Ceprotin (human protein C) / Takeda - LARVOL DELTA

Pharmacokinetic Evidence Supporting Subcutaneous Use of Protein C Concentrate in Patients with Protein C Deficiency. (PubMed, TH Open) - "Protein C concentrate (Ceprotin®; Baxalta US Inc., a Takeda company, Cambridge, MA; Takeda Manufacturing Austria AG, Vienna, Austria) is approved for intravenous (IV) use in severe congenital protein C deficiency (SCPCD), with pharmacokinetic (PK)-guided dosing...Evidence provided by model-based simulations supports the use of various SC dosing regimens across age groups in acute or prophylactic settings according to the intended protein C activity levels. A high loading dose may be required to rapidly attain target therapeutic concentrations."

Journal • PK/PD data • Pediatrics

Real-world use of protein C concentrate for the treatment of patients with protein C deficiency: an international registry. (PubMed, J Thromb Haemost) - "The results of this study provide insights into the real-world use of protein C concentrate in clinical practice in Europe and the USA."

Journal • Real-world evidence • Cardiovascular • Hematological Disorders • Infectious Disease • Pain • Thrombosis

AIFA Board of Directors approves the reimbursability... [Google translation] (Italian Medicines Agency) - "The new medicine that will be eligible for reimbursement is Velsipity (etrasimod), indicated for the treatment of patients aged 16 years or older with moderate to severe ulcerative colitis (UC) with inadequate response, habituation or intolerance to conventional therapy or a biological agent...The therapeutic indication extensions concern the multiple sclerosis (MS) medicine Aubagio (teriflunomide), the antithrombotic Ceprotin (protein C), the monoclonal antibody Evkeeza (evinacumab) for homozygous familial hypercholesterolaemia (two indication extensions)..."

Reimbursement • Genetic Disorders • Homozygous Familial Hypercholesterolemia • Multiple Sclerosis • Ulcerative Colitis

SIMILAR EFFICACY AND SAFETY OF PLASMA-DERIVED PROTEIN C CONCENTRATE BETWEEN ASIAN AND NON-ASIAN PATIENTS WITH SEVERE CONGENITAL PROTEIN C DEFICIENCY (EHA 2025) - P1/2, P2/3 | "[a Takeda company]) for prophylaxis and acute treatment of purpura fulminans (PF), warfarin-induced skin necrosis (WISN) and vascular thrombotic events (TE) in patients with SCPCD have been established... The efficacy and safety of pd-PC concentrate for on-demand treatment and short-term prophylaxis in patients with SCPCD were similar between Asian and non-Asian patients, supporting its use in patients with Asian ancestry."

Clinical • Dermatology • Pruritus

Evaluation of pharmacokinetics of intravenous protein C concentrate in protein C deficiency: implications for treatment initiation and maintenance. (PubMed, Res Pract Thromb Haemost) - "Dosing of intravenous protein C concentrate (Ceprotin) in patients with protein C deficiency is guided by pharmacokinetics (PK) of plasma protein C activity...Age, body weight, and symptomatic disease state should be considered in dose optimization. Model-based simulations support the use of various combined loading and maintenance regimens to quickly and effectively achieve target protein C plasma levels."

Journal • PK/PD data

A Study of TAK-662 for Japanese Patients With Congenital Protein C Deficiency (clinicaltrials.gov) - P1/2 | N=5 | Completed | Sponsor: Takeda | Active, not recruiting ➔ Completed

Trial completion

Comprehensive literature review of protein C concentrate use in patients with severe congenital protein C deficiency. (PubMed, Res Pract Thromb Haemost) - "Three adverse events in 1 publication were identified as being possibly related to Ceprotin administration. Although published data are limited, this review provides valuable insights into the treatment of patients with SCPCD in clinical practice, including protein C concentrate dosing regimens, administration routes, and associated clinical outcomes."

Journal • Review • Cardiovascular • Hematological Disorders • Rare Diseases • Retinal Disorders • Thrombosis • Venous Thromboembolism

A Study of Freeze-dried Human Protein C Concentrate (TAK-662) in Participants with Congenital Protein C Deficiency (clinicaltrials.gov) - P=N/A | N=7 | Recruiting | Sponsor: Takeda

New trial

High-concentration protein C concentrate: in vitro and in vivo feasibility studies (ISTH 2024) - "All PC samples complied with acceptance criteria for visual appearance, reconstitution time, pH and osmolality (Table 1). When reconstituted in a 50% reduced volume, mean PC values for protein C activity, protein content, sodium chloride content and sodium citrate content were approximately double those of PC reconstituted in the standard volume. Storing samples at room temperature for up to 24 hours did not negatively affect product quality."

Preclinical

Pharmacokinetics of protein C concentrate after subcutaneous and intravenous administration in Göttingen minipigs (ISTH 2024) - "Systemic exposure to PC appeared to be sex-independent following IV or SC administration. Mean absolute bioavailability of PC was 37.8% after SC administration, with a median (range) time to peak PC concentration of 8 (4–12) hours. Mean plasma half-life of PC after IV and SC administration was 21.0 hours and 21.1 hours, respectively."

PK/PD data

Pharmacokinetics of protein C in neonates with severe congenital protein C deficiency (ISTH 2024) - "Rich PK data were analyzed from two neonates: one female (aged 15 days) and one male (aged 4 days). The observed half-life of protein C activity was approximately 1.5 hours (versus median of 9.8 hours reported for all patients [product label]). The popPK model included these two neonates along with pediatric and adult patients, and showed that older patients have an increased rate of endogenous protein C production and a reduced volume of distribution than younger patients."

PK/PD data • Cardiovascular • Pediatrics • Venous Thromboembolism

A Study of TAK-662 for Japanese Patients With Congenital Protein C Deficiency (clinicaltrials.gov) - P1/2 | N=5 | Active, not recruiting | Sponsor: Takeda | Trial completion date: Jul 2024 ➔ Oct 2024

Trial completion date

Development and evaluation of an aptamer-based affinity purification method for activated protein C (APC) (ISTH 2023) - " In this work, one-step thrombin-mediated activation of APC from a commercial source of protein C (PC, Ceprotin®) was followed by rapid and efficient purification of generated APC using the APC-specific aptamer HS02-52G chemically immobilized on MyOne® superparamagnetic beads... Due to the Ca2+-dependent binding manner of APC to HS02-52G, an efficient capturing of APC was applied in the presence of Ca2+ ions, while a gentle release of captured APC achieved using elution buffer containing 5 mM EDTA. In addition, using the MyOne® beads having smaller diameter (1 µm) showed more efficient purification capacity in comparison to M-270® magnetic beads (2.8 µm). The purification yield of 72.6% was calculated when 5 µg PC was activated, however this yield reduced to 11.5% using 20 µg PC starting amount."

APC

Population pharmacokinetics of subcutaneous protein C concentrate in patients with protein C deficiency (ISTH 2023) - "The dataset included 86 observations from 13 patients receiving subcutaneous protein C concentrate (female, n=7; median [range] age, 0.17 [0.003-18] years). Model-based simulations predicted that, at steady-state (approximately 11 days), >90% of patients would attain Ctrough >25 IU/dL for all dosing scenarios and between 24.44–68.28% of patients would reach Cmax >100 IU/dL. Steady-state was governed by the maintenance dose, regardless of the initial dose or the 3 subsequent doses."

Clinical • PK/PD data

Preventing thrombosis in moderate-severe protein C deficiency: the effects of different treatment regimens in a boy with protein C level of 4 IU/dl. (ISTH 2023) - "Figure 1 shows the effect of the different treatment regimens on d-dimers and fibrinogen levels. This demonstrates that dalteparin and rivaroxaban were evenly effective, but did not lead to complete normalization of fibrinogen and d-dimers. Addition of Ceprotin 3 times a week led to almost complete normalization of laboratory parameters."

Cardiovascular • Hematological Disorders • Thrombosis • PROC

POPULATION PHARMACOKINETICS OF INTRAVENOUS PROTEIN C CONCENTRATE IN PATIENTS WITH PROTEIN C DEFICIENCY (EAHAD 2023) - "Introduction: Understanding the pharmacokinetic (PK) characteristics and interpatient variability of protein C concentrate (Ceprotin®; Baxalta US Inc., a Takeda company, Lexington, MA, USA) will help to inform dose selection and treatment regimens... The PK characteristics of IV protein C concentrate in patients with either SCPCD or SAPCD were well described by a robust PopPK model. Model-based simulations support the potential use of various combined loading and maintenance dosing regimens for protein C concentrate in the acute or long-term treatment of patients with SCPCD."

Clinical • PK/PD data • Pediatrics

EFFECTS OF DEMOGRAPHIC AND DISEASE-RELATED FACTORS ON THE PHARMACOKINETICS OF PROTEIN C CONCENTRATE IN PATIENTS WITH PROTEIN C DEFICIENCY (EAHAD 2023) - "Introduction: The objective of this retrospective exploratory analysis was to assess the effects of demographic and disease-related factors on the pharmacokinetic (PK) characteristics of protein C concentrate (Ceprotin®; Baxalta US Inc., a Takeda company, Lexington, MA, USA) in adult and pediatric patients with severe congenital or acquired protein C deficiency (SCPCD or SAPCD). The analysis dataset was compiled manually by extracting demographic and disease-related information from the clinical study reports (CSRs) of three clinical studies, of which two had enrolled patients with SCPCD and one had enrolled patients with SAPCD, and one retrospective data collection study of patients with SCPCD... Current findings demonstrate apparent trends in protein C concentrate PK characteristics based on age, body weight, and symptomatic state of disease. The most prominent differences were observed in neonates and infants."

Clinical • PK/PD data • Pediatrics

A Study of TAK-662 for Japanese Patients With Congenital Protein C Deficiency (clinicaltrialsregister.eu) - P1/2 | N=5 | Sponsor: Takeda

New P1/2 trial

Real-world treatment of severe congenital protein C deficiency with protein C concentrate including prophylaxis: A physician survey in Europe and the US (ISTH 2022) - "This analysis included responses from 19 physicians (US, n=7; Europe, n=12) who reported using protein C concentrate to treat 32 patients (US, n=8; Europe, n=24), of whom 23 (71.9%) received LTP (Table 1). Among those receiving LTP, 16 patients (69.6%) received intravenous LTP and 12 (52.2%) received subcutaneous LTP. Five patients (21.7%) received both intravenous and subcutaneous LTP."

Clinical • HEOR • Real-world evidence • Cardiovascular

Aptamer loaded superparamagnetic beads for selective capturing and gentle release of activated protein C. (PubMed, Sci Rep) - "In this work, we present one-step activation of APC from a commercial source of protein C (PC, Ceprotin) followed by rapid and efficient purification using an APC-specific aptamer, HS02-52G, loaded on MyOne superparamagnetic beads...Altogether, this method is recommended for rapid and efficient PC activation and APC purification. The purified APC can be used directly for downstream processes where high concentration of pure and active APC is needed."

Journal

A Study of TAK-662 for Japanese Patients With Congenital Protein C Deficiency (clinicaltrials.gov) - P1/2 | N=3 | Active, not recruiting | Sponsor: Takeda | Trial completion date: Jun 2023 ➔ May 2024

Trial completion date

A Study of TAK-662 for Japanese Patients With Congenital Protein C Deficiency (clinicaltrials.gov) - P1/2 | N=3 | Active, not recruiting | Sponsor: Takeda | Recruiting ➔ Active, not recruiting | Trial primary completion date: Dec 2021 ➔ Mar 2022

Enrollment closed • Trial primary completion date

A Study of TAK-662 for Japanese Patients With Congenital Protein C Deficiency (clinicaltrials.gov) - P1/2; N=3; Recruiting; Sponsor: Takeda; Trial completion date: Dec 2021 ➔ Jun 2023

Clinical • Trial completion date

A Study of TAK-662 for Japanese Patients With Congenital Protein C Deficiency (clinicaltrials.gov) - P1/2; N=3; Recruiting; Sponsor: Takeda; Not yet recruiting ➔ Recruiting

Clinical • Enrollment open

A Study of TAK-662 for Japanese Patients With Congenital Protein C Deficiency (clinicaltrials.gov) - P1/2; N=3; Not yet recruiting; Sponsor: Takeda

New P1/2 trial