While some RNA technology companies are still exploring the accompanying science, 足球在线买球, based in Gaithersburg MD with subsidiaries in Suzhou and Guangzhou, China, has already established 10 pre-clinical and clinical RNA based programs focused on oncology and fibrosis. Two of these lines of research impressively have Orphan Drug status from the Food and Drug Administration. But the company’s key differentiating feature is its proprietary Polypeptide Nano-Particle (PNP) technology for small interfering RNA (siRNA) drug delivery. This technology allows accessing of the tumor micro-environment (TME), as well as various cell types in the liver.
RNA technology-based therapeutics is a new and novel way to treat diseases. RNA medicines utilize biological processes to express proteins and create a therapeutic effect, offering the potential for treatment in a broad range of diseases, many of which cannot be addressed with current medicines.
As part of WuXi AppTec’s new series on RNA technology we spoke with 足球在线买球 Founder, President and Chief Executive Officer, Patrick Lu. Ph.D. about what he foresees as the future of RNA technology, how it differs from DNA technology, and how his company is using RNA to develop new drugs. Patrick has led 足球在线买球 from an early discovery effort to a siRNA therapeutics product company, with multiple programs currently at clinical stage. He brings 25+ years of nucleic acid drug development experience in Novartis, Digene and Intradigm – the latter he co-founded. Patrick is also serving as Chairman of the 足球在线买球 Board.
WuXi: What are RNA-based therapeutics and what differentiates them from DNA-based therapeutics?
Patrick Lu: RNA-based therapeutics target and modify patients’ ribonucleic acid molecules in the cell to silence gene expressions. Although both RNA and DNA based therapies target the cells, RNA based therapeutics focus on post-transcriptional therapy, targeting mRNA or using mRNA in the cytoplasm. Whereas DNA-based therapeutics act in the nucleus, even manipulating the genome. RNA based therapeutics have direct biological targets that have specific functions within the cell, and by tweaking the RNA code, we can adjust the therapy indication. This allows RNA therapy to be more targeted and more adaptable than DNA-based therapeutics.
WuXi: Do researchers know the full impact/potential of RNA on diseases, or is there much more to learn?
Patrick Lu: RNA interference (RNAi) has been a significant field of drug development over the past two decades during which researchers have gained expanded knowledge of the full potential of RNAi as therapeutic candidates for various disease targets. Notably, the RNAi drug Onpattro was developed by Alnylam and received approval from the US Food and Drug Administration in August 2018.
As we continue to gain the understanding of potential RNA application in additional disease targets, I believe the technology can be successfully applied to diseases such as pancreatic cancer, colorectal cancer, and glioblastoma multiform.
WuXi: Will RNA technologies emerge as a dominant treatment modality and if so, how soon?
Patrick Lu: Yes, RNA technology has great potential to emerge as a dominant treatment modality for various diseases. We already know that RNAi and antisense drug candidates have the potential to dominate treatment of liver diseases, compared to existing treatments using mAb and small molecules that require daily and weekly administrations. RNAi drug candidates may allow longer periods of time between administrations due to precise targeting of disease causing protein production. We see greater “knock-down” of target genes than seen in small molecule or mAB drugs. We also see a more prolonged effect of the drug, and therefore we are able to administer much lower doses than traditional drugs and can dose at much longer intervals. This allows for more convenient dosing schedules for patients, potentially increasing patient compliance and better outcomes for various disease states.
WuXi: What are the leading RNA technologies, and what diseases do they target?
Patrick Lu: RNA technology in regard to disease treatment may have the following modalities: first, targeting RNA molecules for drug development – for example, siRNA, miRNA, antisense, ribozyme, aptamer, saRNA and shRNA; second, using RNA molecules for therapeutic usage – mRNA. The leading technology right now is RNAi technology due to its therapeutic benefits and the success of Onpattro and Givosiran. RNAi drugs have the potential to target many diseases if the delivery technology expands to organs other than liver.
WuXi: What scientific advances are needed to make RNA technologies more effective medicines?
Patrick Lu: The next step in the evolution of RNAi as a leading therapeutic will be the ability to safely target organs outside the liver such as lung, brain, etc. This will revolutionize disease treatments if the industry can demonstrate similar data sets for non-liver targets as we have seen in liver-based diseases.
WuXi: Considering the wide variety of treatment modalities, where would you rank RNA-based technologies in importance?
Patrick Lu: RNAi based technologies have been validated by recent phase 3 studies as well as Phase 2 data that have been released by industry leaders. Based on the examination of the data sets provided by companies like Alnylam and Arrowhead, it appears that RNAi therapies have provided among the best results of any therapeutics for liver-based non-druggable disease targets. This would rank RNAi based therapies at the top of liver related diseases based on objective data sets from ongoing and completed clinical trials.
WuXi: What regulatory challenges do you face? Are they different from DNA-based therapeutics and other types of drugs?
Patrick Lu: Due to the growth in the field of RNAi therapeutics, the regulatory bodies in USA, Europe and China are closely following this field of drug development. Many recently identified issues were addressed and US FDA guidelines have been established. As the technology evolves, the regulatory system will continue to adapt accordingly.
Unlike RNA-based therapies, DNA-based therapies (such as gene therapies) change the genetic outcome of the patient’s cell and require special Recombinant DNA Advisory Committee (RAC) oversight.
WuXi: What kinds of manufacturing challenges do you face?
Patrick Lu: Although oligonucleotide drug and API manufacturing is well-established, the industry continues to face difficulties in large scale production for oligonucleotide-based drug and nanoparticle drug formulation, and chemical conjugation because it is expensive and difficult to produce chemically modified oligonucleotides. However, the industry is dedicated to improve manufacturing capacity and efficacy.
WuXi: What RNA-based technology is your company pursuing in which diseases indications and what are the key characteristics of 足球在线买球’ siRNA platform?
Patrick Lu: 足球在线买球 is a biopharmaceutical company focused on the discovery and development of RNA interference (RNAi) therapeutics. The company is advancing a robust pipeline of siRNA and mRNA candidates in oncology and fibrosis indications. Within our pipeline, we have two clinical indications for which we have received orphan drug designation from the US FDA.
Our siRNA therapeutic platform is comprised of a proprietary Polypeptide Nanoparticle (PNP) delivery system and a dual targeted siRNA drug design, such as TGF-β1 and Cox-2. The company’s lead therapeutic candidate (STP705) is a double stranded TGF-β1 and COX-2 siRNA with dual targeting properties. The unique asset of TGF-β1 inhibitory drug works effectively either as single agent or in combination with PD-L1 mAb. STP705 is currently being investigated for treatment of non-melanoma skin cancer in a Phase II clinical study and is on track to enter a second Phase II clinical trial for treatment of cholangiocarcinoma and hepatocellular in the second half of 2019.
WuXi: Can you explain how your delivery system works?
Patrick Lu: The PNP is composed of a branched Histidine Lysine polymer (HKP) that has an extensive literature on its use across a number of oncology cell models. This polypeptide nanoparticle provides a number of advantages for our therapeutic platform. The peptide is composed on natural amino acids so that degradation produces natural, non-toxic products. The PNP consists of a branched (HKP) that is readily synthesized. This PNP wraps around the siRNAs and serves to protect them from the surrounding environment while in the bloodstream. Once in the target cell though, the HKP groups protonate and allow release of the payload into the cytoplasm where the siRNAs can then induce gene silencing. Each PNP can carry multiple siRNA sequences. Delivery of multiple siRNAs can produce a synergistic effect by targeting more than one essential gene in cancer cells resulting in better efficacy. Our target gene discovery and siRNA validation programs seek to leverage this benefit by identifying these synergistic targets in cancer cells.
WuXi: One final question: 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?
Patrick Lu: In recent years, we have seen promising results in RNA-targeting drugs for some rare diseases. If RNAi-focused companies continue to make progress, RNAi therapeutics have the potential to receive approvals for treatment of multiple indications – including cardiovascular disease, hemophilia and cancer over the next five years
At 足球在线买球 specifically, we are forging a path to bring RNAi therapeutics to the mainstream as therapeutic modalities for treatment of many diseases, such as non-melanoma skin cancer, liver cancer, liver fibrosis and NASH.
足球在线买球, Inc., a leading privately held biopharmaceutical company for discovery and development of RNAi therapeutics, is a Delaware corporation headquartered in Gaithersburg, Maryland, USA, with subsidiaries in Suzhou and Guangzhou, China. The Company’s mission is to develop novel therapeutics to alleviate human suffering and advance patient care in areas of high unmet medical need. The guiding principles of the company are: Innovation, Global Vision with a Patient Centered focus. Members of the senior management team have a great deal of combined experience in the biopharmaceutical industry, financial, clinical and business management in both the USA and China. The company is supported by funding from institutional investors and corporate partnerships. 足球在线买球 has developed a strong portfolio of intellectual property with an enriched product pipeline. The therapeutic areas of focus include oncology and anti-fibrotic therapeutics. Learn more at www.nzhnm.com.