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Cancer continues to be a big draw for biotech investors, and cancer research is well represented in the past week’s financing activity. Seven biotech companies announced financing rounds to support a range of tumor-targeting therapeutic approaches that include small molecules, oncolytic viruses, and peptide drugs. Peptides are the focus of FogPharma, which raised the largest financing round of the Thanksgiving holiday-shortened week. The Cambridge, Massachusetts-based biotech is developing a new class of peptide drugs that address therapeutic targets deemed “undruggable.” FogPharma is led by CEO Greg Verdine, a former Harvard professor who has become a biotech entrepreneur. Verdine is also chief executive of LifeMine Therapeutics, a GSK-partnered startup that analyzes fungal genes to discover new drugs. Arch Venture Partners and Invus are among the financial backers of LifeMine, and those firms also participated in FogPharma’s new $178 million round of funding. The Series D financing comes as the biotech prepares for its first clinical trial. The company says polypeptide drugs from its Helicon platform combine the targeting abilities of antibodies with the features of small molecule drugs: broad tissue distribution, intracellular target engagement, and oral dosing. Lead program FOG-001 is designed to block TCF-blocking beta-catenin to address a dysregulated signaling pathway found in an estimated 20% of all human cancers. In preclinical research, FogPharma says FOG-001 stopped tumor growth and led to tumor regression. The company plans to submit an investigational new drug application and start Phase 1 testing by mid-2023. The new capital will also support development of FogPharma’s preclinical pipeline, which addresses other biologically validated but elusive cancer drug targets such as TEAD, NRAS, Pan-KRAS, and Cyclin E1. Here’s a look at the other biotech financings for the past week: —Nearly three months after Roche reached a deal to acquire cancer drug developer Good Therapeutics in a $250 million deal, a spinout from the biotech called Bonum Therapeutics has raised $93 million in Series A financing. Seattle-based Bonum is developing cytokine cancer therapies for cancer therapies. These drugs will be conditionally activated, meaning that they will activate only when the antibody sensor component of the therapy binds to its target, which is intended to reduce toxicity. The technology that is the basis for Bonum’s drugs was validated by Good. Good’s financial backers, including Rivervest Venture Partners, Roche Venture Fund, Digitalis Ventures, 3×5 Partners, and Codon Capital, teamed up again for Bonum’s Series A financing, which added a new investor, Vivo Capital. —Clinical-stage CG Oncology closed a $120 million Series E financing. The Irvine, California-based biotech’s lead drug candidate, CG0070, is an oncolytic virus that has reached Phase 3 testing as a monotherapy for non-muscle invasive bladder cancer that does not respond to Bacillus Calmette-Guerin, the most common intravesical immunotherapy used for treating early-stage bladder cancer. A Phase 2 study is also underway testing CG0070 in combination with Merck immunotherapy Keytruda. CG Oncology said it will use the new capital to advance its lead programs toward FDA review and broaden its drug pipeline to address other unmet needs in urologic cancer. —CatalYM closed a €50 million Series C financing to expand Phase 2 clinical testing of its lead program, which is in development for treating solid tumors. The antibody drug candidate, visugromab, is engineered to neutralize Growth Differentiation Factor-15 (GDF-15), a tumor-produced protein that regulates immune cell activation and stops immune cells from infiltrating tumor tissue. Visugromab’s solid tumor test is evaluating the drug in combination with a type of immunotherapy that blocks the checkpoint protein PD-1. Preliminary data are expected in early 2023. Munich, Germany-based CatalYM’s new round of financing was co-led by Brandon Capital and Jeito Capital. —Casma Therapeutics closed $46 million in Series C financing to bring its lead program for MYD88 mutant lymphoma through the preclinical research that will support an investigational new drug application. The Cambridge, Massachusetts-based company develops therapies that leverage autophagy, a mechanism for recycling old or damaged cellular components. A similar approach called targeted protein degradation focuses only on proteins and peptides. But autophagy can address larger cellular components such as organelles. —Rezo Therapeutics, a University of California at San Francisco spinout that is developing new cancer drugs, launched with $78 million. The technology of the San Francisco-based company identifies how mutations rewire cancer-driving networks, using that insight to uncover tumor-specific drug targets. This tech platform comes from UCSF’s Quantitative Biosciences Institute. Rezo’s Series A financing was led by SR One, a16z Bio + Health, and Norwest Venture Partners. —Opna Bio, a startup developing cancer therapies acquired from Plexxikon, unveiled $38 million in Series A financing. The company’s co-founders include Douglas Hanahan, a distinguished scholar in the Lausanne Branch of the Ludwig Institute for Cancer Research and emeritus professor at the Swiss Federal Institute of Technology Lausanne. Opna’s launch and financing comes as research from Hanahan’s EPFL laboratory was published in the journal Science describing the role of fragile X mental retardation protein (FMPL) as an immuno-oncology target. Opna has licensed this FMPL technology. Longitude Capital and Northpond Ventures led the Series A round of Opna, which maintains operations in Lausanne, Switzerland, and South San Francisco. —In non-cancer biotech funding news, MBX Biosciences raised $115 million to develop therapies in a new class of peptide drugs, including a lead program in early-stage clinical development for hypoparathyroidism. Carmel, Indiana-based MBX says its precision endocrine peptides, or PEPS, overcome limitations of traditional peptide drugs. In addition to supporting lead PEP product candidate MBX 2109, MBX said the new capital will support its preclinical drug pipeline. The Series B round of funding was led by Wellington Management. —Bain Capital Life Sciences led a $107 million investment in Jnana Therapeutics as the biotech continues Phase 1 testing that could demonstrate clinical proof of concept for its lead program, a potential treatment for phenylketonuria. The inherited metabolic disorder leads to a deficiency of phenylalanine hydroxylase, an enzyme required to break down an amino acid called phenylalanine. Jnana’s drug, JNT-517, is small molecule designed to block phenylalanine reabsorption in the kidney, which in turn reduces blood levels of phenylalanine. Separate from Jnana’s Series C financing, the biotech announced a second collaboration with Roche focused on the discovery of small molecule drugs for cancer, immune-mediated diseases, and neurological disorders. The Swiss pharmaceutical giant is paying Jnana $50 million up front; milestone payments could reach up to $2 billion. Image by nopparit, Getty Images

LAUSANNE, Switzerland & SOUTH SAN FRANCISCO, Calif.--(BUSINESS WIRE)-- Opna Bio, a clinical-stage biopharmaceutical company focused on the discovery and development of novel oncology therapeutics, announced today that it has raised $38 million in a Series A financing, led by Longitude Capital and Northpond Ventures, with additional participation from Menlo Ventures. The proceeds will be used to develop novel fragile-X mental retardation protein (FMRP) inhibitors in oncology as well as a diverse portfolio of clinical and preclinical oncology programs acquired from Plexxikon Inc. This press release features multimedia. View the full release here: https://www.businesswire.com/news/home/20221121005179/en/ Opna was co-founded by Gideon Bollag, PhD, who was appointed chief executive officer; Douglas Hanahan, PhD, distinguished scholar in the Lausanne Branch of the Ludwig Institute for Cancer Research and emeritus professor at the Swiss Federal Institute of Technology Lausanne (EPFL); and Joseph Schlessinger, PhD, professor of pharmacology at Yale University School of Medicine. “We are thrilled to be a lead investor in Opna and to support this top-tier team of drug discovery and development experts who bring a strong track record of paradigm-changing cancer drug innovation and value creation,” said Patrick Enright, managing director of Longitude Capital. “I’m very excited about our rich drug candidate portfolio, which is focused on targeting immune suppression and other hallmarks of cancer,” said Dr. Bollag. “As a new company, Opna offers that rare combination of a compelling novel drug target as well as a diverse pipeline of preclinical and clinical programs, some of which have shown combinatorial activity in our FMRP models.” Novel FMRP Oncology Discovery Program Suggests Potential for Both Single Agent Use and Combination Therapy Opna’s launch coincides with a Science* publication from the Hanahan Laboratory EPFL about FMRP’s emerging role as an immuno-oncology target. In the paper, “Aberrant hyperexpression of the RNA binding protein FMRP in tumors mediates immune evasion,” Dr. Hanahan showed for the first time that knocking out or knocking down the FMRP gene in cancer cells enables the body to launch an immune response against tumors that are otherwise resistant to immune attack. Opna has an exclusive license for technology associated with FMRP from EPFL. Previous research has shown that FMRP expression is elevated in certain cancers, including pancreatic, colon, breast, prostate and lung cancer. Importantly, some of these cancers are largely resistant to immune checkpoint therapy, potentially because of suppression of proinflammatory signals associated with elevated FMRP. Data from the Hanahan Laboratory demonstrate that upregulated expression of FMRP in cancer cells suppresses the recruitment and capability of T cells to attack and kill tumors. Consequently, blocking FMRP expression resulted in T cell activation leading to anti-tumor immunity. The data also showed additional anti-tumor benefit when FMRP depletion was combined with immune checkpoint inhibitors. Acquisition of Plexxikon’s Oncology Assets Rounds Out Diversified Portfolio with Strong IP As part of Opna’s formation, the company acquired a portfolio of small molecule oncology therapeutics from Plexxikon Inc. The clinical-stage assets include: OPN-2853 (formerly PLX2853), a potential best-in-class bromo and extra terminal (BET) domain inhibitor currently in a Phase 1/2 clinical trial in combination with ruxolitinib (Jakafi®) for myelofibrosis, a rare myeloid cancer OPN-7486 (formerly PLX7486), a colony-stimulating factor 1 (CSF1) receptor inhibitor expected to begin a Phase 2 study in 2023 Pre-clinical programs include: E1A binding protein (EP300) inhibitor Cluster of differentiation 73 (CD73) inhibitor Transcriptional enhanced associated domain (TEAD) inhibitor Opna has assembled a top-tier team of experienced leaders and advisors. The executive leadership team includes: Gideon Bollag, PhD, chief executive officer. Dr. Bollag previously served as Plexxikon’s chief executive officer. Under his scientific leadership, the team developed two FDA-approved drugs, Zelboraf® for metastatic melanoma and Turalio® for tenosynovial giant cell tumor (TGCT). Dr. Bollag was also a member of the founding scientific team at Onyx Pharmaceuticals, where he oversaw Onyx support for the discovery of Nexavar® and Ibrance®. He serves on the external advisory board of the NCI RAS initiative and on the scientific advisory board at Ambagon Therapeutics. Dr. Bollag received his PhD in biochemistry from the University of California, Berkeley. Reinaldo Diaz, chief business officer. Mr. Diaz brings more than 30 years of investment, financing and business development expertise. He concurrently serves as a venture partner at Longitude Capital and previously served as managing director of Auven Therapeutics, a life sciences private equity firm. He is a member of the board of Inozyme Pharma and Lexeo Therapeutics. Mr. Diaz received his undergraduate and MBA degrees from Harvard University. Gaston Habets, PhD, chief development officer. Previously, Dr. Habets was senior director of research at Plexxikon, where he helped spearhead the discoveries of Zelboraf® and Turalio®. Prior to Plexxikon, he held scientific leadership positions at Syrrx and Onyx Pharmaceuticals. Dr. Habets received his PhD in tumor biology from the Netherlands Cancer Institute. Jackie Walling, MBChB, PhD, chief medical officer. Dr. Walling brings extensive experience in global clinical development of oncology and rare disease drugs, most recently serving as chief medical officer for Plexxikon. She was previously vice president, clinical development at BioMarin. She received her PhD in biology from the University of Southampton, UK and her MBChB from the University of Bristol. The Opna Board of Directors includes: Joseph Schlessinger, PhD, chairman of the board, professor of pharmacology at Yale University, current and previous strategic affiliations with Sugen, Plexxikon, Kolltan and Inozyme Gideon Bollag, PhD, chief executive officer, former CEO of Plexxikon and founding member of Onyx Pharmaceuticals Patrick Enright, managing director, Longitude Capital Shaan C. Gandhi, MD, DPhil, director, Northpond Ventures Douglas Hanahan, PhD, distinguished scholar, Ludwig Institute for Cancer Research, and emeritus professor, Swiss Federal Institute of Technology Lausanne Brian Pusch, JD, chairman and CEO, Microbes, co-founder of Inozyme Pharma The Scientific Advisory Board (SAB) includes: Douglas Hanahan, PhD, chairman of the SAB, distinguished scholar, Ludwig Institute for Cancer Research, and emeritus professor, Swiss Federal Institute of Technology Lausanne (EPFL) Benjamin Cravatt, PhD, professor, Scripps Research Institute; co-founder of Activx Biosciences, Abide Therapeutics and Vividion Therapeutics Robert Darnell, MD, PhD, professor and senior physician at Rockefeller University Frank McCormick, PhD, professor and chair of tumor biology and cancer research, UCSF Cancer Center; current and previous strategic affiliations with Chiron, Onyx, BridgeBio, Olema, Avidity Joseph Schlessinger, PhD, professor of pharmacology at Yale University, current and previous strategic affiliations with Sugen, Plexxikon, Kolltan and Inozyme Berta Strulovici, PhD, former director of The Israel National Center for Personalized Medicine at Weizmann Institute of Science, iPierian, Merck & Co About Longitude Capital Longitude Capital is a leading healthcare venture capital firm that invests in transformative biotechnology, medical technology, and health solutions companies seeking to improve clinical outcomes, enhance quality of life, and drive efficiency of healthcare delivery. Founded in 2006, Longitude Capital invests in both privately held and publicly traded companies through a variety of investment approaches. Longitude Capital has offices in Menlo Park, CA, Greenwich, CT, and Boston, MA. For more information, please visit longitudecapital.com or LinkedIn. About Northpond Ventures Northpond Ventures is a multi-billion dollar science-driven venture capital firm based in Cambridge, MA; San Francisco, CA; and Bethesda, MD. Northpond has consistently been named one of the most active lead life science investors by both Crunchbase and Silicon Valley Bank. It is deeply engaged in the academic ecosystem, having founded The Laboratory for Bioengineering Research and Innovation at Harvard’s Wyss Institute; launched the MIT-Northpond Program created to advance innovation in engineering and life sciences; and sponsored a prize for women entrepreneurs at MIT. It has led or co-led over 60 financings over the past several years, and sits on the board of the vast majority of these businesses. Learn more at npv.vc. About Menlo Ventures Menlo Ventures helps founders transform existing industries, create new categories, and build a better future. In 45 years of investing, Menlo Ventures has backed 75+ public companies and in the process, grown a portfolio that includes 160+ M&A and $5+ billion under management. Menlo Ventures invests at every stage, from seed to series A+B to inflection points with focus in consumer, enterprise, and healthcare technologies. For more information, visit menlovc.com. About Opna Bio Opna Bio is a clinical-stage biopharmaceutical company focused on the discovery and development of novel oncology therapeutics. The company’s broad portfolio targets multiple drivers of cancer, including a novel oncology discovery program focused on the fragile-X mental retardation protein (FMRP) and a diversified pipeline of validated oncology assets acquired from Plexxikon. The Opna team has a proven track record of scientific expertise and commercial value creation, having advanced multiple FDA-approved drugs to market. In addition to its discovery-stage FMRP program, Opna’s lead clinical compound, OPN-2853, a bromo and extra terminal (BET) domain inhibitor, is currently in a Phase 1/2 trial with ruxolitinib (Jakafi®) in myelofibrosis, a chronic bone marrow disorder. The company also expects to initiate a Phase 2 study with OPN-7486, a colony stimulating factor 1 (CSF1) receptor inhibitor, in 2023. For more information, please visit opnabio.com.

Scientists have identified a key protein that helps tumors evade attacks by the immune system, contributing to poor responses to immunotherapy in the clinic. Immunotherapy is a cutting-edge approach to treating cancer by turning the patient's own immune system against their tumor. Our increasing knowledge of the mechanisms by which the body regulates immune responses has been transformative to our fight against cancer. But despite success rates, immunotherapy has time and again met with a stubborn obstacle: tumor cells often evade the "radar" of immune cells seeking to destroy them. This in turn leads to treatment resistance, which in many cases would benefit from a deeper understanding of mechanisms that can help circumvent it. A new study led by scientists at EPFL has now uncovered a protein that plays a key role in helping tumors evade immune destruction. The protein, named "fragile X mental retardation protein" (FMRP), regulates a network of genes and cells in the tumor microenvironment that contribute to its ability to "hide" from immune cells. Normally, FMRP is involved in regulating protein translation and the stability of mRNA in neurons. But the researchers found that it is aberrantly up-regulated in multiple forms of cancer. The study, published in Science, was led by researchers in the group of Douglas Hanahan at the Swiss Institute for Experimental Cancer Research (ISREC) and the Lausanne Branch of the Ludwig Institute for Cancer Research, along with colleagues from the University Hospital of Lausanne (CHUV) and other Swiss institutions. The discovery has also led to an EPFL spin-off, Opna Bio, whose staff were also involved in the research. But why FMRP? The idea came from previous studies showing that cancer cells that naturally overexpress FMRP are invasive and metastatic. Other studies show that if, in contrast, FMRP fails to be expressed in developing neurons it can lead to cognitive defects (hence the "mental retardation" part of the protein's name). With this evidence in mind, the researchers set off to investigate the expression of FMRP in human tumors. They then assessed its tumor-promoting functions in mouse models of cancer, and finally studied its association with prognosis for human cancer patients. The study involved several data-gathering steps. First, the scientists performed immunostaining for FMRP on tissue from human tumors. The majority of the tumors tested positive, while corresponding normal tissue did not. This meant that FMRP is specifically and highly expressed in cancer cells. The team then moved onto the main part of their research, which was to determine the functional significance of FMRP in those tumors -they express the protein, but what does it do? FMRP is involved with the immune system To explore this, the scientists developed lines of so-called "knockout" cancer cells. Knockout cells or organisms are genetically engineered to lose -- "knock out" -- a specific gene in order to find clues about its function. Essentially, whatever change occurs in knockout cells compared to cells that still have the gene -- called "wild-type"- can generally be traced back to the missing gene. In this case, the scientists used the famous CRISPR-Cas9 gene-editing technique to knock out the gene (called FMR1) that produces FMRP in mouse cancer cells arising from pancreas, colon, breast, and skin melanocytes. They then compared the FMRP-knockout cancer cells to cancer cells that still had the FMR1 gene and thus expressed the FMRP protein. The researchers evaluated survival rates between mice with tumors containing FMRP-knockout cancer cells and those with FMRP-wild-type cells, first in mice whose immune systems had been compromised. The comparison revealed similar survival rates. In notable contrast, when they compared the knockout tumors to wild-type tumors growing in mice with properly functioning immune systems, they found that tumors without FMRP were growing slower, and the animals survived longer. What this part of the study showed was that that FMRP is not involved in stimulating tumor growth per se, and rather implicated the adaptive immune system (the part of our immune system that we "train" with vaccines). This was further confirmed by the observation that wild-type tumors had very few infiltrating T lymphocytes, whereas knockout tumors were highly inflamed. Depleting T cells from the FMRP-knockout tumors caused them to start growing more rapidly and reduced the survival rates of the mice, meaning that FMRP is somehow involved in tumors evading the immune system. How tumors with FMRP defend against immune cells The team continued with molecular genetic profiling of both knockout and wild-type tumors. This revealed significant differences in gene transcription across the entire genome, suggesting that FMRP interacts with multiple genes. In addition, the tumors showed marked differences in the abundance of cancer cells, macrophages, and T cells, further implicating the role of FMRP in modulating components of the immune system. The next phase of the study looked at the production of specific factors associated with the distinctive immune responses -- evasion vs. attack. The tumors expressing FMRP were found to produce interleukin-33, a protein that induces the production of regulatory T cells, a specialized subpopulation of T cells that inhibit immune responses. They also produce protein S, a glycoprotein that is known to promote tumor growth. Finally, the tumors produce exosomes -- cell organelles that proved to trigger the production of a type of macrophage cell that normally helps with wound healing and tissue repair. Collectively, all three factors are immunosuppressive and contribute to the tumor's barrier against attacks from T lymphocytes. In contrast, the FMRP knockout tumors cells actually downregulated all three factors (interleukin-33, protein S, and exosomes) while they up-regulated a different chemokine called "C-C motif chemokine ligand 7" (CCL7), which helps recruit and activate T cells. This process is further aided by inducing immunostimulatory (and not immunosuppressive) macrophages. These cells produce three other proinflammatory proteins that work with CCL7 in recruiting T cells. Predicting immunotherapy outcomes in human patients In a clinical context, the question is whether levels of FMRP can help form a prognosis for patients undergoing immunotherapy. Counterintuitively, both mRNA of the FMR1 gene and FMRP protein levels were insufficient for predicting outcomes in cohorts of cancer patients. To address this, the researchers built on the fact that, in the cell, FMRP up- and down-modulates the stability of mRNA by binding it directly. This means that FMRP might change RNA levels that could be picked up in transcriptome datasets, which could be collected to define a "gene signature" to help track its functional activity. The approach worked, allowing the scientists to track a gene signature of FMRP's cancer regulatory activity with a network of 156 genes. The FMRP cancer network activity signature proved to be prognostic for poor survival across multiple human cancers, consistent with the immunosuppressive effects of FMRP, and, in some patients, it was linked to poor responses to immunotherapy treatments. The work shows that FMRP regulates a network of genes and cells in the tumor microenvironment, all of which help tumors to evade immune destruction. Douglas Hanahan says: "Having studied the complex cellular composition of solid tumors for decades, I am personally astonished by our discovery that a co-opted neuronal regulatory protein -- FMRP -- can orchestrate the formation of a multi-faceted protective barrier against attack by the immune system that consequently limits the benefit of immunotherapies, thereby presenting FMRP as a new therapeutic target for cancer." Other contributors