULN). Mild hepatic impairment did not affect the pharmacokinetics of marstacimab. No dataare available on the use of marstacimab in patients with moderate or severe hepatic impairment.
Marstacimab is a monoclonal antibody and is cleared via catabolism rather than hepatic metabolismand a change in dose is not expected to be required for patients with hepatic impairment.
5.3 Preclinical safety data
Nonclinical data reveal no special hazard for humans based on repeat-dose toxicity, including safetypharmacology endpoints, and local tolerance. Reversible mixed cell infiltration, haemorrhage, andnecrosis were observed at the injection sites in rats following subcutaneous injection. No studies havebeen conducted to assess the potential for carcinogenicity, mutagenicity, or effects on embryo-foetaldevelopment.
Impairment of fertilityMarstacimab did not affect fertility or early embryonic development when administered as a repeatdose to male rats at doses up to 1 000 mg/kg/dose and an exposure margin of 212× the AUC exposureat a clinical dose of 300 mg subcutaneous weekly.
Drug-drug interaction
Coadministration of marstacimab (50 mg/kg) with rFVIIa in haemostatically normal rats was toleratedat a dose of 0.8 mg/kg rFVIIa but at a higher dose of rFVIIa (3 mg/kg) was associated with anincreased incidence and/or severity of acute thrombi/emboli in the lung and injection site.
Coadministration of marstacimab (30 mg/kg) with aPCC (10-100 U/kg/day) in haemostatically normalrats resulted in higher mean thrombin-antithrombin complexes and mean platelet volume than wereobserved with aPCC alone.
6. PHARMACEUTICAL PARTICULARS
6.1 List of excipients
Disodium edetate
L-Histidine
L-Histidine monohydrochloride
Polysorbate 80 (E 433)
Sucrose
Water for injections
6.2 Incompatibilities
In the absence of compatibility studies, this medicinal product must not be mixed with other medicinalproducts.
6.3 Shelf life
3 years.
6.4 Special precautions for storage
Store in a refrigerator (2 °C - 8 °C).
Do not freeze.
Keep the pre-filled syringe or pre-filled pen in its original carton in order to protect from light.
The medicinal product may be removed from refrigerated storage and stored in its original carton forone single period of maximum 7 days at room temperature (up to 30 °C). The medicinal product mustnot be returned to refrigerated storage. Prior to the end of this period of room temperature storage, themedicinal product must be used or discarded.
6.5 Nature and contents of container
Hympavzi 150 mg solution for injection in pre-filled syringe
Each carton contains one single-dose pre-filled syringe (Type I glass) with a plunger stopper(chlorobutyl elastomer) and a stainless steel 27 gauge, ½ inch staked needle with a needle shield(thermoplastic elastomer).
Each pre-filled syringe contains 1 mL solution for injection.
Hympavzi 150 mg solution for injection in pre-filled pen
Hympavzi 150 mg solution for injection in pre-filled pen is available in a pack containing1 single-dose pre-filled pen and in multipacks containing 4 (4 packs of 1) single-dose pre-filled pens.
The syringe inside the pen is made from Type I glass with a plunger stopper (chlorobutyl elastomer)and a stainless steel 27 gauge, ½ inch staked needle with a needle shield (thermoplastic elastomer).
Each pre-filled pen contains 1 mL solution for injection.
Not all pack sizes may be marketed.
6.6 Special precautions for disposal and other handling
This medicinal product is for single use only.
Do not shake.
For a more comfortable injection, allow the medicinal product to warm up to room temperature in thecarton protected from direct sunlight for about 15 to 30 minutes.
Inspect the solution visually prior to use. Hympavzi is a clear and colourless to light yellow solution.
Do not use if the medicinal product is cloudy, dark yellow, or contains flakes or particles.
Comprehensive instructions for the preparation and administration of the medicinal product areprovided in the package leaflet and ‘Instructions for Use’.
Hympavzi does not contain preservatives; therefore, unused portions should be discarded.
Any unused medicinal product or waste material should be disposed of in accordance with localrequirements.
10. DATE OF REVISION OF THE TEXT
Detailed information on this medicinal product is available on the website of the European Medicines
Agency https://www.ema.europa.eu.