SBIR-STTR Award

In the US, ?160,000 people per year develop heart failure from acute heart damage, mostly from heart attacks. Approximately 50% of them die within 5 years of the heart failure diagnosis. Currently, there are no therapies to prevent the development of heart failure after acute heart damage. A growing body of evidence points at Pirfenidone, a pyridone currently approved for the treatment of a rare disease through an unknown mechanism of action, as a powerful cardioprotective drug. Pirfenidone is a poorly tolerated drug because of its unfavorable pharmacokinetics. Innovative research recently conducted at Washington University in St Louis discovered that Pirfenidone protects the heart through an immunomodulatory effect on B lymphocytes. Pinpointing the cellular target of Pirfenidone, this research created the opportunity to optimize Pirfenidone. We expect that PEGylation of Pirfenidone with small PEG chains (<500 Daltons) will produce a cardioprotective pyridone with favorable pharmacological properties. PEGylation has been shown to be an effective method to improve the pharmacokinetic profile of small molecules. We have shown that PEGylated-Pirfenidone maintains its immunomodulatory effect on B cells in vitro and has prolonged half-life after IV administration in vivo. We have secured IP on PEGylated-Pirfenidone. In this Phase I application, we seek support to optimize the pharmacokinetics of PEGylated Pirfenidone through highly targeted medicinal chemistry modifications and in vivo measurements in mice, and to test the cardioprotective effects of PEGylated Pirfenidone in clinically relevant in vivo murine models of acute heart injury. In Phase II we will refine the properties of the lead PEGylated compound, characterize its cardioprotective effects in large animal models, and perform initial toxicology studies in preparation of Investigational New Drug(IND) application. If successful, this project will produce a first in class immunomodulatory small molecule for the treatment of acute heart damage and for the prevention of injury-induced heart failure. Based on available pre-clinical data on Pirfenidone and on available clinical data on damage induce heart- failure, just in the US such drug would be expected to save >16,000 lives and >3$bn in projected cost of care every year.

Public Health Relevance Statement:
Project narrative/ public health statement In the US, ≈160,000 people per year develop heart failure from acute heart damage and 50% of them end up dying within 5 years from the heart failure diagnosis. Currently there are no therapies to prevent the development of heart failure after acute heart damage. In this Phase I SBIR, i-Cordis seeks support to develop a first in class immunomodulatory small molecule to severe the connection between acute heart damage and heart failure.

Project Terms:
Architecture; Engineering / Architecture; B-Lymphocytes; B-cell; B-Cells; B cells; B cell; B blood cells; Biological Availability; Physiologic Availability; Biologic Availability; Bioavailability; Brain; Encephalon; Brain Nervous System; Pharmaceutic Chemistry; Medicinal Chemistry; Pharmaceutical Chemistry; Diagnosis; drug/agent; Pharmaceutic Preparations; Medication; Drugs; Pharmaceutical Preparations; Investigational New Drugs; Investigational Drugs; Goals; Half-Life; Heart; cardiac failure; Heart failure; cardiac injury; Heart Injuries; In Vitro; indexing; heavy metal lead; heavy metal Pb; Pb element; Lead; lung disorder; disorder of the lung; disease of the lung; Respiratory System Disorder; Respiratory System Disease; Respiratory Disease; Pulmonary Disorder; Pulmonary Diseases; Lung diseases; Methods; Molecular Weight; Murine; Mice Mammals; Mice; Mus; heart infarction; heart infarct; heart attack; coronary infarction; coronary infarct; coronary attack; cardiac infarct; Myocardial Infarct; Cardiac infarction; Myocardial Infarction; Persons; Patents; Legal patent; Pharmacokinetics; Drug Kinetics; Pharmacology; Reticuloendothelial System, Serum, Plasma; Plasma Serum; Blood Plasma; Plasma; Polyoxyethylenes; Polyethyleneoxide; Polyethylene Oxide; Macrogols; Polyethylene Glycols; Public Health; Scientific Publication; Publications; Pyridinones; Pyridones; Reperfusion Damage; Ischemia-Reperfusion Injury; Reperfusion Injury; Research; Risk; Savings; Technology; Testing; tibia; Toxicology; Universities; Washington; Weight; Healthcare Costs; Health Costs; Health Care Costs; symposia; summit; convention; conference; symposium; injury prevention; Investigational New Drug Application; base; improved; Acute; Penetration; Phase; heart function; function of the heart; cardiac function; Licensing; Measurement; analog; Pirfenidone; Therapeutic Agents; Oral; functional group; Animal Model; model organism; model of animal; Animal Models and Related Studies; cellular targeting; dalton; Rare Diseases; orphan disorder; Rare Disorder; Orphan Disease; immunoregulation; immunoregulatory; immunomodulatory; immunologic reactivity control; immune regulation; immune modulation; Immunomodulation; novel; Prevention; Modeling; Property; B-Cell Activation; heart formation; heart development; cardiogenesis; preventing; prevent; small molecule; Length; International; in vivo; Clinical Data; research clinical testing; clinical test; Clinical Testing; Clinical Evaluation; Small Business Innovation Research Grant; Small Business Innovation Research; SBIR; Preparation; Modification; Cardiac; Development; developmental; Immunomodulators; immunomodulatory therapeutics; immunomodulatory drugs; immunomodulatory agents; immunomodulating agents; immune modulatory drugs; immune modulatory agents; immune modulating therapeutics; immune modulating drug; immune modulating agents; IMiD; pre-clinical; preclinical; design; designing; Outcome; innovation; innovative; innovate; clinically relevant; clinical relevance; mouse model; murine model; commercialization; FDA approved; Secure; immunomodulatory therapies; immune modulatory therapies; immune modulating therapies; care costs; lead optimization; cardioprotection; cardioprotective; cardioprotectant; heart damage; cardiac damage; side effect; off-patent

Heart Failure with preserved Ejection Fraction (HFpEF) is one of the major drivers of healthcare costs in the western world and arguably the largest unmet need in cardiology. Currently, there are no FDA approved drugs to treat the vast majority of patients with HFpEF. Recently, the Phase II PIROUETTE trial showed that the immunomodulatory drug pirfenidone, marketed for the treatment of a rare lung disease, has marked beneficial effects in patients with HFpEF. Unfortunately, pirfenidone is a suboptimal drug. In fact, because of its poor pharmacokinetics, patients need to take 2 large pills three times a day and they often develop mild to moderate side effects that lead to dose reduction or discontinuation of treatment (38% of treated patients had to discontinue pirfenidone in the PIROUETTE trial). Moreover, from a commercial point of view, pirfenidone has no intellectual property protection and therefore pharmaceutical companies have no incentive to develop it for further applications. i-Cordis has PEGylated pirfenidone to obtain "Pegydone", a new molecular entity with better exposure, less toxicity and superior therapeutic effects than pirfenidone. i-Cordis has completed proof of concept studies in rodent models. In this SBIR Phase II grant i-Cordis requests support to complete critical pre-clinical studies to de-risk its drug development effort in the eyes of potential investors. Following completion of the Phase II grant, the company plans to raise dilutive funding to complete IND filing, and progress through clinical trials, FDA approval and commercialization of Pegydone as a prescription drug for the treatment of HFpEF.

Public Health Relevance Statement:
PROJECT NARRATIVE Heart Failure with preserved Ejection Fraction (HFpEF) affects about 4 million Americans and accounts for about 2% of healthcare spending in the US. Currently there are no FDA approved drugs for the treatment of the vast majority of patients with HFpEF. In this Phase II SBIR grant, i-Cordis LLC is seeking support to accelerate the development of Pegydone, a PEGylated derivative of the FDA approved immunomodulatory drug pirfenidone, for the treatment of HFpEF.

Project Terms:
Accounting; Affect; Biological Availability; Bioavailability; Biologic Availability; Physiologic Availability; Cardiology; chemical synthesis; Clinical Trials; Disease; Disorder; Canis familiaris; Canine Species; Dogs; Dogs Mammals; canine; domestic dog; Pharmacotherapy; Drug Therapy; drug treatment; Pharmaceutical Preparations; Drugs; Medication; Pharmaceutic Preparations; drug/agent; Eye; Eyeball; Fibrosis; Goals; Grant; Half-Life; Heart failure; cardiac failure; Human; Modern Man; Incentives; Lead; Pb element; heavy metal Pb; heavy metal lead; Lung diseases; Pulmonary Diseases; Pulmonary Disorder; disease of the lung; disorder of the lung; lung disorder; Magnetic Resonance Imaging; MR Imaging; MR Tomography; MRI; MRIs; Medical Imaging, Magnetic Resonance / Nuclear Magnetic Resonance; NMR Imaging; NMR Tomography; Nuclear Magnetic Resonance Imaging; Zeugmatography; Marketing; Liver Microsomes; Mus; Mice; Mice Mammals; Murine; Persons; Patients; Pharmacokinetics; Drug Kinetics; Blood Plasma; Plasma Serum; Reticuloendothelial System, Serum, Plasma; Plasma; Drug Prescribing; medication prescription; prescribed medication; Drug Prescriptions; Production; Pyridinones; Pyridones; Common Rat Strains; Rat; Rats Mammals; Rattus; Risk; Safety; Temperature; Time; Toxicology; Measures; Health Care Costs; Health Costs; Healthcare Costs; Healthcare; health care; Treatment Failure; therapy failure; improved; Phase; Failure; insight; Funding; Phase 2 Clinical Trials; phase II protocol; Phase II Clinical Trials; Intellectual Property; Esbriet; Pirfenidone; Therapeutic; Exposure to; Myocardial depression; cardiac dysfunction; heart dysfunction; Myocardial dysfunction; Intravenous; Western World; Complex; Oral; Ejection Fraction; EFRAC; extracellular; American; chemical stability; cardiac fibrosis; myocardial fibrosis; coronary fibrosis; Toxicities; Toxic effect; Immunomodulation; immune modulation; immune regulation; immunologic reactivity control; immunomodulatory; immunoregulatory; immunoregulation; novel; Modeling; Property; drug development; pill; Pharmaceutical Agent; Pharmaceuticals; Pharmacological Substance; Pharmacologic Substance; small molecule; Incubated; Dose; Data; Rodent Model; Small Business Innovation Research Grant; SBIR; Small Business Innovation Research; Molecular; Process; Myocardial; Therapeutic Effect; Development; developmental; Immunomodulators; IMiD; Immune modulatory therapeutic; immune modulating agents; immune modulating drug; immune modulating therapeutics; immune modulators; immune modulatory agents; immune modulatory drugs; immunomodulating agents; immunomodulatory agents; immunomodulatory drugs; immunomodulatory therapeutics; Pathway interactions; pathway; pre-clinical; preclinical; preclinical study; pre-clinical study; scale up; Prevalence; prospective; commercial application; commercialization; FDA approved; stability testing; constriction; precision medicine; precision-based medicine; experimental study; experiment; experimental research; preservation; cardioprotection; cardioprotectant; cardioprotective; side effect; Prognosis