ACS, IMT-358, and the potential for improving cardiac outcomes
ACS, IMT-358, and the potential for improving cardiac outcomes
Acute coronary syndrome (ACS), either a heart attack or angina pectoris that can rapidly lead to a heart attack, is caused by insufficient blood flow to the heart muscle due to a clot (“thrombosis”) in a coronary artery. This causes heart muscle to be starved of oxygen and nutrients which causes cardiac instability that can lead to immediate cardiac arrest and causes permanent damage (infarction).
ACS manifests as chest pain or discomfort, shortness of breath, dizziness, nausea, sweating, and discomfort in left or both arms, the jaw, neck, back or stomach. At that point, immediate medical attention is needed.
Thrombolytic (“clot busting”) therapy, antiplatelet drugs, and the direct opening of the coronary artery via percutaneous coronary intervention (PCI: angioplasty) and coronary bypass surgery. All these procedures are performed after arrival at the hospital, by when the heart has already suffered significant irreversible damage due to heart muscle cell death.1
IMT-358 is an investigational drug under development by IMMEDIATE Therapeutics to provide metabolic protection, potentially to to minimize cardiac damage and instability during ACS.
Although the mechanism of action of IMT-358 has yet to be definitively established, during ACS, the components of IMT-358 provide glucose to the heart muscle tissue. This glucose may help sustain metabolism and prevent arrhythmias, and the insulin may act as an anti-apoptotic (countering cell death) and anti-inflammatory agent. In preclinical studies2 and clinical trials3 to date, IMT-358 has been observed to reduce the buildup of free fatty acids (FFAs) that may contribute to arrhythmias and cardiac arrest.3 (68 patients in IMT 358 and 69 in placebo)
In the original IMMEDIATE trial (IMMEDIATE-1), IMT-358 was administered as soon as possible after the onset of symptoms of ACS, in the ambulance following a 9-1-1 call, or at the hospital emergency department. IMMEDIATE-1 showed that time-to-treatment after the onset of ACS symptoms was a critical factor.4 The timing of administration of IMT-358 will be further evaluated in the upcoming Phase 3 trial.
IMT-358 showed outstanding efficacy in our IMMEDIATE-1 Trial when administered in a timely manner by EMS paramedics and ER nurses in pre-hospital settings.
Patients in the IMMEDIATE-1 trial who were treated with IMT-358 showed 80% smaller infarcts (dead heart muscle), and far fewer large and very large infarcts, with far more of the infarcts being small or undetectable. In addition, IMT-358 also reduced cardiac arrest or mortality by 50% among all patients with ACS symptoms.4
Patients, healthcare providers, and payers could benefit from IMT-358 therapy, if and when approved by the FDA.
IMMEDIATE Therapeutics is preparing to for a Phase 3 trial (IMMEDIATE-2) of IMT-358. We are aiming to enroll 1600 patients and expect to initiate the trial in Q4 2022.
A future Standard of Care that includes administering IMT-358 immediately to patients experiencing symptoms of ACS will:
We are planning to explore the use of IMT-358 for patients with high risk for complications from major surgery, those who are older and/or have conditions such as diabetes, cardiac or lung disease, or other factors that make major surgery riskier. We also intend to investigate if IMT-358 will have any impact for other acute conditions beyond ACS and the risk of major surgery for e.g., in Sepsis and Stroke.
Selker HP et al. Effect of out-of-hospital administration of intravenous glucose, insulin, and potassium (GIK) in patients with suspected acute coronary syndromes: The IMMEDIATE randomized controlled trial. 2012;307(18):1925-1933. PMID 22452807.
Grossman AN et al. Glucose-insulin-potassium revived: current status in acute coronary syndromes and the energy-depleted heart. 2013;127:1040-1048. PMID 23459576.
Selker HP et al. Very Early Administration of Glucose-Insulin-Potassium (GIK) by Emergency Medical Service for Acute Coronary Syndromes: Biological Mechanisms for Benefit in the IMMEDIATE Trial. Amer Heart J. 2016;178:168–175. PMID 27502865.
Selker HP et al. One-year outcomes of out-of-hospital administration of intravenous glucose, insulin and potassium (GIK) in patients with suspected acute coronary syndrome in the IMMEDIATE (Immediate Myocardial Metabolic Enhancement During Initial Assessment and Treatment in Emergency care) trial. Am J Cardiol. 2014;113(10):1599-605 PMID 24792735; PMCID PMC4043184.
Maehara A et al. Relationship Between Infarct Size and Outcomes Following Primary PCI: Patient-Level Analysis From 10 Randomized Trials. J Am Coll Cardiol. 2016;57(14):1674-1683.
Selker HP et al. Relationship Between Therapeutic Effects on Infarct Size in Acute Myocardial Infarction and Therapeutic effects on One-year Outcomes: A Patient-Level Analysis of Randomized Clinical Trials. Am Heart J. 2017 Jun;188:18-25. PMID 28577674.
Beshansky JR et al. A community consultation survey to evaluate support for and success of the IMMEDIATE trial. Clinical Trials. 2014;11(2):178-186. PMID 24686107; PMCID PMC4025913.
Sullivan AL et al. Factors associated with longer time to treatment for patients with suspected acute coronary syndromes. Circ Cardiovasc Qual Outcomes. 2014;7:86-95. PMID 24425697; PMCID PMC3985420.
Ray M et al. A predictive model to identify patients with suspected acute coronary syndromes at high risk of cardiac arrest or in-hospital mortality: An IMMEDIATE Trial sub-study. Int J Cardiol Heart & Vasculature. 2015;9:37-42.
Peter I et al. Common Variants Associated with Changes in Levels of Circulating Free-Fatty Acids after Administration of Glucose-Insulin-Potassium (GIK) Therapy in the IMMEDIATE Trial. The Pharmacogenomics J. Epub 2015 Dec 8. PMID 26644202.
Ellis KL et al. Common variants associated with changes in levels of circulating free fatty acids after administration of glucose-insulin-potassium (GIK) therapy in the IMMEDIATE trial. Pharmacogenomics J. 2017; 76-83. PMID 26644202.
1. 2021 AHA/ACC/ASE/CHEST/SAEM/SCCT/SCMR Guideline for the Evaluation and Diagnosis of Chest Pain: A Report of the American College of Cardiology/American Heart Association Joint Committee on Clinical Practice Guidelines. Martha Gulati et al. Originally published 28 Oct 2021. Circulation. 2021;144:e368–e454.
2. Maroko PR et al. Effect of glucose-insulin-potassium infusion on myocardial infarction following experimental coronary artery occlusion. Circulation. 1972;45:1160-75.
3. Selker HP et al. Relationship between therapeutic effects on infarct size in acute myocardial infarction and therapeutic effects on 1-year outcomes: A patient-level analysis of randomized clinical trials. Am Heart J. 2017 Jun;188:18-25. doi: 10.1016/j.ahj.2017.02.028. Epub 2017 Feb 23. PMID: 28577674.
4. Selker HP et al. Out-of-hospital administration of intravenous glucose-insulin-potassium in patients with suspected acute coronary syndromes: the IMMEDIATE randomized controlled trial. JAMA. 2012 May 9;307(18):1925-33. doi: 10.1001/jama.2012.426. Epub 2012 Mar 27. PMID: 22452807; PMCID: PMC4167391.