GRAD-1405

GRAD1405 uses Gradalis’ breakthrough gene silencing bi-shRNAi technology to specifically reduce the expression of certain mutated KRAS genes Existing therapies have experienced rapid drug resistance due to KRAS gene mutations GRAD1405 reduces the three key KRAS mutant proteins driven by KRAS gene mutations and has shown it can control tumor cell growth in resistant cancer Gradalis’ gene silencing platform has been proven to dramatically reduce gene expression activity when applied as part of its Vigil immunotherapy, which has demonstrated positive results in ovarian and other cancers DALLAS, Jan. 04, 2024 (GLOBE NEWSWIRE) -- Gradalis Inc., a clinical-stage biotechnology company developing personalized anti-cancer therapies, announced GRAD1405 has demonstrated robust, dose-related tumor growth control. GRAD1405 is a single agent that has demonstrated the ability to consistently reduce three KRAS mutant proteins: KRAS G12C, G12D and G12V, which are responsible for the rapid resistance to existing therapies and a resulting loss of efficacy. This approach may eliminate the need for multiple therapeutic compounds to address the different genes. Additionally, a precursor of GRAD1405 tested in a pancreatic cancer animal model showed improved benefit, suppression of tumor growth beyond 30 days and no evidence of resistance, over existing therapies. GRAD1405 achieves the silencing of specific genes using Gradalis’ proprietary bi-shRNAi technology, which has consistently reduced targeted genes in clinical trials in multiple cancer indications. John Nemunaitis, MD, Gradalis’ Chief Scientific Officer and a co-founder of the company, stated, “We believe this gene silencing technology platform is a major step forward in treating solid tumors and will be applicable beyond NSCLC, colon cancer and pancreatic cancer. This approach can be used to target any mutation driving cancer growth. RNAi interference technology was first approved for disease treatment in August 2018. Since then, four siRNA single gene silencing products have been approved for disease management. Preliminary head-to-head preclinical evidence comparing the same cancer at the same cleavage site supports that this bi-shRNAi approach may be more active than the siRNA approaches and also less toxic (Rao et al Adv Drug 2009; Phadke et al DNA and Cell Biol 2011; Barve et al Mol Ther 2015). We expect this improved mechanism will correlate with more robust clinical benefit.” Donald Rao, PhD, Gradalis’ Director of Interference Technology and the inventor of bi-shRNAi technology, stated, “The unique aspect of bi-shRNAi technology relates to its bi-functional mechanism. Other RNAi molecular technologies like siRNA disrupt mRNA to protein gene expression by only one mechanism: cleavage dependence. Gradalis’ bi-shRNAi technology controls the DNA to protein pathway by an unprecedented two mechanisms: mRNA cleavage dependence and cleavage independence. This mechanism has shown a five-fold improvement in cancer gene and protein target expression knockdown compared to siRNA controls in two prior clinical trial products, pbi-shRNA STMN1 lipoplex (Barve et al Mol Ther 2015; Wang et al Toxicol Sci 2017) and pbi-shRNA EWS/FLI1 lipoplex (Rao et al Mol Ther 2016).” About KRAS protein and GRAD1405 KRAS protein acts as a switch to control cell growth. When mutated the KRAS protein switch goes into “hyperdrive” and stimulates uncontrolled cancer growth. KRAS mutations are particularly common in lung cancer (20-40%), colon cancer (30-50%) and pancreatic cancer (90%). KRAS mutations of the C, D and V types at the G12 position are the most frequent cancer driver mutations found in solid tumors. The G12C mutation is the most common KRAS mutation in lung cancer, and KRAS G12D and G12V are common in colon and pancreatic cancer. GRAD1405 also demonstrated robust reduction of key KRAS activated downstream cancer promoting signals Myc and elF4A1 (p < 0.000001). Gradalis’ GRAD1405 vector features reduced unmethylated CpG bacterial sequences which reduces off target cytokine release and improves safety via stimulation of Myc and elF4A1 pathways. GRAD1405 can block cancer growth and return Myc, efF4A1 to normal function. We have effectively demonstrated this in preclinical testing of bi-shRNAKRAS-cdv using a proprietary delivery vehicle (DOTAP-cholesterol) complex in mice (Rao et al PLoS ONE 2018). Preclinical studies indicate that this bi-shRNAi approach selectively decreases the expression of targeted genes better than any other approach. About bi-shRNAi Gradalis’ patented bi-functional short hairpin RNA interference (bi-shRNAi) technology platform is a DNA vector-based technology that produces both siRNA-like and miRNA-like molecules in cells for degrading certain mRNA targets. By utilizing both the siRNA and miRNA modes of action, the bi-shRNAi technology enables and enhances RNAi drug action in a broad spectrum of diverse cell populations resulting in wide bioavailability and pharmacodynamics and pharmacokinetics. As a DNA vector-based technology, bi-shRNAi technology can be constructed within a single plasmid to impact multiple targets thereby further broadening the range of drug action. bi-shRNAi delivery has also been optimized in preclinical testing of delivery with a proprietary DOTAP cholesterol vehicle, but based on small plasmid length can likely be utilized in multiple delivery approaches. About Gradalis, Inc. Founded in 2006, Gradalis is a privately held, clinical-stage biotechnology company developing a new category of personalized therapies based on proprietary bi-shRNAi technology. It’s lead product, called Vigil, is an immunotherapy that has been tested in multiple studies in ovarian and other cancer tumor types. Vigil is the first cellular immunotherapy to demonstrate longer-term survival benefits in a randomized controlled trial of patients with solid tumors. The results of the company’s Phase 2b study have been published in Lancet Oncology, Gynecologic Oncology and presented at the American Society of Clinical Oncology. The company is preparing to initiate a confirmatory Phase 2 clinical study in platinum-sensitive recurrent ovarian cancer patients with the HRP profile. Vigil is also being studied in other women’s 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 a pioneering oncology platform that is designed to decloak the full repertoire of a patient’s tumor antigens, including all clonal 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. Our clinical trials 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-shRNAi technology that has been proven to silence multiple genes EWS/FLI1, KRAS, STMN1, PDX-1 in a variety of cancers and has the potential to be used in other diseases. Forward-Looking Statements This press release contains forward-looking statements, including, without limitation, statements regarding the success, cost, and timing of our product development activities and clinical trials, our plans to research, develop, and commercialize our product candidates, and our plans to submit regulatory filings and obtain regulatory approval of our product candidates. These forward-looking statements are based on Gradalis’ current expectations and assumptions. Because forward-looking statements relate to the future, they are subject to inherent uncertainties, risks, and changes in circumstances that may differ materially from those contemplated by the forward-looking statements, which are neither statements of historical fact nor guarantees or assurances of future performance. Important factors that could cause actual results to differ materially from those in the forward-looking statements include but are not limited to: (a) the timing, costs, and outcomes of our clinical trials and preclinical studies, (b) the timing and likelihood of regulatory filings and approvals for our product candidates, and (c) the potential market size for our product candidates. These forward-looking statements speak only as of the date made and, other than as required by law, we undertake no obligation to publicly update or revise any forward-looking statements. This press release does not constitute an offer to sell, or a solicitation of an offer to buy, any securities. Gradalis Contact Mark Early (214) 442-8161 mearly@gradalisinc.com LifeSci Advisors Contact Joyce Allaire +1 (617) 435-6602 jallaire@lifesciadvisors.com