InteRNA Boldly Exploring New RNA Technologies to Tackle Cancer

Innovation That Matters

Innovation in the biotech industry often comes from nimble, emerging companies. This is especially true with new scientific discoveries like RNA technology. One such company is InteRNA, which is a Netherlands-based biotechnology company specializing in the development of RNA therapeutics for the treatment of cancer. Using its leading microRNA (miRNA) discovery and functional validation platform, InteRNA is developing a pipeline of proprietary preclinical miRNA drug candidates targeting key processes in cancer initiation and progression. Enabled with a 3rd generation drug delivery formulation, these miRNA compounds can mount a coordinated anti-cancer attack by engaging multiple signal transduction targets simultaneously. With this approach, InteRNA can address the high need for novel therapeutics with improved efficacy and less drug resistance – and cancer patients are a major beneficiary. The company’s lead drug INT-1B3 is primarily for the treatment of patients with hepatocellular carcinoma (HCC), but subsequent uses could also target triple-negative breast cancer (TNBC), melanoma and lung cancer (NSCLC).

In this third installment, WuXi AppTec’s Innovator RNA series asked InteRNA’s Chief Executive Officer, Roel Schaapveld to discuss the use and future of RNA technologies, as well as how his company is using the new technology to develop novel treatments.

Roel Schaapveld became InteRNA’s CEO in 2009. Prior to InteRNA, Roel was Senior Manager in the corporate finance biotech team at the Dutch merchant bank Kempen & Co, involved in private funding, M&A and IPO’s at Euronext of life sciences companies. Previously, he held several management positions at Kreatech Diagnostics (sold to Leica Biosystems), including VP Corporate and Business Development. Roel holds an MSc and PhD from Radboud University Nijmegen (NL). During his academic career he worked at the Roche Institute for Molecular Biology (Nutley, NJ), at the Dana-Farber Cancer Institute (Boston, MA) and at the Netherlands Cancer Institute in Amsterdam. Roel received his MBA from Nyenrode Business School (NL).

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

Roel Schaapveld:
RNA-based therapeutics are able to utilize the inner workings of a person’s own cells to change the expression of certain genes, resulting in a wide variety of possible therapeutic applications and a high flexibility to address previously untreatable targets. It is important to note that the RNA therapeutics field consists of a variety of different approaches that either result in the up- or down-regulation of certain proteins in a cell. Based on the approach, this can be targeted to a very specific protein (e.g. via mRNA, antisense-RNA, siRNA (small interfering RNA) and saRNA (small activating RNA)) or a certain set of proteins (via microRNAs). What is commonly described as DNA-based therapeutics includes gene therapy or gene editing technologies such as CRISPR. Here the main goal is to either repair a dysfunctional gene or reintroduce an intact version to produce a functional protein. These approaches are currently mainly used in the rare disease field, as the risk of permanently altering the human genome is high. In contrast, RNA therapeutics as mentioned earlier, promise to offer a larger variety of applications, but due to the challenges in stability and delivery technologies, have taken longer to bring to patients. However, over the last years, we have seen a significant uptick in development as the technology has advanced and novel solutions for these challenges have been identified. This is exemplified by the FDA/EMA approvals of certain antisense and siRNA therapeutics, and as such RNA-based therapeutics are now representing a new drug class next to small molecules and antibodies.

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

Roel Schaapveld: The field of RNA therapeutics has rapidly advanced in the last ten years. Despite the noteworthy strides forward in uncovering the full potential of RNAs, there is still a lot to learn and understand, as with any novel therapeutic approach. Nonetheless, the information we have to-date indicates that RNA-based therapeutics offer several advantages such as high efficacy, high levels of flexibility in structure and customization as well as fast and cost-effective production. Based on this, the field of RNA therapeutics will undoubtedly continue to grow, which will enable a broader and deeper understanding of the impact and potential this approach may have on a range of diseases.

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

Roel Schaapveld: The market for RNA-based therapeutics is currently dominated by RNA interference technology and mRNA technologies. Numerous companies have demonstrated their interest in these approaches, as they have shown a high potential to treat a variety of chronic diseases such as cancer, diabetes, AIDS, tuberculosis and certain cardiovascular conditions. Underlining this, as mentioned above, SPINRAZA® is an antisense oligonucleotide that addresses the underlying genetic cause of spinal muscular atrophy (SMA) by making the back-up gene, SMN2, to produce more functional protein. ONPATTRO® is a siRNA knocking down the expression of mutant TTR protein to treat the polyneuropathy caused by a disease called hATTR (hereditary transthyretin-mediated amyloidosis).

Furthermore, current research and development is concentrated on infectious diseases and oncology due to their high global prevalence and unmet medical need. As such, both RNAi- and mRNA-based approaches are currently being explored to activate the immune system to fight a specific target structure. In contrast to classical RNAi approaches, microRNA offer the benefit to address a variety of targets within a specific and/or across several disease-associated pathways with one therapeutic which – especially in multigene diseases like cancer – offers the potential for a combination treatment in one drug.

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

Roel Schaapveld: RNA, by its chemical nature, is prone to degradation, especially within the human body. Improving stability as well as optimizing delivery strategies to the specific target tissues/cells are two key points that the RNA community has been working on to address in the current therapeutic development. For InteRNA this has also been a crucial focus and we have identified both a stabilization modification of the RNA, as well as a delivery technology that together provide a highly attractive drug product.

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

Roel Schaapveld: For a long time, cancer therapeutics were developed by the “one fits all” principle, but survival and remission rates are still poor for many cancer types. Moreover, the advances in screening technologies showed that no two individual tumors are the same in their mutational landscape, a property very important for their resistance and immune evasion abilities. Targeting several hallmarks simultaneously in diseases with various or multiple origins is therefore key in fighting heterogeneous and fast adapting diseases like cancer and influenza, respectively. Especially in these indications, RNA therapeutics could offer a competitive advantage.

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?

Roel Schaapveld: The last couple of years have truly been a turbulent time for RNA-based technology. If we focus on the microRNA field, due to collective hype and optimism, many companies pushed their product into the clinic prematurely, which lead to major setbacks for the field despite the immense potential the technology holds. The scientific consensus has shifted towards the necessity of a therapeutic approach that addresses multiple components of a pathway rather than knocking out single genes when developing treatment for multiple types of cancer. Regarding the upward trajectory of RNAs in the biotech industry, particularly during 2018 – with the launch of ONPATTRO®, the first-ever RNAi therapeutic to be approved in the US and EU? Well, 2019 could be seen in years to come as the start of a new era for RNA therapeutics. Based on a variety of products in clinical development, I believe we can expect several additional success stories over the next years.

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

Roel Schaapveld: InteRNA develops sophisticated microRNA drug candidates to create effective monotherapies for various cancer types. Our lead candidate INT-1B3 has shown powerful immune system activation, tumor regression and pronounced long term immunity based on a CD8+ T cell immune response. The safety profile and pronounced anti-tumor efficacy demonstrated in preclinical studies make INT-1B3 stand out as a promising alternative where current combinatorial strategies with anti-PD1/PD-L1 fail. Our goal is to enter the clinic with this lead candidate later this year in liver cancer and triple negative breast cancer. In parallel, we will also continue to advance our pipeline of microRNA drug candidates for other oncology indications based on our differentiated functional screening platform.

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

Roel Schaapveld:  SPINRAZA®, ONPATTRO® and other late-stage RNA-based drugs, have already helped to pave the way for the regulatory process, which has been helpful. As this is still a young field, we are in contact with KOLs and will get in touch with regulators early on to discuss the best path forward. However, we are still in an early developmental stage where we cannot foresee all possible upcoming challenges.

WuXi: What kinds of manufacturing challenges do you face?

Roel Schaapveld: Our high level of experience in the field of RNA biology, and the fact that we have been working on the technology since 2008, has resulted in a steady improvement of our platform and manufacturing capabilities through our qualified CMOs. In doing so, we already addressed a lot of the current drawbacks, as we significantly improved the stability of our lead microRNA candidate and optimized the delivery strategy towards specific tissues.

WuXi: What are the next milestones for InteRNA?

Roel Schaapveld: Our near-term milestones for 2019 include the completion of GLP tox studies and entry into the clinic with our lead candidate, INT-1B3, with the objective of testing it in solid tumors. Achieving these milestones will be an important step for the corporate development of InteRNA and will give us the opportunity to further explore the promising potential of our unique microRNA approach.

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

Roel Schaapveld: Although it is difficult to say what the future holds for RNA technologies, the approach has already gained significant attention, especially in recent years with the market approvals of SPINRAZA® (antisense) and ONPATTRO® (siRNA). As such, the biotechnology industry has shined a spotlight on RNAs and their potential therapeutic benefits for indications ranging from cancer to hemophilia. Only time will tell whether this approach will emerge as a dominant treatment modality, but for the time being, it is gaining traction in the industry with more companies harnessing the potential of RNAs to tackle diseases where current treatment options fail to deliver durable responses.

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