Innovation Competition (Boston, MA)

Riparian Pharmaceuticals

Therapeutics

Will Adams is Riparian’s Chief Scientific Officer and President. Prior to co-founding Riparian, Will performed his dissertation research at Brigham & Women's Hospital and Harvard Medical School where he developed stem cell-based platforms for drug discovery and personalized medicine. He was a fellow at the Startup Leadership Program, a global network of mentors and startup founders, which continues to be an invaluable resource. Will received a PhD in Biomedical Engineering, a MS in Applied Mathematics and a BS in Biomedical Engineering from Harvard University. Guillermo Garcia-Cardena co-founded Riparian and serves as a scientific advisor. Guillermo is an Associate Professor of Pathology at Harvard Medical School and the Director of the Laboratory for Systems Biology at Brigham & Women's Hospital. His expertise in vascular biology, and in particular on the biochemical pathways responsible for protection against vascular inflammation, is widely recognized. He received his PhD from Yale University. Philip Astley-Sparke leverages his extensive experience in therapeutic development to advise Riparian. Philip is currently President of UniQure, a clinical stage gene therapy company, and is a Venture Partner at Forbion Capital Partners and Chairman of Oxyrane, a biopharmaceutical company. Prior to this, he was a Vice President and General Manager at Amgen, following the acquisition of BioVex in 2011. Philip served as the BioVex's President and CEO where he was instrumental in raising $150M from venture capital groups, setting corporate strategy and navigating the FDA regulatory framework. Riparian does not have a CEO and will leave this position vacant until acquiring proof of principle animal efficacy results. We estimate this will coincide with the need to raise capital for further development from private institutional investors. At this stage, we will fill the CEO role with an individual with successful experience growing and exiting a therapeutics business.

Riparian is seeking to discover first-in-class therapeutics targeting vascular inflammation. Specifically, we are targeting the disease process known as endothelial dysfunction. The vascular endothelium is the single cell layer lining blood vessels. As the interface between moving blood and the body’s organs, the endothelium is responsible for mediating inflammatory responses, triggering thrombosis, controlling vasotone and modulating vascular permeability. Dysfunction of the endothelium is a pro-inflammatory state which can significantly contribute to human disease. Endothelial dysfunction is frequently observed in autoimmune and inflammatory diseases including systemic lupus erythematosis, rheumatoid arthritis, and sickle cell disease. In these settings, endothelial dysfunction can significantly heighten the risk of atherosclerosis and its devastating sequelae heart attacks and strokes, despite the absence of classical cardiovascular risk factors such as dyslipidemia and hypertension. Endothelial dysfunction also contributes to the failure of transplanted organs such as kidneys, livers and hearts. The procurement of organs for transplantation removes the organ vasculature from circulation which causes significant adverse changes to endothelial phenotype. After transplantation, endothelial dysfunction is frequently observed in the organ’s vessels. This endothelial dysfunction is associated with delayed function and reduced survival time of the transplanted organ.

The therapeutics for endothelial dysfunction which we are discovering could provide therapeutic benefit in multiple clinical settings and hence markets. The most prominent application of a therapeutic for endothelial dysfunction is to treat atherosclerotic cardiovascular diseases. Cardiovascular disease is the most common cause of mortality in the world for which $36B was spent on pharmaceutical therapies in the United States in 2010. We intend to initially focus on patient populations with chronic systemic inflammation who are at heightened risk of developing atherosclerosis. In these disorders, the sales of recently marketed anti-inflammatory therapies offer estimates of potential market size. The most popular treatments (etanercept and adalimumab) for the 1.5m U.S. patients with rheumatoid arthritis together had sales over $17B in 2012. A new therapeutic (belumimab) for the 500,000 patients with systemic lupus erythematosis had sales of $65M in 2012. Additionally, we believe a therapeutic reversing endothelial dysfunction could provide benefit in organ transplantation by improving graft survival and patient outcomes. In the United States, there were 16,500 kidney, 6,250 liver and 2,450 heart transplants in 2012. The market for therapeutics to prevent transplant rejection is dominated by a generic immunosuppressant, tacrolimus, which is prescribed to >85% of transplant recipients. Before patent expiry, proprietary tacrolimus had annual sales of $2B in 2009.

Riparian Pharmaceuticals is discovering first-in-class therapeutics to improve endothelial function to ultimately reduce the vascular complications among patients with inflammatory and autoimmune disorders and to improve the survival and function of transplanted organs. Our therapeutic approach is based on the observation that particular anatomical regions of the arterial tree are predisposed to developing endothelial dysfunction and subsequently atherosclerotic plaques, while other regions are resistant. The locations of these regions are predictable patient to patient and even species to species. Research from our academic collaborators identified a signaling pathway and specific transcription factor, KLF2, responsible for maintaining an anti-inflammatory, anti-thrombotic, vasodilatory and anti-oxidative phenotype in the vascular endothelium. The activation of this pathway is anatomical site-specific in the vasculature and regulates protection from endothelial dysfunction. The vasoprotective role of this pathway has been well-validated in numerous cell-based assays and animal models of disease by our academic collaborators and other research groups. Riparian is translating these observations into a novel drug discovery effort. We are currently performing high throughput chemical screens to identify novel pharmacological agents able to induce the expression of KLF2 and hence an anti-inflammatory phenotype in vascular endothelium. Optimized hits from our screen will be extensively characterized in several pathophysiologically relevant cell-based assays before evaluating their effects in animal models of disease.

Current therapeutic approaches to inflammatory diseases target blood cells (e.g. hydroxychloroquine or anti-BAFF mAb for lupus, methotrexate or anti-TNFa mAb for rheumatoid arthritis, hydroxyurea for sickle cell disease, tacrolimus for organ transplantation). For atherosclerosis, therapeutics target classical risk factors (dyslipidemia, hypertension, hyperglycemia). Clinical trials are underway exploring how chronic inflammation affects the vasculature in atherosclerosis (anti-IL1b mAb in CANTOS, methotrexate in CIRT, salsalate in TINSAL-CVD). In contrast, we are targeting dysfunctional vascular endothelium. As an essential constituent of the diseased blood vessel and a participant in propagating the inflammatory state, the dysfunctional endothelium is a critical and unexplored target for inflammatory and vascular diseases. We are employing several proprietary technologies recently developed by our collaborators. We are using a device to mimic complex hemodynamic stimulation to uniquely induce the endothelial dysfunctional phenotype in vitro in combination with a cell-based reporter assay designed to monitor KLF2 expression. Also, we identified a set of biomarkers defining the healthy versus dysfunctional endothelial phenotype for characterizing hit compounds. We anticipate that integrating these novel tools in a discovery setting focusing on KLF2-driven rescue of endothelial dysfunction will establish a new therapeutic strategy for inflammatory and vascular diseases.

Riparian is uniquely striving to discover a first-in-class therapeutic to reverse endothelial dysfunction. To our knowledge, there are no existing therapies in the market or in current pharmaceutical development pipelines focused on drugging the dysfunctional vascular endothelium. We are not seeking to displace existing therapies in the market which target various blood cells for inflammatory disorders or mitigate risk factors such as dyslipidemia or hypertension for atherosclerosis. The biology, both the target cell type and biomolecular pathway, underlying our therapeutic program is unique, and therefore we anticipate developing therapeutics to act as adjuncts to existing treatment options. The most relevant question will be, how do our putative new therapeutics, when applied in conjunction with standard of care therapies, improve patient outcomes. Unfortunately, this definitive answer is not easily obtained in the absence of randomized controlled trials which will be a part of our clinical development. But, we are currently performing experiments to gain insight into this question early in our preclinical research.

Business Grants (e.g. SBIR)

Riparian sees two key milestones in our near term focus on discovery. Our first goal, building upon our chemical screening and validation work, will be to file intellectual property around our screen hits. Second, we will test the efficacy of our screen hits in relevant animal disease models. Acquiring in vivo proof of concept will validate targeting endothelial dysfunction as a therapeutic strategy and guide further development. Pursuing a novel therapeutic discovery and development program in a nascent biotechnology company carries multiple inherent scientific, business and regulatory challenges and risks. There is a risk our chemical screening will not identify hits able to reverse endothelial dysfunction or that successful performance in cell-based assays will not translate to efficacy in relevant in vivo disease models. We are mitigating these risks by building incredibly detailed understanding of the relevant biology of endothelial function/dysfunction and the role our screen hits play early in the discovery process. Riparian is a new company and is led by a talented yet relatively inexperienced team. We are mitigating this risk by recruiting experienced advisors and in the future a seasoned CEO. Raising sufficient capital for drug development presents a significant challenge, though we are optimistic that innovative therapeutic programs with compelling data will attract the necessary financing. In the near term, we are addressing our milestones in a capital-efficient model. Also, a promising market for endothelial dysfunction therapeutics is for atherosclerosis in patients with inflammatory disorders and in the larger population at risk. Due to the capital-intensive demands on cardiovascular drug development, we will seek a partnership with a larger pharmaceutical company for this indication. While focused on our discovery program, we are mindful of the regulatory risks associated with the development of novel therapeutics subject to FDA oversight.

Riparian is seeking funds to expand our initial chemical screening efforts. While operating with high capital-efficiency, we are seeking $200k to perform further target identification and validation with our hit compounds as we are phenotypically screening compounds for their ability to activate a particular biological pathway and so are probing a set of molecular targets. Also, we are seeking to raise $150k for further medicinal chemistry studies to help understand the molecular mechanism of action of our hit compounds. Excited to be situated in such a pharmaceutical and biotechnology-steeped atmosphere, we are interested in meeting attorneys with significant experience from niche firms specializing in intellectual property for novel therapeutics, other CEOs or founders of therapeutics companies and representatives from larger pharmaceutical companies able to speak to their firms’ strategic interests.