XT-150- A novel immunomodulatory gene therapy for osteoarthritis pain in phase 2b development

Purpose: Xalud Therapeutics, Inc., is developing XT-150, a novel immune-modulating gene therapy platform based upon a non-integrating DNA plasmid containing a long-acting variant of human IL-10 (hIL-10v). IL-10 is a potent anti-inflammatory cytokine that resolves pro-inflammatory environments caused by cytokines such as TNFα, IL-1β and IL-6. IL-10 is well understood to be important in modulating the pathogenesis of inflammatory diseases. Previously IL-10 has eluded drug development, since as a systemically delivered protein it is rapidly cleared and attains low target concentrations. Xalud Therapeutics has a novel, breakthrough treatment approach which allows delivery to the target inflamed tissue and uses the native inflammatory cells there to produce a long acting variant of human Il-10. XT-150 is taken up by immune-surveying cells such as synoviocytes and causes those cells to manufacture and release Xalud's hIL-10v protein which Results in a decrease in inflammatory drivers over an extended period of time. Significant informative data has been generated for XT-150. It has been administered as a single injection in a double-blind, placebo-controlled study of pet dogs with severe OA and significant pain relief and improvement of function was observed. In the open-label, extension phase of this study, significant pain relief and improved function was last observed to last on average of 38 weeks after the single initial injection. Potential disease-modification has been demonstrated in an equine model of mild-to-moderate OA. GLP toxicology studies of XT-150 in rodents and dogs have demonstrated a good safety profile with a No Observed Adverse Event Level (NOAEL) being the highest doses tested, roughly 3-fold higher than projected human doses. Additionally, no antibodies to native IL-10 or hIL-10v have been found in any animals following single or multiple injections. Because XT-150 is a plasmid, there is no risk of, nor actual genomic integration. Methods: Our initial clinical target is in the treatment of pain associated with osteoarthritis (OA) of the knee. Two First-In-Human Phase 1 studies in a total of 56 subjects with severe osteoarthritic knee pain have been completed. Subjects had a single intra-articular injection over a range of doses from 15 μg to 600 μg, or a saline control. In a third extension study, a second intra-articular injection of XT-150 (450 μg) was given. Fifteen μg was predicted and confirmed to be below the Minimal Anticipated Biological Effect Level (MABEL) based on preclinical studies A Randomized, Double-blind, Placebo-controlled Phase 2b study with planned enrollment of 270 subjects is currently underway with 215 subjects enrolled as of February 2021. This study includes subjects with moderate-to-severe knee pain with radiographically documented OA (Kellgren-Lawrence grades 2 and 3). Study duration previously for safety and efficacy was six months in the two initial Phase 1 studies, with an additional six month follow up in the extension study, whereas, duration is up to a year in the current Phase 2b study. Results: To date, Eight Serious Adverse Events have been seen over the four studies combined. None have been attributed to study drug. Small numbers of "related" adverse events (N=8 in the first 3 studies) attributed to drug have shown no dose relationship. All were mild to moderate, transient, and predominantly characterized as local injection site pain. No antibodies to native IL-10 or hIL-10v have been found following single or double-injections in any subjects. . Exploratory efficacy analyses of the combined First-In-Human studies has shown XT-150 treatment provided clinically significant reductions in pain (as measured by both WOMAC Pain and BPI Worst Pain scales) as well as improvements in the BPI Walking Ability functional scores when compared to pooled data from placebo and a no-effect dose of 15 μg. For example, in a WOMAC Responder analysis for Pain (30% reduction from baseline vs Day 180), the placebo group demonstrated a 21% response rate vs. 67% for the 150 μg group (p=0.01). These improvements began at first study visit on Day 7 and continued through the primary endpoint on Day 180. Conclusions: In summary, XT-150 is a novel, immune modulating plasmid gene therapy which has an excellent safety profile in all studies to date with the potential to have long lasting pain relief and improvement of function in people who suffer from osteoarthritis of the knee.