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Report

Teaser, summary, work performed and final results

Periodic Reporting for period 1 - NanoMed-CKD (Feasibility of mCura1: A kidney-targeted nanomedicine that promotes self-healing of Chronic Kidney Disease with messenger RNA.)

Teaser

Summary

Introduction
As the 9th cause of death worldwide, chronic kidney disease (CKD) affects 10-13% of the population, translating into 74-100 million patients in the EU, a number that will continue to rise in the near future. CKD is caused when the progressive loss of kidney function (~1% per year in healthy and >1% in unhealthy people) and is often accelerated by life style-associated factors. As such more than half of the population will eventually be confronted with CKD during their life-time. Often an underestimated problem because of its slow progression, the chronic nature of the disease combined with the number of patients and high drug costs causes CKD to consume 4-17% of European healthcare budgets. Currently, standard-of-care treatment is unable to stop or reverse the disease progression and is in most cases associated a variety of side effects that affect quality of life, shorten life-expectancy, but even paradoxically cause renal damage.
To solve the inefficacy, safety issues and high costs of current CKD treatments, Mercurna develops a novel mRNA-based kidney-targeted nanomedicine, mCura1, that could not only stop, but also restore (part of) the renal function. mCura1 is a lipid nanoparticle system that delivers mRNA exactly into the cells in the kidney that are essential in the pathogenesis of the disease. Each successfully delivered mRNA is translated into thousands of proteins, which encode for 4 different therapeutic proteins that selectively affect multiple causative disease processes that are common to various CKD. Incorporation of control sequences in the mRNA render the protein expression conditional to the disease state of the cell. mCura1â€™s nanoparticle system protects the mRNAs from degradation and prevents immunogenicity, while its outside is coated with a lipidated peptide that binds to a previously unknown receptor on the targeted kidney cells. mCura1 unique selling points are its efficacy and enhanced safety profile provided by the use of multi-target mRNA therapeutics and LNP-based kidney targeting. Pre-clinical studies involving mCura1 has already shown among others the superior kidney-targeting, absence of toxicity and the potential to reduce pathogenic processes in kidney cells. Currently, the mCura1 is prepared for the treatment of advanced animal disease models and an extended safety and toxicity testing.
The NanoMed-CKD feasibility study was aimed to develop a roadmap to bring mCura to the clinic and market. By integrating competitor analysis, real-options analysis, clinical development plan, IP strategy and regulatory strategy into a quantified decision model, we calculated the risk-adjusted net present value of each option during the development program of mCura1. In this way we could de-risk of the further development of the project as much as possible and adapt pre-clinical studies perfectly to the human application. In particular, the flexibility of mCura1 for application to different types of CKD, to different stages of CKD, in different dosages, in different volumes etc., were taken into account. Based on this model, different development scenarios were examined.

Work performed

In this call, the following activities were performed to bolster our business case, select a primary indication and develop a decision model which allows for a rational way to make development choices and anticipate on future events.
First, the competitive landscape for the treatment of chronic kidney disease was further investigated with particular emphasis on the patient journey (i.e. when is patient diagnosed, what is the state-of-the-art treatment, first-line/second-line/etc. treatment). We discovered that mCura1 is initially best applied in the later stages of the disease, because there is the greatest unmet need compared to the current available medicines. Furthermore, we expect mCura1 to display the most prominent therapeutic activity in the later, more complicated stages of disease. Next, we identified for each indication within the CKD-category the most appropriate sub-groups. Initial proof-of-concept in these groups lays the foundation to role mCura1 out in the larger CKD-population.
In the second step of the project, we analyzed the IP-landscape in further detail and found our current strategies to maintain freedom-to-operate to be effective. The deeper analysis, however, also showed some trends in the type of matter that is being claimed and areas that might become more crowded in the near-future. Based on this information, we prioritized some of our development programs involving the technological basis of our platform, and that might be potentially impacted by advances in the aforementioned areas.
Next, we built a decision model with as much detail as possible, delineating possible development paths, anticipating experimental outcomes and most importantly, the consequences of choices being made. Using the risk-adjusted net-present-value (rNPV) as a well-established mathematical model to weight possible choices against each other, we identified some significant late-stage risks in the mCura1 development plan. We designed various risk-mitigating measures, including advancing another drug candidate ahead of mCura1, to validate common components. To this end, we built a decision matrix, which allows for the comparison of over 200 indications across more than 25 parameters, including unmet need, market value and the competitive landscape. Based on this, we selected 16 indications and designed development programs for each. Together, these results form a decision model to guide mCura1 and various other drug candidates through development and onward to commercialization.
Finally, we calculated a rNPV for the mCura1 program in various development scenarios and conclude that mCura1 should be further developed (Go).

The updated business plan is currently being used in discussions with private investors, with the ultimate goal to obtain financing for further development.

Final results

The results of the project help to accelerate, streamline and de-risk the development program of mCura1, the first multi-mRNA treatment for chronic kidney disease. In particular, the results of the project have increased the chances of mCura1 reaching the market and the many patients with chronic kidney disease requiring a better treatment. If mCura1 reaches the market, it will transform the treatment of chronic kidney disease by preventing, as opposed to slowing, the progression of the disease to end-stage-renal disease, majorly improving the quality-of-life and life-expectancy of the patients. In addition, due to the vast number of patients (10-13% of European population or 74-100 million patients in EU), and the high cost per patient (â‚¬15,000 to â‚¬80,000 per patient per year, depending on the stage of the disease), a significant reduction in healthcare costs can be achieved.