Efficacy of Mirococept (APT070) for Preventing Ischaemia-Reperfusion Injury associated with Kidney Transplantation-2 (EMPIRIKAL-2)

About half of all kidney transplant patients experience a delay in the recovery of the new organ, and this puts them at greater risk of losing the kidney prematurely through inflammation, rejection and scarring.

We have invented an anti-inflammatory treatment that targets a key component of the inflammatory system produced in the kidney. The particular component is called 'complement' due to its natural ability to complement the immune response against infection. In the absence of infection, however, complement proteins can turn against the organ being transplanted.

Our solution is to inhibit the complement system, borrowing from natural protection against self-injury. The finished product is called Mirococept. It has a unique design where the natural complement inhibitor CR1 (meaning complement receptor type 1) has been cloned and engineered to have a tail. The tail allows us to plant the therapeutic in the donor kidney, where it is retained and protects the organ following its implantation into the recipient. Work in laboratory animals has shown that treated kidneys undergo better recovery, raising the prospect of using less-damaged kidneys for clinical transplantation and giving the donor organ a longer life.

The treatment has already undergone safety evaluation in humans and no safety concerns have arisen. A randomised controlled trial would determine whether it fulfils the promise to reduce the rate of delayed graft function and identify the most effective dose. The proposed trial will be a springboard for wider development to determine whether Mirococept improves the lifespan of the kidney and the recipient and is cost-effective for the NHS. This is crucial since donor organs are in short supply and the number of transplants with delayed function has increased and is likely to rise further with the recent change in legislation allowing presumed consent for organ donation.

The potential indications for complement inhibitors go wider than organ transplantation and include conditions such as coronary artery surgery, age-related blindness and current clinical trials for COVID-19 lung inflammation. The proposal would add proof to the idea that 'organ painting' with anti-inflammatory drugs will improve the effectiveness of treatment without causing general side effects.

Delayed graft function (DGF) is a manifestation of ischaemia-reperfusion injury (IRI) and has a deleterious effect on the lifespan of the graft and the patient. We are seeking to define a therapeutic approach for the prevention of IRI to the kidney during the period immediately after transplantation. This damage is linked to activation of the complement system that occurs through recognition of the grafted organ as foreign and/or damaged, as shown in a MRC funded programme of work. We have approached this problem firstly by engineering a recombinant form of a human complement-regulatory molecule known to be present in the normal kidney at low density and secondly by modifying this molecule so that it can be delivered to the graft by perfusion before transplantation and retained within the kidney at increased density during the period that damage is thought to occur. Preclinical and exploratory clinical studies have indicated that this approach is safe and has the potential to reduce the incidence of DGF in renal transplantation. A Phase IIb dosing/efficacy study has completed the first cohort of 80 patients, the results of which indicate the need for dose escalation. We are now seeking to extend the study using a revised design based on the results of a new dose escalation study in isolated pig kidneys. The revised clinical design involves two stages: Stage 1, a Phase II dosing/efficacy study (for which funding is presently sought); and Stage 2, a Phase III confirmatory study (for which no funding is sought at the present time). This design will enable us to reach a satisfactory endpoint with a smaller number of patients than the original trial. The study will show whether treatment of the donor kidney with the engineered construct lowers the incidence of DGF and improves the mid-term function of the graft.