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Improving kidney transplantation outcome with Renaparin® for patients with End-Stage Renal Disease by attenuating graft ischemia reperfusion injury

Periodic Reporting for period 3 - Renaparin (Improving kidney transplantation outcome with Renaparin® for patients with End-Stage Renal Disease by attenuating graft ischemia reperfusion injury)

Reporting period: 2019-03-01 to 2020-05-31

For patient with end-stage renal disease (ESRD), kidney transplantation will save lives. However, donor kidneys lack natural blood flow during the preservation stage prior to transplantation which can lead to ischemia, defined as a shortage of oxygen and glucose supply to the kidney tissue. When connected to the recipient’s blood flow, this in turn leads to ischemia reperfusion injury (IRI). IRI poses a major challenge in many thrombotic conditions and in whole organ transplantation. IRI is estimated to result in delayed graft function, which is when patients re-enter dialysis treatment already in the first week after transplantation, in up to 40 % of kidney transplants. IRI may also lead to acute kidney failure.

There is an alarming shortage of organs available for transplantation and in order to make wise use of all donor organs, the prevention of IRI has become a top priority for the transplantation community. Consequently, this medical field also constitutes a significant business opportunity for biotech companies. While several 100,000 patients globally (more than 93,000 in the US and more than 70,000 in the EU) are on the waiting list for a kidney transplantation, in the year 2014 only 79,950 patients received a kidney transplant to treat end stage renal failure . Of these transplantations, 43,198 were performed in the EU and USA. Due to the imbalance between need for transplantation and organ availability, many patients on the waiting list die before receiving a transplanted kidney. In the US alone, 4,761 patients lost their lives in 2014 while on the waiting list and 3,668 people became too sick to receive a kidney transplant. For the EU member states it is estimated that each year more than 4,100 patients die while awaiting transplantation.

This project has delivered a first-in-man study validate the safety and efficacy of Corline Biomedical’s pharmaceutical compound Renaparin®, which is a novel cell replacement technology, developed to prevent IRI and used to coat the lining of the blood vessels of kidneys prior to transplantation. Renaparin® is used when the kidney has been extracted from the donor and is stored in preservation solution awaiting transplantation.

The detailed scientific objectives were:

● to demonstrate (in a Phase I/IIa clinical trial) that Renaparin® is safe for its intended use,
● to show that Renaparin® has the potential to improve transplantation outcome by attenuating ischemia reperfusion injury,
● to produce data on user experience and to identify potential opportunities for optimization in regard to drug administration, formulation, packaging and handling,
● to prepare for a phase IIb/III study which should be designed in accordance to regulatory standards to confirm the clinical efficacy of the compound, and with the goal of subsequent market introduction.

The dissemination and business development goals were:
● to spread information about Renaparin’s® ability to mitigate IRI in transplanted kidneys to transplantation surgeons and/ or nephrologists at transplantation centres ,
● to educate and inform European and North American transplantation associations about the assumed benefits of Renaparin®,
● to present Renaparin® to patients and patient organizations as a pharmaceutical product with the hope of extending donor criteria, increasing the success rate of kidney transplantations and consequently reducing the waiting time for receiving a new organ,
● to present scientific data to pharmaceutical companies and investors with the goal of finding a suitable partner with whom to co-operate for further clinical validations and product commercialisation,
The activities proposed in this project has brought bring Renaparin® through a Phase I/IIa clinical trial in humans, with the intent to demonstrate its potential to improve the number of successful kidney transplantations and to prove that it is safe for its intended use. The study has been concluded and both the primary and secondary endpoints have been met.
At present, there is no pharmaceutical therapy approved anywhere in the world that has been shown to attenuate IRI and improve the quality and function of transplanted kidneys. Organs are for the most part (75% - 85%) preserved in cold storage before transplantation. The remaining organs are treated by Hypothermic Machine Perfusion (HMP), a medical device emulating natural perfusion at decreased temperatures.

Attempts of preventing IRI have been made by optimizing the choice and concentration of components comprising preservation solutions, applicable both for machine perfusion and for cold storage. Preservation solutions have in many cases been specifically devised to minimize injury associated with reperfusion. Besides physiological buffers such as phosphate or citrate to maintain pH they contain large molecules to maintain the intravascular osmotic potential in the absence of blood.6 Taken together, these two features are thought to attenuate IRI. However, the results of these attempts still do not adequately mitigate the problem; As mentioned earlier, IRI leading to DGF is still today associated with up to 40% of all transplanted kidneys.

In contrast to competitor drugs under development, Renaparin® is used to repair the kidney ex vivo prior to transplantation in order to prevent an immune response (primary prevention). It is locally administered with low systemic risk, whereas competitor products are systemically administered drugs. Renaparin’s® main function is to repair and protect the damaged endothelium of the kidney blood vessels from the recipient’s immune system.
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