Welcome to another edition of our Sponsor Atlas series, which focuses on startups and young pharmaceutical and biotechnology companies that are in early stages or stealth mode. In this edition of Sponsor Atlas: Discovering Biotech Startups, we’re looking at Twentyeight-Seven Therapeutics, Inc., and exploring the current affairs and future orientation of this emerging Massachusetts - based stealth biotech startup. To accomplish this, we will give a business overview of their current operations, summarize their outsourcing needs, map out their development goals and decision-makers, and highlight their current strategies for capturing innovation. If you haven’t already read our other blogs on new biotech startups, be sure to check them out here.
Twentyeight-Seven Therapeutics (28-7) are explorers leading the revolution in RNA drug discovery to develop an entirely new class of therapies, beginning with a novel pipeline of microRNAs designed to target regulatory proteins. The company is modulating short non coding RNAs that inhibit target gene expression by suppressing mRNA translation and promoting mRNA decay, to in turn develop small molecules that can modulate levels of miRNAs by targeting proteins that interact with these miRNAs. This enables users to target miRNAs directly involved in cancer initiation, progression, and metastasis. 
Twentyeight-Seven Therapeutics is a start-up focused on the modulation of non-coding RNA functions to treat cancer and other human diseases. The company is targeting RNA modulating proteins to use small molecules to control the expression levels of oncogenes and other valuable proteins. Twentyeight-Seven Therapeutics has a fully developed website, loaded with information about their executive team, product development, and R&D pipeline. The company was established in Delaware as a C-Corp on 4/7/2016, and they are currently categorized as doing work under Biotechnology & Drug Development. Twentyeight-Seven Therapeutics’s principal place of business, as noted on their website, is located at 490 Arsenal Way, Unit 100B, Watertown, MA 02472, as well as having a registered agent address located in Cambridge, MA. Data also shows that the company has an annual revenue of <$1M, and employs a staff of approximately 11-50.
In 2018, 28-7 announced the successful completion of its $65M Series A financing, with MPM Capital and Novartis Venture Fund co-leading the financing. They were joined by additional investors including Johnson & Johnson Innovation, Vertex Ventures HC, Longwood Fund, and Astellas Venture Management. The funding will be used to advance 28-7’s lead program, aimed at the discovery and development of small molecules that increase the levels of the tumor suppressor microRNA (miRNA), Let-7, into serious cancer indications. Twentyeight-Seven Therapeutics has raised a total of $80M in funding over 3 rounds. Their latest funding of $15M was raised on May 9, 2019, from a Series A round as well. 
“This strong financing round was achieved thanks to the new biological understanding and impressive scientific data around non-coding RNA produced by our four scientific founders and the progress the 28-7 team has made since it was founded two years ago,” said Kazumi Shiosaki, Ph.D., founding President and Chief Executive Officer, 28-7. “Our experienced investors realize the promise in this new field of therapeutics and in the robust leads produced by our founders, who have made many of the seminal discoveries in this field, and by the exceptional scientists within the company.” 
There isn’t much online information about 28-7’s outsourcing needs, but their huge amount of venture funding ($80M+) suggests that the company is well on their way to launching a unique development pipeline with innovative and potentially valuable discoveries in miRNA based therapeutics. 28-7 Therapeutics is at an early point in their development pipeline and they will be working through the usual steps before reaching the IND stage with potential products. As mentioned above, their prospective pipeline consists of therapies focused on the modulation of functional non-coding RNA to treat cancer and other human diseases. By targeting these RNA modulating proteins, the research team can then use small molecules to modulate expression levels of oncogenes and other proteins of significance in the disease. Any experience in modulating miRNAs by targeting proteins and the technologies surrounding it would be of tremendous benefit to 28-7 at this point.
We think business development teams in the realms of pilot scale CMOs, preclinical CROs with experience in cancerous animal model development, and bioanalytical service providers with expertise in modulating functional non-coding RNA should definitely contact 28-7 Therapeutics for potential outsourcing work in the near future.
The company’s core technology comes from the four founding scientists, all leading researchers in the fields of RNA biology and cancer. As mentioned before, 28-7’s initial focus is on modulating miRNAs, which are short ncRNAs that inhibit target gene expression by suppressing mRNA translation and promoting mRNA decay. It is now well recognized that miRNAs are directly involved in multiple activities of disease progression. 28-7’s technology does not focus on directly targeting the RNA itself or on developing oligonucleotides, but rather targets RNA modulating proteins (RMPs), enabling the use of small molecule drug candidates with broader access to cells and tissues. Specifically, Let-7 is an miRNA that suppresses the translation of oncogenes in cells, and low levels of this miRNA are correlated with greater cancer aggressiveness. The company’s leading protein target is LIN28, an RMP that reduces the levels of Let-7 is an oncogene, promoting cellular transformation as well as tumorigenesis. Bases on this early research, 28-7 is developing first-in-class drugs that inhibit Lin28’s activity and thus raise levels of Let-7 for the treatment of various cancers.
Rather than attempt to drug RNA directly, 28-7’s platform builds on the extensive tradition of drugging proteins. They carefully select those proteins that bind regulatory RNAs to achieve simultaneous suppression of multiple oncogenic pathways, as well as a wide safety margin by working on RNA-binding proteins that are up-regulated or re-expressed in cancer but are absent or limited in healthy cells. To review, 28-7’s lead target is LIN28, a highly evolutionarily conserved RNA-binding protein involved in determining cell fate during embryogenesis of many organisms, including humans. LIN28 is largely absent in healthy individuals, but is re-expressed in certain cancers and reactivates multiple oncogenes by reducing the level of Let-7, a microRNA. In some cancers, LIN28 is re-expressed, binds to pre-Let-7, and targets it for degradation, thereby decreasing Let-7. Oncogenes, such as MYC, KRAS, and HMGA2, are coordinately re-expressed. Analysis of clinical samples from multiple tumor types shows a strong correlation between high LIN28 and/or low let-7 and decreased survival. Not surprisingly, restoring high Let-7 levels reverses tumor growth in some of 28-7’s early in vitro and in vivo studies. Analysis of clinical samples from multiple tumor types shows a correlation between high LIN28 (or low Let-7) and decreased survival. Also not surprisingly, inhibition of the pathway reverts cancer cells in their preclinical models. 
Nearly two decades of research has shown that the LIN28 pathway centrally controls many oncogenic pathways via its dysregulation of Let-7, a key tumor suppressor.  By restoring beneficial levels of Let-7, 28-7’s programs have the potential to inhibit many cancer pathways simultaneously, which is a more robust approach than the single target agents currently deployed by other companies. The LIN28 / Let-7 pathway is also dysregulated in other serious non-oncology diseases with high unmet needs, such as metabolic, auto-immune, and cardiovascular diseases. While 28-7’s current focus is on oncology, they are also seeking partners to explore many other therapeutic areas, with the main goal of becoming a leader in the therapeutic regulation of RNA. Beyond the LIN28 pathway, they are developing compounds to other novel RNA-binding proteins as well.
Recent science has cast a new light on RNA as a fundamental regulator of diverse cellular processes, including development, differentiation, growth, and metabolism. Just as cancer exploits these fundamental mechanisms to dysregulate these important RNA regulators to cause disease, 28-7 in innovatively targeting key RNA regulators to reverse the disease process. Traditional cancer drugs work by shutting down a single cellular pathway to halt or slow the growth of a cancer cell. However, cancer cells use many oncogenic pathways to maintain their aggressive growth and can activate new pathways over time. Hence, these cellular pathways may also be used, but to a lesser extent, by healthy cells, so patients may suffer from potentially severe drug toxicities by the same drugs intended to treat their cancer.
Alternatively, 28-7’s therapeutic goal is fundamentally different. Their first program is designed to amplify multiple pathways that maintain a cell’s normal, differentiated phenotype. In a cancer cell context, activating these pathways reverses tumor growth. To put it simply, 28-7 is fighting cancer by restoring a healthy state, and they have set their first sights on cancer, an incredibly difficult disease to cure, dynamically evolving against the drugs used to treat it. Despite annual approvals of new cancer therapies, cancer remains the second leading cause of death in the U.S.  Unfortunately, relapse is common. Over time, cancer can activate multiple processes to become more and more aggressive, and potentially resist multi-drug regimens, and this is where 28-7’s therapeutic platform will potentially shine.
“Our founders have made important scientific contributions to the field of ncRNA biology, including the discovery of the Lin28/Let-7 pathway and its role in normal development, metabolism, and malignancy. Overall, our studies have established Lin28/Let-7 as a major regulatory pathway in stem cells and cancer,” said George Daley. “We felt that the time was right to move these insights from the laboratory to pharmaceutical development, and we are very pleased by the progress the company achieved in the first two years of its existence. With this impressive round of funding and continued support, 28-7 will unlock the therapeutic potential of our work.” 
If you would like a simple solution for keeping an eye on drug sponsor companies, like 28-7 Therapeutics, without relying on a database and generic lists of leads each week, we at Zymewire are here to help. Reach out today, and stay tuned for the next installment of the Sponsor Atlas: Discovering Biotech Startups. If you enjoy these articles, please feel free to give them a share through the social links below!