denecimig (Mim8) / Novo Nordisk, Genmab - LARVOL DELTA

Mim8 improves the In Vivo hemostasis of select hemophilia B causing factor IX variants (ASH 2025) - "Mim8 (denecimig) is a next-generation FVIIIa-mimetic with distinct binding epitopes and increased potency compared toemicizumab; it is in late-stage clinical development for HA. This clot size approaches the clot size inour previous studies of wild-type mice (platelets 400 ± 40 µm2 and fibrin 280 ± 40 µm2).ConclusionMim8 improves the in vitro and in vivo hemostatic activity of select HB-causing FIX variants. Themagnitude of this improvement for some variants—such as R333Q and I397T, which account for 5.7% ofpeople with HB—is likely therapeutically relevant."

Preclinical • Hematological Disorders • Hemophilia • Hemophilia A • Hemophilia B • Rare Diseases • EGF

From efficacy to experience: 52-week patient-reported outcomes with Mim8 in adolescents and adults with hemophilia A with or without inhibitors (FRONTIER2) (ASH 2025) - P3 | "Mean changes in JPRS joint painscores were –1.8 in Arm 1 (n=13), –1.5 in Arms 2a/2b (n=29), and –0.4 in Arms 3/4 (n=184). Improvementsin PGI-C pain intensity were reported by 15/17 (88%) of participants in Arm 1, 38/40 (95%) in Arms 2a/2b,and 115/192 (60%) in Arms 3/4.Discussion/ConclusionMim8 PPX was associated with improvements across all assessed PROs over 52 weeks, including reducedtreatment burden, improved physical function, decreased joint pain, and strong treatment preference.These findings are consistent with Week 26 results, indicating sustained patient-perceived benefits withcontinued Mim8 use.PROs were comparable between QW and QM dosing, supporting the flexibility of Mim8 tiered dosing.In Arms 3/4, the smaller magnitude of change may reflect a ceiling effect among participants on PPX atbaseline.Patient preference data were highly favorable, including among participants already receiving PPX.These results support the long-term benefit of Mim8 in HA..."

Clinical • Patient reported outcomes • Hematological Disorders • Hemophilia • Hemophilia A • Musculoskeletal Diseases • Musculoskeletal Pain • Orthopedics • Rare Diseases

Mim8 prophylaxis in adults and adolescents with hemophilia A: 52-week efficacy and safety outcomes from the phase 3 FRONTIER2 study (ASH 2025) - P3 | "Participants completingFRONTIER2 are eligible for the open-label extension, FRONTIER4 (NCT05685238). Mim8 may offer aneffective and convenient approach to reducing disease and treatment burden in this population."

Clinical • P3 data • Cardiovascular • Hematological Disorders • Hemophilia • Hemophilia A • Immunology • Rare Diseases

fss25-110: Advancing Hemophilia Care—Uniting Expert Insights and Community Voices to Shape the Future of Non-Factor Replacement Therapy (ASH 2025) - "This dynamic event combines expert panel discussions, real-world case challenges, and insights from patients and community HCPs to explore the latest data on novel therapies including fitusiran, concizumab, marstacimab, and Mim8. Through interactive polling and audience Q&A, attendees will gain practical guidance on integrating these therapies into personalized care strategies for patients with moderate to severe hemophilia A and B. Discover how to navigate evolving safety profiles, improve joint health outcomes, and tailor treatment based on patient needs and preferences. This symposium offers a comprehensive view of current challenges, cutting-edge solutions, and future directions in hemophilia management, equipping you with actionable insights to improve clinical practice."

Hematological Disorders • Hemophilia • Hemophilia A • Hemophilia B • Rare Diseases

Comparative ex vivo analysis of Mim8 in thrombin generation assays triggered by activated factor XI or tissue factor. (PubMed, Res Pract Thromb Haemost) - P2, P3 | "These differences were consistent in both ex vivo and in vitro TG assessments. While both assays are considered relevant for assessing Mim8 pharmacodynamic response, systematic and consistent differences between TGAs triggered by FXIa and TF were observed, indicating different kinetics in the intrinsic and extrinsic pathways."

Journal • Preclinical • Hematological Disorders • Hemophilia • Hemophilia A • Rare Diseases

FRONTIER1 multiple ascending dose extension: a safety, tolerability, pharmacokinetics, and pharmacodynamics study of Mim8 in people with hemophilia A. (PubMed, Res Pract Thromb Haemost) - P2 | "Most patients experienced no bleeds during maintenance dosing. Mim8 was well tolerated, with no safety concerns nor anti-Mim8 antibodies during the FRONTIER1 MAD extension, supporting phase 3 development of Mim8 once weekly and once every 4 weeks."

Journal • PK/PD data • Hematological Disorders • Hemophilia • Hemophilia A • Rare Diseases

FVIII Inhibitors can Accurately be Measured in the Presence of Mim8 in Hemophilia A Plasma (ASH 2023) - "Using aPTT-based Modified Nijmegen-Bethesda Assays in the presence of FVIIIa Mimetics such as Mim8 is not recommended due to interference. This study showed that by using FVIII chromogenic assays containing bovine reagents, FVIII inhibitors levels up to at least ⁓5. 0 BU/mL can be accurately determined in severe hemophilia A plasma in the presence of up to 40 µg/mL Mim8."

Hematological Disorders • Hemophilia • Hemophilia A • Rare Diseases

In Vitro Effects of Mim8 and Combined Mim8-Bypassing Therapy on Thrombin Generation and Thromboelastography (ASH 2024) - "This enhances the proteolytic activity of FIXa and allows effective activation of FX, making it suitable for prophylaxis in patients with hemophilia A. While Mim8 and emicizumab have similar modes of action, differences in their respective anti-FIXa and anti-FX arms influence their FVIIIa-like function.Aim : This study investigates the in vitro hemostatic activity of Mim8 in blood samples from six patients with severe hemophilia A using a thrombin generation assay (TGA) and thromboelastography. The combination of Mim8 with rFVIIa at 90 µg/kg does not induce hypercoagulability, whereas the combination of Mim8 with APCC may carry a significant risk of hypercoagulability. The TGA can effectively monitor the combined treatment with Mim8 and either rFVIIa or APCC, which is not possible with currently available routine laboratory tests."

Preclinical • Hematological Disorders • Hemophilia • Hemophilia A • Rare Diseases

Mim8 Prophylaxis Beyond Bleeding: Investigating Multifaceted, Patient-Reported Outcomes for Hemophilia A in the FRONTIER2 Study (ASH 2024) - P3 | "Joint pain intensity was not severe at baseline in all arms and did not change notably with Mim8 PPX. These findings demonstrate the holistic benefits of Mim8 beyond bleed protection and provide insights into opportunities for individualized care."

Clinical • Patient reported outcomes • Hematological Disorders • Hemophilia • Hemophilia A • Musculoskeletal Diseases • Musculoskeletal Pain • Orthopedics • Pain • Pediatrics • Rare Diseases

Safety and Efficacy of Mim8 Prophylaxis Administered Once Every Two Weeks for Patients with Hemophilia A with or without Inhibitors: Interim Analysis of the FRONTIER4 Open-Label Extension Study (ASH 2024) - P2, P3 | "These data are consistent with the findings from FRONTIER2, which reported no safety concerns and a low number of treated bleeding episodes with either QW or QM prophylaxis. Further data from this ongoing arm of FRONTIER4, as well as data for participants enrolled from other studies in the FRONTIER program, will provide valuable long-term data for different Mim8 dosing regimens."

Clinical • Cardiovascular • Dermatology • Hematological Disorders • Hemophilia • Hemophilia A • Immunology • Rare Diseases

Novo Nordisk seeks EMA approval for bleeding disorder treatment (MedWatch) - "Novo Nordisk announced promising results with Mim8 from the phase 3 Frontier5 study this summer."

EMA filing • Hemophilia A

FRONTIER4: A Research Study Looking at Long-term Treatment With Mim8 in People With Haemophilia A (FRONTIER 4) (clinicaltrials.gov) - P3 | N=451 | Active, not recruiting | Sponsor: Novo Nordisk A/S | Trial completion date: Dec 2030 ➔ Jun 2028 | Trial primary completion date: Dec 2030 ➔ Jun 2028

Trial completion date • Trial primary completion date • Hematological Disorders • Hemophilia • Hemophilia A • Rare Diseases

Novo Nordisk submits Biologics License Application (BLA) to FDA for Mim8; an investigational, prophylaxis treatment for people living with hemophilia A with or without inhibitors (Novo Nordisk Press Release) - "The FDA submission is grounded in the results from the FRONTIER study program, a comprehensive program of studies designed to establish the efficacy and safety profile of denecimig as a prophylaxis treatment to prevent or reduce the frequency of bleeding episodes in people with hemophilia A, with or without inhibitors...FRONTIER2, FRONTIER3 and FRONTIER4 formed the basis of the denecimig BLA submission."

FDA filing • Hemophilia A

FRONTIER4: A Research Study Looking at Long-term Treatment With Mim8 in People With Haemophilia A (FRONTIER 4) (clinicaltrials.gov) - P3 | N=451 | Active, not recruiting | Sponsor: Novo Nordisk A/S | Trial primary completion date: Jun 2028 ➔ Dec 2030 | Trial completion date: Jun 2028 ➔ Dec 2030

Trial completion date • Trial primary completion date • Hematological Disorders • Hemophilia • Hemophilia A • Rare Diseases

Novo Nordisk A/S: Mim8 prophylaxis treatment shown to be well-tolerated when switching from emicizumab in people with haemophilia A in new phase 3 data presented at the ISTH 2025 Congress (GlobeNewswire) - P3b | N=61 | FRONTIER 5 (NCT05878938) | Sponsor: Novo Nordisk A/S | "Novo Nordisk...presented results from the phase 3b FRONTIER5 trial showing that a direct switch to investigational Mim8 (denecimig) prophylaxis from emicizumab treatment...was well-tolerated with no safety concerns in adults and adolescents living with haemophilia A, with or without inhibitors. Additionally, a FRONTIER5 Patient-Reported Outcomes (PROs) assessment found the Mim8 pen-injector easy to use, with an overall strong user preference for the pen-injector compared to the previous emicizumab injection system....The PROs data from FRONTIER5 indicated a strong overall preference for the Mim8 pen-injector, with 97% (n=57/59) of patients reporting a 'very strong' or 'fairly strong' preference....Novo Nordisk expects to submit Mim8 for regulatory review during 2025. Data from the ongoing phase 3 FRONTIER programme will be disclosed at upcoming congresses and in publications in 2025 and 2026."

Filing • P3 data • Patient reported outcomes • Hemophilia A

ASSESSMENT OF NOVEL POINT-OF-CARE WHOLE BLOOD COAGULATION ASSAY TO EVALUATE COAGULATION RESPONSE TO BIAB FVIIIA MIMETIC AND FVIII THERAPY (EHA 2025) - "This study assessed the dose-dependent response of ClotChip to Mim8, a next generation FVIIIa mimetic antibody, and to rFVIII (Novoeight®, Novo Nordisk) in whole blood samples deficient in FVIII clotting factor. The ClotChip Tpeak parameter responds to Mim8 and rFVIII in a dose-dependent manner with no plateau in the range tested (see Figure), demonstrating the potential for ClotChip to evaluate the coagulation response of patient samples to these hemophilia therapies. Ongoing studies are focused on clinical assessment with ClotChip to further assess patient response to various next-generation mimetic and traditional factor-replacement therapies at POC."

Hematological Disorders • Hemophilia • Rare Diseases

In vivo correction of canine hemophilia A by an anti-factor IXa antibody (ISTH 2025) - "These antibodies recognize both human factors IXa and X to enhance factor X activation but do not recognize canine factors IXa and X. However, the factor IXa binding arm of denecimig (Mim8) recognizes an epitope that is identical between human and canine factor IXa...Using a TGA standard curve, recovery of k-IX-2 activity revealed an initial clearance from plasma (half-life 18 hours) with a slower subsequent clearance (5 days). Using a standard curve of factor VIII in HemA plasma, equivalent activity peaked at 0.2 U/mL and declined over 48 hours to about 0.02 U/mL but remained above 0.01 U/mL for 24 days during which there were no bleeding events."

Preclinical • Hematological Disorders • Hemophilia • Hemophilia A • Rare Diseases • Thrombosis

Evaluating pen-injector handling and PROs in patients switching from emicizumab to Mim8 in FRONTIER5 (ISTH 2025) - P3 | "Mean change from baseline [standard deviation] to Week 26 ranged from: –6.2 [9.6] to –3.5 [10.9] for Hemo-TEM scores, none of which were considered clinically relevant (≥8 points); –0.4 [1.4] to 0.6 [2.8] for JPRS; and –0.7 [8.7] to 3.6 [9.1] for PedsQL physical functioning. Table or Figure Upload"

Clinical • Hematological Disorders • Hemophilia • Hemophilia A • Musculoskeletal Diseases • Musculoskeletal Pain • Orthopedics • Pain • Pediatrics • Rare Diseases

FRONTIER5 direct switch study: Safety of initiating Mim8 prophylaxis without washout of emicizumab (ISTH 2025) - P3 | "No exaggerated thrombin peak height response was observed. Table or Figure Upload"

Clinical • Cardiovascular • Hematological Disorders • Hemophilia • Hemophilia A • Immunology • Rare Diseases

Mim8 Enhances Procoagulant Activity of Select Hemophilia B-causing Factor IX Variants (ISTH 2025) - "Background We recently reported that the first-generation FVIIIa-mimetic emicizumab can rescue procoagulant activity of select hemophilia B (HB)-causing FIX variants with dysfunctional Xase formation (Lee et al. Further, with Mim8, a 50% and 70% FIX correction generated a similar amount of thrombin as a 100% correction without Mim8 (for rFIX-R333Q and rFIX-I397T, respectively). Table or Figure Upload"

Hematological Disorders • Hemophilia • Hemophilia A • Hemophilia B • Rare Diseases

Model-informed drug development of Mim8 - a next-generation bispecific antibody for treatment of haemophilia A. (PubMed, Eur J Pharm Sci) - P2 | "Model-informed drug development was used to design a novel treatment paradigm for patients living with haemophilia A by utilising a tiered dosing strategy with Mim8, to be evaluated in phase 3 trials."

Journal • Hematological Disorders • Hemophilia • Hemophilia A • Pediatrics • Rare Diseases

Novo Nordisk to present phase 3 trials across hemophilia portfolio, reinforcing commitment to research in rare blood disorders, at ISTH 2025 (PRNewswire) - "Key presentations include two updates from a phase 3 trial evaluating investigational treatment with Mim8 (denecimig) and five assessing treatment outcomes with concizumab in hemophilia; A phase 3 trial analysis from FRONTIER5 will evaluate the safety of switching directly from emicizumab to Mim8 (denecimig) in people living with hemophilia A/B; Findings from explorer7 and explorer8 phase 3 trials will assess data including non-joint bleeds, annualized bleeding rates and additional studies including thrombin generation with concizumab in hemophilia A/B."

P3 data • Hemophilia A • Hemophilia B

In vitro effects of Mim8 and combined Mim8-bypassing therapy on thrombin generation, thromboelastography and fibrin clot ultrastructure. (PubMed, Thromb Res) - "Mim8 significantly improves TG in vitro in both PPP and PRP from patients with severe HA, with ETP levels comparable to those of FVIII at 100 IU/dL. The TGA can effectively monitor the combined treatment with Mim8 and either rFVIIa or APCC, which is not possible with currently available routine laboratory tests."

Journal • Preclinical • Hematological Disorders • Hemophilia • Hemophilia A • Rare Diseases

FRONTIER2: A Research Study Investigating Mim8 in Adults and Adolescents With Haemophilia A With or Without Inhibitors (clinicaltrials.gov) - P3 | N=281 | Completed | Sponsor: Novo Nordisk A/S | Active, not recruiting ➔ Completed

Trial completion • Hematological Disorders • Hemophilia • Hemophilia A • Rare Diseases

Factor VIII Activity and Factor VIII Inhibitors Can Be Measured Accurately in Plasma Containing Mim8 by Using Specific Chromogenic Assays. (PubMed, Haemophilia) - "FVIII:C of SHL and EHL products and FVIII inhibitor levels can be accurately monitored in the presence of Mim8 using bovine CSAs at all FVIII levels, and bovine-human CSAs at FVIII concentrations >20 IU/dL."

Journal • Hematological Disorders • Hemophilia • Hemophilia A • Rare Diseases