Alphanate (human plasma derived von Willebrand factor/FVIII complex) / Grifols - LARVOL DELTA

Disparities in Real-World Treatment Patterns Among Patients with Von Willebrand Disease in a Large US Population-Based Dataset (ASH 2024) - "On-demand medications included antifibrinolytics and desmopressin, which were used 46% and 31% of the time, respectively, while 23% used VWF replacement therapies. Among prophylaxis users, 49% of patients were treated with VWF replacement therapies, most commonly Humate-P (77%), followed by wilate (16%), Vonvendi (11%), and Alphanate (8%)...Hemlibra was used in 2% of patients, mainly to treat those with joint bleeds...While heavy menstrual bleeding and nosebleeds were the most common bleeding phenotypes among VWD patients with bleeding comorbidities (and likely underrepresented in claims data), only a minority of patients received VWF replacement therapies. These findings suggest a high unmet need for better treatment options for VWD patients who may benefit from prophylactic therapy."

Clinical • HEOR • Real-world • Real-world evidence • Anemia • Gastrointestinal Disorder • Hematological Disorders • Hemophilia

Ex vivo evaluation of the effect of plasma-derived factor VIII/von Willebrand factor in patients with severe hemophilia A on emicizumab prophylaxis. (PubMed, Clin Exp Med) - "Samples from healthy controls (HC) and HA patients were drawn in sodium citrate plus corn trypsin inhibitor tubes and spiked with increasing concentrations of pdFVIII/VWF concentrates (10-400 IU/dL) (Fanhdi®/Alphanate®, Grifols), activated prothrombin complex concentrate (aPCC, 0.5 U/mL) or recombinant activated factor VII (rFVIIa, 0.9 µg/mL). Coagulation parameters of both methods significantly correlated at baseline and with increasing concentrations of pdFVIII/VWF. High doses of pdFVIII/VWF concentrates, similar to those used for ITI, did not trigger a multiplying procoagulant effect to samples from HA patients on emicizumab prophylaxis, evidencing their low thrombotic risk in these patients."

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

Real-World Efficacy and Safety of Plasma-Derived Von Willebrand Factor-Containing Factor VIII Concentrates in Patients With Von Willebrand Disease in Italy. (PubMed, Clin Appl Thromb Hemost) - "As far as safety, no adverse-drug-related episodes, immunogenic or thrombotic events were reported. This study confirmed that Fanhdi® and Alphanate® were effective and safe in the management of bleeding episodes, the prevention of bleeding during surgeries and for SLTP in Italian patients with inherited VWD."

Journal • Real-world • Real-world effectiveness • Real-world evidence • Hemophilia

Spectrum of Von Willebrand Disease (vWD) among children at a paediatric hospital in Singapore (ISTH 2024) - "2 of them were eventually started on prophylaxis (1 with Alphanate® and 1 with Vonvendi®). 26 patients with vWD were included in this study. 76.9% were diagnosed with Type I vWD, 19.2% with Type II vWD and 3.9% with Type III vWD. The median age at diagnosis was 5.8 years (range 0-13.6 years) and 34.6% of them had a positive family history of vWD."

Clinical • Hematological Disorders • Hemophilia • Pediatrics

A novel VWF platelet-dependent assay that differentiates GPIbα-binding activity in multimers of different sizes (ISTH 2023) - "As 6D12 binds to an epitope in the N-terminal AIM, binding of 6D12-activated VWF to GPIbα-LBD in VWF:NCo assay was not affected by the 1472 polymorphism. Healthy controls, type 1 and type 2B VWD samples had VWF:NCo/VWF:Ag ratios similar to VWF:GPIbR/VWF:Ag, while type 3 VWD sample had undetectable VWF:NCo values. The VWF:NCo/VWF:Ag ratio was highest in Vonvendi (1.9±0.3), followed by Humate P (1.2±0.1) and Alphanate (1.0±0.1), which is in accordance with the previous observations that recombinant human VWF have more high-molecular-weight VWF multimers (HMWM) than plasma-derived VWF products."

Hemophilia

REAL-WORLD EFFICACY AND SAFETY OF PLASMA-DERIVED VON WILLEBRAND FACTOR-CONTAINING FACTOR VIII CONCENTRATES IN PATIENTS WITH VON WILLEBRAND DISEASE IN ITALY (EAHAD 2023) - "This real-world evidence study confirmed that pdVWF/FVIII concentrates, Fanhdi and Alphanate, were effective and safe in the management of bleeding episodes and in the prevention of bleeding during surgeries in Italian patients with VWD."

Clinical • Real-world • Real-world effectiveness • Real-world evidence • Hemophilia

EMICIZUMAB IN PAEDIATRIC PATIENT WITH TYPE 3 VON WILLEBRAND DISEASE WITH INHIBITORS: FROM “PROPHYLAXIS” TO “PERIOPERATIVE MANAGEMENT” (EAHAD 2023) - "According to available data, the use of emicizumab is successful in paediatric patients with type 3 VWD and alloantibodies in preventing life-threatening haemorrhagic episodes and it also appears to be useful for perioperative management.Additional data needs to be collected to determine the optimal strategy."

Clinical • Cardiovascular • Critical care • Hematological Disorders • Hemophilia • Infectious Disease • Obstructive Sleep Apnea • Pediatrics • Pulmonary Embolism • Respiratory Diseases • Septic Shock • Sleep Disorder

Plasma-derived FVIII/VWF complex shows higher protection against inhibitors than isolated FVIII after infusion in haemophilic patients: A translational study. (PubMed, Haemophilia) - "Data indicate that FVIII+VWF complexes assembled in the circulation after rFVIII infusion are not equivalent to the naturally formed complex in pdFVIII/VWF. Therefore, rFVIII infused into HA patients with inhibitors would be less protected by VWF than the FVIII in pdFVIII/VWF concentrates."

Journal • Hematological Disorders • Hemophilia • Rare Diseases

Lilly Reports Solid Fourth-Quarter and Full-Year 2021 Financial Results, Recent Late-Stage Pipeline Successes Set Up Next Wave of Innovative Medicines for Patients (PRNewswire) - "Eli Lilly and Company...announced financial results for the fourth quarter and full year of 2021 today....Lilly's lebrikizumab...regulatory submission in 2022. Lilly's mirikizumab...regulatory submissions in 2022....For the fourth quarter of 2021, worldwide Olumiant revenue increased 59 percent compared with the fourth quarter of 2020, to $306.0 million. U.S. revenue was $87.7 million, representing growth of $62.8 million compared with the fourth quarter of 2020....For the full year of 2021, Olumiant generated worldwide revenue of $1.115 billion, an increase of 75 percent compared with the full year of 2020....For the fourth quarter of 2021, Emgality generated worldwide revenue of $161.5 million, an increase of 47 percent compared with the fourth quarter of 2020....For the full year of 2021, worldwide Emgality revenue was $577.2 million, an increase of 59 percent compared with the full year of 2020."

BLA • Sales • Atopic Dermatitis • CNS Disorders • Dermatology • Immunology • Inflammatory Bowel Disease • Migraine • Novel Coronavirus Disease • Pain • Rheumatoid Arthritis • Ulcerative Colitis

Successful Treatment with Emicizumab of Patient with Type 2N Normandy and Severe Hemophilia a (ASH 2021) - "vs. Half-life ADVATE® 5.5 hr.)...To our knowledge this is the first example of successful use of HEMLIBRA® in a patient with Type 2N VWD and severe hemophilia A. It is unclear why the ALPHANATE® was not clinically effective however the combination of VONVENDI® and ADYNOVATE® provided improved hemostasis with frequent infusions and high cost before the start of HEMLIBRA®. HEMLIBRA once a week has significantly reduced the treatment burden and improved bleeding prevention. The genotype of this patient is unusual however this approach may be successful in other types of VWD that result in significant bleeding phenotype."

Clinical • Hematological Disorders • Hemophilia • Musculoskeletal Pain • Pain • Rare Diseases • MRI

CLINICAL EFFICACY AND SAFETY OF PLASMA-DERIVED VON WILLEBRAND FACTOR- FVIII COMPLEX CONCENTRATES, IN PATIENTS WITH VON WILLEBRAND DISEASE IN ITALY: STUDY DESIGN. (BIC 2021) - "Materials and This is a multicentric study of patients diagnosed with congenital VWD and treated with Fanhdi® or Alphanate® for the management of bleeding and surgery and for secondary long-term prophylaxis, when desmopressin is ineffective or contraindicated. In Italy, the efficacy and safety of the study concentrates has been already proven in patients with VWD. However, this retrospective study will provide further evidence supporting the use of highly purified pdFVIII/VWF concentrates Fanhdi® and Alphanate®, for treating VWD in routine clinical practice."

Clinical • Hemophilia

Alphanate in Immune Tolerance Induction Therapy (clinicaltrials.gov) - P2; N=2; Terminated; Sponsor: Grifols Therapeutics LLC; N=25 ➔ 2; Trial completion date: Oct 2022 ➔ Sep 2020; Recruiting ➔ Terminated; Trial primary completion date: Oct 2021 ➔ Sep 2020; Terminated due to limited enrollment (non-safety related decision)

Clinical • Enrollment change • Trial completion date • Trial primary completion date • Trial termination • Hematological Disorders • Hemophilia • Rare Diseases

[VIRTUAL] VWF‐CONTAINING FVIII CONCENTRATES IMPROVE FVIII RECOVERY IN A MOUSE MODEL OF SEVERE HAEMOPHILIA WITH INHIBITORS (EAHAD 2021) - "FVIIInull E16 Knockout (KO) mice (n = 4-12), previously infused with either vehicle or inhibitor (to achieve high titer ̴ 6 BU/mL), were treated with FVIII concentrates at therapeutic doses (100 IU/kg) from different sources: native pdFVIII/VWF complex (Fanhdi®), full length rFVIII from Baby Hamster Kidney cells (Kovaltry®), single-chain (SC) B-domain-deleted (BDD) rFVIII from Chinese Hamster Ovary cells (Afstyla®), BDD-rFVIII from Human Embryonic Kidney (HEK) cells (Nuwiq®) and extended half-life BDD-rFVIII-Fc fusion from HEK cells (Elocta®)... In agreement to previously reported data, native pdFVIII/VWF concentrate was more efficient in the restoration of FVIII circulating levels in FVIIInull E16 KO mice even in the presence of high inhibitor titer. This finding is similar for the different isolated FVIII concentrates analyzed, regardless their origin, molecular form, cell line or involved modifications."

Preclinical • Hematological Disorders • Hemophilia • Rare Diseases

[VIRTUAL] LOW‐DOSE IMMUNE TOLERANCE INDUCTION THERAPY IN SEVERE HEMOPHILIA A CHILDREN WITH HIGH‐TITER INHIBITOR (EAHAD 2021) - "Low-dose ITI treatment strategy using the pdFVIII/VWF concentrate (Koate®, Grifols) achieved satisfactory response rate (80%), reduced annual bleeds, and improved school attendance, in children with inhibitor-positive severe HA and poor-risk status for ITI treatment success."

Clinical • Hematological Disorders • Hemophilia • Rare Diseases • Rheumatology

RESIST EXP: Rescue Immunotolerance Study in Induction of Immune Tolerance (ITI)-Experienced Patients (RES.I.S.T. Experienced) (clinicaltrials.gov) - P=N/A; N=3; Completed; Sponsor: City of Hope Medical Center; Active, not recruiting ➔ Completed; Trial completion date: Jun 2020 ➔ Oct 2020; Trial primary completion date: Jun 2020 ➔ Oct 2020

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

RESIST NAIVE: Study of First TIME Immunotolerance Induction in Severe Hemophilia A Patients With Inhibitor at High Risk of Failure: Comparison With FVIII Concentrates With or Without Von Willebrand Factor - RES.I.S.T. Naive (clinicaltrials.gov) - P=N/A; N=0; Withdrawn; Sponsor: City of Hope Medical Center; N=148 ➔ 0; Active, not recruiting ➔ Withdrawn

Clinical • Enrollment change • Trial withdrawal • Hematological Disorders • Hemophilia • Rare Diseases

[VIRTUAL] Higher Protection against Inhibitors with pdFVIII/VWF Complex Concentrate Compared to Complex Formed in the Circulation between Isolated FVIII and VWF of HA Patients: An ex vivo Study (ISTH 2020) - "Hence, the BU ratios of the HAp-i evaluated with the different sources of FVIII compared with that obtained with a normal plasma were: pdFVIII/VWF=0.9; rFVIII=1.3; BDD-rFVIII=1.6; BDD-rhFVIII=1.6; and BDD-rhFVIII-Fc=1.5... For the first time, the immunologic fate of therapeutic FVIII after being infused to HA patients has been investigated ex vivo. Results suggest that the complex FVIII+VWF formed in the circulation is not equivalent to the natural complex FVIII/VWF. Therefore, isolated FVIII infused into HA patients with inhibitors would be less protected by VWF than the FVIII in pdFVIII/VWF complex concentrates."

Gene Therapies • Hematological Disorders • Hemophilia • Rare Diseases

[VIRTUAL] Rapid Desensitization and Subsequent Immune Tolerance Induction in a Patient with Hypersensitivity and Inhibitor to Factor VIII (ISTH 2020) - "ITI was attempted with ALPHANATE, a pdFVIII, KOGENATE, a second generation rFVIII, and NUWIQ, a fourth generation rFVIII, but he suffered from increasingly severe hypersensitivity reactions to each product...Premedication (methylprednisolone/diphenhydramine) was given on days 1 through 5... The FVIII desensitization regimen described appears to offer a practical, cost-effective therapeutic approach to both the management of hypersensitivity as well as the induction of safe and effective immune tolerance."

Clinical • Dermatology • Dermatopathology • Gene Therapies • Hematological Disorders • Hemophilia • Immunology • Rare Diseases • Urticaria

[VIRTUAL] In vitro model on thrombin generation of hemophilia A patient with inhibitors under simultaneous treatment with emicizumab, plasma-derived VWF/FVIII and rFVIIa (WFH 2020) - "Materials and Individual HA plasma with inhibitors (HAp-i) (15 BU), containing emicizumab (50 ug/mL) plus pdFVIII/VWF (Alphanate(r), Grifols) at 1 to 4.5 IU/mL was combined with rFVIIa (NovoSeven(r), Novo Nordisk), at 0.9 and 7 g/mL. The combination of emicizumab plus pdFVIII/VWF and rFVIIa did not trigger a multiplying, but an additive effect on TG, in an in vitro model of ITI with bleeds. Importantly, TG results were within normal plasma levels. These results are in agreement with those reported elsewhere for a HA patient receiving emicizumab prophylaxis during ITI, who required treatment with rFVIIa."

Gene Therapies • Hematological Disorders • Hemophilia • Rare Diseases • F2

Efficacy of Alphanate FVIII/VWF Concentrate in Type 3 Von Willebrand Patients (clinicaltrials.gov) - P4; N=15; Active, not recruiting; Sponsor: Grifols Biologicals Inc.; Recruiting ➔ Active, not recruiting; Trial completion date: Mar 2021 ➔ Mar 2029; Trial primary completion date: Dec 2020 ➔ Dec 2028

Enrollment closed • Trial completion date • Trial primary completion date • Biosimilar • Genetic Disorders • Hemophilia

Routine clinical care data for population pharmacokinetic modeling: the case for Fanhdi/Alphanate in hemophilia A patients. (PubMed, J Pharmacokinet Pharmacodyn) - "This study shows the feasibility of using real-world data for the development of a population PK model. Evaluation and comparison of the model for Bayesian forecasting resulted in similar results as a model developed using rich sampling data."

Clinical • Journal • PK/PD data

SIPPET, an international randomized study, reports 87% higher incidence of inhibitors with recombinant factor VIII in patients with severe hemophilia A (Grifols Press Release) - P4, N=251; SIPPET (NCT01064284); "Cox regression analysis demonstrated that the treatment of PUPs with severe hemophilia A with recombinant factor VIII was associated with an 87% higher incidence of inhibitors than treatment with plasma-derived factor VIII/VWF. Similar results were found for the development of high-titre inhibitors. The results, published in the May 26 issue of the New England Journal of Medicine, may have implications for the choice of products to treat patients, since the development of inhibitors remains the major challenge in the management of hemophilia A."

P4 data • Hemophilia

Grifols launches new 2000 FVIII IU Alphanate (antihemophilic factor/von Willebrand factor complex [human]) assay (EIN News) - "Grifols, a leader in the production of plasma-derived medicines, announces the launch of a 2000 IU/vial assay size for ALPHANATE. ALPHANATE is indicated for the control and prevention of bleeding in patients with Hemophilia A and for surgical and/or invasive procedures in adult and pediatric patients with von Willebrand disease in whom desmopressin (DDAVP) is either ineffective or contraindicated. It is not indicated for patients with sever VWD (Type 3) undergoing major surgery. The 2000 IU FVIII ALPHANATE assay will be available October 1, 2014."

Launch • Hemophilia

SIPPET study on inhibitors in hemophilia A: Interim analysis confirms the original hypothesis (Grifols Press Release) - P4, N=205; SIPPET (NCT01064284); "...the SIPPET Study is safe to continue, there is no futility issue to stop the study from continuing..."

P4 data • Hemophilia

Inhibitor development in relation to treatment duration in severe hemophilia A in previously untreated patients: Results from the SIPPET trial (ISTH 2015) - Abstract #PO164-MON; P4, N=204; SIPPET (NCT01064284); "Results from this randomised and prospective study show that neutralising antibodies in previously untreated patients with severe haemophilia A develop before 20–40 exposure days."

P4 data • Hemophilia