A Phase 1, Open-Label Study Assessing the Safety, Pharmacokinetics, Pharmacodynamics, and Biomarkers of Single Ascending Dose Regimens of XT-150 for the Treatment of Amyotrophic Lateral Sclerosis (ALS)

This is a Phase 1, open-label, multi-center safety study of XT-150 in adult participants with Amyotrophic Lateral Sclerosis (ALS).
Participants providing informed consent and meeting all study eligibility criteria will be enrolled in the study and will receive a single injection of XT-150 at the Baseline visit. Follow-up visits will occur over 180 days (6 months) after the injection.
8 participants (4 participants per dose level) will be enrolled sequentially in up to 2 ascending, single dose cohorts: Cohort 1: 1.5 mg XT-150 Cohort 2: 4.5 mg XT-150

Start Date01 Feb 2025

Sponsor / Collaborator

Xalud Therapeutics, Inc.

NCT05196919 / CompletedPhase 2

A Placebo-controlled, Double-blind Evaluation of Safety, Tolerability, and Efficacy of XT- 150 for the Treatment of Facet Joint Osteoarthritis Pain

This is a Phase 2a safety and efficacy study of XT-150 in adult participants experiencing back pain due to inflammation of the facet joint, also known as facet joint osteoarthritis (FJOA), and who are eligible for intra articular glucocorticoid injection, or radiofrequency ablation of medial branches of the primary dorsal ramus of the exiting nerve root, which innervates the adjacent facet joints.
Study drug will be administered at Day 0 and Day 90 by bilateral intra-articular (IA) injection into the facet capsule, at the affected spinal level (e.g. Lumbar [L]3-4, L4-5, or L5-Sacrum [S]1) as determined by imaging (e.g., Magnetic resonance imaging [MRI], Computed tomography [CT]), X-ray, etc.) and physical exam.
Up to 72 participants will be randomized to placebo or one of two dose treatment groups (24 participants per treatment group).
0.15 mg XT-150 (1.0 milliliter [mL] total delivered by two 0.5 mL injections)
0.45 mg XT-150 (1.0 mL total delivered by two 0.5 mL injections)
Placebo (Sterile saline) (1.0 mL total delivered by two 0.5 mL injections)

Start Date24 Feb 2022

Sponsor / Collaborator

Xalud Therapeutics, Inc.

NCT04841512 / WithdrawnPhase 1/2

A Placebo-controlled, Double-blind Evaluation of Safety, Tolerability, and Efficacy of XT-150 for the Treatment of Facet Joint Osteoarthritis Pain

Preliminary safety and efficacy of XT-150 in the synovial capsule of osteoarthritic facet joints in the vertebra of the spine.

Start Date01 Oct 2021

Sponsor / Collaborator

Xalud Therapeutics, Inc.

100 Clinical Results associated with XT-150

100 Translational Medicine associated with XT-150

100 Patents (Medical) associated with XT-150

Literatures (Medical) associated with XT-150

01 Mar 2023·Immunobiology

Monocyte-derived immature dendritic cells negatively regulate hepatic stellate cells in vitro by secreting IL-10

Article

Author: Liu, Feng ; Chen, Peng ; Zheng, Xiaoyu ; Han, Lei ; He, Di ; Hu, Mingdao ; Xu, Yang

The development of liver fibrosis is associated with inflammatory responses resulting from chronic liver disease. Immature dendritic cells (imDCs) play an important role in modulating the inflammatory environment of the liver. This study investigated the effects of imDCs on the regulation of hepatic stellate cells (HSCs) during liver fibrosis. We isolated and induced imDCs from monocytes of healthy volunteers, activated LX-2 cells with TGF-β to establish in vivo liver fibrosis HSCs model, and then set up a cell co-culture system with transwell membranes. imDC surface markers and apoptosis rates of LX-2 cells were detected by flow cytometry. The concentration of IL-10 secreted by imDC was measured through ELISA. The expression of α-SMA in LX-2 after co-culture was examined by qRT‑PCR. Proliferation of LX-2 cells were detected by CCK-8. The western blot was used to illustrate the LX-2 activation-related proteins such as Smad3/7 and TGF-β1. The imDCs co-culture group and the interleukin-10 (IL-10) treatment group had similar results, as they were both able to increase apoptosis, inhibit proliferation, downregulate α-SMA mRNA, and reduce TGF-β1 and Smad3 protein expression in LX-2 cells. Additionally, the Smad7 protein level was increased after treatment with imDC and IL-10. However, the results in the IL-10 antagonist group showed the opposite trend to that of imDCs and IL-10 groups. Thus, these results suggest that imDC secretion of IL-10 negatively regulates activated LX-2 cells, probably via inhibition of the TGF-β1/Smad3 pathway and increased expression of Smad7 protein. This may be a potential therapeutic target for liver fibrosis.

01 Sep 2022·PNAS nexus

A filarial parasite-encoded human IL-10 receptor antagonist reveals a novel strategy to modulate host responses

Article

Author: Nutman, Thomas B ; Bennuru, Sasisekhar ; Ricciardi, Alessandra ; Hassan, Sergio A ; Kamenyeva, Olena ; Andersen, John

Abstract:

Interleukin (IL)-10 is the primary cytokine driving the modulation of the host response in filarial infections. We performed binding assays with Brugia malayi antigen extracts and human IL-10R1. Bm5539 was the top-binding hit. We identified a short sequence, termed truncated Bm5339, that has structural similarities to the human IL-10 functional dimer. Sequence comparisons revealed that other filarial parasites possess Bm5539 orthologues. Using recombinant Bm5539 in a modified Luciferase Immunoprecipitation System assay, we confirmed that both the truncated and full-length forms of the protein can bind to human IL-10R1. Truncated Bm5539 could inhibit human IL-10-driven phosphorylation of STAT3, thereby demonstrating that Bm5539 acts as an IL-10 antagonist, most likely through competitive binding to the receptor. We provide a structural basis for these observations using computational modeling and simulations. This parasite-encoded cytokine receptor antagonist provides an additional lens through which parasite-induced modulation of the host immune response can be examined.

01 Jan 2017·Brain, behavior, and immunityQ1 · MEDICINE

Behavioral assessment of neuropathic pain, fatigue, and anxiety in experimental autoimmune encephalomyelitis (EAE) and attenuation by interleukin-10 gene therapy

Q1 · MEDICINE

Article

Author: Mahoney, Melissa J ; Watkins, Linda R ; Christianson, John P ; Grace, Peter M ; Maier, Steven F ; Loram, Lisa C ; van Dam, Anne-Marie ; Chavez, Raymond A ; Penzkover, Kathryn R ; Flyer-Adams, Johanna G ; Forsayeth, John R ; Strand, Keith A

Relapsing-remitting multiple sclerosis is commonly associated with motor impairments, neuropathic pain, fatigue, mood disorders, and decreased life expectancy. However, preclinical pharmacological studies predominantly rely on clinical scoring of motor deficit as the sole behavioral endpoint. Thus, the translational potential of these studies is limited. Here, we have assessed the therapeutic potential of a novel anti-inflammatory interleukin-10 (IL-10) non-viral gene therapy formulation (XT-101-R) in a rat relapsing remitting experimental autoimmune encephalomyelitis (EAE) model. EAE induced motor deficits and neuropathic pain as reflected by induction of low-threshold mechanical allodynia, suppressed voluntary wheel running, decreased social exploration, and was associated with markedly enhanced mortality. We also noted that voluntary wheel running was depressed prior to the onset of motor deficit, and may therefore serve as a predictor of clinical symptoms onset. XT-101-R was intrathecally dosed only once at the onset of motor deficits, and attenuated each of the EAE-induced symptoms and improved survival, relative to vehicle control. This is the first pharmacological assessment of such a broad range of EAE symptoms, and provides support for IL-10 gene therapy as a clinical strategy for the treatment of multiple sclerosis.

News (Medical) associated with XT-150

30 Jan 2024

·www.pharmaceutical-technology.com

Sanofi partners with Synthekine to develop IL-10 therapeutics

Sanofi has entered a partnership with Synthekine for IL-10 therapeutic development. Credit: Keitma via Shutterstock. Canadian immunotherapy company Synthekine has announced a global partnership with Sanofi to develop IL-10 receptor agonists for inflammatory diseases. Under the deal, Sanofi and Synthekine will work together to research cytokine therapies up to a predefined point in preclinical development. After that, Sanofi will be solely responsible for preclinical, clinical and commercial development of any IL-10 therapeutics. Sanofi has agreed to give Synthekine a $40m upfront payment, with the potential for additional payments upon reaching preclinical, development, regulatory and commercial milestones, including possible royalties on net sales. In its programme, the biotech aims to remove the immunostimulatory effects of the drug class, hampering the drug’s toxicity while maintaining efficacy. In its pipeline, the biotech currently has two Phase I candidates and seven candidates in preclinical and investigational new drug application (IND)-enabling stages. These therapies include engineered cytokine partial agonists, surrogate cytokine agonists, and orthogonal cytokine and cell therapy combinations. Synthekine’s most advanced therapy, STK-012, is a modified IL-2 cytokine that selectively stimulates antigen-activated T cells . In September 2023, Synthekine announced the dosing of the first patient in its Phase Ib study (NCT05098132). The ongoing trial is investigating the therapy for solid tumour types, including renal cell carcinoma (RCC) and non-small cell lung cancer (NSCLC). Several companies have investigated IL-10, an immune regulatory cytokine, as a potential target for immunosuppressive agents. The US Food and Drug Administration (FDA) has not yet approved any IL-10 therapeutics. According to GlobalData, six pharmaceutical companies are investigating IL-10 therapeutics in Phase II studies and three Phase I candidates. Xalud Therapeutics is investigating its IL-10 therapy, XT-150 in Phase II studies for neuropathic pain (NCT04466410) and osteoarthritic pain (NCT04124042). Others such as Kolon Life Science and Sunho Biopharmaceutical are also exploring their IL-10 therapeutics in Phase II studies. GlobalData is the parent company of Pharmaceutical Technology. In the 29 January press release, Synthekine’s CEO Debanjan Ray said: “This strategic collaboration will advance our broad efforts on IL-10 to capture the full therapeutic potential of this important target and leverages both our cytokine partial agonist platform and our surrogate cytokine agonist platform.”

Phase 1Phase 2License out/inImmunotherapy

20 Mar 2023

·www.globenewswire.com

Xalud Therapeutics Presents Clinical Data on XT-150 in Knee Osteoarthritis at the 2023 Osteoarthritis Research Society International World Congress

• Results demonstrate that XT-150 can facilitate improved knee function during walking gait, which persists to 180 days following a single injection NEW YORK, March 20, 2023 (GLOBE NEWSWIRE) -- Xalud Therapeutics, a clinical-stage biotechnology company developing novel non-viral gene therapies to treat pathologic inflammation, today announced pooled gait data from a world-renowned gait laboratory in Adelaide, Australia, which served as a study site for two studies of lead candidate XT-150 in patients with knee osteoarthritis (OA). XT-150 is a locally injectable plasmid DNA (pDNA)-delivered gene therapy expressing IL-10v, a proprietary modified version of interleukin-10 (IL-10), which Xalud is evaluating across a broad range of chronic inflammatory diseases in clinical and preclinical studies. The results demonstrate a positive signal supporting the use of XT-150 as a potential effective treatment in knee OA with the goal of improving joint function. The data were presented in a poster presentation titled “Functional improvements in knee kinematics during walking gait over six months following treatment with XT-150: pooled results from two clinical trials” at the 2023 Osteoarthritis Research Society International (OARSI) World Congress. “We’re pleased to share these encouraging gait data at this year’s OARSI Congress as they demonstrate support for how this novel gene therapy can improve knee function including knee range of motion (ROM) and walking speed,” said Dominic Thewlis, Ph.D., principal investigator of the study and associate professor at Adelaide Medical School. “Of note, some of the patients were able to exceed the walking speed required to cross a road safely, which is an example of how XT-150 may impact everyday activities.” Howard Rutman, M.D., MBA, chief medical officer at Xalud Therapeutics, added, “The proposed mechanism of activity of XT-150 is to induce the local production and release of IL-10v. We believe that this supplements the body’s own IL-10 activity and may restore immune system homeostasis in chronic inflammatory diseases such as knee OA. The improvements in knee function in this gait analysis are a critical part of supporting our hypothesis of how XT-150 may be impacting the molecular changes at play in chronic inflammation.” Study Design The aim of this gait analysis was to investigate the effect of two different doses of intraarticular (IA) XT-150 versus a placebo control on knee biomechanics during walking gait over the course of 180 days in people with moderate to severe knee OA. Xalud has included gait analysis as part of its multi-study development program to provide functional assessment in addition to patient reported outcomes. The Phase 1 trial (NCT03282149) was conducted at a single center, and the Phase 2b trial (NCT04124042) was a multi-center (n=6) trial. Both trials used a standardized gait analysis assessment conducted at a single site in Adelaide, Australia. Participants with knee OA were randomized to one of three groups: 1) inactive placebo (saline), (2) low active dose (150 µg of XT-150) or (3) high active dose (450 µg of XT-150). Quantitative gait analysis was performed prior to intervention and at 30-, 60-, 120- and 180-days post intervention. Sixty-two people were recruited with sixty receiving an intervention. Summary of Data The primary outcome measure used in these analyses was an objective measure of function from a three-dimensional (3D) gait analysis of walking at a self-selected speed. Knee joint ROM over a complete gait cycle From baseline to day 180, the knee ROM increased by 4° for the 150 µg group and by 6° for the 450 µg group. Over the same time frame, the placebo group showed no change in knee ROM.At day 120 and 180, post-hoc analysis showed that the change in knee ROM was statistically significant between the placebo and 450-µg group (p=0.042 and 0.022, respectively).We have previously shown that increased knee flexion ROM following total knee replacement is positively associated with improvements in daily physical activity levels.1 Therefore, improvements in knee flexion ROM in this analysis could have a positive impact on physical activity levels as well. Walking speed All groups appeared to increase their walking speed from baseline with small to large effect sizes noted (0.05-0.13 m/s [Cohen’s d = 0.24-1.1]). However, there were no statistically significant differences in walking speed from baseline at any of the time points.Importantly, almost 27% of the participants allocated to the 450 µg group increased their walking speed to exceed 1.3 m/s by day 180 (1/23 to 7/23 patients). The threshold of 1.3 m/s is important as it has been suggested to be the speed required to cross a road safely.2 1 Arnold, J. B., Mackintosh, S., Olds, T. S., Jones, S., & Thewlis, D. (2015). Improvements in knee biomechanics during walking are associated with increased physical activity after total knee arthroplasty. Journal of Orthopaedic Research, 33(12), 1818-1825.2 Middleton, A., Fritz, S. L., & Lusardi, M. (2015). Walking speed: the functional vital sign. Journal of aging and physical activity, 23(2), 314-322. About Xalud Therapeutics Xalud Therapeutics is a clinical-stage biotechnology company advancing a non-viral plasmid DNA (pDNA)-delivered gene therapy platform to treat pathologic inflammation by restoring homeostasis in the immune system. Xalud’s initial approach is focused on harnessing the power of interleukin-10 (IL-10), a potent cytokine that acts as a master regulator for multiple inflammatory pathways, to address the root cause of inflammation in several chronic inflammatory indications with a high unmet need. This includes programs in both musculoskeletal and neurodegenerative diseases. Xalud’s lead candidate, XT-150, is a patent-protected, locally injectable pDNA-delivered gene therapy expressing IL-10v, a proprietary modified version of IL-10. Media Contact Slavena Salve Nissan, M.D. LifeSci Communications snissan@lifescicomms.com718-483-4440

Clinical ResultPhase 2Gene TherapyPhase 1

06 Jun 2022

·www.globenewswire.com

Xalud Therapeutics CEO to Participate in Two Gene Therapy Focused Panels at BIO International Convention 2022

NEW YORK, June 06, 2022 (GLOBE NEWSWIRE) -- Xalud Therapeutics, a clinical-stage biotechnology company developing novel non-viral gene therapies to treat pathologic inflammation, announced today that Chief Executive Officer Diem Nguyen, Ph.D., MBA, will participate in two panels at the BIO International Convention. The conference will be held in person June 13-16 at the San Diego Convention Center in San Diego, California. On June 14, Dr. Nguyen will participate in a panel titled ‘Which Shots, What Goal, and Who Should Shoot? Developing a Sustainable Portfolio for Gene Therapy and Genome Editing Platforms.’ Dr. Nguyen will provide valuable insight about indication prioritization and discuss Xalud’s extensive experience developing a DNA-delivered therapy platform and lead candidate XT-150. With the XT-150 program, the company is harnessing the power of interleukin-10 (IL-10), a potent cytokine that acts as a master regulator for multiple inflammatory pathways, to address the root cause of inflammation across a broad number of indications and subsequently restore homeostasis. On June 15, Xalud’s novel plasmid DNA vector will be spotlighted as Dr. Nguyen and other industry experts discuss gene therapy accessibility concerns ranging from drug development efficacy to manufacturing bottlenecks and safe therapeutic vectors. Other topics covered during this panel, titled ‘A New Era in Gene Therapy,’ will include safety, efficacy, and how to improve manufacturing to broaden the application of gene therapy to challenging diseases. “In the last decade, we have seen incredible advancements in nucleic acid-encoded therapeutics, which has sparked intense interest in other gene therapy modalities,” said Dr. Nguyen. “With these monumental strides and the advantages over RNA and viral approaches, a new era of non-viral DNA-delivered gene therapy is emerging. Xalud’s goal is to help alleviate the high disease burden of chronic and neuro-inflammation and expand the potential of gene therapy to tens of millions of patients.” Both Dr. Nguyen and Xalud’s Chief Financial Officer, Chuck Triano, will be available for one-on-one meetings during the conference. Presentation Details: Title: Which Shots, What Goal, and Who Should Shoot? Developing a Sustainable Portfolio for Gene Therapy and Genome Editing PlatformsDate/Time: June 14, 2022, at 11 AM PDTLocation: Upper Level, Session Room 6FModerator: Sarah Jims, Principal at Triangle Insights Group, LLC Title: A New Era in Gene TherapyDate/Time: June 15, 2022, at 11 AM PDTLocation: Upper Level, Session Room 2Moderator: Julianna LeMieux, Ph.D. Senior Science Writer at Genetic Engineering & Biotechnology News About Xalud Therapeutics Xalud Therapeutics is a biotechnology company developing a DNA-delivered gene therapy platform to treat pathologic inflammation through immune modulation. The company’s lead product candidate, XT-150, harnesses the power of interleukin-10 (IL-10), a potent cytokine that acts as a master regulator for multiple inflammatory pathways, to address the root cause of inflammation and restore homeostasis in the immune system. XT-150 is a locally injectable plasmid DNA gene therapy expressing IL-10v, a proprietary modified version of IL-10, that addresses pathologic inflammation and pain. Media Contact Kara Stephens-WeaverLifeSci CommunicationsKstephens-weaver@lifescicomms.com 407-765-1185

Gene Therapy

100 Deals associated with XT-150

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Indication	Highest Phase	Country/Location	Organization	Date
Osteoarthritis	Phase 3	US	Xalud Therapeutics, Inc.	-
Back Pain	Phase 2	US	Xalud Therapeutics, Inc.	24 Feb 2022
Inflammation	Phase 2	US	Xalud Therapeutics, Inc.	24 Feb 2022
Arthralgia	Phase 2	AU	Xalud Therapeutics, Inc.	01 Oct 2021
Osteoarthritis, Spine	Phase 2	AU	Xalud Therapeutics, Inc.	01 Oct 2021
Osteoarthritis, Knee	Phase 2	US	Xalud Therapeutics, Inc.	14 Feb 2020
Osteoarthritis, Knee	Phase 2	AU	Xalud Therapeutics, Inc.	14 Feb 2020
Pain	Phase 2	US	Xalud Therapeutics, Inc.	14 Feb 2020
Pain	Phase 2	AU	Xalud Therapeutics, Inc.	14 Feb 2020
Amyotrophic Lateral Sclerosis	Phase 1	US	Xalud Therapeutics, Inc.	01 Feb 2025

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