How Xalud Therapeutics Gene Therapy Platform Tackles Chronic Inflammatory Diseases
By Erin Harris, Editor-In-Chief, Cell & Gene
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Xalud Therapeutics’ lead therapeutic candidate, XT-150, is a non-viral gene therapy that expresses IL-10v — a proprietary modified variant of the cytokine IL-10 with durability properties over the naturally occurring wild-type. I caught up with Xalud’s CEO Dr. Diem Nguyen about the safety data to date from previous studies, as Xalud believes XT-150 has the potential to normalize the immune system, reduce tissue damage and resolve pathologic inflammation at the root of chronic inflammatory conditions.
Explain Xalud’s gene therapy platform in detail.
Nguyen: At Xalud, we’re developing novel non-viral gene therapies for chronic inflammatory diseases, where there remains large unmet need on a global scale. Our vision is to make gene therapy technology accessible to the masses and deliver scalable solutions that are effective and safe for over 300 million patients impacted by chronic inflammatory conditions.
Xalud’s approach allows delivery of treatment to the targeted inflamed tissue and uses the native inflammatory cells to produce a long-acting variant of human interleukin-10 (IL-10). We’re harnessing the power of this master regulator of the immune system to restore homeostasis in inflammatory conditions. IL-10 is a potent cytokine with anti-inflammatory properties that plays a critical upstream role in modulating inflammation through multiple pathways, including suppressing production and function of pro-inflammatory cytokines such as TNF- α, IL-1α, IL-1β, IL-6, IL-12 and GM-CSF; down-regulating cytokine receptors and up-regulating antagonists; and inhibiting hydrogen peroxide and nitric oxide production.
Explain Xalud’s broad potential in treating chronic inflammatory diseases, such as osteoarthritis.
Nguyen: A healthy, strong body lives in a state of equilibrium. In a disease state when the immune system is unable to balance itself, a continuous cycle of immune dysregulation results. An uncontrolled cascade of cytokines and inflammatory cells then pushes the body further from its balanced state, and over time, chronic inflammation can lead to damaged cells, tissue death and further disease progression. Across a broad range of diseases, chronic inflammation is associated with debilitating pain that prevents millions of people from living healthy productive lives.
Current treatments for chronic inflammatory diseases are sometimes ineffective or have short-lived effects. Some are too potent, and when systemically delivered, lead to serious adverse events and potential widespread toxicity. Others simply mask the disease symptoms, rather than addressing the root source of inflammation and resulting pain. And for those that do, they only target the inflammatory cytokines further downstream of disease pathogenesis. If we are to truly treat inflammatory diseases in an effective, safe, long-lasting and disease-modifying manner, patients require a therapeutic approach that can reduce inflammation through multiple pathways and relieve chronic pain.
For example, osteoarthritis (OA) is a chronic, progressive joint disease that affects over 30 million people in the United States. One of the most debilitating effects of OA is the chronic pain associated with the condition – even the seemingly most simple tasks like going to work, attending to daily tasks and basic movements often become unmanageable. OA is also associated with increased risk of comorbidity. As a result, this pain takes a significant toll on a patient’s quality of life and yet, available treatment options don’t address the underlying root cause of disease. For patients who fail to achieve benefits from initial therapies, addictive pain medicines or surgeries may be the only options. Because of an aging population and increased prevalence of risk factors such as obesity and prior injury, new solutions are needed to address this health care crisis.
With our lead therapeutic candidate, XT-150, we aim to break the cycle of inflammation by leveraging the body’s intrinsic immune signaling to stimulate the resolution pathway and resolve the pathologic inflammation at the root of chronic inflammatory conditions.
What is the current unmet need for treating neuropathic pain, sclerosis, dermal and ophthalmologic diseases, and how does Xalud plan to treat these diseases?
Nguyen: Chronic inflammation is a hallmark of many serious diseases, having a profound impact on health and quality of life through pain, loss of strength and function, and damage to multiple organ systems, including joints, nerves, skin, eyes, and digestive systems.
For example, facet joint syndrome (FJS) is a painful, progressive inflammatory condition that affects the vertebral joins in the back and neck. When these joints are damaged due to aging or trauma, patients experience chronic neck and back pain. It is estimated that up to 13 million in the US alone experience facet joint syndrome. There are limited options today including multimodal therapies (analgesics), nerve blocks and electrical stimulation. We believe that patients suffering from FJS could benefit from XT-150 much like the potential benefit we see in clinical and non-clinical studies in OA to date.
In chronic neuropathic pain (NP) a cycle of injury/damage is established and reinforced, resulting in persistent, pathological pain. Neuropathic pain can be seen as a manifestation of multiple types of nerve injury, including diabetes, chemotherapy and peripheral nerve impingement, such as lumbosacral radiculopathy. Conventional drugs such as gabapentin used to treat NP work to reduce the signaling activity of the neurons. At the cellular level, transmission of pain signals by neurons activates the surrounding glial cells, which generate pro-inflammatory cytokines (tumor necrosis factor [TNF]-α, IL-1α, IL-1β, IL-6, interferon [IFN]-γ, IL-2, IL-3, and granulocyte/macrophage colony stimulating factor [GM-CSF]) and oxygen radicals. These pro-inflammatory cytokines sensitize neurons in pain pathways to enhance pain signal processing. In several animal models, the spinal administration of IL-10, or a gene that encodes for IL-10, prevented or reversed behavioral signs of NP pain.
Multiple sclerosis affects more than 2.8 million people worldwide and is a result of the breakdown of the blood-brain barrier, demyelination and axonal degeneration. While there are certain disease-modifying treatments for MS, there remains a large unmet need to improve the quality of life of patients. In nonclinical models, gene delivered IL-10 therapy has been able to alleviate pain and impact the progression of functional symptoms.
Explain Xalud’s lead therapeutic candidate, XT-150 in detail.
Nguyen: IL-10 has historically held much promise as a therapeutic target for a broad range of inflammatory and autoimmune diseases. Despite that, previous attempts to tap into its power to restore tissue homeostasis have fallen short. When administered systemically as a protein, it is rapidly cleared and attains low target concentrations with low therapeutic effectiveness due to its short half-life and poor access to target cell populations.
Our lead therapeutic candidate, XT-150, is a locally injectable plasmid DNA gene therapy expressing IL-10v – a long-acting, proprietary modified variant of IL-10 with enhanced therapeutic properties over the naturally occurring wild-type. XT-150 has a favorable safety profile as demonstrated by over 250 subjects to date in multiple Phase 1 and Phase 2 studies. Data from these studies were presented at OARSI in April 2021. By locally delivering the upstream regulator directly to the site of inflammation, XT-150 has been shown to down-regulate proinflammatory cytokines and has the potential to normalize the immune system, reduce tissue damage and resolve pathologic inflammation at the root of chronic inflammatory conditions.
We have designed XT-150 to have an optimized regimen, dosing and formulation – significantly increasing the duration of its benefits compared to current standard of care and other available therapies. And unlike viral gene therapies, our non-viral delivery technology has the potential for redosing.
Explain the plan for the $30 million in an oversubscribed Series C financing led by PBM Capital.
Nguyen: The financing will support our continued clinical evaluation of XT-150 and the expansion of our non-viral gene therapy platform. We are currently evaluating XT-150 in a Phase 2b study for patients with moderate-to-severe osteoarthritis of the knee and recently initiated a Phase 1/2a study in peripheral neuropathic pain. We also have plans to start a study in facet joint syndrome, as well as continue exploring XT-150’s potential in other disease indications.
With a leadership team of experienced scientists, drug developers, immunologists and life science executives and the support of a top-notch group of strategic advisors with neuro-immunology and clinical development expertise, Xalud is well positioned to alleviate the high disease burden experienced by millions of patients and transform how we treat large indications.