STMN1

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

VYD222 is being developed to prevent Covid-19 in vulnerable people, including immunocompromised individuals. Credit: Fusion Medical Animation on Unsplash. Invivyd has received clearance from the US Food and Drug Administration (FDA) for its investigational new drug (IND) application for VYD222 to prevent Covid-19. VYD222 is a new monoclonal antibody (mAb) candidate and is being developed to prevent Covid-19 in vulnerable people, including immunocompromised individuals. Recommended Reports Reports LOA and PTSR Model - Rnai Gene Therapy To Inhibit Stmn1 For Solid Tumor in Solid Tumor GlobalData Reports LOA and PTSR Model - Mezagitamab in Idiopathic Thrombocytopenic Purpura (Immune Thrombocytopenic ... GlobalData View all Engineered from adintrevimab (ADG20), the antibody showed in vitro neutralising activity against dominant variants of concern, including XBB.1.5. It is being assessed in an ongoing Phase I healthy volunteer clinical trial in Australia. The company commenced dosing participants in March 2023. Invivyd chief medical officer Pete Schmidt said: “For the millions of immunocompromised people around the world who may not generate adequate protection from SARS-CoV-2 vaccines, there is an urgent need for new therapeutics that provide the rapid, passive immunity that results from the direct delivery of mAbs. “With the previously authorised anti-SARS-CoV-2 mAbs losing activity against current variants of concern, we look forward to continuing to work with the FDA and global regulators to advance VYD222 and our platform-based approach to development.” The dose-ranging, blinded, placebo-controlled, randomised Phase I trial has been designed for assessing the pharmacokinetics, tolerability, safety and serum virus-neutralising activity of VYD222 in healthy adult volunteers. The trial will assess three different doses of VYD222, each administered as a single IV infusion. The company stated that all dose levels will provide durability in the face of viral evolution and flexibility during the regulatory submission.

Even among hard-to-treat solid tumors, pancreatic cancer is in a league of its own when it comes to survival mechanisms. Criminal profiling can be the key to catching a killer. The same could be said for immune system profiling, which appears to have helped scientists crack the code on one of oncology’s most notorious villains: pancreatic cancer. In a study published Dec. 30 in Nature Cancer, scientists at the University of Texas MD Anderson Cancer Center described how they systematically went about profiling the way pancreatic tumors keep a patient’s immune system from fighting their cancer. The researchers’ sleuthing led them to three proteins, which they then targeted in mouse models with a trio of immunotherapies. Their results showed an overall survival rate of up to 90% through the end of the year-and-a-half-long study—more than half the mice’s life span. The same cancer in people has a five-year survival rate of 11%.   “As a human immunologist who has been involved in a lot of clinical trials, you’d be surprised that I was surprised that it worked so well, but I really was,” John Connolly, Ph.D., who is not involved in the research but is chief scientific officer at the San Francisco-based Parker Institute for Cancer Immunotherapy, told Fierce Biotech Research. Suppressing immune suppression   Even among hard-to-treat solid tumors, pancreatic cancer is in a league of its own when it comes to survival mechanisms. Under normal conditions, the immune system regulates itself with checkpoints, suppression pathways that hold down the “off” switch on T cells that would otherwise attack a person’s own tissue. Pancreatic cancer is especially good at exploiting these pathways by keeping the suppression mechanisms turned on, ultimately “exhausting” the T cells in the area surrounding the tumors, also known as the tumor immune microenvironment. T-cell exhaustion is just what it sounds like: The cells no longer respond to foreign invaders, allowing cancer cells to proliferate undetected. Pancreatic tumors’ unparalleled ability to suppress T cells makes them highly resistant to immunotherapies. That includes checkpoint-inhibiting drugs like Merck’s PD-1 inhibitor Keytruda and Bristol Myers Squibb's Yervoy, a CTLA-4 inhibitor, on their own or in combination. “Over the last 20 years, the field has tried many, many different agents to enhance the therapeutic strategies for this disease,” Ronald DePinho, M.D., senior author of the study, said. The statistically significant survival benefits seen in both mice studies and human trials thus far aren’t enough to make a meaningful difference in the clinic, he added.   But perhaps it was a matter of hunting down and neutralizing the right combination of the right checkpoints, DePinho’s lab reasoned. That would require a clear profile of how pancreatic cancer was impacting the immune system—in other words, its immune “fingerprint,” as Connolly described it. To find that fingerprint, Pat Gulhati, M.D., Ph.D.—a postdoc in DePinho’s lab—set about cataloguing all the immune checkpoint proteins that were expressed in exhausted T cells found in the tumor immune microenvironment of mice with pancreatic cancer. The researchers also took stock of the ones in both treated and untreated samples from  patients to make sure their findings were clinically relevant, with particular attention to the ones that showed up in highly resistant disease. In both samples, the researchers found that in addition to PD-1 and CTLA-4, the checkpoint proteins TIM3, 41BB and LAG were also expressed. They then enlisted their mouse models in multiarm studies with antibodies designed to target these proteins along with others they found in their search. Similar to what had been seen in humans, neither PD-1, TIM3 or CTLA-4 inhibition improved survival. But anti-LAG3 and agonistic 41BB antibodies individually extended the mice’s survival time by about 20% to 30% compared to controls. “And—as expected because mechanistically they worked quite differently—the combination of the two had additive effects,” DePinho explained. The dual therapy more than doubled their survival time. Third drug's the charm   But despite living twice as long as untreated models, the two drugs weren’t enough to keep the mice from succumbing to the disease. The researchers wondered whether they could improve the numbers with a third agent. For that, they turned to CXCR2, a protein that recruits myeloid-derived suppressor cells, or MDSCs, to the tumor immune microenvironment. Summoning MDSCs is another nifty trick up cancer’s sleeve. While normal myeloid cells—which include neutrophils and monocytes—act against foreign invaders, MDSCs have suppressive activity. Cancerous tumors activate them so they turn off T cells. And because they aren’t susceptible to immune checkpoint inhibitors, they’re a common route of treatment resistance. Like the two-drug combo, treating the mice with a CXCR2 inhibitor called SX-682 once again boosted their survival time by about 30% to 40%. Encouraged, the researchers then tried the three agents together. After 540 days, all but one of the 10 mice in a group with a highly virulent pancreatic cancer were still alive. Other groups with tumors grown from different cell lines had overall survival rates of around 70%. In models with multifocal, spontaneously arising tumor—a particularly aggressive form—the survival rate was 20%. None of the animals alive at the study’s end had any signs of cancer. “These were unprecedented cures seen in a very virulent mouse model of this disease,” DePinho said. Cell sequencing and immune profiling confirmed that drugs had indeed induced a potent immune response, overcoming suppression by the tumors. The study’s models were especially strong because the researchers made an effort to ensure that the immunosuppression patterns they saw in mice were the same as those in samples from human patients, Connolly said. “They created a nice resistance model that accurately reflected how resistance works in a human,” he explained. “Then they used advanced immunophenotyping and analytical techniques to really dive in and come up with a fingerprint of how resistance is working.” Speeding to the clinic   All three of the drugs used by the researchers are being studied separately in early-stage clinical trials. Bristol Myers Squibb’s LAG3 inhibitor relatlimab, which is already FDA approved as part of a combination treatment for metastatic melanoma, is one of the drugs being studied in the National Cancer Institute’s MATCH screening trial for solid tumors. Pfizer’s utomilumab, a 41BB agonistic antibody, showed a favorable safety profile in a phase 1 pancreatic cancer trial. And the CXCR2 inhibitor SX-682, developed by Syntrix, is in a phase 1 trial for pancreatic cancer with Bristol Myers Squibb’s Opdivo.     Combined with the results of their study, the work already being done with the agents warrants speeding along the process to trying them together in humans, DePinho said. “I think there’s as much preclinical proof-of-concept one could glean from looking at human specimens, which showed that the targets are there and that they correlate with clinical outcomes,” he said. “And the mouse model, which is a very faithful mouse model of the human disease, shows rather striking and encouraging results.” Connolly agreed. “There’s a lot of good mouse studies out there, but you really want to translate this to the clinic for it to be meaningful to patients,” Connolly said. “We really want to see that clinical trial get out there.” Combos galore Given that only 20 percent of the most aggressive tumors were cured with the triple combination, there’s also potential to try the combo with different agents that work against different suppression mechanisms. DePinho is particularly intrigued by the possibility of testing them with KRAS inhibitors, which have shown signals of efficacy both preclinically and in early stage clinical trials.   “With the advent of KRAS inhibitors, there is now going to be an opportunity to combine KRAS inhibitors with immune modulatory agents,” he said. “Based on our work, I would put at the top of the list anti-LAG3 and agonist 41BB or the CXCR2 inhibitor.” Connolly again agreed, noting that the concept makes sense for outsmarting drug resistance. “You want to try to add therapeutics that don’t share a mechanism of resistance,” he said. “The tumor may be able to escape the immune system, but it’s very difficult to escape the immune system and KRAS suppressors.” In general, the researchers’ approach is ideal for designing multidrug therapies, Connolly said. “Ron’s lab gives you a roadmap on how to make a combination therapy,” Connolly said. “Find the fingerprint of suppression, find the mechanism of resistance and attack that mechanism.”