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Study describes how biotech startups can avoid competing with large pharma companies for financing. A paper published in the Orphanet Journal of Rare Diseases1 concludes that repurposing existing compounds provides various advantages that could directly help early-stage biotech startups—including Unravel Biosciences—with better aligning their business and financing issues with their scientific and medical objectives, enter a space that is not occupied by larger pharmaceutical companies, and accelerate the validation of their drug development platform. According to the Orphan Drug Act of 1983,2 rare or orphan diseases are defined as conditions that affect fewer than 200,000 individuals in the United States. Although any single orphan disease affects a small number of individuals, the argument could be made that in aggregate, there are more patients suffering from a rare disease than from more common ones. There are currently more than 7000 rare diseases identified, with the total population of Americans living with a rare disease estimated at approximately 25-30 million.3 For context, 19 million new cancer cases are detected each year worldwide, and in 2021, 1.9 million individuals4 were diagnosed with cancer in the United States. The Orphan Drug Act was designed to alleviate the challenges of drug development for rare diseases—such as delays in diagnosis due to a lack of public awareness and medical expertise—via incentives such as tax benefits, a 7-year minimum period of market exclusivity, and waivers of Prescription Drug User Fee Act (PDUFA) fees.5 Despite this, the paper reports that large pharma companies continue to prioritize diseases with much larger patient populations, leaving early-stage biotech companies as key participants in the R&D process for rare diseases,6,7 which created a significant obstacle in financing rare disease drug development. However, a possible solution that investigators said may help to tackle the rising cost and low probability of success (PoS) in developing new drugs has emerged over the past two decades. Drug repurposing, or drug repositioning,8 is a concept that identifies new indications for existing, abandoned, or shelved drugs, or for candidates under development.9-11 This process can help lower development costs, shorten development time, and increase the PoS, while also maximizing the potential impact of drug compounds for a broader population of patients.12,13
In short, Unravel Biosciences has proposed two lead compounds to treat Rett syndrome. Because these compounds qualify as repurposed compounds, Unravel plans follow the 505(b)(2) path toward FDA approval,14which gives the company the ability to use previously completed research as part of their FDA application, an approach that is typically cheaper and faster than following a traditional new drug application (NDA) path—the 505(b)(1) path—or an abbreviated NDA path, the 505(j) path. Thus, the researchers consolidate all preclinical development through phase 1 into a single phase. The breakdown, including the PoS, can be viewed in the aforementioned Orphanet Journal of Rare Diseases,1 but the researchers also selected the lower (upper) bound estimate of 14.8% (33.7%) by reducing (increasing) the PoS for the combined discovery, preclinical, and phase 1 development by 5 percentage points, reducing (increasing) the PoS for phase 2 and 3 by 10 percentage points, and leaving the PoS for FDA approval unchanged. References
1. Financing Repurposed Drugs for Rare Diseases: A Case Study of Unravel Biosciences. Orphanet Journal of Rare Diseases. September 12, 2023. Accessed November 3, 2023. https://ojrd.biomedcentral.com/articles/10.1186/s13023-023-02753-y
2. US Food and Drug Administration (FDA). Orphan drug act—relevant excerpts. 2018.  https://www.fda.gov/industry/designating-orphan-product-drugs-and-biological-products/orphan-drug-act-relevant-excerpts . Accessed November 3, 2021. 3. Schieppati A, Henter J, Daina E, Aperia A. Why rare diseases are an important medical and social issue. Lancet. 2008;371:2039–41. Advertisement
4. Siegel RL, Miller KD, Fuchs HE, Jemal A. Cancer statistics, 2021. CA Cancer J Clin. 2021;71(1):7–33. https://doi.org/10.3322/caac.21654 . 5. Fagnan DE, Yang NN, McKew JC, Lo AW. Financing translation: analysis of the NCATS rare-diseases portfolio. Sci Transl Med. 2015;7(276):276ps3. https://doi.org/10.1126/scitranslmed.aaa2360 . 6. O’Neil DA. A better fit? Biotech versus big pharma in orphan/rare disease drug research. Expert Opin Orphan Drugs. 2014;2(4):317–9. https://doi.org/10.1517/21678707.2014.900433 . 7. Sharma A, Jacob A, Tandon M, Kumar D. Orphan drug: development trends and strategies. J Pharm Bioallied Sci. 2010;2(4):290. 8. Langedijk J, Mantel-Teeuwisse AK, Slijkerman DS, Schutjens M-HDB. Drug repositioning and repurposing: terminology and definitions in literature. Drug Discov Today. 2015;20(8):1027–34. https://doi.org/10.1016/j.drudis.2015.05.001 . 9. Naylor S, Schonfeld JM. Therapeutic drug repurposing, repositioning and rescue part I: overview. Drug Discovery World. 2014.  https://www.ddw-online.com/therapeutic-drug-repurposing-repositioning-and-rescue-part-i-overview-1463-201412/ . Accessed November 3, 2023. 10. Naylor S, Kauupi DM, Schonfeld JM. Therapeutic drug repurposing, repositioning and rescue part II: business model. Drug Discovery World. 2015.  https://www.ddw-online.com/therapeutic-drug-repurposing-repositioning-and-rescue-part-ii-business-review-888-201504/ . Accessed November 3, 2023. 11. Naylor S, Kauupi DM, Schonfeld JM. Therapeutic drug repurposing, repositioning and rescue part III: market exclusivity using Intellectual Property and regulatory pathways. Drug Discovery World. 2015.  https://www.ddw-online.com/therapeutic-drug-repurposing-repositioning-and-rescue-part-iii-market-exclusivity-using-intellectual-property-and-regulatory-pathways-1239-201508/ . Accessed 27 Apr 2021. 12. Pushpakom S, Iorio F, Eyers PA, Escott KJ, Hopper S, Wells A, Doig A, Guilliams T, Latimer J, McNamee C, et al. Drug repurposing: progress, challenges and recommendations. Nat Rev Drug Discov. 2019;18(1):41–58. 13. Barratt MJ, Frail DE. Drug Repositioning: Bringing New Life to Shelved Assets and Existing Drugs. 2013. New York: Wiley. https://doi.org/10.1002/9781118274408 . 14. US Food & Drug Administration (FDA). Applications covered by Section 505(b)(2). https://www.fda.gov/regulatory-information/search-fda-guidance-documents/applications-covered-section-505b2 . Accessed November 3, 2023. Related Content:

Report Explores Ways to Finance, Repurpose Rare Disease Drugs

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MeCo Diagnostics and Unravel Biosciences announce prostate cancer partnership
Partnership unlocks synergies to rapidly identify and evaluate novel biomarker-targeted therapies for solid tumors, starting with prostate cancer
Combining MeCo’s unique datasets and innovative 3D in vitro screens with our in silico biological network computation will drive novel precision medicines with clear value to patients and investors”
— Dr. Richard Novak, CEO of Unravel Biosciences
SAN DIEGO, CALIFORNIA, US, October 26, 2023 / EINPresswire.com / -- MeCo Diagnostics Holdings, Inc. (“MeCo”) and Unravel Biosciences, Inc. (“Unravel”) are partnering to leverage their highly complementary platforms to rapidly enhance the response rate of prostate cancer patients through stratification biomarkers combined with novel therapeutics. The partnership builds on both companies’ demonstrated clinical validation in leveraging AI for drug and biomarker discovery: MeCo combines proprietary in vitro functional cell biology assays with RNA sequencing analysis to discover drug response biomarkers, while Unravel is a therapeutics company leveraging a machine-learning model of human health to advance drugs for complex diseases. They will combine AI-enabled discovery with proprietary datasets to generate highly predictive biomarkers of treatment response and neoadjuvant therapies. This collaboration is supported by Certis Oncology Solutions , a San Diego-based precision oncology and translational science company that employs orthotopic patient-derived xenograft (O-PDX) and other advanced preclinical cancer models to assess therapeutic efficacy. “One of the key hurdles to the broad application of AI in cancer treatment is validating efficacy predictions and their related biomarkers,” said Peter Ellman, President & CEO of Certis. “We are honored to play a role in advancing the goals of this important partnership between MeCo Diagnostics and Unravel Biosciences.”
While earlier detection and treatment of prostate have improved survival, castration-resistant prostate cancer remains a devastating outcome for many men, so better therapies and patient stratification are needed. "MeCo excels at predicting new therapeutic strategies, while Unravel excels at predicting which drugs or lead compounds are ideally suited for new therapeutic strategies. Working together, our core competencies dovetail beautifully," says Dr. Adam Watson, CEO of MeCo Diagnostics. "We are excited to partner with MeCo to advance cancer patient care," says Dr. Richard Novak, CEO of Unravel Biosciences. “Combining MeCo’s unique datasets and innovative 3D in vitro screens with our in silico biological network computation will drive novel precision medicines with clear value to patients and investors.”
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About MeCo Diagnostics
MeCo Diagnostics develops predictive biomarker technology to enable drug repurposing or repositioning for early-stage cancer therapy. MeCo pairs its proprietary three-dimensional organotypic cancer models with AI-powered whole transcriptome analysis to reveal new therapeutic strategies. MeCo’s lead asset, the MeCo Score™, is a first-in-class predictive biomarker for antifibrotic therapy in HR+/HER2- breast cancer that leverages a generic-emergent drug to enable low-cost targeted therapy. www.mecodiagnostics.com
About Unravel Biosciences
Unravel Biosciences is the first rapid prototyping therapeutics company, using AI biological network analysis together with existing drugs to discover and clinically derisk entirely novel therapeutics and biomarkers with unprecedented efficiency. Unravel leverages its proprietary BioNAV™ platform combining target and drug discovery, preclinical screening and patient stratification to find treatments for complex diseases. Unravel's platform discovered RVL002, a first-in-class new small molecule targeting mitochondrial metabolism with applications in multiple CNS and metabolic disorders, and RVL027, a molecule targeting a novel mechanism to treat dystonias. www.unravel.bio
Adam Watson, PhD

MeCo Diagnostics and Unravel Biosciences announce a prostate cancer biomarker and drug discovery partnership

By Benjamin Boettner
(BOSTON) — The  Biomedical Advanced Research and Development Authority  ( BARDA ), part of the Administration for Strategic Preparedness and Response (ASPR) at the U.S. Department of Health and Human Services (HHS), partnered with the  Wyss Institute at Harvard University  to support the Institute in advancing its human Organ Chip platform and drug discovery capabilities to better understand the illness and injuries that result from a broad range of health security threats, including high doses of radiation, as well as predicting and evaluating potential treatments. A collection of  human Organ Chips , which have been developed by the team of Wyss Founding Director and Principal Investigator on the award,  Donald Ingber , M.D., Ph.D., over the past 15 years, have unique potential for filling this gap. Importantly, the recently passed FDA  Modernization Act 2.0  enables the FDA to consider data generated in human in vitro models, including human Organ Chips, in lieu of animal data during new drug evaluations, thus potentially greatly accelerating the clinical advancement of life-saving medical countermeasures (MCMs). “Our new partnership with BARDA builds on our work funded previously by the FDA that showed human Organ Chips can mimic the responses of human lung, intestine and bone marrow to radiation exposure. With this new expanded BARDA support, we will be extending this work to get insight into how radiation influences immune responses in the lymph node, and it will allow us to leverage these unique models in combination with AI-based computational discovery tools we have developed here at the Wyss, to discover new and more effective radiation countermeasure drugs," said Ingber. “The insights gained here, and the forthcoming technological fall-out from the project, will undoubtedly also inform our work in other disease areas as well as potentially help to mitigate unforeseen health threats we may face in the future.” Ingber is also the Judah Folkman Professor of Vascular Biology at Harvard Medical School and Boston Children’s Hospital, and the Hansjörg Wyss Professor of Bioinspired Engineering at Harvard School of Engineering and Applied Sciences. Human Organ Chips are engineered microdevices with hollow channels lined by living human cells and tissues that replicate organ-level functions for extended periods when dynamically perfused with a blood-like nutrient fluid through a vascular channel and exposed to physiologically relevant mechanical cues. The Wyss Institute’s Organ Chip platform that will be used in the BARDA radiation program includes models of bone marrow, lymph nodes, lung, and intestine with its resident microbiome, which are particularly sensitive to high doses of radiation and, if injured, affect the rest of the body in the resulting syndrome known as radiation sickness or Acute Radiation Syndrome (ARS). The consequences of ARS can be extremely complex and include organ inflammation, blood leakage and clot formation, bone marrow failure and immune dysfunction increasing vulnerability to infections potentially resulting in life-threatening sepsis, as well as multi-organ failure. The Wyss team will investigate the molecular basis of ARS using human Bone Marrow, Lung, Intestine, and Lymph Node chips. To identify ARS-relevant radiation-induced changes, they will investigate the irradiated microtissues using a comprehensive methodical approach that combines multiomics analysis of different types of molecules ranging from metabolites, to RNA and DNA, to proteins, biochemical studies, and high-resolution microscopic analysis of cell and tissue morphology and integrity. The project will also investigate how radiation affects the impact of the normal human microbiome on intestinal structure and function, as well as other organs when their vascular channels are linked. Besides creating a better understanding of how radiation injury and ARS occurs, another important expected outcome of the studies is the identification of general and tissue-specific biomarkers for ARS that are released into the bloodstream and could be used to accurately measure the state and progression of the condition and, importantly, also the effects of future radiation MCMs. The identification and development of new MCMs that can prevent and treat radiation injury, and ARS is the last important piece in the investigation. Ingber’s team has put a robust drug discovery process into place that is based on a suite of computational tools. One approach is geared toward identifying FDA-approved drugs that can be repurposed for conditions other than the ones they were originally developed for, as well as the discovery of novel drug-like chemical structures that can be developed into actual drugs. The successful identification of repurposed drug candidates with  efficacy against COVID-19  at the peak of the pandemic highlighted the effectiveness of their approach, which since has been integrated into numerous other projects at the Wyss, as well as in startup companies, such as  Unravel Biosciences Inc . In the BARDA-supported studies, the team will apply AI approaches to already available ‘omics data from irradiated tissues as well as new ones generated under this award to identify drugs for repurposing and chemical compounds for further development of ARS-preventing and mitigating treatments. This project has been supported in whole or in part with federal funds from the Department of Health and Human Services; Administration for Strategic Preparedness and Response; Biomedical Advanced Research and Development Authority (BARDA), under contract number 75A50123D00004. PRESS CONTACTS
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The Wyss Institute for Biologically Inspired Engineering at Harvard University ( www.wyss.harvard.edu ) is a research and development engine for disruptive innovation powered by biologically-inspired engineering with visionary people at its heart. Our mission is to transform healthcare and the environment by developing ground-breaking technologies that emulate the way Nature builds and accelerate their translation into commercial products through formation of startups and corporate partnerships to bring about positive near-term impact in the world. We accomplish this by breaking down the traditional silos of academia and barriers with industry, enabling our world-leading faculty to collaborate creatively across our focus areas of diagnostics, therapeutics, MedTech, and sustainability. Our consortium partners encompass the leading academic institutions and hospitals in the Boston area and throughout the world, including Harvard’s Schools of Medicine, Engineering, Arts & Sciences and Design, Beth Israel Deaconess Medical Center, Brigham and Women’s Hospital, Boston Children’s Hospital, Dana–Farber Cancer Institute, Massachusetts General Hospital, the University of Massachusetts Medical School, Spaulding Rehabilitation Hospital, Boston University, Tufts University, Charité – Universitätsmedizin Berlin, University of Zürich, and Massachusetts Institute of Technology. Disclaimer: AAAS and EurekAlert! are not responsible for the accuracy of news releases posted to EurekAlert! by contributing institutions or for the use of any information through the EurekAlert system. Media Contact

Wyss Institute at Harvard University wins BARDA contract to leverage human Organ Chips to advance knowledge and drug-discovery f...

rareSHIFT™ provides industry and foundations access to Unravel's drug discovery engine to accelerate patient-centered drug development. Boston, MA /PRNewswire/ - Unravel Biosciences, Inc., ("Unravel"), a therapeutics company leveraging a machine-learning model of human health to advance drugs for complex diseases, today announced the release of a groundbreaking new initiative, rareSHIFT™, to facilitate patient-centric drug discovery and translation with unprecedented speed. "Unravel has developed a highly innovative and efficient drug discovery platform that serves as the engine for our pipeline of novel assets," said Neal I. Muni, M.D., MSPH, Chief Medical Officer at Unravel. "With the increased urgency expressed by patients, caregivers and their physicians to accelerate the identification of treatments for high unmet need, complex disorders, we are expanding our mission by providing foundation and industry partners with access to our capabilities. We believe that applying our rapid prototyping process with partners will result in a major shift in how highly effective treatment options are identified." rareSHIFT™ offers partners access to Unravel's full suite of industry-leading discovery and development capabilities, purposefully designed to provide a streamlined path to the clinic. Patient RNAseq data generation using home collection enables stratification of patient populations; BioNAV™, an AI network model of human health powered with a deep understanding of the true activity of over 40,000 compounds predicts therapeutic targets and drug candidates based on patients' RNA signatures. SquishyWare™, on-demand CRISPR-engineered in vivo models of genetic disorders, enables rapid screening using clinically-relevant metrics from the start. The integrated drug prototyping process uses existing drugs to derisk novel targets and repurposing opportunities while enabling development of even more effective novel therapeutics. Dr. Vinodh Narayanan. M.D., a pediatric neurologist at Arizona Pediatric Neurology and Neurogenetics Associates added, "Even in this time of tremendous advancement in the areas of gene-based therapies, there remains a great need for rapid discoveries of small molecule treatments for genetic neurological disorders, drastic reduction in the time taken from gene discovery to FDA approval for a compound." "Efforts such as rareSHIFT™ are indispensable for families and patients impacted by rare disease," said Kasey Edwards, CureAP4 Foundation Co-Founder and Community Coordinator. "A rare disease diagnosis instills deep fear in the lives of those it touches, but the potential for rapidly discovering effective treatments gives us hope, and a reason to smile." About Unravel Biosciences
Unravel Biosciences is the first rapid prototyping therapeutics company, integrating AI systems biology computation with rapid in vivo screening and clinical validation of discovered targets with unprecedented efficiency. Unravel leverages its proprietary BioNAV™ platform combining target and drug discovery, preclinical screening and patient stratification to find treatments for complex diseases. Unravel's platform discovered RVL002, a first-in-class new small molecule targeting mitochondrial metabolism with applications in multiple CNS and metabolic disorders, and RVL027, a molecule targeting a novel mechanism to treat dystonias. www.unravel.bio and www.rareshift.org
Source: Unravel Biosciences, Inc.

Unravel Announces rareSHIFT™, An End-To-End Solution For Drug Discovery

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rareSHIFT™ provides industry and foundations access to Unravel's drug discovery engine to accelerate patient-centered drug development. BOSTON, Sept. 18, 2023 /PRNewswire/ -- Unravel Biosciences, Inc., ("Unravel"), a therapeutics company leveraging a machine-learning model of human health to advance drugs for complex diseases, today announced the release of a groundbreaking new initiative, rareSHIFT™, to facilitate patient-centric drug discovery and translation with unprecedented speed. "Unravel has developed a highly innovative and efficient drug discovery platform that serves as the engine for our pipeline of novel assets," said Neal I. Muni, M.D., MSPH, Chief Medical Officer at Unravel. "With the increased urgency expressed by patients, caregivers and their physicians to accelerate the identification of treatments for high unmet need, complex disorders, we are expanding our mission by providing foundation and industry partners with access to our capabilities. We believe that applying our rapid prototyping process with partners will result in a major shift in how highly effective treatment options are identified." rareSHIFT™  offers partners access to Unravel's full suite of industry-leading discovery and development capabilities, purposefully designed to provide a streamlined path to the clinic. Patient RNAseq data generation using home collection enables stratification of patient populations; BioNAV™, an AI network model of human health powered with a deep understanding of the true activity of over 40,000 compounds predicts therapeutic targets and drug candidates based on patients' RNA signatures. SquishyWare™, on-demand CRISPR-engineered in vivo models of genetic disorders, enables rapid screening using clinically-relevant metrics from the start. The integrated drug prototyping process uses existing drugs to derisk novel targets and repurposing opportunities while enabling development of even more effective novel therapeutics. Dr. Vinodh Narayanan. M.D., a pediatric neurologist at Arizona Pediatric Neurology and Neurogenetics Associates added, "Even in this time of tremendous advancement in the areas of gene-based therapies, there remains a great need for rapid discoveries of small molecule treatments for genetic neurological disorders, drastic reduction in the time taken from gene discovery to FDA approval for a compound." "Efforts such as rareSHIFT™ are indispensable for families and patients impacted by rare disease," said Kasey Edwards, CureAP4 Foundation Co-Founder and Community Coordinator. "A rare disease diagnosis instills deep fear in the lives of those it touches, but the potential for rapidly discovering effective treatments gives us hope, and a reason to smile." About Unravel Biosciences
Unravel Biosciences is the first rapid prototyping therapeutics company, integrating AI systems biology computation with rapid in vivo screening and clinical validation of discovered targets with unprecedented efficiency. Unravel leverages its proprietary BioNAV™ platform combining target and drug discovery, preclinical screening and patient stratification to find treatments for complex diseases. Unravel's platform discovered RVL002, a first-in-class new small molecule targeting mitochondrial metabolism with applications in multiple CNS and metabolic disorders, and RVL027, a molecule targeting a novel mechanism to treat dystonias. www.unravel.bio and www.rareshift.org
SOURCE Unravel Biosciences, Inc.

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Unravel announces rareSHIFT™, an end-to-end solution for drug discovery

MeCo Diagnostics is a biotechnology research company. It protects breast cancer patients from the risk of metastasis. The company develops a prognostic and predictive biomarker for the risk of metastasis caused by mechanical conditioning, and it provides the rationale for targeted prevention in high-risk patients using low-toxicity antifibrotic drugs, enabling breast cancer patients to get benefits from the therapy. MeCo Diagnostics was founded in 2022 and is based in San Diego, California.

MeCo Diagnostics

`` We are honored to play a role in advancing the goals of this important partnership between MeCo Diagnostics and Unravel Biosciences , Inc. . ''

Netnoids Rx Laboratories operates as a rare cancer laboratory-services contract research organization (CRO). The company's services focus on generating patient-derived organoids (PDOs) for certain rare cancers to test drug therapy options. It was founded in 2017 and is based in Houston, Texas.

Netnoids Rx Laboratories

TMA Precision Health is a healthcare company. The company focuses on providing services for rare disease patients. The company offers comprehensive genome sequencing, reporting, and research tools to help patients and their doctors build personalized care plans. TMA Precision Health also provides a database of deidentified medical records and genomic sequencing for pharmaceutical companies and research partners. It was founded in 2019 and is based in Boston, Massachusetts.

TMA Precision Health

Wyss Institute

Microfluidic Innovations

Companies developing artificial intelligence solutions, including cross-industry applications, industry-specific products, and AI infrastructure solutions.

Artificial Intelligence

The digital health collection includes vendors developing software, platforms, sensor & robotic hardware, health data infrastructure, and tech-enabled services in healthcare. The list excludes pureplay pharma/biopharma, sequencing instruments, gene editing, and assistive tech.

Digital Health

Grant - II

Unravel Biosciences operates as a therapeutics company operating in the biotechnology and healthcare domain. The company focuses on developing new treatments for complex disorders by integrating artificial intelligence, systems biology computation, and rapid in vivo screening. It was founded in 2021 and is based in Boston, Massachusetts.

Name	Work History	Title	Status
Richard Novak	Wyss Institute, and Microfluidic Innovations	Founder, Chief Executive Officer	Current
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