Psyadon Pharmaceuticals (United States)

The strategies and experimental methods for implementation of process analytical technology (PAT) on the mobile pharmaceutical manufacturing system, Pharmacy on Demand (PoD), are discussed. With mu...

Abstract Phosphorylated p68 (p-p68 or phospho-DDX5) has been shown to be associated with cell transformation, epithelial mesenchymal transition (EMT) and cell migration, and furthermore play a vital role in cell proliferation and tumor/cancer progression by promoting the nuclear translocation of β-catenin. RX-5902 is an oral, small molecule inhibitor of β-catenin nuclear translocation mediated by p-p68. Previous studies have shown that RX-5902 inhibits the growth of cancer cells at low nanomolar IC50 (10 to 24nM) and disrupts the p-p68-β-catenin signaling pathway through an interaction with p-p68 on Tyr 593. By interfering with the p-p68-β-catenin signaling pathway cancer cells undergo apoptosis. In this study, we expanded our investigation to study the effect of RX-5902 on nuclear β-catenin in several types of cancer cell lines that include colon, gastric, hepatic, head and neck, melanoma, breast, pancreatic, ovarian, and prostate. Western blot data, in the cell lines tested, showed a decrease of nuclear β-catenin protein as well as p-p68 and c-myc in a concentration-dependent manner. Furthermore, an in vivo study of the MDA-MD-231 xenograft model demonstrated the ability of RX-5902 to inhibit the tumor growth by decreasing p-p68, β-catenin, cyclin D1 and c-myc proteins. Collectively our findings in both in vitro and in vivo studies support the potential therapeutic effect of RX-5902 in multiple cancer indications through the disruption of the phospho-p68/nuclear β-catenin interaction and blocking the nuclear translocation of β-catenin. Citation Format: Young B. Lee, Christina George, Deog J. Kim. The anticancer effects of RX-5902 result from inhibition of phosphorylated p68-mediated β-catenin nuclear translocation [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 1298.

1097Background: RX-5902 is a novel oral anti-cancer compound targeting phosphorylated p68 (P-p68) (RNA helicase DDX5, a member of the DEAD box family of RNA helicases) affecting the Wnt canonical p...

501 Background: RX-3117 is an oral small molecule hypomethylating agent, cyclopentyl pyrimidyl nucleoside that is activated by uridine cytidine kinase 2. RX-3117 shows efficacy in various xenograft models, including those of gemcitabine resistant bladder cancer. Preliminary data from Stage 2 of a Phase 2a clinical study of RX‐3117 as a single agent in subjects with aUC is described below. Methods: This Phase 2a study (2‐stage design, NCT02030067) evaluates the efficacy of RX‐3117 in eligible patients (aged ≥ 18 years) with refractory aUC. Primary objectives include safety and efficacy of the recommended Phase 2 dose and schedule identified in the Phase 1 portion of the study. Patients received 700 mg of oral RX‐3117 daily for either 3 weeks with 1 week off in each 4-week cycle or 4 continuous weeks. The primary endpoint is a ≥ 20% rate of progression free survival benefit (i.e., proportion of patients with stable disease for at least 4 months) and/or a 10% of evaluable patients with a partial response or better. Results: As of October 2017, 17 patients (12 males, 5 females) with aUC were treated with RX‐3117. The median age was 66 years, ECOG performance status was 0 to 1 and 53% received ≥ 3 prior therapies. Metastatic disease sites included lung, liver, lymph nodes, and mediastinum. Four patients achieved stable disease for 4 cycles of RX‐3117 treatment; one patient received treatment for 168 days and another patient for 301 days. One patient showed tumor shrinkage as measured by RECIST (‐15.5%) after 4 cycles of RX-3117; another patient showed a 19% tumor reduction after 1 cycle. The most frequent related adverse events were G1 diarrhea (13%), fatigue (13%), nausea (10%), G1/G2 anemia (10%), vomiting (10%) and G3 thrombocytopenia (10%). Conclusions: RX‐3117 is safe and well tolerable and shows preliminary evidence of anti-tumor activity. The study continues to enroll patients with aUC in Stage 2. Clinical trial information: NCT02030067.

2559Background: RX-0201 is a novel, oligonucleotide that binds native AKT-1 mRNA, preventing downstream phosphorylation to p-AKT. RX-0201, in combination with everolimus, to treat metastatic clear cell renal carcinoma. In vitro RX-0201, in combination with everolimus, additively inhibited Caki-1 cell growth. Methods: The Phase 1b/2 proof-of-concept, multicenter, open label study is conducted in 2 stages (NCT02089334). Stage 1 is a dose-escalation Phase 1b/2 study of RX-0201 in combination with everolimus (10 mg daily). RX-0201 was given as a continuous intravenous infusion for 14 days followed by 7 days of rest. Subjects were enrolled at increasing doses of RX-0201 in a 3+3 design. The target dose of RX-0201 identified in Stage 1 is being studied further evaluated in Stage 2, which is a randomized, 2-arm study of RX-0201 in combination with everolimus versus everolimus alone. Plasma concentrations were measured in Stage 1 and noncompartmental pharmacokinetic parameters were calculated using WinNonlin, Ver...

550 Background: Archexin (RX-0201) is a 20-mer oligonucleotide that is complementary to AKT-1 messenger ribonucleic acid (mRNA). The specificity of Archexin's effect on AKT-1 mRNA levels was examined in human renal cell carcinoma (von Hippel-Lindau protein-deficient renal cell carcinoma cell line) UMRC2 cells and resulted in decreased AKT-1 mRNA levels. Methods: The current study is a proof of concept phase Ib/2, multicenter, open label 2-stage study for subjects who progressed on at least 1 VEGF-targeted therapy. Stage 1 is an open-label, dose-escalation phase Ib study of Archexin administered in combination with everolimus. Archexin is administered by a 24 hour continuous intravenous infusion for 14 days followed by 7 days of rest. It is hypothesized that 250 mg/m2/day or a lower dose of Archexin will be identified as safe and well-tolerated when administered in combination with 10 mg of everolimus. The dose of Archexin identified in Stage 1 will be studied further in Stage 2 which is the randomized, open-label, 2-arm study of Archexin in combination with 10 mg of everolimus versus 10 mg of everolimus alone. Plasma concentrations were measured using a validated LC-MS/MS assay, and noncompartmental pharmacokinetic parameters were calculated using WinNonlin, Version 6.4. Results: Five subjects with metastatic clear cell renal carcinoma received 125 mg/m2/day (n = 3) or 200 mg/m2/day (n = 2) of Archexin with 10 mg of everolimus administered daily. Two subjects have had stable disease for 160 and 257 days. The most frequently reported treatment related adverse events for the combination were thrombocytopenia, vomiting and fatigue; no dose limiting toxicities have been reported currently. At all dose levels post-infusion, Archexin plasma concentrations increased rapidly and quickly reached a virtual plateau. Upon cessation of infusion on Day 14, plasma concentrations declined rapidly. Conclusions: At the dose levels tested, Archexin, in combination with everolimus, appears to be well tolerated in patients with metastatic renal cancer. Dose escalation/modification is ongoing to determine the recommended phase II dose of Archexin to be studied further in Stage 2 (randomized) when combined with everolimus. Clinical trial information: NCT02089334.

Electroconvulsive therapy (ECT) continues to be an effective treatment option for patients who fail to respond to pharmacological interventions, are unable to tolerate medications, and show a suboptimal response to behavioral and psychotherapeutic treatments. However, risks for cognitive impairment may contribute to some patients' refusal of ECT. The present study examined galantamine as a pharmacological intervention to reduce cognitive adverse effects from ECT. Thirty-nine inpatients diagnosed with major depressive disorder; bipolar disorder, depressed type; or schizoaffective disorder, depressed type and admitted for ECT were randomized to galantamine or placebo. Study drugs were initiated 24 to 48 hours before starting ECT and continued throughout the course of ECT. A neuropsychological test battery was administered at baseline and 24 to 48 hours after completing a course of ECT treatments. Depression severity was monitored using the 17-item Hamilton Rating Scale for Depression and Clinical Global Impression Scale at baseline, weekly, and end point. Self-rated adverse effects were monitored weekly. Thirty participants (12 patients in the galantamine group, 18 patients in the placebo group) had both pretreatment and posttreatment neuropsychological ratings. Those in the galantamine group scored significantly higher at discharge for delayed memory (t28 = 2.44, P < 0.05). Hierarchical regressions examined if treatment condition predicted changes in delayed memory scores from baseline to discharge. Inclusion of the treatment condition in the final model made a significant incremental improvement in prediction (ΔR = 0.12, F1,27 change = 4.65, P < 0.05; β = 0.37, t = 2.16, P < 0.05). Galantamine was well tolerated with no clinically significant bradycardia or prolonged paralysis when administered with ECT. Galantamine may be protective against impairment in retention of new learning. Galantamine exhibited minimal adverse effects and was safe when administered during ECT. The present findings require replication by future researchers using larger samples before broad conclusions can be drawn.

HIF-1alpha plays a major role in activating gene transcription and is important for maintaining homeostasis under hypoxic conditions. Since tumors are often in a hypoxic state, HIF-1alpha is a potential target for the development of novel cancer therapeutics. This study was performed to determine the antitumoral efficacy of an antisense HIF-1alpha inhibitor, RX-0047 on different human cancer cell lines (MDA-MB 231, HME50-T, PC-3, Panc-1 and A549) in vitro. A549 lung cancer and PC-3 prostate cancer cells containing a luciferase gene reporter were used for in vivo xenograft animal models. Progressive tumor development was quantified using live animal BLI (bioluminescence imaging) in addition to ex vivo imaging and histology. All cell lines tested were sensitive to inhibition of cell growth with 10 nM and higher ranges of RX-0047, additionally RX-0047 sensitizes cells to ionizing radiation treatments. Finally, RX-0047 (30 mg/kg) inhibited the formation of human lung metastasis in xenograft mouse models and reduced tumor size in flank models.

Outer dense fiber 2 (Odf2) was initially identified as a major component of sperm tail cytoskeleton and later was suggested to be a widespread component of centrosomal scaffold that preferentially associates with the appendages of the mother centrioles in somatic cells. Here we report the identification of two Odf2-related centrosomal components, hCenexin1 and hCenexin1 variant 1, that possess a unique C-terminal extension. Our results showed that hCenexin1 is the major isoform expressed in HeLa cells, whereas hOdf2 is not detectably expressed. Mammalian polo-like kinase 1 (Plk1) is critical for proper mitotic progression, and its association with the centrosome is important for microtubule nucleation and function. Interestingly, depletion of hCenexin1 by RNA interference (RNAi) delocalized Plk1 from the centrosomes and the C-terminal extension of hCenexin1 was crucial to recruit Plk1 to the centrosomes through a direct interaction with the polo-box domain of Plk1. Consistent with these findings, the hCenexin1 RNAi cells exhibited weakened gamma-tubulin localization and chromosome segregation defects. We propose that hCenexin1 is a critical centrosomal component whose C-terminal extension is required for proper recruitment of Plk1 and other components crucial for normal mitosis. Our results further suggest that the anti-Odf2 immunoreactive centrosomal antigen previously detected in non-germ line cells is likely hCenexin1.