RG6512 / Roche - LARVOL DELTA

Chugai Announces 2025 1st Quarter Results (Chugai Press Release) - "Core revenue, core operating profit, and core net income at ¥288.5 billion (+21.8%), ¥139.5 billion (+36.6%), and ¥99.2 billion (+30.5%), respectively (all changes year-on-year)...Regarding revenue, domestic sales remained nearly flat with a slight decrease of 0.2% year-on-year. In the oncology field, sales decreased by 5.3% compared to the previous year. While our new product Phesgo performed well, this was offset by the decline in Perjeta and Herceptin along with the market penetration of Phesgo which includes the same active pharmaceutical ingredients. Additionally, products including our mainstay product Avastin were affected by NHI drug price revisions and biosimilars...Overseas sales increased significantly by 54.7% year-on-year, driven by a substantial increase in exports of Hemlibra and Actemra to Roche."

Commercial • Ankylosing Spondylitis • Hemophilia • HER2 Breast Cancer • Lupus • Myelodysplastic Syndrome • Non Small Cell Lung Cancer • Ovarian Cancer • Rheumatoid Arthritis • Schizophrenia

Insights from in vitro global assays on possible doses of concomitant hemostatic agents in the presence of NXT007 in hemophilia A. (PubMed, J Thromb Haemost) - "Concomitant addition of coagulation agents increased coagulation potentials in vitro in the presence of NXT007. A dose of 10 U/kg may serve as a rough indicator for the initial dose when exploring the concomitant use of aPCC at plasma NXT007 levels of approximately 30 μg/mL. Importantly, plasma NXT007 at ≥10 μg/mL demonstrated non-hemophiliac coagulation potentials in vitro."

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

A Study to Evaluate the Safety, Tolerability, Pharmacokinetics, Pharmacodynamics, and Efficacy of NXT007 in Persons With Severe or Moderate Hemophilia A (clinicaltrials.gov) - P1/2 | N=60 | Recruiting | Sponsor: Hoffmann-La Roche | N=40 ➔ 60

Enrollment change • Hematological Disorders • Hemophilia • Hemophilia A • Rare Diseases

A Study to Evaluate Single Subcutaneous Doses of NXT007 Among Injection Sites Abdomen, Upper Arm, and Thigh in Healthy Male Participants (clinicaltrials.gov) - P1 | N=48 | Completed | Sponsor: Hoffmann-La Roche | Active, not recruiting ➔ Completed

Trial completion

Preclinical Evaluation of NXT007 Using in Vitro and In Vivo Models of Hemostasis and Thrombosis (ASH 2024) - "The molecule was developed by optimizing the framework of emicizumab to increase FVIIIa-mimetic activity and half-life, with the goal of improving potency, efficacy and dosing convenience. Further, there was no evidence of hypercoagulability or prothrombotic effects at anticipated therapeutic or supratherapeutic concentrations. Overall, our preclinical data support the ongoing clinical evaluation of NXT007 and suggest that it has the potential to bring even greater benefit to PwHA."

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

NXT007 does not interfere with the anticoagulant effects on tissue factor pathway inhibitor. (PubMed, Haemophilia) - No abstract available

Journal

NXT007, a novel bispecific antibody, in FVIII chromogenic substrate assays (ISTH 2024) - "NXT007 was engineered and optimized based on emicizumab, which shows FVIII-like activity in CSAs containing human, but not bovine coagulation factors. NXT007 concentration dependent increase in FVIII-like activity was seen in CSA with human reagents and using the human-bovine Technoclone kit, which gave the highest FVIII-like activities (137 IU/dL at 30 µg/mL of NXT007) (Table 1). Some FVIII-like activity (9-13 IU/dL at 30 µg/ml NXT007) was observed in the other human-bovine CSAs. No FVIII-like activity of NXT007 was detected in purely bovine CSAs."

Hematological Disorders • Hemophilia • Rare Diseases

A Study to Evaluate Single Subcutaneous Doses of NXT007 Among Injection Sites Abdomen, Upper Arm, and Thigh in Healthy Male Participants (clinicaltrials.gov) - P1 | N=48 | Active, not recruiting | Sponsor: Hoffmann-La Roche | Recruiting ➔ Active, not recruiting

Enrollment closed

Directed Assembly of Bispecific Antibodies by Electrostatic Steering—The FAST-Ig Platform (IO-SUMMIT EUROPE 2024) - "Using NXT007 as an example, I will discuss critical factors like pairing potency, titre, physicochemical properties, and purification when applying FAST-Ig to clinical candidate antibodies. Additionally, I will introduce a next-generation T cell engager targeting CLDN6 that also utilises FAST-Ig."

CLDN6

Antithrombin exhibits anticoagulant effects on the emicizumab-based engineered bispecific antibody (NXT007)-mediated blood coagulation. (PubMed, Thromb Res) - No abstract available

Journal • Hematological Disorders • Hemophilia • Rare Diseases

Directed Assembly of Bispecific Antibodies by Electrostatic Steering—The FAST-Ig Platform (IO-SUMMIT EUROPE 2024) - "Using NXT007 as an example, I will discuss critical factors like pairing potency, titre, physicochemical properties, and purification when applying FAST-Ig to clinical candidate antibodies. Additionally, I will introduce a next-generation T cell engager targeting CLDN6 that also utilises FAST-Ig."

CLDN6

A Study to Evaluate Single Subcutaneous Doses of NXT007 Among Injection Sites Abdomen, Upper Arm, and Thigh in Healthy Male Participants (clinicaltrials.gov) - P1 | N=48 | Recruiting | Sponsor: Hoffmann-La Roche | Not yet recruiting ➔ Recruiting

Enrollment open

A Study to Evaluate Single Subcutaneous Doses of NXT007 Among Injection Sites Abdomen, Upper Arm, and Thigh in Healthy Male Participants (clinicaltrials.gov) - P1 | N=48 | Not yet recruiting | Sponsor: Hoffmann-La Roche

New P1 trial

NXT007-mediated hemostatic potential is suppressed by activated protein C-catalyzed inactivation of activated factor V. (PubMed, Res Pract Thromb Haemost) - "NXT007, an emicizumab-based engineered therapeutic bispecific antibody, enhances the coagulation potential of FVIII-deficient plasma (FVIIIdef-plasma) to near normal levels. The NXT007-driven thrombin generation in FVIII-depleted FV plasma was suppressed by APC, similar to the reaction in native FV plasma. NXT007 did not impair APC-mediated downregulation of FVa in FVIIIdef-plasmas, regardless of the presence of FV mutation with APC resistance."

Journal • Hematological Disorders • Hemophilia • Rare Diseases

A bispecific antibody NXT007 exerts a hemostatic activity in hemophilia A monkeys enough to keep a non-hemophiliac state. (PubMed, J Thromb Haemost) - "NXT007, a potent BsAb, was successfully created. Non-clinical results suggest that NXT007 would have a potential to keep a non-hemophilic range of coagulation potential in PwHA or to realize more convenient dosing regimens than emicizumab."

Journal • Hematological Disorders • Hemophilia • Rare Diseases

A Study to Evaluate the Safety, Tolerability, Pharmacokinetics, Pharmacodynamics, and Efficacy of NXT007 in Persons With Severe or Moderate Hemophilia A (clinicaltrials.gov) - P1/2 | N=40 | Recruiting | Sponsor: Hoffmann-La Roche | Not yet recruiting ➔ Recruiting

Enrollment open • Hematological Disorders • Hemophilia • Rare Diseases

A Study to Evaluate the Safety, Tolerability, Pharmacokinetics, Pharmacodynamics, and Efficacy of NXT007 in Persons With Severe or Moderate Hemophilia A (clinicaltrials.gov) - P1/2 | N=40 | Not yet recruiting | Sponsor: Hoffmann-La Roche

New P1/2 trial • Hematological Disorders • Hemophilia • Rare Diseases

Safety, Pharmacokinetics, and Pharmacodynamics of Single Subcutaneous Injection of NXT007, an Emicizumab-Based Next-Generation Bispecific Antibody, in Healthy Volunteers (NXTAGE Study) (ISTH 2023) - "NXT007 exposure increased dose-dependently. Mean elimination half-life was approximately 10 weeks in anti-NXT007 antibody (ADA)-negative subjects. With ex vivo neutralization of endogenous factor VIII in plasma samples, activated partial thromboplastin time was shortened and thrombin generation was promoted in a dose-dependent manner."

Clinical • PK/PD data • Cardiovascular • Dermatology • Hematological Disorders • Hemophilia • Rare Diseases

Efficient production of bispecific antibody by FAST-Ig and its application to NXT007 for the treatment of hemophilia A. (PubMed, MAbs) - "FAST-Ig was also applicable to stable CHO cell lines for industrial production and demonstrated robust chain pairing with different subclasses of parent BsAbs. Thus, it can be applied to a wide variety of BsAbs both preclinically and clinically."

Journal • Hematological Disorders • Hemophilia • Rare Diseases

Activated Protein C-Catalyzed Inactivation Pathway Down-Regulates NXT007-Mediated Hemostatic Function (ASH 2022) - "NXT007, emicizumab (Emi)-based engineered therapeutic bispecific antibody (Ab), is currently undergoing the phase 1 clinical trial. While, the %inhibition of PeakTh by APC (16 nM) in FV-L plasma with FVIIIAb and NXT007 was similar to FV-L plasma alone (~20%), indicating that APC could regulate NXT007-catalyzed hemostatic reaction by inactivation of FV(a) under the FV-L condition. We conclude that APC-catalyzed inactivation mechanisms could play a significant role on the down-regulation of coagulation in NXT007-mediated hemostasis."

Cardiovascular • Hematological Disorders • Thrombosis • Venous Thromboembolism • PROS1

Quantitative Estimation of the In Vivo Equivalent Factor VIII Activity of NXT007, an Emicizumab-Based, Next-Generation, Activated Factor VIII-Mimetic Bispecific Antibody, from Nonclinical Data (ASH 2022) - "Model-based approaches supported application of the ternary complex approach for predicting the in vivo equivalent FVIII activity of NXT007. Findings from this research provided a basis for designing a phase I/II clinical study of NXT007 that is currently ongoing (NXTAGE; JapicCTI-194919)."

Preclinical • Hematological Disorders • Hemophilia • Rare Diseases

"B Anderson: the bar for NXT007 is it needs to be better than Hemlibra. Also looking at dosing intervals, and peak & trough $RHHBY" (@JacobPlieth)

"$RHHBY's Hemlibra follow-on: NXT007, a factor 9a x factor 10 bispecific. Apparently a Chugai-originated project" (@JacobPlieth)