Background: Lung cancer is the leading cancer cause of death in the US, and non-small cell lung cancers (NSCLCs) account for 85% of those cases. Among NSCLCs, mutations resulting in ectopic activation of the RAS signal transduction pathway account for at least a quarter of cases, and the activating KRASG12Cmutation is found in 11% of all NSCLC patient samples. When treated with RAS pathway-inhibiting therapeutics, KRAS-driven tumors have been shown to become dependent on autophagy for continued survival. Simultaneous targeting of both the RAS pathway and autophagy therefore presents an opportunity to block multiple mechanisms of tumor growth and survival. Materials and methods: We have demonstrated the added benefit of KRAS inhibition and autophagy inhibition in an animal model, using the NCI-H2122 cell line (homozygous for the activating KRASG12C mutation) as flank xenografts in NOD/SCID mice. ENV-201 is a selective and potent antagonist of the autophagy-initiating kinase, ULK1, one which also inhibits the related ULK2. Mice were treated via daily oral dosing of (1) vehicle, (2) ENV-201 (20 mg/kg), (3) the KRASG12C-specific inhibitor adagrasib (Mirati Therapeutics, 25 mg/kg), or (4) combination of both ENV-201 and adagrasib at the same doses. Treatment lasted 30 days, body weight was monitored daily, and tumor size was measured three times a week. All animal work was carried out at and met necessary approvals at Crown Bioscience. Results: Both ENV-201 and adagrasib treatments resulted in significant tumor growth inhibition when either drug was used as a single agent (32% or 55% TGI, respectively). Significant additive tumor growth inhibition (78%) was also observed when animals were treated with both drugs in combination. Conclusions: ENV-201-mediated ULK1 inhibition thus shows promise as both a single agent or in combination with a growth factor/RAS/MAPK pathway-targeting cancer treatment. Conflict of interest: Corporate-sponsored Research: All authors are employees of Endeavor BioMedicines.

ENV-101 is a Hh pathway inhibitor (Smo inhibitor) originally developed as a treatment for patients with advanced solid tumors. Clinical responses have been reported in patients with gene mutations affecting PTCH1 treated with other Hh pathway inhibitors. Endeavor is studying ENV-101 in advanced cancer patients with solid tumors harboring PTCH1 loss of function mutations. This study aims to evaluate dose as well as the efficacy and safety of ENV-101, a potent Hh pathway inhibitor, in patients with refractory advanced solid tumors characterized by loss of function mutations in the PTCH1 gene. Two distinct mechanisms are responsible for inappropriate and uncontrolled Hh pathway activation in human malignancies: ligand-dependent, due to overexpression of Hh ligand, and ligand-independent, resulting from genetic mutations in pathway components such as Ptch and Smo. The ligand-dependent mediated Hh pathway activation is implicated in a number of malignancies, including basal cell carcinoma (BCC), medulloblastoma, rhabdomyosarcoma, breast cancer, esophageal cancer, gastric cancer, pancreatic cancer, prostate cancer, small cell lung cancer, bladder cancer, oral cancer, and melanoma. Hedgehog pathway activation due to the ligand-independent mechanism involving Ptch1 loss of heterozygosity (LOH) or Smo mutations are primarily reported in medulloblastoma and BCC. However, data indicate that these mutations may be present in other solid tumors as well. In addition, as the Hh pathway is known to be primarily active in embryonic development and is not required for survival in adults, this type of targeted therapy should provide improved outcomes to defined cancer patient populations. This is a Simon 2 stage design that aims to evaluate the efficacy and safety of ENV-101, a potent Hedgehog (Hh) pathway inhibitor, in patients with refractory advanced solid tumors characterized by loss of function (LOF) mutations in the PTCH1 gene. Stage 1 (phase IIa) of this protocol will enroll a total of 44 patients randomized between two dose levels. In the presence of acceptable efficacy, stage 2 (phase IIb) of this protocol will expand enrollment using a single dose level. NCT05199584 January 20, 2022. Endeavor Biomedicines. Endeavor Biomedicines.

Following the discovery of the JAK2V617F mutation in myeloproliferative neoplasms in 2005, fedratinib was developed as a small molecular inhibitor of JAK2. It was optimized to yield low-nanomolar activity against JAK2 (50% inhibitory concentration = 3 nM) and was identified to be selective for JAK2 relative to other JAK family members (eg, JAK1, JAK3, and TYK2). It quickly moved into clinical development with a phase 1 clinical trial opening in 2008, where a favorable impact on spleen and myelofibrosis (MF) symptom responses was reported. A phase 3 trial in JAK2 inhibitor treatment-naive MF patients followed in 2011 (JAKARTA); a phase 2 trial in MF patients resistant or intolerant to ruxolitinib followed in 2012 (JAKARTA-2). Clinical development suffered a major setback between 2013 and 2017 when the US Food and Drug Administration (FDA) placed fedratinib on clinical hold due to the development of symptoms concerning for Wernicke encephalopathy (WE) in 8 of 608 subjects (1.3%) who had received the drug. It was ultimately concluded that there was no evidence that fedratinib directly induces WE, but clear risk factors (eg, poor nutrition, uncontrolled gastrointestinal toxicity) were identified. In August 2019, the FDA approved fedratinib for the treatment of adults with intermediate-2 or high-risk MF. Notably, approval includes a "black box warning" on the risk of serious and fatal encephalopathy, including WE. FDA approval was granted on the basis of the JAKARTA studies in which the primary end points (ie, spleen and MF symptom responses) were met in ∼35% to 40% of patients (JAKARTA) and 25% to 30% of patients (JAKARTA-2), respectively.

BACKGROUND CONTEXT Abnormal Wnt signaling in intervertebral discs (IVDs) progresses degenerative disc disease (DDD) pathogenesis by impairing nucleus pulposus cell function, decreasing matrix deposition, and accelerating fibrosis. PURPOSE This study was conducted to evaluate the effects of lorecivivint (LOR; SM04690), a small-molecule Wnt pathway inhibitor, on IVD cells and in an animal model of DDD. STUDY DESIGN We used in vitro assays and a rat model of DDD to test the effects of LOR on nucleus pulposus cell senescence and viability, annulus fibrosus (AF) cell fibrosis, and cartilage regeneration and protection. METHODS Wnt pathway gene expression was measured in human NP and AF cell cultures treated with LOR or DMSO (vehicle). Chondrocyte-like differentiation of rat and human NP cells, NP cell senescence and protection, and AF cell fibrosis were assessed using gene expression and immunocytochemistry. Disc and plasma pharmacokinetics were analyzed following intradiscal LOR injection in rats. In vivo effects of LOR and vehicle on AF integrity, AF/NP junction, NP cellularity and matrix, and disc height were compared using histopathology and radiography in a rat coccygeal IVD needle-puncture model of DDD. RESULTS In NP and AF cell cultures, LOR-inhibited Wnt pathway gene expression compared with vehicle. In NP cells, LOR inhibited senescence, decreased catabolism, and induced differentiation into chondrocyte-like cells; in AF cells, LOR decreased catabolism and inhibited fibrosis. A single intradiscal LOR injection in rats resulted in therapeutic disc concentrations (~30 nM) for >180 days and minimal systemic exposure. DDD-model rats receiving LOR qualitatively demonstrated increased cartilage matrix and reduced AF lamellar disorganization and fragmentation with significantly (p<.05) improved histology scores and increased disc height compared with vehicle. CONCLUSIONS LOR showed beneficial effects on IVD cells in vitro and reduced disease progression in a rat model of DDD compared with vehicle, suggesting that LOR may have disease-modifying therapeutic potential. CLINICAL SIGNIFICANCE The current therapeutic options for DDD are pain management and surgical intervention; there are no approved therapies that alter the progression of DDD. Our data support advancing LOR into clinical development as an injectable, small-molecule, potential disease-modifying treatment for DDD in humans.

Objectives: Wnt pathway upregulation contributes to knee osteoarthritis (OA) through osteoblast differentiation, increased catabolic enzymes, and inflammation. The small-molecule Wnt pathway inhibitor, lorecivivint (SM04690), which previously demonstrated chondrogenesis and cartilage protection in an animal OA model, was evaluated to elucidate its mechanism of action. Design: Biochemical assays measured kinase activity. Western blots measured protein phosphorylation in human mesenchymal stem cells (hMSCs), chondrocytes, and synovial fibroblasts. siRNA knockdown effects in hMSCs and BEAS-2B cells on Wnt pathway, chondrogenic genes, and LPS-induced inflammatory cytokines was measured by qPCR. In vivo anti-inflammation, pain, and function were evaluated following single intra-articular (IA) lorecivivint or vehicle injection in the monosodium iodoacetate (MIA)-induced rat OA model. Results: Lorecivivint inhibited intranuclear kinases CDC-like kinase 2 (CLK2) and dual-specificity tyrosine phosphorylation-regulated kinase 1A (DYRK1A). Lorecivivint inhibited CLK2-mediated phosphorylation of serine/arginine-rich (SR) splicing factors and DYRK1A-mediated phosphorylation of SIRT1 and FOXO1. siRNA knockdowns identified a role for CLK2 and DYRK1A in Wnt pathway modulation without affecting beta-catenin with CLK2 inhibition inducing early chondrogenesis and DYRK1A inhibition enhancing mature chondrocyte function. NF-kappa B and STAT3 inhibition by lorecivivint reduced inflammation. DYRK1A knockdown was sufficient for anti-inflammatory effects, while combined DYRK1A/CLK2 knockdown enhanced this effect. In the MIA model, lorecivivint inhibited production of inflammatory cytokines and cartilage degradative enzymes, resulting in increased joint cartilage, decreased pain, and improved weight-bearing function. Conclusions: Lorecivivint inhibition of CLK2 and DYRK1A suggested a novel mechanism for Wnt pathway inhibition, enhancing chondrogenesis, chondrocyte function, and anti-inflammation. Lorecivivint shows potential to modify structure and improve symptoms of knee OA. (C) 2019 The Authors. Published by Elsevier Ltd on behalf of Osteoarthritis Research Society International.

The Wnt/β-catenin signaling pathway is aberrantly activated in colorectal (CRC) and many other cancers, and novel strategies for effectively targeting it may be needed due to its complexity. In this report, SM08502, a novel small molecule in clinical development for the treatment of solid tumors, was shown to reduce Wnt pathway signaling and gene expression through potent inhibition of CDC-like kinase (CLK) activity. SM08502 inhibited serine and arginine rich splicing factor (SRSF) phosphorylation and disrupted spliceosome activity, which was associated with inhibition of Wnt pathway-related gene and protein expression. Additionally, SM08502 induced the generation of splicing variants of Wnt pathway genes, suggesting that its mechanism for inhibition of gene expression includes effects on alternative splicing. Orally administered SM08502 significantly inhibited growth of gastrointestinal tumors and decreased SRSF phosphorylation and Wnt pathway gene expression in xenograft mouse models. These data implicate CLKs in the regulation of Wnt signaling and represent a novel strategy for inhibiting Wnt pathway gene expression in cancers. SM08502 is a first-in-class CLK inhibitor being investigated in a Phase 1 clinical trial for subjects with advanced solid tumors (NCT03355066).

The Wnt pathway is upregulated in tendinopathy, affecting inflammation and tenocyte differentiation. Given its potential role in tendinopathy, this signaling pathway may be a relevant target for treatment. The current study examined the therapeutic potential of SM04755, a topical, small-molecule Wnt pathway inhibitor, for the treatment of tendinopathy using in vitro assays and animal models. In vitro, SM04755 decreased Wnt pathway activity, induced tenocyte differentiation, and inhibited catabolic enzymes and pro-inflammatory cytokines in human mesenchymal stem cells, rat tendon-derived stem cells, and human peripheral blood mononuclear cells. Evaluation of the mechanism of action of SM04755 by biochemical profiling and computational modeling identified CDC-like kinase 2 (CLK2) and dual-specificity tyrosine phosphorylation-regulated kinase 1A (DYRK1A) as molecular targets. CLK and DYRK1A inhibition by siRNA knockdown or pharmacological inhibition induced tenocyte differentiation and reduced tenocyte catabolism. In vivo, topically applied SM04755 showed therapeutically relevant exposure in tendons with low systemic exposure and no detectable toxicity in rats. Moreover, SM04755 showed reduced tendon inflammation and evidence of tendon regeneration, decreased pain, and improved weight-bearing function in rat collagenase-induced tendinopathy models compared with vehicle control. Together, these data demonstrate that CLK2 and DYRK1A inhibition by SM04755 resulted in Wnt pathway inhibition, enhanced tenocyte differentiation and protection, and reduced inflammation. SM04755 has the potential to benefit symptoms and modify disease processes in tendinopathy.

Objectives: Osteoarthritis (OA) is a degenerative disease characterized by loss of cartilage and increased subchondral bone within synovial joints. Wnt signaling affects the pathogenesis of OA as this pathway modulates both the differentiation of osteoblasts and chondrocytes, and production of catabolic proteases. A novel small-molecule Wnt pathway inhibitor, SM04690, was evaluated in a series of in vitro and in vivo animal studies to determine its effects on chondrogenesis, cartilage protection and synovial-lined joint pathology. Design: A high-throughput screen was performed using a cell-based reporter assay for Wnt pathway activity to develop a small molecule designated SM04690. Its properties were evaluated in bone-marrow-derived human mesenchymal stem cells (hMSCs) to assess chondrocyte differentiation and effects on cartilage catabolism by immunocytochemistry and gene expression, and glycosaminoglycan breakdown. In vivo effects of SM04690 on Wnt signaling, cartilage regeneration and protection were measured using biochemical and histopathological techniques in a rodent acute cruciate ligament tear and partial medial meniscectomy (ACLT thorn pMMx) OA model. Results: SM04690 induced hMSC differentiation into mature, functional chondrocytes and decreased cartilage catabolic marker levels compared to vehicle. A single SM04690 intra-articular (IA) injection was efficacious in a rodent OA model, with increased cartilage thickness, evidence for cartilage regeneration, and protection from cartilage catabolism observed, resulting in significantly improved Osteoarthritis Research Society International (OARSI) histology scores and biomarkers, compared to vehicle. Conclusions: SM04690 induced chondrogenesis and appeared to inhibit joint destruction in a rat OA model, and is a candidate for a potential disease modifying therapy for OA. (c) 2017 The Author(s). Published by Elsevier Ltd on behalf of Osteoarthritis Research Society International.

Introduction: Despite compelling efficacy data from Phase II and Phase III trials, clinical development of fedratinib was halted in 2013 after 8 of 670 treated patients presented with neurological symptoms suggestive of Wernicke's encephalopathy (WE). WE is a neurological disorder that develops due to thiamine deficiency that is treated or prevented simply by using thiamine supplementation. Autopsy studies indicate WE has a prevalence between 0.8-2.8% in the general population with a higher rate in MPN and cancer patients. Confirming a diagnosis of WE is complicated by comorbidities in patients with myeloproliferative neoplasms (MPN) including a high incidence of stroke, hepatic encephalopathy secondary to hepatic extramedullary hematopoiesis or sepsis related to marrow failure in an elderly population. Analysis of patients in fedratinib trials by a panel of neurology and neuroradiology experts indicates that between 1-5 patients of 670 treated experienced WE, less than what might be expected based on historical norms. WE is commonly caused by either poor nutritional status or chronic alcohol use. The most common non-hematological adverse events for fedratinib are nausea, vomiting and diarrhea, suggesting they may be exacerbating factors for malnutrition in patients. Nonetheless, inhibition of thiamine transporter (THTR) has been proposed as a putative mechanism based on Caco-2 studies. Interpretation of data from these studies is complicated based on use of protein-free culture medias that don't replicate protein binding of drug in patients (96% protein bound) and for which the drug is sparingly soluble. No CNS lesions that would be predictive of WE were reported in the IND-enabling toxicology studies with fedratinib, but subtle neurological signs or histology signs may not be clear to non-experts. To evaluate the potential of fedratinib to inhibit thiamine uptake, thiamine transporter studies were run using previously published methods with Caco-2 cells that overexpress thiamine transporters with the significant exception that they were performed using human FBS rather than cell culture media. This addresses concerns about protein binding, solubility and replicates conditions experienced by patients. Further, to evaluate the potential of fedratinib to induce WE non-clinically, rats were dosed orally with 40 mg/kg fedratinib (140% of 500 mg patient dose by allometric scaling) daily for 28 days with careful monitoring of neurological signs of disease followed by evaluation of brains for any signs of lesions consistent with WE. Results: Fedratinib had no effect on THTR-1 at concentrations up to 30 µM (6-12X higher than Cmax at highest dose of drug). Fedratinib IC50 against THTR-2 was >30 µM. This indicates that fedratinib does not inhibit either thiamine transporter at plasma concentration achievable in patients. This is consistent with patient data in which plasma thiamine levels were normal for the 161 patients sampled at end of treatment in the fedratinib clinical studies. In rats dosed orally with 40 mg/kg fedratinib for 28 days, there was no observed ataxia, opisthotonus, nystagmus, loss of righting reflex or any other overt neurological signs of thiamine deficiency. Examination of the brains of these animals found no lesions consistent with focal damage to vulnerable areas of brain, e.g. thalamus, inferior colliculus or brainstem. There was no difference in weight gain in these animals compared to control animals. This data indicates that at doses comparable or higher than the highest fedratinib dose used in phase III studies, there is no nonclinical evidence that fedratinib induces thiamine deficient disease. Conclusion: Transporter studies performed in the presence of human serum indicate that fedratinib does not inhibit thiamine transport at clinically achievable concentrations. This is consistent with plasma thiamine data available from patients. Rodent studies indicate that fedratinib does not induce thiamine deficient disease when administered orally at clinically relevant concentrations. Notably, rats are incapable of emesis, so this model doesn't account for effects of gastric distress. In total, these data suggest that fedratinib does not increase the risk of thiamine deficiency, beyond its potential to exacerbate malnutrition through poor management of preventable GI adverse events. Disclosures Hood: Impact Biomedicines, Inc.: Employment, Equity Ownership. Hazell: Impact Biomedicines, Inc.: Research Funding; University of Montreal Neurosciences: Employment.

Introduction: In the phase III study, JAKARTA I, the JAK2 inhibitor, fedratinib, elicited responses in 47% (400mg) and 50% (500mg) of patients with intermediate 2 or high risk myelofibrosis (MF). In JAKARTA II, 53% of MF patients who were resistant and 63% of patients who were intolerant to ruxolitinib responded to fedratinib, indicative of clinical benefit for the majority of patients not responding to standard therapy. Fedratinib development was discontinued after the FDA placed a clinical hold on November 15, 2013 as a result of neurological symptoms, suggestive of Wernicke9s encephalopathy (WE) in 8 of 670 subjects, exposed to fedratinib. WE develops in the setting of thiamine deficiency and is typified by diplopia, ataxia, confusion and characteristic brain MRI findings. Confirming a diagnosis of WE is complicated by comorbidities in patients with myeloproliferative neoplasms (MPN) including a high incidence of stroke, hepatic encephalopathy secondary to hepatic extramedullary hematopoiesis or sepsis related to marrow failure in an elderly population. While autopsy studies indicate that rates of WE range from 0.8-2.8% of the general population, the incidence in MPN patients is reportedly 3-fold higher. WE can be diagnosed based on clinical signs and specific MRI findings; prevented by ensuring that nutritional status is not exacerbated by nausea and vomiting; and treated with thiamine. To evaluate the epidemiology of potential WE subjects treated with fedratinib, we conducted a retrospective analysis of the 8 fedratinib-treated subjects. Patient demographics, clinical signs together with thiamine levels, when available, and MRI scans were evaluated to determine the likelihood of WE and elucidate contributory factors by an independent expert panel. Results: Eight patients (1 male, 7 females) from 7 countries and 5 fedratinib trials were identified. Median age was 69.1 years (IQR 67-71). Of these patients, 6 had MF, 1 had polycythemia vera and 1 had metastatic head and neck cancer. Based on retrospective analysis of clinical reports, thiamine levels and MRI results the data was either inconclusive or not supportive of WE in three patients, one of which likely had hepatic encephalopathy. Of the remaining 5 patients, 1 clearly had WE, 2 likely had WE, and 2 had inconclusive diagnosis. All potential WE patients had preceding protracted nausea and vomiting suggesting this as a contributing factor to malnutrition and thiamine deficiency. Concerning the 3 subjects thought to have WE: one was severely malnourished and refused gastrostomy during study suggesting malnutrition as a cause of thiamine deficiency. The two other likely WE patients had preceding sustained nausea and vomiting with recovery from neurological deficits while continuing fedratinib treatment suggesting fedratinib did not inhibit thiamine uptake. Consistent with that, mean patient thiamine levels from 161 patients available at end of treatment were normal and in vitro experiments in the presence of human serum show fedratinib at physiologically achievable levels does not inhibit thiamine transport. The two other patients that may have had WE had preceding nausea and vomiting; one developed neurological symptoms while not on drug and the other developed disseminated metastases, including an edematous brain metastases, preceding neurological symptoms confounding the diagnosis. Conclusion: Across 9 fedratinib trials enrolling 670 MPN or solid tumor patients between 3 to 5 patients experienced WE (0.4-0.7%). The overall prevalence of WE observed was less than published levels for a patient population of this size. For the 5 potential WE patients, one subject had malnutrition related to protracted nausea and vomiting as well as clinical signs and MRI findings consistent with WE. Additionally, 2 other subjects likely experienced WE, both of which recovered without a dose interruption suggesting fedratinib does not inhibit thiamine absorption. The remaining 2 had an unclear diagnosis with 2 of 3 experts believing the data were either inconclusive or not supportive of WE. Notably, one of the patients was not on fedratinib at the time of neurological symptoms. In total, these data suggest that fedratinib does not increase the risk of thiamine deficiency beyond its potential to exacerbate malnutrition through poor management of preventable GI adverse events. Disclosures Harrison: Novartis: Honoraria, Research Funding, Speakers Bureau; Gilead: Consultancy, Speakers Bureau; Shire: Speakers Bureau; Celgene: Consultancy; CTI: Speakers Bureau. Mesa: Galena Biopharma, Inc.: Consultancy; Promedico: Research Funding; Novartis Pharmaceuticals Corporation: Consultancy; Celgene Corporation: Research Funding; CTI BioPharma Corp.: Research Funding; Gilead Sciences, Inc.: Research Funding; Incyte Corporation: Research Funding; Ariad: Consultancy. Hood: Impact Biomedicines, Inc.: Employment, Equity Ownership. Bykowski: Impact Biomedicines, Inc.: Consultancy, Honoraria. Zuccoli: Impact Biomedicines, Inc.: Consultancy, Honoraria. Brewer: Elan: Other: Advisory Board; Bristol-Myers Squibb: Other: Advisory Board; Avanir: Other: Advisory Board; Novartis: Other: Advisory Board; Genentech: Other: Advisory Board; Eli Lilly: Other: Advisory Board; CorTechs Labs, Inc.: Equity Ownership; Human Longevity, Inc.: Equity Ownership.

Objective: To assess the safety, pharmacokinetics, and exploratory efficacy of SM04690, a novel Wnt pathway inhibitor, as a potential disease modifying treatment for knee osteoarthritis (OA).Design: Subjects with Kellgren-Lawrence grade 2-3 knee OA were randomized in successive dose-escalation cohorts to receive a knee intra-articular (IA) injection with 0.03, 0.07, or 0.23 mg SM04690, or placebo (PBO) (4: 1 ratio). Safety, pharmacokinetics, efficacy (WOMAC Total/Function/Pain, Pain VAS, Physician Global Assessment [MDGA], and OMERACT-OARSI Response), OA-related biomarker (P1NP, beta-CTX, and cartilage oligomeric matrix protein [COMP]), and radiographic/imaging data were collected at baseline and during 24-week follow-up.Results: 61 subjects (SM04690 n = 50; PBO n = 11) enrolled. Two dose limiting toxicities (DLTs), increased pain following injection and paroxysmal tachycardia (also the single serious AE), were reported in the 0.07 mg cohort. A total of 72 AEs were reported; Sixteen (occurring in eight subjects) were considered related to study medication. There were three discontinuations; one due to an AE (0.03 mg cohort). Bone marrow edema (BME) remained constant for most subjects. No doses were excluded from further study due to DLT criteria. Plasma levels of SM04690 were below the limit of detection at all time points. At Week 24, improvements from baseline were seen in all cohorts for the exploratory measures WOMAC Total, WOMAC Function, WOMAC Pain, MDGA, Pain VAS, and OMERACT-OARSI response. Joint space width (JSW) improvement was observed in the 0.07 mg cohort (P = 0.02 vs PBO).Conclusion: SM04690 appeared safe and well tolerated, with no evidence of systemic exposure. Exploratory efficacy analyses suggested positive trends for measurements of OA pain, function and disease-modifying osteoarthritis drug (DMOAD) properties. ClinicalTrials.gov registration: NCT02095548. (C) 2017 The Author(s). Published by Elsevier Ltd on behalf of Osteoarthritis Research Society International.

Background Wnt signaling pathway plays a central role in joint tissue formation and altered Wnt signaling has been associated with cartilage loss in preclinical/clinical studies.1 SM04690 is an IA small molecule inhibitor of the Wnt pathway. Objectives To report safety, clinical and imaging efficacy results from a 24 week phase 1 randomized, double-blind, placebo-controlled, dose-escalation clinical trial of a small molecule Wnt pathway inhibitor, SM04690, in knee OA. Methods Subjects with symptomatic, radiographic knee OA were randomized to receive a single IA injection in the target knee with either 0.03, 0.07, 0.23 mg SM04690 or vehicle (volume 2mLs) in a 4:1 SM04690 (N=16): vehicle (N=4) ratio. Safety, pharmacokinetics, WOMAC Total, Function, Pain subscales and strict OARSI responses2, and radiographs were collected at baseline and during the 24 week trial. Analyses of efficacy outcomes were conducted using a modified Intention-To-Treat (mITT) baseline-adjusted analysis of covariance (ANCOVA) and logistic regression. Results A total of 61 subjects (female N=41, mean age 62.6 yrs, BMI 30.4 kg/m2) were enrolled. Serum levels of SM04690 in all subjects were below limits of detection at all time points. Two dose limiting toxicities (DLTs), paroxysmal tachycardia, (also an SAE), and increased pain were reported in 0.07 mg cohort. A total of 72 AEs were reported in 28 (46%) subjects; 16 AEs in 8 subjects were considered possibly or probably related to study drug. At Week 24, improved WOMAC Total Score was seen for both 0.03 mg and 0.07 mg cohorts (change from baseline, -27.4 and -26.6 respectively) compared to placebo (-21.7) (Figure 1). Odds of having an OMERACT-OARSI strict response in 0.07 mg cohort were higher than in the placebo cohort at week 12 (odds ratio=5.7, 95% CI: 1.1, 30.0, P=0.04); odds of an OMERACT-OARSI strict response in 0.03 mg cohort were higher than in the placebo cohort at week 24 (odds ratio=4.8, 95% CI: 0.9, 25.8, P=0.07) (Figure 2). Joint space width by radiographs showed no change from baseline to Week 24 in the 0.03 mg cohort (0.00 mm), an increase in the 0.07 mg cohort (0.49 mm), and a decrease in the 0.23 mg cohort (-0.15 mm), with the placebo cohort exhibiting a larger decrease (-0.33 mm). Compared to placebo, the change in joint space width seen in 0.07 mg cohort was statistically significant (P=0.02). Conclusions These phase 1 data suggested that an intra-articular injection with a novel Wnt inhibitor SM04690 into the knee of OA patients was safe and well-tolerated. SM04690 appeared to potentially improve function, pain and knee joint space width. Additional studies are underway to further evaluate safety, tolerability, efficacy and potential DMOAD properties. References Gelse K. Osteoarthr Cartil 2002; 20(2): 162–71. Pham T, et al. J Rheumatol. 2003;30(7):1648–1654 Disclosure of Interest Y. Yazici Employee of: Samumed, LLC, T. McAlindon Consultant for: Pfizer, Regeneron, Flexion, Fidia, R. Fleischmann Grant/research support from: Samumed, LLC, A. Gibofsky Shareholder of: AbbVie, Amgen, J&J, GSK, Regeneron, Consultant for: AbbVie, Pfizer, Horizon, Iroko, Celgene, Novartis/Sandoz, Speakers bureau: AbbVie, Amgen, Celgene, Pfizer, N. Lane Consultant for: Samumed, LLC, A. Kivitz Grant/research support from: Samumed, LLC, Consultant for: Samumed, LLC, S. Majumdar Consultant for: Samumed, LLC, V. Strand Consultant for: Abbvie, Afferent, Bioventus, Carbylan, Eupraxia, Iroko, Pfizer, Regeneron, SKK, C. Swearingen Employee of: Samumed, LLC, A. DiFrancesco Employee of: Samumed, LLC, J. Tambiah Employee of: Samumed, LLC, J. Hood Employee of: Samumed, LLC, M. Hochberg Consultant for: Bioiberica, EMD Serono, Novartis Pharma AG, Plexxikon, Regeneron, Samumed, Theralogix LLC