Status of Clinical Development
https://proteo.us/proteo-inc/r-und-d/clinical-development.html
CLINICAL DEVELOPMENT
Acute Therapy
Phase I Safety and tolerability
completed
Phase II Esophageal cancer surgery completed
Phase II Coronary artery bypass surgery completed
Phase III Esophageal cancer surgery preparing
Chronic Therapy
Phase I Safety and tolerability planned
Phase II Pulmonary arterial hypertension planned
Safety and Tolerability in Acute Therapy
In a double-blind, randomized and placebo-controlled Phase I single dose escalating trial Elafin was well tolerated by healthy human subjects. In two Phase II studies with patients undergoing surgery for esophageal cancer and with patients undergoing coronary artery bypass grafting the excellent tolerability was confirmed.
Esophageal Cancer Surgery
Esophageal cancer mainly occurs in elder patients over 50. Complete surgical removal of the tumor offers the best chance of a cure. This surgical procedure, which can last up to 6 hours, is one of the most invasive surgical interventions and is associated with frequent and severe postoperative inflammatory complications leading to delayed recovery, prolonged need of intensive care and substantial postoperative mortality.
In a double-blind, randomized and placebo-controlled Phase II clinical trial intravenously administered Elafin had a positive effect on the period of recovery: 63 percent of the Elafin treated patients required only one day of intensive care in contrast to patients receiving placebo which all needed several days.
Currently, Proteo is preparing a double-blind, randomized and placebo-controlled Phase III clinical trial in this acute therapy indication. Proteo has already obtained protocol assistance by the European Medicines Agency (EMA) and the trial is scheduled to start in 2016. The trial is designed to demonstrate efficacy which is required for an application to receive marketing approval for the European market.
The European Commission has granted Orphan Drug Designation for Elafin to be used in the treatment of esophageal cancer and the FDA has granted Orphan Drug Designation for Elafin for the prevention of inflammatory complications of transthoracic esophagectomy within the United states. The EMA and the FDA agreed that no investigations in pediatric populations will be performed, as children are almost not affected by this kind of cancer.
Coronary Artery Bypass Surgery
Coronary artery bypass surgery is a procedure performed to relieve angina pectoris and reduce the risk of death from coronary artery disease. It is the most frequently performed operation in cardiovascular surgery. This surgical procedure is associated with postoperative myocardial and systemic inflammation which contributes to the substantial risk of postoperative myocardial infarction, pulmonary and renal failure as well as stroke. Cardiovascular surgeons agree that there is an urgent need for pharmaceuticals that can be administered to prevent these postoperative complications, to improve the overall benefit of bypass surgery for the patients.
A double-blind, randomized and placebo-controlled Phase II clinical trial (EMPIRE) has been conducted at the University of Edinburgh under the lead of Dr. Peter Henriksen with 85 patients undergoing coronary artery bypass graft surgery (Alam et al., Heart 2015). The patients have been treated with a single perioperative infusion of either Elafin or placebo. This trial contributed much to our understanding of the therapeutic potential of Elafin and the time course of myocardial injury in CABG. Troponin I plasma concentrations, a marker of myocardial damage, was reduced by 41% as long as pharmacologically relevant concentrations of Elafin were present in the blood. This trial provided sufficient information for the design of a follow up study. The trial was supported by the Medical Research Council (MRC) and Chest Heart & Stroke Scotland (CHSS) with more than GBP 500,000.
Safety and Tolerability in chronic therapy
A Phase I trial in the US with subcutaneously administered Elafin funded by the NIH is planned to commence with recruitment in December 2018. The designs of the Phase I clinical trial and a Phase II proof of concept trial in Pulmonary Arterial Hypertension (PAH) have been discussed with the FDA.
Pulmonary Arterial Hypertension
Pulmonary Arterial Hypertension (PAH) is a severe and, as yet, incurable lung disease which, if left untreated, is fatal within a few years.PAH is caused by the progressive narrowing of the pulmonary arterial blood vessels. This is due to a pathological proliferation of the muscle cells within the vessel wall and the subsequent transformation of the muscle cells into connective tissue. The resulting narrowing of the pulmonary artery blood vessels leads to a decrease in oxygen supply to the body and, due to increased pulmonary blood pressure, to a substantial overexertion of the heart. Affected patients suffer from severely reduced exercise capacity. While currently available treatments have increased life expectancy by 5 to 7 years by retarding the advancement of the disease, they cannot completely stop disease progression. Elafin represents a novel therapeutic approach to suppress and reverse the underlying arterial wall pathology, and address an unmet therapeutic need for PAH.
Proteo has received orphan drug designations for Elafin in the USA for the treatment of pulmonary arterial hypertension (PAH) and in the European Union for the treatment of PAH and chronic thromboembolic pulmonary hypertension.
Since 2008, Proteo has been cooperating with a team of scientists at Stanford University in California lead by Dr. Marlene Rabinovitch for the preclinical development of Elafin in the field PAH. Marlene Rabinovitch has published over 150 scientific papers and is among the leading scientists worldwide in the area of pulmonary hypertension. For more than a decade, she has been studying the significance of Elafin in vascular disease. Since 2011, the NIH National Heart, Lung and Blood Institute (NHLBI) has been supporting the Elafin PAH development program at Stanford University with a five-year high volume grant.
In November 2015, Proteo and investigators from Stanford University School of Medicine were invited by the FDA for a pre-IND meeting to discuss the development plan for Elafin in the treatment of PAH after major advances in preclinical research had been made by a Stanford team of researchers led by Professor Marlene Rabinovitch (Nickel et al., Am J Respir Crit Care Med. 2015).
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