NI006 / Neurimmune, AstraZeneca - LARVOL DELTA

New therapies to treat cardiac amyloidosis. (PubMed, Curr Opin Cardiol) - "The therapeutic landscape for ATTR-CM and AL-CM is rapidly evolving, driven by novel therapies targeting diverse mechanisms. Ongoing clinical trials promise to further refine the standard of care and improve outcomes for patients with cardiac amyloidosis."

Journal • Amyloidosis • Cardiac Amyloidosis • Cardiovascular

Prediction of Cardiac ATTR Depletion by NI006 (ALXN2220) Using Mechanistic PK/PD Modeling. (PubMed, Clin Pharmacol Ther) - "These predictions were in good agreement with the observed primary results of the clinical phase Ib study where amyloid burden was measured by imaging. This novel translational PK/PD model provided important predictions to guide the design of the phase Ib study of NI006, indicating the value of this approach to integrate preclinical results into clinical trial design and increase translational success."

Journal • PK/PD data • Cardiomyopathy • Cardiovascular • Congestive Heart Failure • Heart Failure

Structural Basis for Monoclonal Antibody Therapy for Transthyretin Amyloidosis. (PubMed, Pharmaceuticals (Basel)) - "Aiding these recent achievements has been the remarkable ability of cryo-electron microscopy (EM) to determine high-resolution structures of amyloid fibrils obtained from individual patients. Here, we will examine the cryo-EM structures of transthyretin amyloid fibrils to explore the structural basis of the two monoclonal antibody therapies for ATTR that are in clinical trials, ALXN-2220 and Coramitug, as well as to point out potential applications of this approach to other systemic amyloid diseases."

Journal • Review • Amyloidosis • Cardiac Amyloidosis

Long-term safety and efficacy of antibody ALXN2220 for depletion of cardiac amyloid transthyretin: results of treatment beyond 12 months in the open-label extension of study NI006-101 (ESC 2024) - "Up-titration and long-term treatment at a dose level of 30 mg/kg in the OLE was safe and well tolerated, with overall good adherence to treatment. Cardiac imaging and cardiac biomarker data indicated continued treatment effects beyond 12 months and supported the up-titration of patients to 30 mg/kg."

Clinical • Cardiac Amyloidosis • Cardiomyopathy • Cardiovascular

Recent advances in the diagnostic methods and therapeutic strategies of transthyretin cardiac amyloidosis. (PubMed, World J Cardiol) - "Tafamidis is the only disease-modifying approved therapy in ATTR amyloidosis so far. Agents including acoramidis, eplontersen, vutrisiran, patisiran and anti-monoclonal antibody NI006 are being investigated on cardiac function in large, multicenter controlled trials which are expected to be completed within the next 2-3 years, providing promising results in patients with ATTR cardiac amyloidosis. However, further and ongoing research is required in order to improve diagnostic methods that could provide an early diagnosis, as well as survival and quality of life of these patients."

Journal • Amyloidosis • Cardiac Amyloidosis • Cardiovascular

AstraZeneca demonstrates commitment to patients living with amyloidosis at the 2024 International Symposium on Amyloidosis (ISA) (Businesswire) - P1 | N=46 | NCT04360434 | Sponsor: Neurimmune AG | "An encore poster presentation will report results from the first-in-human study of ALXN2220. Initial treatment with ALXN2220 was well tolerated with a transient increase in C-reactive proteins, suggesting initial targeted immune activation and recruitment of phagocytic immune cells. Additionally, an encore poster presentation will describe the pharmacokinetic and pharmacodynamic (PK/PD) model used for the selection of the dose range, dose escalation, dosing interval and study duration. Further, a poster will outline the baseline demographics and characteristics of the 406 participants of the Alexion CARES clinical program evaluating anselamimab in patients with Mayo Stage IIIa and IIIb AL amyloidosis..."

Clinical • P1 data • Amyloidosis • Cardiomyopathy • CNS Disorders

DepleTTR-CM: Study of ALXN2220 Versus Placebo in Adults With ATTR-CM (clinicaltrials.gov) - P3 | N=1000 | Recruiting | Sponsor: Alexion Pharmaceuticals, Inc. | Trial primary completion date: Aug 2025 ➔ Jul 2028

Trial primary completion date • Amyloidosis • Cardiac Amyloidosis • Cardiomyopathy • Cardiovascular

A poster from #HeartFailure2024 showing safety and details of immune activation of ALXN2220 in patients with ATTR-CM (previously NI006, now enrolling in the phase III DepleteTTR trial) CRP increases, but no increase in cytokines or complement activation. No severe adverse events directly related to treatment #CardioTwitter #Amyloidosis

Clinical data

Prediction of cardiac ATTR depletion by ALXN2220 using mechanistic PK/PD modeling (HEART FAILURE 2024) - "This novel mechanistic PK/PD model provided valuable estimates to guide the design of the first study of ALXN2220 in ATTR-CM. Model results were instrumental in the selection of the dose range, dosing interval and study duration. Overall, model predictions were consistent with the study results, indicating the value of a comprehensive integration of non-clinical data into clinical trial design to increase translational success."

PK/PD data • Cardiovascular

Initial safety of targeted immune activation with the amyloid depleter ALXN2220 (HEART FAILURE 2024) - "No acute severe or serious electrocardiographic or echocardiographic alterations were observed in relation to treatment with ALXN2220. Transient increases in CRP at higher doses may be consistent with an initial targeted immune activation by ALXN2220 upon binding to ATTR amyloid deposits and recruitment of phagocytic immune cells, but were no longer observed in the OLE phase."

Clinical • Cardiovascular • Congestive Heart Failure • Heart Failure • CXCL8 • IL6

A poster from hashtag#HeartFailure2024 showing safety and details of immune activation of ALXN2220 in patients with ATTR-CM (previously NI006, now enrolling in the phase III DepleteTTR trial) CRP increases, but no increase in cytokines or complement activation. No severe adverse events directly related to treatment hashtag#AMYLOIDOSIS (LinkedIn)

Clinical

Treatment of transthyretin cardiac amyloidosis. (PubMed, Curr Opin Cardiol) - "Therapies targeting different mechanism in the pathophysiology of ATTR-CM provide new alternatives for treating patients with ATTR-CM. Future research should focus on comparing their effectiveness, the potential of combined treatment with agents from different classes and on identifying the patients who will benefit most from each class of medication."

Journal • Amyloidosis • Cardiac Amyloidosis • Cardiovascular

DepleTTR-CM: Study of ALXN2220 Versus Placebo in Adults With ATTR-CM (clinicaltrials.gov) - P3 | N=1000 | Recruiting | Sponsor: Alexion Pharmaceuticals, Inc. | Not yet recruiting ➔ Recruiting | Trial completion date: Oct 2028 ➔ Jul 2028 | Trial primary completion date: Oct 2028 ➔ Oct 2025

Enrollment open • Trial completion date • Trial primary completion date • Amyloidosis • Cardiac Amyloidosis • Cardiomyopathy • Cardiovascular

DepleTTR-CM: Study of ALXN2220 Versus Placebo in Adults With ATTR-CM (clinicaltrials.gov) - P3 | N=1000 | Not yet recruiting | Sponsor: Alexion Pharmaceuticals, Inc.

New P3 trial • Amyloidosis • Cardiac Amyloidosis • Cardiomyopathy • Cardiovascular

Mathematical Modeling Predicts Treatment Efficacy in Transthyretin Cardiac Amyloidosis (AHA 2023) - "The secondary mechanism of diflusinil did not change equilibrium behavior compared to tafamidis. MEC values and time to clearance at MEC were lowest for NI006 (14.7%; 65 days) and doxycycline (16.1%; 36 months)... This mathematical model predicts ATTR clearance by four distinct mechanisms of action. The novel anti-ATTR antibody NI006 is a promising treatment with predicted faster onset and higher effectiveness for clearance of ATTR fibrils from the myocardium. This model can evaluate future treatment strategies and therapeutic targets."

Clinical • Amyloidosis • Cardiac Amyloidosis • Cardiovascular • CLU

First-in-Human Study of NI006 in Patients With Amyloid Transthyretin Cardiomyopathy (clinicaltrials.gov) - P1 | N=46 | Completed | Sponsor: Neurimmune AG | Active, not recruiting ➔ Completed | Trial completion date: Nov 2023 ➔ Jul 2023

Trial completion • Trial completion date • Cardiomyopathy • Cardiovascular

Antibody NI006 for Cardiac Transthyretin Amyloid Depletion. (PubMed, N Engl J Med) - No abstract available

Journal • Amyloidosis

Antibody NI006 for Cardiac Transthyretin Amyloid Depletion. Reply. (PubMed, N Engl J Med) - No abstract available

Journal • Amyloidosis

"【Heart Failure 2023】フェーズ1b試験より、トランスサイレチン型心アミロイドーシス（ATTR-CM）の慢性心不全患者において、抗ATTR抗体NI006の安全性は良好で、イメージングやバイオマーカーの変化からはATTRの除去が示唆されたことが発表された。https://t.co/tBkBRRkZuY #HeartFailure2023" (@tcross_news)

Cardiovascular • Congestive Heart Failure • Dyslipidemia • Heart Failure

Primary results of the Phase Ib proof-of-concept study of NI006, a recombinant human antibody to deplete amyloid deposits in ATTR-cardiomyopathy (HEART FAILURE 2023) - No abstract available

Late-breaking abstract • P1 data • Cardiomyopathy • Cardiovascular

"Closing sessionでは今回strikingだった研究10選が各領域に関して発表されてましたが、CHF領域かな？では、やはりNI006が一位と発表されてました！ Phase1でNEJMという点も、本当にすごいですよね #HeartFailure2023 https://t.co/q1of3IPZ4D" (@CardioSM)

Cardiovascular • Congestive Heart Failure • Dyslipidemia • Heart Failure

"#ATTR 心アミロイドーシスの画期的な治療薬NI006 @NEJM (遺伝子組換えヒト抗ATTRモノクローナルIgG1抗体) 図の③に相当する治療で、抗体を介したATTR線維の貪食と組織からのATTR沈着物の除去を誘導することにより、ATTRを消失させる治療であり、第1相試験(first-in-human)にて安全性確認。効果も…！" (@JP_HFpEF)

P1 data

Phase 1 Trial of Antibody NI006 for Depletion of Cardiac Transthyretin Amyloid. (PubMed, N Engl J Med) - P1 | "In this phase 1 trial of the recombinant human antibody NI006 for the treatment of patients with ATTR cardiomyopathy and heart failure, the use of NI006 was associated with no apparent drug-related serious adverse events. (Funded by Neurimmune; NI006-101 ClinicalTrials.gov number, NCT04360434.)."

Journal • P1 data • Amyloidosis • Cardiomyopathy • Cardiovascular • Congestive Heart Failure • Heart Failure

Neurimmune: Promising Phase 1 Results for Antibody NI006 in ATTR Cardiomyopathy Published in the New England Journal of Medicine (PharmiWeb) - P1 | N=46 | NCT04360434 | Sponsor: Neurimmune AG | "Neurimmune announced today that primary results of its Phase 1 proof-of-concept study of NI006...Results indicate that the safety profile of NI006 is favorable up to the highest dose tested. No apparent dose-limiting toxic effects or drug-related serious adverse reactions were observed. The pharmacokinetic profile was consistent with that of an IgG antibody, and no antidrug antibodies were detected. At doses of at least 10 mg per kilogram, cardiac amyloid deposition (detected by either scintigraphy or cardiac magnetic resonance imaging) was substantially reduced over a period of 12 months....Neurimmune will continue to be responsible for completion of the current Phase 1 clinical trial on behalf of Alexion, and Alexion will pay certain trial costs. Following the Phase 1 trial, Alexion will be responsible for further clinical development, manufacturing, and commercialization."

P1 data • Amyloidosis • Cardiomyopathy • Cardiovascular

First-in-Human Study of NI006 in Patients With Amyloid Transthyretin Cardiomyopathy (clinicaltrials.gov) - P1 | N=46 | Active, not recruiting | Sponsor: Neurimmune AG | Recruiting ➔ Active, not recruiting | Trial completion date: Feb 2023 ➔ Nov 2023 | Trial primary completion date: Feb 2023 ➔ Aug 2023

Enrollment closed • Trial completion date • Trial primary completion date • Cardiomyopathy • Cardiovascular