VALHALLA THERAPEUTICS Biotechnology for better health Valhalla Therapeutics is a privately-held biopharmaceutical development company that is paving the way for early commercialization of groundbreaking therapeutic technology! Founded in 2019 and based in Berwyn, PA, we're on a thrilling journey to revolutionize healthcare! Our pipeline represents our philosophy of identifying the best unique approaches to fill the underserved therapeutic needs of disease states. As new mechanisms of action can offer a larger impact beyond incremental advances in treatment over current therapies, we strive to develop novel classes of agents possessing breakthrough potential to help patients, reduce healthcare costs and deliver maximal ROI for our investors rather than developing “me-too” follow-on drugs. Halting The Progression Of Type 2 Diabetes VTX-31 is our most advanced program currently in the pre-IND stage of development. Based on the breakthrough research conducted by Dr. Salim Merali and Dr. Wayne Childers at Temple University, VTX-31 is a designer compound with a novel mechanism of action that directly inhibits the lipotoxicity induced by highly elevated fatty acid levels causing insulin-resistance of Type 2 diabetes and ultimately leading to its complications. Studies in multiple animal models of genetic Type 2 diabetes and diet-induced obesity/Type 2 diabetes have demonstrated reversal of insulin-resistance by increasing glucose uptake into various tissues and providing long-term glucose control. We are actively pursuing private and non-dilutive funding for this program as it is IND-capable. No agent has been developed that directly addresses the underlying cause of T2D Restoring Vascular Blood Flow To Tissues In Type 1 and 2 Diabetes Restoring Vascular Blood Flow To Tissues In Type 1 and 2 Diabetes VTX-4 is a monoclonal antibody that selectively binds to the RAGE receptor that is activated by Advanced Glycation Endproducts (A.G.E.s) as part of the glucotoxicity of diabetes. As a consequence, blood flow and new vessel formation is inhibited preventing the delivery of oxygen and nutrients to tissues giving rise to cell damage and development of diabetic complications. VTX-4 was developed by Dr. Lynne Johnson and her colleagues at Columbia University and extensively studied in mouse and pig models of Type 1 and Type 2 diabetes. These studies demonstrated the ability to create new blood vessels, restore tissue blood flow, prevent muscle mass loss and accelerate diabetic wound healing by inhibiting RAGE activation. The program is in preclinical development with an SBIR Phase I grant recently submitted for further pharmacological profiling. No current agent exists that restores blood flow and has a significant effect on the development of diabetic complications. Increasing Brain Lysosomal Activity To Reduce Brain Damage In Gauchers VTX-GD The VTX-GD program has identified several primary lead agents derived by screening a chemical library. The aim of the program is to identify a compound with a novel mechanism of action to increase the function of the brain form of the enzyme β-glucocerebrosidase that is defective in neuronal Gaucher Disease (nGD), a rare infant disease that leads to early death. Using a novel, high-throughput cell-based screening assay developed at Temple University, the best “hit” was used for preliminary structure-activity medicinal chemistry studies to enhance potency and pharmacological parameters. The discovery was made by Dr. Wayne Childers and Dr. Marlene Jacobson. There is additional potential for use in a subpopulation of Parkinson’s patients with a similar genetic mutation in the β-glucocerebrosidase enzyme. The program is at the lead optimization stage with an STTR grant submitted for further medicinal chemistry, pharmacokinetic profiling and testing efficacy in a mouse model of nGD. Unlike peripheral GD, no therapy exists for treating neuronal GD

VTX-GD Gauchers Disease Gauchers Disease (GD) is a rare, lysosomal storage disease with a prevalence of 1 in 57,000 births. The hallmark feature of GD is a deficiency in the β-glucocerebrosidase enzyme (GCase) caused by mutations in the GBA1 enzyme gene that reduces its activity. This deficiency results in the build-up of the toxic sphingolipid substrates glucosylceramide (GluCer) and glucosylsphingosine (GluSph) that are metabolized by GCase and play an integral part in disease pathophysiology. Three GD subtypes exist: GD1 affecting the periphery, and GD2 and GD3 affecting the brain (neural GD) all of which are lethal. GD3 has a juvenile or early adult onset with patients living into early teens or adulthood. Onset of GD2, the most severe form of the disease, begins within 6 months of birth and progresses rapidly resulting in death within two years of age. Furthermore, between 5-15% of Parkinsons’s patients also have a mutation in the GBA1 gene (GBA-PD). The loss of GCase activity and lysosomal dysfunction may impair alpha-synuclein metabolism. GBA-PD patients have earlier disease onset, more frequent cognitive impairment, and more rapid disease progression. The Need: An Effective Therapy For Brain GBA1 Enzyme Deficiency Presently, no cure or treatment is available for patients with nGD. As such, there is a critical need to pursue novel strategies to discover and develop effective treatments for neural GD which may also have utility for Parkinson’s GBA-PD as well. Previous therapeutic strategies to develop small molecule drugs have targeted low GCase enzyme activity to identify “chaperones” for stabilizing the misfolded enzyme or agents to reduce substrate accumulation by inhibiting glucosylceramide synthase that produces the toxic GluCer. Current drugs are effective for peripheral GD1, but due to lack of CNS penetration do not work for neural GD. Examples include eliglustat (Cerdelga™) and miglustat (Zavesca®) for treatment of GD1. Enzyme replacement therapy (ERT) using recombinant GCase (Cerezyme®) has a significant impact on GD1, yet has no effectiveness in nGD. Lead Compounds Developed Using Novel Patient Cell-Based Assay Impaired calcium homeostasis and reduction in lysosomal calcium stores is a cellular characteristic seen in both Gaucher and Parkinson’s GBA1-PD patient cells. A high-throughput phenotypic screen using patient-derived fibroblast cells was optimized to identify small molecules as potential leads for further medicinal chemistry structure-activity studies. Detection of differences in lysosomal calcium release between patient and normal, healthy cells is used to identify active compounds. Modification of the structures from several initial “hits” resulted in the synthesis of several potent lead compounds that displayed the ability to penetrate into the CNS with a good pharmacokinetic profile and metabolic stability. The next step is to evaluate the effect of these lead compounds in an animal model of neural GD, then to continue medicinal chemistry optimization.

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Meet The Team Founder & CEO Ihor Terleckyj Ph.D 30+ years experience in pharmaceutical industry VP-in-residence, Shifa Biomedical Executive Director, Matinas Director, GSK, Global Product Strategy Scientific Advisor Dr. Salim Merali, Ph.D. Co-founder, VTX-31 inventor Associate Dean of Research, Temple University Carnell Professor of Pharmacy, Temple University School of Pharmacy Scientific and Medical Advisor Dr. Lynne Johnson, MD Co-founder, Inventor VTX-4 Professor of Medicine, Columbia University Internationally-renowned expert in RAGE research and clinical imaging Scientific Advisor Dr. Ying Sun, Ph.D. Research collaborator, developed GD mouse model Professor of Pediatrics, Children's Hospital Medical Center, University of Cincinnati Medicine, Columbia University Expert in genetic brain diseases Head, Clinical Development Douglass Greene, MD Former Chief Medical Officer, Sanofi-Aventis VP, Clinical Science Product Development, Merc Expert in diabetes basic science and clinical R&D Scientific Advisor Dr. Wayne Childers, Ph.D. Co-founder, Inventor VTX-31, VTX-GD Associate Professor of Medicinal Chemistry, Temple University School of Pharmacy Associate Director of the Moulder Center for Drug Discovery Research, Temple University School of Pharmacy Former Senior Scientist, Medicinal Chemistry, Wyeth-Ayerst Research Scientific and Medical Advisor Dr. Greg Grabowski, MD Professor Emeritus, Departments of Pediatrics, and of Molecular Genetics, Biochemistry, and Microbiology, University of Cincinnati College of Medicine Internationally-renowned expert in lysosomal disease including Gaucher Former CSO at Synageva and Kiniksa Business Advisor Ezra Felker, MBA Grants Park Advisors Former COO, VenatoRx VP, Operations at NuPath Entrepreneur-in-residence at BioAdvance

VTX-31 The global prevalence of Type 2 diabetes is estimated at 300 million patients, accounting for 12% of global healthcare spending. In the United States, 38 million Americans suffer from diabetes representing 12% of the total population. Left untreated, diabetes leads to the development of kidney disease, neuropathy, retinopathy, poor wound healing, GI dysfunction, cognitive impairment, liver fibrosis and cardiovascular disease. The total healthcare costs for managing diabetes to the US healthcare system is $413 billion. Glucose lowering drugs account for 12% of total diabetes care at $48 billion. Sales of the Top 5 agents for 2023 totaled $33 billion. Even at a 15% effect for an agent that decreases disease progression, the downstream savings to the healthcare system would amount to at least $55 billion.   The Need: Current Type 2 Therapies Lack Durable Glucose Control The GRADE trial sponsored by the NIH NIDDK Institute evaluated agents from all classes for long-term glucose control over a 4 year period. Patients taking metformin were enrolled and study drugs were added to their treatment regimen. At the conclusion of the study, 71% of the patients did not maintain their target HbA1c, the gold standard measure for glucose control, due to ongoing disease progression. While developed to exert glucose lowering effects, none of the current therapies were designed to directly impact the underlying disease pathophysiology 4-HNE Induces Lipotoxicity And Insulin Resistance With overnutrition, high levels of free fatty acids (FFA) are made from glucose and stored as fat in adipose cells. FFAs are also metabolized in the mitochondria through the oxidation cycle. During this process, highly reactive lipoperoxide byproducts are produced, including 4-HNE (4-hydroxynoneal). Under normal circumstances, 4-HNE is deactivated by cellular anti-oxidants such as glutathione. However, in obesity and Type 2 diabetes, larger amounts of 4-HNE are produced due to the increased levels of FFAs that overwhelms the anti-oxidant system. As a result, 4-HNE can bind irreversibly to proteins giving rise to adducts and impair their normal metabolic functioning. The GLUT4 transporter that shuttles glucose from the blood into muscle and fat cells is one of the proteins inactivated by 4-HNE which causes insulin resistance. As a consequence, blood levels of glucose are elevated and adipose cells release stored fatty acids due to the loss of feedback control of metabolic processes. Other tissues and proteins that are inactivated by lipotoxicity include: Pancreatic calmodulin: impaired insulin release and production, beta-cell death Liver ATPase: loss of mitochondrial integrity, decreased ATP synthesis, fatty liver Glutathione synthetase; decreased glutathione synthesis, loss of anti-oxidant   VTX-31 Directly Addresses Underlying Cause Of Insulin-Resistance Orally-available compound specifically designed to bind and neutralize 4-HNE Prevents lipotoxicity by decreasing its availability Decreases protein adduct formation in adipose, pancreas and liver Restores GLUT4 glucose uptake in brown adipose tissue and muscle Decreases HbA1c levels in genetic and diet-induced animal models of disease VTX-31 Exhibits Excellent Drug Properties Roughly 95% oral bioavailability No significant liver metabolism; 99% excretion by kidneys as unchanged compound Half-life supports 2x/day dosing at estimated single doses around 300 mgs Preliminary acute toxicity studies in rat, dog and monkey indicate VTX-31 is well-tolerated with no major adverse events seen at therapeutic doses 6-step simple, low cost synthesis; 1-year minimum stability in capsule form

VTX-4 Diabetic Peripheral Artery Disease Peripheral artery disease (PAD) is a chronic and progressive vascular disorder with high morbidity and low quality of life. The worldwide prevalence of PAD was estimated at 236 million, with 9 million patients in the United States. Of these, 30% are diabetic, predisposing this subgroup to the most severe complications. Additional high-risk populations include the elderly, African-Americans, veterans, and low-income populations. The hallmark characteristic of PAD is narrowing of the arteries resulting in reduced blood flow to the limbs. In its early stage, symptoms include muscles pain in the legs during walking which limits mobility (intermittent claudication). Because of reduced blood flow, the decrease in tissue perfusion promotes chronic limb-threatening ischemia, poor wound healing, and tissue loss including muscle. In its severe manifestation, gangrene may develop and if the limb cannot be salvaged amputation is required. Annual US healthcare costs exceed $62 billion, representing a large burden on healthcare providers. Due to the increase in the aging population and incidence of diabetes, PAD will reach epidemic status by 2026 which will drastically increase overall health spending, primarily for Federal and state insurance agencies. The Need: Restoration Of Blood Flow To Starved Tissues A recent AHA scientific statement includes the observation that the extent and severity of PAD is generally underappreciated by health care professionals and patients. It also mentions that a major gap in its management is the unavailability of efficacious medications. Clinical management for PAD includes exercise, anti-hypertensive drugs, cholesterol lowering agents, anticoagulation therapy and vasodilators. Despite these strategies, many patients will require a revascularization procedure to restore blood flow as the disease progresses. There is also a high rate for the need of a second revascularization procedure as well. Within 30 days of the initial surgery, 16% of patients will need a second procedure and 24% will require one within 1 year. Overall, the current therapeutic status for the treatment of PAD is suboptimal. VTX-4 will be the first therapeutic modality with the ability to restore blood flow. Activation Of The RAGE Receptor Prevents New Vessel Growth The RAGE receptor (receptor for advanced glycation endproducts) plays an important role in the etiology and progression of PAD through multiple pathways. Pathological examination of limbs from patients with PAD reveals increased expression of RAGE. Glucose can be irreversibly crosslinked to proteins forming advanced glycation end products (A.G.E.s) that can activate the RAGE receptor. Under normal circumstances, A.G.E. levels are low and the RAGE receptor is relatively inactive. In diabetes, due to elevated glucose and A.G.E. concentrations, RAGE is highly activated triggering an inflammatory cascade within the vascular wall. The multiple pathways increase reactive oxygen species, increase vascular permeability to activated immune cells and cause the release of pro-inflammatory cytokines. These events lead to atherogenesis, microvascular disease expression, inhibition of the normal capillary angiogenic response to tissue hypoxia and prevents the growth of larger collateral arteries thru arteriogenesis. VTX-4 Blocks RAGE Activation By A.G.E.s VTX-4 is a humanized, IgG monoclonal antibody raised against the A.G.E. recognition domain of the RAGE receptor. In preliminary studies, VTX-4 decreased the activation of RAGE by A.G.E.s in vascular smooth muscle cell-based assay by reducing cytokine production and activation of the RAGE-associated kinase signal transduction pathway. Administration to mouse and pig models of Type 1 diabetic peripheral artery disease before and after femoral artery occlusion increased new arteriole sprouting, collateral artery formation, restored blood flow to lower limbs and prevented muscle mass loss. In both the Type 1 PAD pig and a Type 2 mouse model without an occluded artery, an increase in wound healing was observed that correlates with the increase in tissue blood flow and confirming a clinically relevant endpoint has been achieved. Effect On Arteriogenesis in Type 1 Model Effect On Wound Healing In Type 2 Model