Leaflet HYMPAVZI 150mg 150mg / ml solution for injection in pre-filled pen

Hympavzi 150 mg solution for injection in pre-filled syringe

Hympavzi 150 mg solution for injection in pre-filled pen

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.

Hympavzi contains 0.2 mg polysorbate 80 in each mL of solution.

For the full list of excipients, see section 6.1.

Solution for injection (injection).

Clear, colourless to light yellow solution with pH of 5.8, and osmolarity of approximately324 mOsm/L.

Hympavzi is indicated for routine prophylaxis of bleeding episodes in patients 12 years of age andolder, weighing at least 35 kg, with:

- severe haemophilia A (congenital factor VIII deficiency, FVIII < 1%) without factor VIIIinhibitors, or

- severe haemophilia B (congenital factor IX deficiency, FIX < 1%) without factor IX inhibitors.

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.

The 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.

Hympavzi is intended for long-term prophylactic treatment.

A 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 infection, sepsis, and crushinjuries, potentiation of the inflammatory response via concomitant tissue factor 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).

If a dose is missed, administer as soon as possible before the day of the next scheduled dose, and thenresume usual weekly dosing schedule.

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.

Switching to Hympavzi

Switching from prophylactic factor replacement therapy to Hympavzi: Prior to initiation of Hympavzi,patients should discontinue treatment with clotting factor concentrates (factor VIII or factor IXconcentrates). Patients can initiate Hympavzi at any time after discontinuing clotting factorconcentrates.

Switching from non-factor-based haemophilia medicinal products to Hympavzi: No clinical study dataare available to guide converting patients from non-factor-based medicinal products to marstacimab.

Although a washout period has not been studied, one approach is to allow an adequate washout period(at least 5 half-lives) of the prior agent based on labelled half-life before initiating treatment with

Hympavzi. Haemostatic support with clotting factor concentrates may be needed during the switchfrom other non-factor-based haemophilia medicinal products to Hympavzi.

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.

No 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.

No dose adjustments are recommended in patients over 65 years of age (see section 5.2).

Hympavzi 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 discontinue Hympavzi 6 to 12 days prior and initiatemanagement per local standard of care with clotting factor concentrate and measures to manage therisk of venous thrombosis which can be elevated in the perioperative period. The product informationfor the clotting factor concentrate should be consulted for dose guidelines in patients with haemophiliaundergoing major surgery. Resumption of Hympavzi therapy should take into account the overallclinical status of the patient, including the presence of post-surgical thromboembolic risk factors, useof other haemostatic products and other concomitant medicinal products (see Missed dose sectionabove).

Hympavzi 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.

Hypersensitivity to the active substance or to any of the excipients listed in section 6.1.

In order to improve the traceability of biological medicinal products, the name and the batch numberof the administered product should be clearly recorded.

Removal of TFPI inhibition may increase a patient’s coagulation potential and contribute to a patient’sindividual, multifactorial risk for thromboembolic events. Venous thrombotic events, includingembolism, were reported in clinical studies with marstacimab (see section 4.8). These events occurredin individuals with multiple risk factors for thromboembolism. The following patients may be at anincreased 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).

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 use of other anti-tissue factor pathway inhibitor (anti-TFPI) products has been associated with thedevelopment of thromboembolic complications in patients exposed to additional haemostatic agents(i.e. bypassing agents) in close proximity. Factor VIII and factor IX products have been safelyadministered for the treatment of breakthrough bleeds in patients receiving marstacimab. If factor VIIIor factor IX products are indicated in a patient receiving Hympavzi prophylaxis, the minimumeffective dose of factor VIII or factor IX product according to the product label is recommended.

The benefit and risk 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 prophylaxismeasures against thromboembolism should be instituted according to current recommendations andstandard of care. Hympavzi prophylaxis should be interrupted if diagnostic findings consistent withthromboembolism occur and manage as clinically indicated.

Guidance on treating breakthrough bleeds

Factor VIII and factor IX products can be administered for the treatment of breakthrough bleeds inpatients receiving Hympavzi. Additional doses of Hympavzi should not be used to treat breakthroughbleeding events. Healthcare professionals should discuss with all patients and/or caregivers about thedose and schedule of clotting factor concentrates to use, if required, while receiving Hympavziprophylaxis, including using the lowest possible effective dose of clotting factor concentrate.

Healthcare professionals should refer to the product information for the clotting factor concentratebeing used.

Cutaneous 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.

Patient with factor inhibitor

In an ongoing clinical study outside the approved indication, in haemophilia patients with inhibitorstreated with marstacimab, one (2.9%) patient with severe haemophilia B and a history of allergicreaction to exogenous factor IX experienced severe rash with onset at approximately 9 months. Thepatient required a prolonged course of oral corticosteroids for resolution, and treatment withmarstacimab was discontinued.

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).

Polysorbate content

This medicinal product contains polysorbate 80. Polysorbate 80 may cause hypersensitivity reactions.

This medicinal product contains less than 1 mmol sodium (23 mg) per 1 mL, that is to say essentially‘sodium-free’.

No clinical drug interaction studies with marstacimab have been conducted.

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.

Women of childbearing potential receiving Hympavzi should use effective contraception during, andfor at least 1 month after cessation of Hympavzi treatment.

There 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).

It 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.

Animal 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.

Hympavzi has no or negligible influence on the ability to drive and use machines.

The overall safety profile of marstacimab is based on data from clinical studies. The most seriousadverse drug reaction reported from the clinical studies with marstacimab was thrombosis (0.9%) (seesection 4.4).

The most frequently reported adverse reactions after treatment with marstacimab were injection sitereactions (ISRs) (11.2%).

Safety data in Table 1 are based on pooled data from the Phase 3 safety and efficacy study (BASIS)and its open-label extension (OLE) study (see section 5.1). The data from the pivotal Phase 3 study12-month Active Treatment Phase reflects exposure of 116 male patients with haemophilia A or Bwithout inhibitors to marstacimab administered once weekly. Ninety-seven (83.6%) patients wereadults (18 years of age and older) and 19 (16.4%) were adolescents (12 years up to < 18 years). At thetime of data cut-off, a total of 87 of the 116 patients completing the 12-month treatment periodsubsequently enrolled in the OLE study. The median duration of exposure was 518.5 days (range 28 to847 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 Headache Common

Vascular disorders Hypertension Common

Thromboembolic events (thrombosisb) Uncommon

Skin and subcutaneous tissue Pruritus Commondisorders Rasha Uncommon

General disorders and administrations Injection site reactionsa Very commonsite conditions

a. see ‘Description of selected adverse reactions’

b. ADR reported in the open-label extension study post-data cut-off.

In total, 11.2% of 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 induration,injection site oedema, injection site pain, injection site pruritus, and injection site swelling.

In the non-inhibitor population, 0.9% of patients reported non-serious rash (Grade 1).

The paediatric population studied comprises a total of 19 adolescent patients (from 12 to < 18 years ofage). The safety profile of marstacimab was overall consistent between adolescents and adults.

Reporting 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.

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.

Doses 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.

Pharmacotherapeutic group: antihemorrhagics, other systemic hemostatics, ATC code: B02BX11

Marstacimab 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.

Consistent with its anti-TFPI mechanism, marstacimab administration to haemophilia patients causesan increase in total TFPI and downstream biomarkers of thrombin generation such as prothrombinfragments 1+2, peak thrombin, and D-Dimer. These changes were reversible after treatmentdiscontinuation. Sporadic or transient increases in D-Dimer and prothrombin fragments 1+2 abovephysiological values were reported in the Phase 3 study with no associated safety concerns.

Clinical 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 in 116 adult andadolescent males (aged 12 years and older and ≥ 35 kg) with severe haemophilia A without FVIIIinhibitors or severe haemophilia B without FIX inhibitors who previously received “on-demand”(N = 33) or prophylactic (N = 83) treatment with FVIII or FIX. Patients with previous or currenttreatment for or history of coronary artery disease, venous or arterial thrombosis or ischaemic diseasewere excluded from the study.

The study population was characterised by a severe bleeding phenotype. The mean annualisedbleeding rates (ABRs) were 39.86 and 7.90 in a 6-month Observational Phase for the on-demand andprophylaxis cohorts, respectively, prior to crossing over to weekly marstacimab prophylaxis. All(100%) patients in the on-demand cohort had one or more target joints at study entry and 36% had 3 ormore target joints at study entry. In the routine prophylaxis cohort, 56.6% of the patients had one ormore target joints at study entry and 15.7% had 3 or more target joints at study entry.

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 study 48.3% of patients were

White, 50.0% were Asian, 0.9% were Black or African American, and 0.9% race information missing;10.3% of patients identified as Hispanic or Latino. All patients were non-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

In the OLE of the pivotal Phase 3 study, 87 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 16 months (mean 7 months) where marstacimab was shown to maintain long-term(> 12 months) efficacy.

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

Endpoint First 6 months of ATP Second 6 months of ATP B7841007*(N = 116) (N = 112) (N = 87)

Treated Bleeds

Mean ABR 4.96 3.26 2.79(95% CI) (3.67, 6.70) (2.39, pct. 4.44) (1.90, 4.10)

Median ABR 2.00 1.91 0.00(IQR) (0.00, 5.99) (0.00, 4.09) (0.00, 4.10)

*Patients received marstacimab for up to an additional 16 months (mean 7 months) during B7841007.

- 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 comes from thedescriptive summary.

- ABR = Annualised Bleeding Rate; CI = Confidence Interval; IQR = Interquartile Range; ATP = Active

Treatment Phase (B7841005); N = number of patients who contributed data for analyses at each timeinterval

During the 12-month Active Treatment Phase in the pivotal Phase 3 Study B7841005, 23 of the 116(19.8%) ADA-evaluable marstacimab-treated patients developed ADAs. ADAs were transient in 61%(14/23) and persistent in 39% (9/23) of the ADA-positive patients, indicative of a transient ADAprofile in the majority of the patients. ADA titres resolved in 22/23 (95.7%) patients by the end of thestudy. Neutralising antibodies (NAbs) developed in 6/116 (5.2%) ADA-evaluable marstacimab-treatedpatients during the study. The NAbs were transient in all patients and no patients were NAb positive atthe end of the study. Although slightly lower mean marstacimab concentrations (approximately24%-32% lower) were reported in ADA-positive patients compared to ADA-negative patients,concentrations largely overlapped between these 2 groups and there was no identified clinicallysignificant effect of ADAs, including NAbs, on safety or efficacy of marstacimab over the treatmentduration of 12 months. Overall, the safety profile of marstacimab was similar between those patientswith ADAs (including NAbs) and those without.

In the Phase 3 OLE study, only one of the 44 ADA-evaluable patients continuing to receivemarstacimab for at least 6 months was persistently positive for ADAs.

The 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.

The pharmacokinetics of marstacimab were determined via non-compartmental analysis in healthyparticipants and haemophilia A and B patients as well as using a population pharmacokinetic analysison a database composed of 213 participants (150 haemophilia patients and 63 healthy participants)who received once weekly subcutaneous (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.

Mean steady-state accumulation ratio for marstacimab was approximately 3 to 4, 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 4.

Table 4. Steady-state marstacimab plasma concentrations following once-weekly subcutaneousadministration of 150 mg (with a loading dose of 300 mg subcutaneous)

Parameter Adults Adolescents

Cmin,ss (ng/mL) 13 700 (90.4%) 27 300 (53.2%)

Cmax,ss (ng/mL) 17 900 (77.5%) 34 700 (48.5%)

Cavg,ss (ng/mL) 16 500 (81.2%) 32 100 (49.5%)

- 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

Following 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 modeling. No relevant differences wereseen in marstacimab bioavailability between arm, thigh and abdomen.

Marstacimab steady-state volume of distribution in haemophilia patients was 8.6 L based on apopulation pharmacokinetic analysis. This limited extravascular distribution suggests that marstacimabis restricted to the intravascular space.

Metabolism 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.

Excretion 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 0.019 L/hr. Mean effectivesteady-state half-life of marstacimab was estimated to be approximately 16 to 18 days for both adultsand adolescents and across dose groups.

Body 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 clearance(CL) was 29% lower in adolescents (12 to < 18 years of age) compared to adults (18 years and older).

After adjusting for weight, CL (L/hr/kg) in adolescents was estimated to be approximately 3% lowercompared to that in adults, indicating that weight accounts for most of the differences in CL. Thisdifference in PK did not translate to a clinically relevant difference in levels of the downstreampharmacodynamic 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. Marstacimab weight-adjusted clearance was 32% higher in Asian patients ascompared to non-Asian patients. This difference is not considered clinically relevant. There areinsufficient data to evaluate potential differences in the exposure of marstacimab in other races orethnicity.

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 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 = 129; eGFR ≥ 90 mL/min/1.73 m2) or mild renal impairment (N = 21; 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.

Clinical 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 = 135;total bilirubin and AST ≤ ULN) or mild hepatic impairment (N = 15; 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.

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.

Marstacimab 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.

Disodium edetate

L-Histidine

L-Histidine monohydrochloride

Polysorbate 80 (E 433)

Sucrose

Water for injections

In the absence of compatibility studies, this medicinal product must not be mixed with other medicinalproducts.

3 years.

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.

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.

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.

Pfizer Europe MA EEIG

Boulevard de la Plaine 171050 Bruxelles

Belgium

Hympavzi 150 mg solution for injection in pre-filled syringe

EU/1/24/1874/001

Hympavzi 150 mg solution for injection in pre-filled pen

EU/1/24/1874/002 1 pre-filled pen

EU/1/24/1874/003 4 pre-filled pens

Date of first authorisation: 18 November 2024

Detailed information on this medicinal product is available on the website of the European Medicines

Agency https://www.ema.europa.eu.