Alhemo (concizumab) / Novo Nordisk - LARVOL DELTA

Gene Therapy and Hemophilia A: What Is the Future of Curative Therapy in the Age of Emicizumab? (ASH 2024) - "Additionally, the beneficial results seen in hemophilia A gene therapy clinical trials have occurred with meaningful challenges. This talk will review the risks and benefits of gene therapy for hemophilia A and consider them within the context of therapies (emicizumab and Fc-VWF-XTEN fusion protein-eht) that have shown consistent benefit compared with previously available factor VIII products as well as other promising therapies (Mim8, fitusiran, concizumab, and marstacimab) in late-stage clinical trials."

Gene therapy • Gene Therapies • Hematological Disorders • Hemophilia • Hemophilia A • Rare Diseases

Examining Downstream Effects of Concizumab in Hemophilia A with a Mathematical Modeling Approach. (PubMed, J Thromb Haemost) - "The effectiveness of concizumab is mediated through blockade of TFPI anticoagulant activities in plasma and on multiple physiological surfaces. An important and previously unrecognized function of concizumab was sequestration of plasma TFPIα to the endothelium."

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

Concizumab As a Possible Treatment for Bleeding Disordersof Unknown Cause (ASH 2024) - "There are few studies on the management of bleeding in BDUC and most relate to the use of tranexamic acid (Baker et al, J Thromb Haemost. In these cases, concizumab at concentrations similar to the trough plasma levels observed in haemophilia clinical trials (350-550 ng/ml, Matsushita T et al, N Engl J Med. 2023 Aug 31; 389(9):783-794) and rFVIIa emerge as potential therapeutic alternatives for these patients."

Hematological Disorders • Hemophilia • Rare Diseases

Low Normal Levels of Factor V Enhance Thrombin Generation in Hemophilia a in a Tissue Factor Pathway Inhibitor Independent Manner (ASH 2024) - "In some experiments, concizumab (4 μg/mL, NovoNordisk) and/or anti-A2 and anti-C2 FVIII function blocking antibodies (GMA-8015, GMA-8006, Green Mountain Antibodies) were added to the plasma... These data support the FXa substrate competition mechanism independent of TFPIα. As FVIII levels are reduced, the effect size of lowering FV levels increases in TF-initiated thrombin generation. Based on these results we hypothesize that lower levels of FVIII yield faster activation of FV during the initiation of coagulation."

Hematological Disorders • Hemophilia • Hemophilia A • Rare Diseases

Annualized Bleeding Rates in Patients with Hemophilia a or B and Inhibitors with and without Target Joints at Baseline: Results from the Concizumab Phase 3 Explorer7 Study (ASH 2024) - P3 | "Overall safety data showed no new findings. Conclusion In the explorer7 study, once-daily, subcutaneous concizumab prophylaxis effectively reduced ABR irrespective of the presence of target joints at baseline at the 32-week cut-off, and low ABRs were maintained at the 56-week cut-off."

Clinical • P3 data • Hematological Disorders • Hemophilia • Hemophilia A • Hemophilia B • Rare Diseases • Rheumatology

CDSCO Panel Grants Novo Nordisk Protocol Amendment Proposal To Study Concizumab (Medical Dialogues) - "Recommending to increase the number of subjects from 15 to 35, the Subject Expert Committee (SEC) functional under the Central Drug Standard Control Organisation (CDSCO) has approved the protocol amendment proposal presented by Novo Nordisk to study the efficacy, safety, and pharmacokinetics of concizumab prophylaxis in children below 12 years with hemophilia A or B with or without inhibitors. This came after the firm presented protocol amendment version 2.0 dated 06 October 2023 protocol no. NN7415-4616 and increased the number of subjects from India. This is an open-label study investigating the efficacy, safety, and pharmacokinetics of concizumab prophylaxis in children below 12 years with hemophilia A or B with or without inhibitors."

Clinical protocol • New trial • Genetic Disorders • Hemophilia • Hemophilia B

Novo Nordisk A/S: Alhemo recommended for European approval as first once-daily subcutaneous prophylactic treatment for people living with haemophilia A or B with inhibitors (GlobeNewswire) - "Novo Nordisk today announced that the European Medicines Agency’s (EMA) Committee for Medicinal Products for Human Use (CHMP) has adopted a positive opinion, recommending approval of Alhemo (concizumab) as the first once-daily subcutaneous prophylactic treatment for people aged 12 years or older living with haemophilia A or B with inhibitors....The CHMP positive opinion is based on data from the phase 3 explorer7 study..."

CHMP • Genetic Disorders • Hemophilia • Hemophilia B

Antibodies to watch in 2024. (PubMed, MAbs) - "In this installment, we discuss key details for 16 antibody therapeutics granted a first approval in 2023, as of November 17 (lecanemab (Leqembi), rozanolixizumab (RYSTIGGO), pozelimab (VEOPOZ), mirikizumab (Omvoh), talquetamab (Talvey), elranatamab (Elrexfio), epcoritamab (EPKINLY), glofitamab (COLUMVI), retifanlimab (Zynyz), concizumab (Alhemo), lebrikizumab (EBGLYSS), tafolecimab (SINTBILO), narlumosbart (Jinlitai), zuberitamab (Enrexib), adebrelimab (Arelili), and divozilimab (Ivlizi))...These nearly 50 product candidates include numerous innovative bispecific antibodies, such as odronextamab, ivonescimab, linvoseltamab, zenocutuzumab, and erfonrilimab, and antibody-drug conjugates, such as trastuzumab botidotin, patritumab deruxtecan, datopotamab deruxtecan, and MRG002, as well as a mixture of two immunocytokines (bifikafusp alfa and onfekafusp alfa)...Our analyses indicate that these molecules have approval success rates in the range of 14-32%, with higher rates..."

Journal • Infectious Disease • Novel Coronavirus Disease • Oncology • Respiratory Diseases

explorer7: Research Study to Look at How Well the Drug Concizumab Works in Your Body if You Have Haemophilia With Inhibitors (clinicaltrials.gov) - P3 | N=136 | Active, not recruiting | Sponsor: Novo Nordisk A/S | Trial completion date: Dec 2025 ➔ Feb 2027

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

The Concizumab Pen-Injector is Easy to Use and Preferred by Hemophilia Patients and Caregivers: A Usability Study Assessing Pen-Injector Handling and Preference. (PubMed, Patient Prefer Adherence) - "This preference and handling study was conducted in accordance with authority guidelines for approval of new devices and included adults and adolescents with HA/HB with or without inhibitors and caregivers currently administering factor replacement therapy or factor VIII mimetic (emicizumab) therapy. 88% of participants preferred the pen-injector (n=70; 95% CI 78-94%) over their current injection system, and 9% (n=7) reported "no preference". Participants found the concizumab pen-injector easy to learn and easy to use and preferred it over their current injection systems."

Journal • Hematological Disorders • Hemophilia • Rare Diseases

Concizumab prophylaxis in persons with hemophilia A or B with inhibitors: patient-reported outcome results from the phase 3 explorer7 study. (PubMed, Res Pract Thromb Haemost) - P3 | "The majority of patients receiving concizumab expressed a preference for concizumab over their previous treatment, the main reasons being "fewer bleeds," "require less time," and "less painful to inject." Across all PROs, there were less responses collected than anticipated, limiting interpretations. PROs collected during the explorer7 study showed improvements in some domains of HRQoL, treatment burden, and patient treatment preference in persons with hemophilia A or B with inhibitors receiving concizumab prophylaxis compared with no prophylaxis."

Journal • P3 data • Patient reported outcomes • Cognitive Disorders • Hematological Disorders • Hemophilia • Pain • Rare Diseases

Disease and treatment burden of patients with haemophilia entering the explorer6 non-interventional study. (PubMed, Eur J Haematol) - "Despite receiving routine clinical care, historical and baseline information from patients enrolled in explorer6 showed that patients with HA/HB treated episodically and patients with HAwI/HBwI had higher ABRs, higher treatment burden and participated in sports less than those with HA/HB treated with prophylaxis. Emerging treatments could be beneficial in addressing these unmet medical needs."

Journal • Observational data • Hematological Disorders • Hemophilia • Rare Diseases

Minimal interference of concizumab with standard clinical coagulation laboratory assays - An in vitro study. (PubMed, Haemophilia) - "The presence of concizumab did not, or only slightly, influence the outcome of standard clinical coagulation assays relevant for HA and HB."

Journal • Preclinical • Hematological Disorders • Hemophilia • Rare Diseases

Targeting Tissue Factor Pathway Inhibitor with concizumab to improve haemostasis in patients with Glanzmann thrombasthenia: an in vitro study. (PubMed, J Thromb Haemost) - "Concizumab enhanced thrombin generation, decreased the ROTEM CT, improved thrombus formation under flow and reduced clot lysis. Our results demonstrate the potential of concizumab for subcutaneous prophylaxis in GT patients."

Journal • Preclinical • Hematological Disorders • Thrombosis

Daily difference: Patient and physician experience with Alhemo® (ISTH 2024) - "Sponsored by Novo Nordisk Healthcare AG"

Clinical • Gene Therapies • Hematological Disorders • Hemophilia • Rare Diseases

Everyday protection: Exploring clinical outcomes with Alhemo® (ISTH 2024) - "Sponsored by Novo Nordisk Healthcare AG"

Clinical • Clinical data • Gene Therapies • Hematological Disorders • Hemophilia • Rare Diseases

Providing Innovation in Care: Daily Protection With Alhemo® for Haemophilia With Inhibitors (ISTH 2024) - "Sponsored by Novo Nordisk Healthcare AG"

Hematological Disorders • Hemophilia • Rare Diseases

Advancing Care with Concizumab: A Novel Class of Anti-TFPI Monoclonal Antibody for Haemophilia With Inhibitors (ISTH 2024) - "Sponsored by Novo Nordisk Healthcare AG"

Hematological Disorders • Hemophilia • Rare Diseases

Management of breakthrough bleeding episodes in the phase 3 concizumab studies (ISTH 2024) - P3 | "At the 56-week cut-off, BTBs that occurred in patients receiving concizumab were most frequently in joints, occurred spontaneously, and were reported as mild/moderate in severity (Table 1). Most BTBs of mild/moderate severity were treated with one injection of the respective BTB treatment (Table 2). In people with HAwI/HBwI, bleeds were most often managed with recombinant activated factor VII (median consumption per injection: mild/moderate bleeds in HAwI 90.0 µg/kg and HBwI 90.0 µg/kg; severe bleeds in HAwI 82.0 µg/kg and HBwI 68.0 µg/kg)."

P3 data • Hematological Disorders • Hemophilia • Rare Diseases

Concizumab efficacy results at 56-week cut-off in patients with hemophilia A/B without inhibitors: an intra-patient analysis from the phase 3 explorer8 study (ISTH 2024) - P=N/A, P3 | "Descriptive assessments for treated spontaneous and traumatic bleeding episodes are presented by hemophilia subtype (Table 1): for patients with HA, median annualized bleeding rate (ABR) (interquartile range [IQR]) was 2.2 (0.8–6.2) on previous factor prophylaxis and 1.7 (0.5–4.8) on concizumab at the 56-week cut-off; for patients with HB, median ABR (IQR) was 2.1 (0.9–4.2) on previous prophylaxis and 1.3 (0.0–6.4) on concizumab at the 56-week cut-off. Conclusion(s) : Low median ABRs for treated spontaneous and traumatic bleeding episodes were maintained at the 56-week cut-off, consistent with 32-week cut-off results, in patients with HA/HB without inhibitors, previously on stable factor prophylaxis."

Clinical • P3 data • Hematological Disorders • Hemophilia • Rare Diseases

Comparison of FVIII and concizumab in thrombin generation assays under different conditions (ISTH 2024) - "Under these conditions, FVIII (NovoEight, Novo Nordisk; 0.03–2.0 IU/mL) was compared with 4,000 ng/mL concizumab. The activity of FVIII increased with increasing FXIa concentrations, whereas the activity of concizumab was consistent under all conditions tested, independent of FXIa concentration (Figure 1). Consequently, the level of FVIII similar in activity to 4,000 ng/mL concizumab decreased as the FXIa concentration increased. In the absence of supplemented FXIa, the thrombin peak with 4,000 ng/mL concizumab corresponded to 0.9 IU/mL FVIII, and the endogenous thrombin potential (ETP) to 1.3 IU/mL FVIII."

Hematological Disorders • Hemophilia • Rare Diseases

Synthetic llama-derived single-domain antibodies blocking tissue factor pathway inhibitor increase thrombin generation in FVIII-, FIX- and FXI-deficient plasma (ISTH 2024) - "As such, anti-TFPI monoclonal antibodies such as Concizumab have been developed to treat hemophilia... 21 out of 188 screened sdAbs specifically bound to TFPIα, and two of them (26E5 and 26E8) were found to dose-dependently increase thrombin generation in the plasma of patients with HB (Figure 1A). These sdAbs also efficiently increased thrombin generation in HA and FXI-deficient plasmas (Figure 1B). 26E5 and 26E8 impaired the ability of rhTFPIα to inhibit the amidolytic activity of FXa and TF/FVIIa complex."

Hematological Disorders • Hemophilia • Rare Diseases

Concizumab improves clot formation in hemophilia A under flow. (PubMed, J Thromb Haemost) - "TFPI inhibition by concizumab enhanced activation and aggregation of platelets and fibrin clot formation in hemophilia A to levels comparable to that of rFVIIa."

Journal • Hematological Disorders • Hemophilia • Rare Diseases

HEALTH-RELATED QUALITY OF LIFE AND TREATMENT BURDEN IN PATIENTS WITH HEMOPHILIA A/B WITHOUT INHIBITORS ON CONCIZUMAB PROPHYLAXIS: RESULTS FROM THE PHASE 3 EXPLORER8 STUDY (THSNA 2024) - P3 | "Concizumab prophylaxis is associated with improvements in certain aspects of HRQoL. Concizumab is associated with lower treatment burden compared with no prophylaxis and may enhance treatment adherence."

Clinical • HEOR • P3 data • Hematological Disorders • Hemophilia • Pain • Rare Diseases

HEMOSTATIC OUTCOME OF SURGICAL PROCEDURES IN PATIENTS WITH HEMOPHILIA RECEIVING CONCIZUMAB PROPHYLAXIS: DATA FROM THE PHASE 3 EXPLORER7 AND EXPLORER8 TRIALS (THSNA 2024) - P3 | "Approximately 11% of patients who received concizumab treatment during the explorer7 and explorer8 trials underwent minor surgical procedures. Most minor surgeries were dental procedures, and most surgery-related bleeding episodes were characterized as mild or moderate. These data indicate that minor surgeries can be conducted safely during treatment with concizumab."

Clinical • P3 data • Hematological Disorders • Hemophilia • Rare Diseases