Targeting inflammation with LSALT peptide
LSALT Peptide (Metabloktm)
LSALT peptide is the company’s lead drug candidate for treating inflammation in the lungs, liver and kidneys.
Arch is focused on a path to drug approval for LSALT peptide and has been working to conduct further human safety and efficacy trials (April 2023) and, targeting organ inflammation in common injury and disease applications where organ inflammation is an unmet need.
In June 2023, the company received FDA permission to proceed with a planned Phase II trial to prevent cardiac surgery associated-acute kidney injury (CS-AKI).
About LSALT Peptide
Arch believes that LSALT peptide has the potential to deliver a major breakthrough in the treatment of diseases where inflammation plays a major role.
In August 2019, a scientific team led by Arch scientists Dr. Donna Senger and Dr. Stephen Robbins published a paper in the journal Cell describing a novel mechanism of action for organ inflammation.
In the paper, the enzyme dipeptidase-1 (DPEP1) was identified as a major neutrophil (white blood cell) adhesion receptor on the lung, liver and kidney endothelium – additionally, DPEP1 was shown to be the target of LSALT Peptide – identifying a target for neutrophil-driven inflammatory diseases of the lungs.
CELL – August 2019
Dipeptidase-1 Is an Adhesion Receptor for Neutrophil Recruitment in Lungs and Liver
“…we identified dipeptidase-1 (DPEP1) as the target and established its role as a physical adhesion receptor for neutrophil sequestration…”
Arch is pursuing clinical development of LSALT Peptide to treat acute injury in the lungs, kidneys and liver caused by inflammation
In 2023 the company has been working on multiple tasks to advance the LSALT peptide organ inflammation program, including:
- completed a dose escalation Phase I human trial which increased the safe dose limit of LSALT peptide in humans;
- completed manufacturing of new drug product supply to support future human trials and increased manufacturing scale to prepare for future commercialization;
- successfully obtained the U.S. FDA’s permission to proceed with a new Phase II trial to prevent cardiac surgery-associated acute kidney injury (CS-AKI); and
- conducting additional non-clinical studies to discover potential biomarkers and to further understand the mechanism of action related to LSALT peptide.
Upon completion of a Phase I trial in 2020, Arch also completed a Phase II trial conducted in the United States, Turkey and Canada. The Phase II trial was designed to investigate LSALT peptide’s efficacy in the prevention of acute inflammation in the kidney, known to trigger acute respiratory distress syndrome (ARDS) and acute kidney injury (AKI) in patients infected with SARS-CoV-2.
The drug’s Phase II trial results led to LSALT peptide being the first novel therapeutic to join the Canadian Treatments for COVID-19 (CATCO) trial, a multi-centre, adaptive, randomized, open-label, controlled Phase III clinical trial to treat organ inflammation patients in hospitals across Canada during the pandemic.
LSALT Trial Information
In April 2023, the company announced that it is preparing a new Phase II study to target cardiac surgery-associated acute kidney injury (CS-AKI) with LSALT peptide.
The news followed the U.S FDA’s review of the Company’s investigational new drug (IND) application submitted to the FDA’s Division of Cardiology and Nephrology in May, 2023. The IND application included preclinical data, Phase I and Phase II clinical data to date, manufacturing processes, and the protocol design for the CS-AKI Phase II trial.
The CS-AKI trial is planned to recruit up to 240 patients and will be a double-blind, placebo-controlled study conducted in hospital sites in the U.S., Turkey, and Canada. Patient recruitment is expected to begin in the fall of 2023, pending approvals from local health authorities, ethics committees and internal review boards. There will be an independent Data Safety Monitoring Board which will monitor the safety of the patients enrolled in the trial. This study is designed to produce a signal of efficacy that would justify a larger Phase III trial of LSALT peptide.
Details of the Phase II trial, entitled “Phase 2 Global, Multicenter, Randomized, Double-Blind, Placebo-Controlled Study of LSALT peptide for the Prevention or Attenuation of Acute Kidney Injury (AKI) in Patients Undergoing On-Pump Cardiac Surgery” can be viewed at clinicaltrials.gov.
EXPANDED DOSING AND SAFETY
In April 2023, the company announced that it had safely increased the maximum daily dose of LSALT peptide to 20 mg per day in healthy, normal volunteers in a phase II human safety trial in Australia. Prior to this dose escalation trial, LSALT peptide was administered at a maximum of 5mg once daily, for up to 14 days, in hospitalized patients during a Phase II trial targeting inflammation in the lungs.
About the 2020-21 Phase II Trial
The Phase II trial was an international, multi-center, randomized, double-blind, placebo-controlled, proof of concept study of LSALT peptide (Metablok) as a treatment to prevent organ inflammation known to trigger acute respiratory distress syndrome (ARDS) and acute kidney injury (AKI) in patients infected with SARS-CoV-2 (COVID-19).
The primary composite endpoint of the trial included the prevention of acute respiratory distress syndrome (ARDS) and acute kidney injury (AKI). Additional secondary endpoints included reducing coagulopathy, cardiomyopathy and acute liver injury experienced by hospitalized COVID-19 patients.
The trial dosed 61 patients in an international, multi-center, randomized, double-blind, placebo-controlled, proof of concept study of LSALT peptide as prevention of organ inflammation known to trigger acute respiratory distress syndrome (ARDS) and acute kidney injury (AKI) in patients infected with COVID-19 or emergent variants of the virus.
Additional information about the company’s Phase II trials can be found at ClinicalTrials.gov:
This Phase III study was an adaptive, randomized, open-label, controlled clinical trial, in collaboration with countries around the world through the World Health Organization.
In the later stages of the global pandemic, subjects were randomized, across one, two, three or up to four separate randomizations (including LSALT Peptide vs. Standard of care, alongside other therapies), to receive either standard-of-care products or the study medication plus standard of care, while being hospitalized for COVID-19.
The primary outcome measures for LSALT Peptide measured patients’ number of respiratory support free days.
The secondary outcome measures included measures of clinical effectiveness, need for invasive mechanical ventilation, CU admission, hospital and ICU length of stay, days alive and free of vasopressors, ventilation, and renal replacement therapy (RRT), severe adverse events, and 1, 3 and 6 months mortality, laboratory (cardiac pulmonary coagulation, and renal) and clinical evaluation using standardized pre-defined COVID-19 virtual and/or in person follow-up and mortality after randomization
Due to waning numbers of hospitalizations at the end of the pandemic, there were not enough patients recruited into the CATCO trial to make any conclusions on trial data related to LSALT peptide dosing. Arch has since refocused on further testing LSALT peptide in other indications where organ inflammation and injury is a problem.
The company has successfully conducted multiple Phase I human trials of LSALT peptide. The most recent, completed in 2023, was a double-blind, placebo-controlled and randomized dose-escalation study, where single and multiple ascending doses were administered to evaluate the safety and pharmacokinetic profile of LSALT peptide.
About the 2023 Phase I Trial
Six participants in each group of the trial received a daily dosing of LSALT peptide for one day followed by three consecutive days of dosing. Two people per group received a placebo with the same dosing schedule. In the first group, six people received a once daily, 10 mg intravenous (IV) dose of LSALT peptide. In the second group, six volunteers received a 10 mg IV dose of LSALT peptide twice a day, approximately every 12 hours. In both groups, LSALT peptide met the primary endpoints of safety and tolerability.
“Prior to this dose escalation trial, LSALT peptide was administered at a maximum of 5mg once daily, for up to 14 days, in hospitalized COVID-19 patients during a Phase II trial targeting inflammation in the lungs.” (Arch Biopartners April 2023)
EARLIER LSALT peptide Phase I Trials
In March 2020, Arch announced that LSALT peptide had successfully met the primary endpoints of safety and tolerability in a Phase I Human Trial involving 52 healthy, normal volunteers. The placebo-controlled, double-blind study was conducted in Australia.
Previously, in December 2019, Arch made an announcement that LSALT peptide had achieved primary endpoints of safety and tolerability. Based on the initial completion of the Phase I trial, Arch announced that it had expanded the dosing in trial, to increase the dose range for future Phase II studies.
PreClinical Data and Background
Arch scientists have demonstrated LSALT peptide’s ability to block the inflammatory response triggered in the lung and liver with lipopolysaccharide (LPS) induced inflammation and in the kidney with ischemia/reperfusion (IRI) induced injury. Currently, there are no specific or effective treatments to prevent acute kidney injury.
Following publication in the peer-reviewed journal Cell in August 2019, Arch Scientists released a series of preclinical videos using Intravital Microscopy data to show the real-time effects of LSALT peptide when used to reduce inflammation in preclinical mouse models.
The video series includes demonstrations of LSALT peptide compared to normal and injured organs. In each video, the treated liver, kidneys and lungs are shown to have a reduction of the action of inflammation present in the organ.
From the publication in Cell, August 2019
“Using biochemical, genetic, and confocal intravital imaging approaches, we identified dipeptidase-1 (DPEP1) as the target and established its role as a physical adhesion receptor for neutrophil sequestration independent of its enzymatic activity. Importantly, genetic ablation or functional peptide blocking of DPEP1 significantly reduced neutrophil recruitment to the lungs and liver and provided improved survival in models of endotoxemia.”
Inflammation Based Disease
Inflammation is a localized physical condition that involves the activation of the immune system in response to infection, tissue injury, or autoimmunity. Inflammation is involved in the pathogenesis of many diseases and contributes to organ dysfunction and failure.
Metablok was originally invented to prevent organ inflammation related to sepsis.
Sepsis represents a large unmet medical need in the world today. Sepsis alone occurs in 1 to 2% of all hospitalizations in the US. It affects at least 700,000 individuals per year.
Permanent organ damage can occur in patients who survive sepsis. Under the current standard of care, mortality rates are over 20% for sepsis and over 50% for septic shock.
LSALT peptide (Metablok) was invented by Arch scientists Dr. Stephen Robbins, Dr. Donna Senger, Dr. Jennifer Rahn and their University of Calgary colleague, Dr. Paul Kubes. The inventors have assigned the intellectual property to the Company.