When the introduction of DNA technologies were first introduced, researchers saw great possibilities for this new technology in medicines, vaccines and food products. Originally, the process involved isolating a desired gene from an organism and then transferring it to an alternative vector to create a new cellular mechanism. Later developments in RNA technologies allowed for the use of a patient’s own cells to combat disease pathways. These novel techniques are now seeing rapid advances in medical research, with even more diverse possibilities offered – we are redesigning the art of the possible. For example, one advantage RNA technology has is that it is not a one-size-fits-all approach. There are multiple modalities within the technology which can be utilized for various diseases.

London-based MiNA Therapeutics is exploring one of those new modalities called saRNAs (small activating RNAs). saRNAs share many features with other RNA therapies but work through an entirely distinct mechanism called RNA activation. By triggering a cell’s normal gene regulation, saRNA medicines are able to restore normal levels of proteins that are currently “undruggable” by conventional medicines. This means they can be used to restore proteins, such as transcription factors, with powerful biological effects to fight disease. MiNA’s saRNA medicine is currently in clinical testing in patients with advanced liver cancer.

As part of a new WuXi AppTec Innovators series on RNA technologies, we spoke with MiNA’s Chief Executive Officer, Robert Habib. He explains how RNA technology is differentiating itself from DNA technologies, the role MiNA is playing in applying RNA technology, and what we can expect to come from this new field of scientific research.

Mr. Habib joined MiNA as Chief Executive Officer in 2013, and he has been a driving force in establishing the company as the pioneer of saRNA medicines. Prior to this Mr. Habib held roles in private equity and investment banking. He has a BSc from the University of Bristol and an MBA from Columbia Business School.

We began by asking Mr. Habib for his definition of what RNA technology is all about.

WuXi: What are RNA-based therapeutics and what differentiates them from DNA-based therapeutics?

Robert Habib: Simply put RNA-based therapeutics are medicines which seek to increase, decrease or change a cell’s ability to manufacture proteins. The benefit of RNA-based therapeutics is that by engaging with a cell’s own manufacturing machinery, we can modulate proteins in disease that cannot be targeted with conventional medicines. Unlocking a large number of biological pathways provides radically new ways of treating patients with society’s worst diseases. Beneath the surface, however, RNA-based therapeutics comprise of several different modalities, engaging various components of a cell’s manufacturing machinery by distinct mechanisms of action. In that sense it is important to consider RNA-based therapeutics as a battery of novel modalities, not just one. Apart from our focus on using small activating RNAs to upregulate the transcription of a specific gene, there are a number of different approaches including antisense oligonucleotides, exon skipping oligonucleotides, RNA interference, aptamers, microRNA mimetics and antimirs, immunomodulatory CpG, mRNA and a variety of other technologies. Based on this broad range, RNA therapeutics therefore offer a more flexible approach to address a variety of diseases from different angles compared to DNA-based therapeutics. Initially, DNA-based approaches were favored in drug development, based on the inadequate delivery technologies for the less stable RNA. However, over the last ten years the field has seen major advances in both delivery technologies and manufacturing capabilities.

WuXi: Do researchers know the full impact/potential of RNA on diseases, or is there much more to learn?

Robert Habib: As the impact for every RNA modality is different, I can only speak in depth about the small activating RNA field in which MiNA Therapeutics is operating. Together with our scientific founders, we have worked on elucidating the underlying mechanisms of RNA activation and the therapeutic impact we can provide to patients, with some early but promising success stories for patients in immuno-oncology. We are also focused on applying saRNA medicines to treat liver diseases and other therapeutic areas. In science there is always more to learn, and I am sure that we will see further exciting developments in the future.

WuXi: Will RNA technologies emerge as a dominant treatment modality and if so, how soon?

Robert Habib: What matters is finding a way for all these various RNA modalities to deliver superior outcomes for patients poorly served by today’s conventional medicines. To emerge as a dominant treatment modality alongside small molecules and antibodies means delivering those outcomes to a very large number of patients and only certain RNA technologies are suited to have that kind of impact. For example, certain technologies can only modulate proteins that are relevant to genetic disease effecting relatively small patient numbers. Other technologies may use chemistry that limits their breadth of use due to safety, route of administration or manufacturing costs.

WuXi: What are the leading RNA technologies and what diseases do they target?

Robert Habib: I don’t believe that you can rank RNA technologies; they all have their applications and merits. However, antisense oligonucleotides are at a very mature stage of development with a large number of clinical and commercial successes including CNS, oncology and cardiometabolic diseases. Additionally, we were all very excited when the first RNAi medicine was approved in 2018. mRNA therapeutics have garnered tremendous attention over the past few years, largely because of the technology’s flexibility in modulating such a large range of proteins. However, using mRNA technology for therapeutic intervention is not trivial and the pioneers are appropriately digging in the trenches for the long-term. Our saRNA approach, which shares several features of RNAi, is quickly drawing attention in immuno-oncology.

WuXi: What scientific advances are needed to make RNA technologies more effective medicines?

Robert Habib: The underlying challenge for many RNA-based therapeutics remains efficient delivery to a target cell. RNA-based therapeutics inherently have few drug-like properties, which means they have a hard time getting inside cells in the body. Huge strides have been made to enable the effective delivery of RNA-based therapeutics, but the reality is we are only at the tip of the iceberg. Some RNA-based therapeutics will also require breakthroughs in manufacturing technology in order to be a realistic proposition in general medicine.

WuXi: Considering the wide variety of treatment modalities, where would you rank RNA-based technologies in importance?

Robert Habib: Researchers around the world are consistently pushing the limits of small molecules and biologics and emerging modalities like cell and gene therapies are making their case also. However, the flexibility to modulate a vast range of target biology, with chemically manufactured drugs, with a tunable duration of action, sets RNA-based therapeutics apart as a drug class with extraordinary potential.

WuXi: What RNA-based technology is your company pursuing and what are your disease targets?

Robert Habib: We are pioneering a new class of medicines called saRNAs (small activating RNAs). saRNAs share many features with other RNA therapies but work through an entirely distinct mechanism called RNA activation. saRNAs can upregulate intracellular or secreted proteins for therapeutic benefit and have been shown to increase protein levels for both naturally expressed and epigenetically silenced targets. We are currently focused on three therapeutic areas: immuno-oncology, metabolic diseases, and genetic diseases. Our lead candidate MTL-CEBPA is currently in Phase 1b development in patients with advanced liver cancer. Pre-clinical and early clinical testing suggests that MTL-CEBPA may enhance the efficacy of a range of cancer therapies principally by modulating the tumour microenvironment. We have been very encouraged by the early clinical results and plan to initiate more clinical trials of MTL-CEBPA in the future. Together with Boehringer Ingelheim we are also working on a set of undisclosed targets to treat NASH and liver fibrosis.

WuXi: What regulatory challenges do you face? Are they different from DNA-based therapeutics and other types of drugs?

Robert Habib: Like any new technology there have been learnings for both company sponsors and regulatory agencies, but numerous approvals have established a clear path to market.

WuXi: What kinds of manufacturing challenges do you face?

Robert Habib: As saRNAs are short oligonucleotide sequences, they can be manufactured using methods advanced by antisense and RNAi such as solid phase synthesis and purification by chromatography. A number of contract manufacturers around the world have optimized and harmonized these methods to establish platforms that rapidly scale to commercialization. Additionally, thanks to economies of scale, the suppliers of the amidite raw materials have been able to offer successively lower prices, making RNA-based therapies an economically feasible proposition in diseases affecting growing numbers of patients. Approval of an RNA-based therapeutic in a patient population as large as cardiovascular disease could be the next milestone for the supply chain to improve yet further.

WuXi: What benefits do saRNA therapeutics offer compared to other modalities?

Robert Habib: By working at the gene level, saRNA-based medicines are able to restore a cell’s own biology, such as powerful transcription factors, currently “undruggable” by conventional medicines. The beauty of saRNA is also that well-established oligonucleotide designs can be used as triggers for gain of function. That allows MiNA to leverage years of pharmaceutical development, from assays to delivery, which have enabled a robust pipeline in short order.

WuXi: After two decades of research, the first RNAi therapeutic was approved in 2018. How will this class of medicines evolve over the next five years?

Robert Habib: We are already seeing a significant uptake in RNA therapies entering the clinic and I believe in the coming years, it will be a key contributor to the RNA success story, with more approvals and therapies entering the market. My personal prediction is that drug discovery for the most mature modalities will start to uncouple from the pioneers and be distributed globally – such that academic labs, new biotech ventures and also pharmaceutical generalists join in to unlock the fullest potential for RNA-based therapeutics. In my mind that would be the ultimate affirmation of RNA-based therapeutics.

WuXi: What are the next milestones for MiNA?

Robert Habib: By the end of 2019 we hope to initiate a new clinical trial evaluating MTL-CEBPA in combination with checkpoint inhibition in a range of solid tumor malignancies. In early 2020 we look forward to presenting the results of our Phase 1b study of MTL-CEBPA in combination with sorafenib in patients with advanced liver cancer.