FLI1

-Pilot study in Ewing's Sarcoma supports the therapeutic potential of Vigil in multiple solid tumor types- -Circulating tumor DNA levels, used to monitor therapeutic response, corresponded to changes in disease burden- -Vigil in combination with temozolomide/irinotecan had a favorable safety and tolerability profile- DALLAS, March 14, 2023 (GLOBE NEWSWIRE) -- Gradalis, Inc., a privately held, late-stage clinical biotechnology company developing a personalized immunotherapy called Vigil® for patients with ovarian and other cancer tumor types, today announced that data from a pilot study evaluating Vigil in combination therapy for the management of recurrent Ewing’s Sarcoma was published online in Clinical Cancer Research. Study results demonstrated the efficacy of Vigil in combination with temozolomide/irinotecan (TEM/IRI) in recurrent Ewing’s patients who had failed prior TEM/IRI treatment. In this study, changes in circulating tumor DNA (ctDNA) levels, an assessment used to monitor therapeutic response, corresponded to changes in disease burden. Furthermore, the combination of Vigil/TEM/IRI had a favorable safety and tolerability profile. These results build on Gradalis’ earlier Phase 1 studies involving 19 solid tumor types, as well as the Phase 2a and Phase 2b studies in patients with ovarian cancer, which have all shown positive activity in solid tumors. Vigil is a novel, personalized cellular immunotherapy platform that is designed to decloak the full repertoire of a patient’s tumor antigens, reactivate the immune system, and summon key effector cells, like T cells, to deliver a durable clinical response. “While treatment options for recurrent or refractory Ewing’s Sarcoma are limited, we are encouraged by the potential of Vigil in combination with TEM/IRI to contribute to antitumor activity and address the unmet need for these patients,” John Nemunaitis, M.D., Chief Scientific Officer of Gradalis. “Results in this publication demonstrated the efficacy of Vigil in combination with TEM/IRI, which was highlighted by corresponding changes in ctDNA levels. This builds on our previous research involving multiple recurrent disease patients who achieved 75% one-year survival compared to historical expected survival of only 23%. Together with the growing safety data, results support future evaluation of Vigil-based combinations in multiple solid tumor types and use of sensitivity biomarkers to track disease response. We look forward to further utilizing ctDNA assessment tools in our Ewing’s Sarcoma investigation and beyond.” Key takeaways in the paper include: Overview: This was a pilot study of Vigil in combination with TEM/IRI in patients with recurrent or refractory Ewing’s Sarcoma. Eight of 10 enrolled patients were evaluable for safety and efficacy, two did not receive Vigil. Seven of eight patients previously received TEM/IRI.Efficacy: Observed two partial response (PR) patients by RECIST, both showed histological complete response (CR) without additional cancer therapy at long term follow up. Median PFS was 8.2 months (95% CI, 4.3-NA). Five of eight patients showed stable disease (SD) or better for ≥ 6 months.Patient specific EWS/FLI1 ctDNA was detectable in all eight evaluable patients at baseline.Changes in ctDNA levels corresponded to changes in disease burden. Safety: No Vigil-related ≥ Grade 3 adverse events were reported. About Ewing’s Sarcoma Ewing’s Sarcoma is a malignant tumor of the bone and surrounding soft tissues occurring predominantly in young adults. It is classified as a peripheral neuroectodermal tumor (PNET) and is defined by specific chromosomal translocations resulting in gene fusions of EWSR1 with FLI1, ERG, and other transcription factors. Five year overall survival for patients receiving standard of care with recurrent metastatic Ewing’s Sarcoma is less than 15%. Median overall survival with temozolomide/irinotecan approaches 12 months but is typically much lower after failure of this approach. About Gradalis, Inc.Gradalis is a privately held, late-stage clinical biotechnology company developing a personalized immunotherapy called Vigil, that has been tested in multiple studies in ovarian and other cancer tumor types. The company has received clearance from the FDA to initiate a Phase 3 trial designed for product registration of Vigil in patients with advanced ovarian cancer. Vigil is the first cellular immunotherapy to demonstrate survival benefits in a randomized controlled trial of ovarian cancer patients. The results of the company’s Phase 2b trial have been published in Lancet Oncology and presented at the American Society of Clinical Oncology. Vigil is being studied in other cancer types and has shown positive results in combination with checkpoint inhibitors. Gradalis’ Vigil platform uses the patient’s immune system to target the entire tumor. Based on multiple clinical studies, Gradalis has developed an oncology platform that is designed to decloak the full repertoire of a patient’s tumor neoantigens, reactivate the immune system, and summon key effector cells to deliver a durable clinical response. When combined, these are a powerful Trifecta of anti-cancer activities, potentially eliminating even the elusive metastatic cells, and as shown in Phase 2 clinical studies in ovarian cancer, a potential gamechanger in oncology. Clinical trials of Vigil have also demonstrated that Gradalis’ platform is better tolerated compared to standard cancer treatments since Vigil uses the patient’s immune system operating within its natural state of balance rather than in an artificial overdrive as with some technologies. Vigil utilizes proprietary bi-shRNA technology that has been proven to silence multiple genes in a variety of cancers and has the potential to be used in other diseases. About VigilVigil® is a novel, personalized immunotherapy platform designed to achieve a Trifecta of immune anticancer activity using a unique bi-shRNA DNA based plasmid and the patient’s own tumor tissue. The Trifecta of systemic activity involves knock down of TGFβ1 and TGFβ2 which function as tumor suppressor cytokines, increased GM-CSF expression to enhance local immune function and presentation of the patient’s clonal neoantigen epitopes via use of autologous cancer tissue. By utilizing the patient's own tumor as the antigen source, Vigil is designed to elicit an immune response that is specifically targeted and broadly relevant to each patient's unique “clonal” tumor neoantigens. Vigil therapy has been well tolerated in Phase 1, 2a and 2b clinical studies. In VITAL, a multicenter, randomized, double-blind, placebo-controlled Phase 2b trial (NCT02346747), Vigil showed a positive trend in the primary endpoint of recurrence free survival (RFS) in the overall population and a statistically significant improvement in RFS and overall survival (OS), with a median time of three years to date, in a pre-planned subgroup analysis of Stage III/IV newly diagnosed ovarian cancer patients with the BRCAwt molecular profile. In patients with tumors of the HRP type, significant additional improvement was seen in RFS and OS. Additionally, Phase 1 results in a “basket” clinical trial have shown positive signals of activity in 19 tumor types and some patients treated with Vigil remain in the trial 48 months later. The company is preparing to initiate a clinical trial intended for product registration in patients with the HRP subtype ovarian cancer. Gradalis ContactMark Early(214) 442-8161mearly@gradalisinc.com Life Sci Advisors ContactJoyce Allaire+1 (617) 435-6602jallaire@lifesciadvisors.com

SAN DIEGO, Nov. 15, 2021 (GLOBE NEWSWIRE) -- Oncternal Therapeutics, Inc. (Nasdaq: ONCT), a clinical-stage biopharmaceutical company focused on the development of novel oncology therapies, today announced updated interim clinical data from the Phase 2 expansion cohort of its ongoing Phase 1/2 clinical trial evaluating ONCT-216 (formerly TK216), an investigational, potentially first-in-class, targeted small-molecule inhibitor of the E26 transformation-specific (ETS) family of oncoproteins, in patients with relapsed or refractory Ewing sarcoma. The data update was delivered in an oral presentation at the Connective Tissue Oncology Society (CTOS) 2021 Virtual Annual Meeting. Session Title: Session 12: Ultra-Rare and Translocation Sarcomas Session Date: Saturday, November 13, 2021 Presentation Title: Paper 74 - TK216 FOR EWING SARCOMA- INTERIM PHASE 1/2 RESULTS A copy of the presentation will be accessible on the Events & Presentations page of the Investors section on the Company’s website at investor.oncternal.com. “We remain encouraged by the two complete responses to ONCT-216 in heavily pre-treated patients with relapsed or refractory Ewing sarcoma, including one patient who had a durable CR for 24 months on treatment, and remains with no evidence of disease off of all treatments for several months,” said James Breitmeyer, M.D., Ph.D., Oncternal’s President and CEO. “We believe that an intensified dosing schedule, which we are investigating in a new study cohort that is now enrolling, holds promise to address the significant unmet needs for patients suffering from this devastating disease.” ONCT-216 remains generally well tolerated. As of the October 1, 2021 data cutoff date, the most common drug-related adverse events included myelosuppression, fatigue, alopecia, nausea, pyrexia, and decreased appetite. The myelosuppression was primarily neutropenia, which was transient and readily managed. No unexpected off-target toxicities have been observed. About Ewing sarcoma Ewing sarcoma is the second most common bone tumor among children and adolescents. The median age at diagnosis of patients with Ewing sarcoma is 15, the incidence is about 3 cases per 1 million per year in children under the age of 20 and about 1.3 cases per 1 million overall in the U.S. and prevalence is about 12 per million people overall in the US. Nearly all Ewing sarcoma cases are driven by translocations of ETS family oncogenes, including 85-90% of cases driven by the EWS-FLI1 fusion, and approximately 10% by EWS-ERG. Patients diagnosed with metastatic disease have five-year survival rates between 18% and 30%. The prognosis for patients with recurrent Ewing sarcoma is particularly poor, and five-year survival after recurrence is approximately 10 to 15%. About ONCT-216 ONCT-216 is an investigational, potentially first-in-class, targeted small-molecule inhibitor of the E26 transformation-specific (ETS) family of oncoproteins including fusion proteins. Tumorigenic fusion proteins involving the EWS protein and an ETS protein can be found in most cases of Ewing sarcoma. ETS-related translocations or overexpression are also found in many other tumors such as diffuse large B-cell lymphoma (DLBCL), prostate cancer and acute myeloid leukemia (AML). ONCT-216 was developed based on discoveries in the laboratory of Jeffrey Toretsky, M.D., at Georgetown Lombardi Comprehensive Cancer Center, who discovered inhibitors of EWS-FLI1 using a novel chemical screening assay. In preclinical models, ONCT-216 was observed to bind to EWS-FLI1, blocking the interaction between this fusion protein and other transcriptome proteins such as RNA helicase A, leading to tumor cell apoptosis and inhibiting tumor growth in animal models. The U.S. Food and Drug Administration (FDA) has granted Rare Pediatric Disease Designation, Orphan Drug Designation and Fast Track Status to ONCT-216 for the treatment of Ewing sarcoma. ONCT-216 is an investigational medication that has not been approved by the FDA for any indication. About the Study ONCT-216 is being evaluated in a Phase 1/2 clinical study as a single agent and in combination with vincristine in heavily pretreated patients with relapsed or refractory Ewing sarcoma, a rare pediatric cancer with no standard treatment available after first-line chemotherapy. The current Phase 2 expansion cohort targeting up to 21 evaluable Ewing sarcoma patients is active and enrolling patients, designed to evaluate clinical responses to single agent ONCT-216 using an optimized dosing regimen, treating for 28 days per cycle, to intensify the amount of ONCT-216 administered over time. This multi-center study is currently enrolling patients at nine clinical trial centers across the U.S. Additional information about the ONCT-216 study may be accessed at ClinicalTrials.gov (NCT02657005). About Oncternal Therapeutics Oncternal Therapeutics is a clinical-stage biopharmaceutical company focused on the development of novel oncology therapies for the treatment of cancers with critical unmet medical need. Oncternal focuses drug development on promising, yet untapped biological pathways implicated in cancer generation or progression. The clinical pipeline includes zilovertamab (formerly cirmtuzumab) an investigational monoclonal antibody designed to inhibit the ROR1 pathway, a type I tyrosine kinase-like orphan receptor, that is being evaluated in a Phase 1b/2 clinical trial in combination with ibrutinib for the treatment of patients with mantle cell lymphoma (MCL) and chronic lymphocytic leukemia (CLL) and in an investigator-sponsored, Phase 1b clinical trial in combination with paclitaxel for the treatment of women with HER2-negative metastatic or locally advanced, unresectable breast cancer, as well as a Phase 2 clinical trial of zilovertamab in combination with venetoclax, a Bcl-2 inhibitor, in patients with relapsed/refractory CLL. Oncternal is also developing ONCT-808, a chimeric antigen receptor T cell (CAR-T) therapy that targets ROR1, which is currently in preclinical development as a potential treatment for hematologic cancers and solid tumors. The clinical pipeline also includes ONCT-216 (formerly TK216), an investigational targeted small-molecule inhibitor of the ETS family of oncoproteins, that is being evaluated in a Phase 1/2 clinical trial for patients with Ewing sarcoma alone and in combination with vincristine chemotherapy. The early-stage pipeline also includes ONCT-534 (formerly GTX-534), a dual-action androgen receptor inhibitor, that is in pre-clinical development as a potential treatment for castration resistant prostate cancer and other androgen-receptor dependent diseases. More information is available at . Forward-Looking Information Oncternal cautions you that statements included in this press release that are not a description of historical facts are forward-looking statements. In some cases, you can identify forward-looking statements by terms such as “may,” “will,” “should,” “expect,” “plan,” “anticipate,” “could,” “intend,” “target,” “project,” “contemplates,” “believes,” “estimates,” “predicts,” “potential” or “continue” or the negatives of these terms or other similar expressions. These statements are based on Oncternal’s current beliefs and expectations. Forward-looking statements include statements regarding the potential for ONCT-216 dosing changes to address unmet medical needs. Forward-looking statements are subject to risks and uncertainties inherent in Oncternal’s business, including risks associated with the clinical development and process for obtaining regulatory approval of Oncternal’s product candidates, such as potential delays in the commencement, enrollment and completion of clinical trials; the risk that results seen in a case study of one patient likely will not predict the results seen in other patients in the clinical trial; the risk that interim results of a clinical trial do not predict final results and that one or more of the clinical outcomes may materially change as patient enrollment continues, following more comprehensive reviews of the data, as follow-up on the outcome of any particular patient continues, and as more patient data become available; and other risks described in Oncternal’s filings with the U.S. Securities and Exchange Commission. All forward-looking statements in this press release are current only as of the date hereof and, except as required by applicable law, Oncternal undertakes no obligation to revise or update any forward-looking statement, or to make any other forward-looking statements, whether as a result of new information, future events or otherwise. All forward-looking statements are qualified in their entirety by this cautionary statement. This caution is made under the safe harbor provisions of the Private Securities Litigation Reform Act of 1995. Investors Richard Vincent Chief Financial Officer 858-434-1113 rvincent@oncternal.com Media Corey Davis LifeSci Advisors 212-915-2577 cdavis@lifesciadvisors.com

Every week there are numerous scientific studies published. Here’s a look at some of the more interesting ones. A Completely Sequenced Human Genome (Probably) When the results of the Human Genome Project were announced in 2000, it was a rough draft of the human genome. About 8% was missing, largely because of the technology used at the time. No one has completely sequenced the human genome since, at least until now (probably). An international research consortium co-led by the University of California, Santa Cruz, recently reported they had completely sequenced the human genome, although it has not yet been published, and Karen Miga, a researcher at UCSC, indicated she won’t consider it official until the paper is peer-reviewed and published in a technical journal. It was published on a pre-print server, bioRxiv. Earlier technology, using Illumina sequencers, took small fragments of DNA, sequenced them, then reassembled them. This works well for the majority of the genome, but not in parts of the DNA that is made up of long repeating patterns. For example, if a sequence that was AGAGAGA went on for hundreds of base pairs, that approach doesn’t work well. The new technology, developed by Pacific Biosciences (PacBio) and Oxford Nanopore, doesn’t cut the DNA. The PacBio sequencers leverage lasers to analyze the same DNA sequence over and over, creating a highly accurate readout. The Oxford Nanopore runs the DNA through a minuscule hole, forcing it into a very long sequence. Although long repeating units of DNA were often viewed as “non-coding,” no one really knows. And one very interesting aspect of these repeating areas is they make up the centromeres, the bundles of DNA that hold chromosomes together and play a significant role in cell division. Miga remembers asking, as a graduate student, “Why are the regions that are so fundamental to life, so fundamental to how the cell operates, positioned over parts of our genome that are these giant seas of tandem repeats?” And it was that question that led to her and NIH researcher Adam Phillippy, forming the consortium and the initiative, called the Telomere 2 Telomere Consortium in 2019. Ewing Sarcoma Finding Might Prevent Tumor Metastases Researchers at the University of British Columbia found that Ewing sarcoma cells create a kind of shield that protects them from the blood stream and other locations. They believe it may also occur in other types of cancer cells. Ewing sarcoma, an aggressive and often fatal childhood cancer, turns on a naturally occurring gene on the cell surface called IL1RAP, which results in a protein protective shield. The researchers believe that they should be able to develop treatments that target IL1RAP without producing toxic side effects in non-cancerous cells. More Vaccine Side Effects Associated with Previous COVID-19 Infection A new study published in the Journal of Infection found that there was an increased risk of side effects after the first Pfizer-BioNTech COVID-19 vaccine if people had previous COVID-19 infection. The study surveyed 974 UK healthcare workers. One in four had a previous positive test and 30 of them, out of 974, said they had long COVID-19 with a median duration of 9.3 months. Being female and younger was associated with an increased risk of vaccination adverse events. The most common symptoms were fever, fatigue, muscle pain, joint pain, and lymph node pathology. Gene IDed that is Associated with Ewing Sarcoma Investigators at University of North Carolina Lineberger Comprehensive Cancer Center discovered a gene, OTUD71, that is involved in the development of Ewing sarcoma, a bone cancer found in children. They also identified a molecule that might block OTUD7A protein activity. The EWS-FLI1 fusion protein is found in about 85% of Ewing sarcoma patients. It is made up of pieces of two other proteins and is unique to Ewing sarcoma and only produced in cancer cells. Working with Atomwise, an AI company focused on identifying and developing drugs, they screened four million small molecules and identified 7Ai, which showed the ability to decrease tumor formation in mice that were grafted with human Ewing sarcoma cells. Possible Nano-Particle Drug to Treat Concussion Odyssey Group International completed development of their novel nano-particle drug formulation. This formulation was engineered to improve brain distribution of its PRV-002 to treat concussion, or mild traumatic brain injury. The drug is a novel neurosteroid that has been formulated into a nano-particle powder. The powder can be pre-filled into the company’s nasal device for clinical trials expected to start this summer. The drug formulation is to improve the drug’s chances of crossing the blood-brain barrier, which decreases systemic exposure to other organs. Diet Plays Major Role in NASH Progressing to Liver Cancer Non-alcoholic steatohepatitis (NASH) is a fatty liver disease that occurs in people who drink little or no alcohol but can progress to cirrhosis. It is associated with type 2 diabetes and obesity. Patients with non-alcoholic fatty liver disease (NAFLD) is the most common cause of chronic liver disease and these patients are at higher risk of NASH. NASH patients appear to be a high risk of developing hepatocellular carcinoma (HCC), a type of liver cancer. A recent study out of the University of California San Diego School of Medicine in a mouse model found that diet played a critical role in NASH progressing to liver cancer. They published their research in the journal Cellular and Molecular Gastroenterology and Hepatology. “While the mice that continued on a Western diet developed HCC and had an increased risk of death, 100% of the mice that stopped the diet survived the length of the study without developing HCC,” said Debanjan Dhar, co-senior author of the study and assistant professor in the Department of Medicine, Division of Gastroenterology at UCSD School of Medicine. “This indicates that NASH and HCC may be a preventable disease and that diet plays a crucial role in the disease outcome.”