bentracimab (PB2452) / SFJ Pharma, PhaseBio Pharma - LARVOL DELTA

REVERSE-IT: Bentracimab in Ticagrelor-treated Patients With Uncontrolled Bleeding or Requiring Urgent Surgery or Invasive Procedure (clinicaltrials.gov) - P3 | N=226 | Completed | Sponsor: SFJ Pharmaceuticals, Inc. | Recruiting ➔ Completed | Trial completion date: Jan 2025 ➔ Sep 2024 | Trial primary completion date: Jan 2025 ➔ Sep 2024

Surgery • Trial completion • Trial completion date • Trial primary completion date • Hematological Disorders

REVERSE-IT: Bentracimab in Ticagrelor-treated Patients With Uncontrolled Bleeding or Requiring Urgent Surgery or Invasive Procedure (clinicaltrials.gov) - P3 | N=200 | Recruiting | Sponsor: SFJ Pharmaceuticals, Inc. | Trial completion date: Aug 2024 ➔ Jan 2025 | Trial primary completion date: Aug 2024 ➔ Jan 2025

Surgery • Trial completion date • Trial primary completion date • Hematological Disorders

FDA has accepted a BLA for bentracimab, the first and only ticagrelor reversal agent, for filing and priority review (GlobeNewswire) - "SFJ Pharmaceuticals...announced today that the US Food and Drug Administration (FDA) has accepted the bentracimab BLA for filing and priority review with a target action date in Q1 of 2025....The BLA submission is based on the planned second interim analysis results of the Phase 3 REVERSE-IT trial."

FDA filing • PDUFA • Hematological Disorders

ANMCO/SIMEU consensus document on the use of reversal agents for antithrombotic therapies in patients with ongoing bleeding or at high risk of haemorrhagic events. (PubMed, Eur Heart J Suppl) - "This joint document of the Italian Association of Hospital Cardiologists (Associazione Nazionale Medici Cardiologi Ospedalieri) and the Italian Society of Emergency Medicine (Società Italiana di Medicina d'Emergenza-Urgenza) delineates the key features and efficacy of available reversal agents. It also provides practical flowcharts to guide their use in patients with active bleeding or those at elevated risk of major bleeding events."

Journal • Atherosclerosis • Atrial Fibrillation • Cardiovascular • Dyslipidemia • Venous Thromboembolism

Study to Evaluate the Safety, Tolerability, PK and PD of PB2452 in Healthy Younger, Older and Elderly Subjects (clinicaltrials.gov) - P2 | N=23 | Completed | Sponsor: SFJ Pharmaceuticals, Inc. | Phase classification: P2a ➔ P2

Phase classification

Phase 2B Study to Evaluate the Efficacy of Bentracimab (PB2452) in Reversal of Ticagrelor in Subjects Aged 50-80 Years Old (clinicaltrials.gov) - P2 | N=207 | Completed | Sponsor: SFJ Pharmaceuticals, Inc. | Phase classification: P2b ➔ P2

Phase classification

REVERSE-IT: Bentracimab in Ticagrelor-treated Patients With Uncontrolled Bleeding or Requiring Urgent Surgery or Invasive Procedure (clinicaltrials.gov) - P3 | N=200 | Recruiting | Sponsor: SFJ Pharmaceuticals, Inc. | Trial completion date: Dec 2023 ➔ Aug 2024 | Trial primary completion date: Dec 2023 ➔ Aug 2024

Surgery • Trial completion date • Trial primary completion date • Hematological Disorders

Study to Evaluate the Safety, Tolerability, PK, and PD of PB2452 With and Without Ticagrelor Pretreatment in Chinese Healthy Volunteers (clinicaltrials.gov) - P1 | N=34 | Terminated | Sponsor: SFJ Pharmaceuticals, Inc. | Recruiting ➔ Terminated; After recruitment of Cohorts 1-4 was completed, Sponsor decided to terminate study, initially due to COVID and then considering that PK data from the dose planned to be tested in Cohort 5 (18000 mg) would be available from the ongoing Phase 3 study.

Trial termination

Fluorescence quenching-based immunological probe for ticagrelor monitoring. (PubMed, Front Bioeng Biotechnol) - " Both ATTO-labeled MEDI2452 (2452A) Q-body and TAMRA-labeled IgG 152 (152T) Q-body demonstrated efficient detection of ticagrelor and its active metabolite (TAM). It enabled the completion of analysis within 3 min, facilitating rapid preoperative detection of blood drug concentration in ACS to determine the feasibility of surgery and mitigate the risk of intraoperative and postoperative hemorrhage. The swift detection of ticagrelor holds promise for enhancing individualized drug administration, preventing adverse reactions, and providing preoperative guidance."

Journal • Acute Coronary Syndrome • Cardiovascular • Hematological Disorders

Clinical and Pre-Clinical Pharmacokinetics and Pharmacodynamics of Bentracimab. (PubMed, Clin Pharmacokinet) - "The fact that many antiplatelet agents, such as aspirin and thienopyridines (i.e., clopidogrel and prasugrel), bind irreversibly to their targets represents a challenge for the development of a drug-specific reversal agent. In 2015, bentracimab (also known as PB2452 or MEDI2452), a neutralizing monoclonal antibody fragment that binds free plasma ticagrelor and its major active metabolite, was identified. This systematic overview provides a comprehensive summary of the drug development program of bentracimab, focusing on its pharmacodynamic, pharmacokinetic, and safety profiles."

Journal • PK/PD data • Preclinical • Review • Atherosclerosis • Cardiovascular • Dyslipidemia

"SFJ Pharmaceuticals Announces Closing of Transfer of Bentracimab Assets from PhaseBio Pharmaceuticals https://t.co/cl4z48iOJV" (@NewsFromBW)

"Now in #EWCCongress Prof @DLBHATTMD talk about Bentracimab and Reverse-IT trail: Safe and efficient to revert tricagrel treatment" (@nicolasrennamd)

THE BRIGHAM PRESENTS FOUR LATE-BREAKING CLINICAL TRIALS AT ACC 2022 (Brigham Health On a Mission) - "'What we showed with bentracimab infusion is an immediate and complete reversal of ticagrelor's antiplatelet effect,' says Deepak L. Bhatt.... 'This potentially would be a drug of great interest to cardiologists and cardiac surgeons for patients who are currently being treated with ticagrelor but need emergent or urgent surgical procedures or have severe bleeding.'"

Media quote

"$PHAS PhaseBio Announces Successful Pre-BLA Meeting with U.S. FDA for Bentracimab https://t.co/xVzh1gRSv5" (@stock_titan)

FDA event

"#DAPT #SAPT #Bentracimab #MA at #ACC2022 an overview with Dr Guedj Meynier. My wife is Italian but guess who speaks with hands ? 🙃😎" (@SABOURETCardio)

Bentracimab Immediately And Significantly Reverses The Antiplatelet Effects Of Ticagrelor In Older People (ACC 2022) - No abstract available

Late-breaking abstract

Experts Review Clinical Trials in Cardiovascular Death, Antiplatelet Therapies (Pharmacy Times) - P3 | N=NA | SCORED (NCT03315143) | Sponsor: Lexicon Pharmaceuticals | REVERSE-IT (NCT04286438) | Sponsor: PhaseBio Pharmaceuticals Inc | SOLOIST (NCT03521934) | Sponsor: Lexicon Pharmaceuticals | "Deepak Bhatt, MD, MPH, reviewed data from both the SCORED trial of sotagliflozin and the REVERSE-IT trial investigating bentracimab to reverse the antiplatelet effects of ticagrelor....Importantly, Bhatt noted that the SCORE trial was stopped early in the context of COVID-19, which shortened the duration and limited the statistical power to see significant reductions in cardiovascular death. This also limited the magnitude of absolute risk reductions in MACE."

Media quote • P3 data

Bentracimab Swiftly Reverses Ticagrelor, Platelet-Function Study Affirms (TCTMD) - "'Based on these data, bentracimab appears to be a very promising option for ticagrelor reversal.'....Therefore, Bhatt said he 'wouldn't be shocked' to see a cluster of thrombotic events around the time ticagrelor-treated patients have the drug stopped due to bleeding or a surgical procedure. 'But that's not the bentracimab that's doing it. It's the removal of ticagrelor's beneficial effect,' he explained."

Media quote

"I m not expecting major changes, except for #Mavacamten in #HCM and #bentracimab with @DLBHATTMD . But maybe I’m wrong 🤔" (@SABOURETCardio)

"#LBCT #ACC22 by @CNCFCardio . “Only 2” presented by @DLBHATTMD 🙃 #Bentracimab #SGLT2i" (@SABOURETCardio)

"New on https://t.co/AIzVsuDqGs • RTA by @JPBertok • IgAN in 2022 + Bentracimab and Ticareglor: both by @ckd_ce • Paxlovid and the EPIC-HR trial by @nickmmark 240K scientific tweets in the CVRM space: indexed & searchable." (@nephondemand)

Glomerulonephritis • IgA Nephropathy

"$PHAS PhaseBio Pharmaceuticals Announces Bentracimab Manufacturing Update https://t.co/e3FySb4XTb" (@stock_titan)

"35) So as per the graphs below, platelet hyper-reactivity, or rebound, between 5 minutes & 48 hours after administration of #bentracimab was ruled out by the response to low-dose #ADP versus high-dose ADP. Thanks @DLBHATTMD" (@cardiomet_CE)

"New article by @DLBHATTMD et al. #Ticagrelor #Bentracimab with @md_pollack 👌" (@SABOURETCardio)

"Population pharmacokinetic–pharmacodynamic modeling of bentracimab, a monoclonal antibody fragment being developed as a ticagrelor reversal agent, in healthy volunteers https://t.co/G8zZnynqlM #CardioTwitter #Cardiology #bleeding #surgery @PhaseBio" (@DLBHATTMD)

Clinical • PK/PD data • Cardiovascular