The new big is small: Leveraging knowledge from small trials for rare disease drug development: Blarcamesine for Rett syndrome.

Big data in drug development may not satisfactorily address the demands of precision medicine in a rare disease population, making the use of smaller clinical trials necessary. Consequently, the use of innovative design and analysis of these clinical trials using model-informed approaches have become indispensable. This requires informative exposure-outcome analysis, together with formal statistical analysis, which should include the strength of evidence for a study outcome. We demonstrate how knowledge can be gained, with supporting strength of evidence, from a small (data) clinical trial with a low dose of blarcamesine in the treatment of Rett syndrome. Based on a small data paradigm, pharmacometrics item response theory modelling and Bayes factor analysis were used to demonstrate the efficacy of blarcamesine in Rett syndrome.

Health care utilization and costs of systemic lupus erythematosus in the United States: A systematic review.

OBJECTIVES: To evaluate health care utilization and costs for patients with systemic lupus erythematosus (SLE) by disease severity. METHODS: We searched PubMed and Embase from January 2000 to June 2020 for observational studies examining health care utilization and costs associated with SLE among adults in the United States. Two independent reviewers reviewed the selected full-text articles to determine the final set of included studies. Costs were converted to 2020 US $. RESULTS: We screened 9224 articles, of which 51 were included. Mean emergency department visits were 0.3-3.5 per year, and mean hospitalizations were 0.1-2.4 per year (mean length of stay 0.4-13.0 days). Patients averaged 10-26 physician visits/year. Mean annual direct total costs were $17,258-$63,022 per patient and were greater for patients with moderate or severe disease ($19,099-$82,391) compared with mild disease ($12,242-$29,233). Mean annual direct costs were larger from commercial claims ($24,585-$63,022) than public payers (Medicare and Medicaid: $18,302-$27,142). CONCLUSIONS: SLE remains a significant driver of health care utilization and costs. Patients with moderate to severe SLE use more health care services and incur greater direct and indirect costs than those with mild disease.

The risk of infections in adult patients with systemic lupus erythematosus: systematic review and meta-analysis.

OBJECTIVES: We conducted a systematic review and meta-analysis to determine the magnitude of infection risk in patients with SLE and evaluate the effect of general and SLE-related factors on infection risk. METHODS: We searched MEDLINE and Embase from inception to July 2018, screening for observational studies that evaluated infection risk in patients with SLE compared with the general population/healthy controls. Outcomes of interest included overall severe infection, herpes zoster infection/reactivation, opportunistic infections, pneumonia and tuberculosis. Random-effects models were used to calculate pooled risk ratios (RRs) for each type of infection. Sensitivity analysis assessed the impact of removing studies with high risk of bias. RESULTS: Eleven retrospective or prospective cohort studies were included in the meta-analysis: overall severe infection (n = 4), pneumonia (n = 6), tuberculosis (n = 3) and herpes zoster (n = 2). Pooled RRs for overall severe infection significantly increased for patients with SLE compared with the general population/healthy controls [RR 2.96 (95% CI 1.28, 6.83)]. Pooled RRs for pneumonia, herpes zoster and tuberculosis showed significantly increased risk compared with the general population/healthy controls [RR 2.58 (1.80, 3.70), 2.50 (2.36, 2.65) and 6.11 (3.61, 10.33), respectively]. Heterogeneity and evidence of publication bias were present for all analyses, except herpes zoster. Sensitivity analyses confirmed robustness of the results. CONCLUSION: Patients with SLE have significantly higher risk of infection compared with the general population/healthy controls. Efforts to strengthen strategies aimed at preventing infections in SLE are needed. PROTOCOL REGISTRATION: PROSPERO number: CRD42018109425.

Heparanase Inhibition by Pixatimod (PG545): Basic Aspects and Future Perspectives.

Pixatimod is an inhibitor of heparanase, a protein which promotes cancer via its regulation of the extracellular environment by enzymatic cleavage of heparan sulfate (HS) and non-enzymatic signaling. Through its inhibition of heparanase and other HS-binding signaling proteins, pixatimod blocks a number of pro-cancerous processes including cell proliferation, invasion, metastasis, angiogenesis and epithelial-mesenchymal transition. Several laboratories have found that these activities have translated into potent activity using a range of different mouse cancer models, including approximately 30 xenograft and 20 syngeneic models. Analyses of biological samples from these studies have confirmed the heparanase targeting of this agent in vivo and the broad spectrum of anti-cancer effects that heparanase blockade achieves. Pixatimod has been tested in combination with a number of approved anti-cancer drugs demonstrating its clinical potential, including with gemcitabine, paclitaxel, sorafenib, platinum agents and an anti-PD-1 antibody. Clinical testing has shown pixatimod to be well tolerated as a monotherapy, and it is currently being investigated in combination with the anti-PD-1 drug nivolumab in a pancreatic cancer phase I trial.

Heparanase-neutralizing antibodies attenuate lymphoma tumor growth and metastasis.

Heparanase is an endoglycosidase that cleaves heparan sulfate side chains of proteoglycans, resulting in disassembly of the extracellular matrix underlying endothelial and epithelial cells and associating with enhanced cell invasion and metastasis. Heparanase expression is induced in carcinomas and sarcomas, often associating with enhanced tumor metastasis and poor prognosis. In contrast, the function of heparanase in hematological malignancies (except myeloma) was not investigated in depth. Here, we provide evidence that heparanase is expressed by human follicular and diffused non-Hodgkin's B-lymphomas, and that heparanase inhibitors restrain the growth of tumor xenografts produced by lymphoma cell lines. Furthermore, we describe, for the first time to our knowledge, the development and characterization of heparanase-neutralizing monoclonal antibodies that inhibit cell invasion and tumor metastasis, the hallmark of heparanase activity. Using luciferase-labeled Raji lymphoma cells, we show that the heparanase-neutralizing monoclonal antibodies profoundly inhibit tumor load in the mouse bones, associating with reduced cell proliferation and angiogenesis. Notably, we found that Raji cells lack intrinsic heparanase activity, but tumor xenografts produced by this cell line exhibit typical heparanase activity, likely contributed by host cells composing the tumor microenvironment. Thus, the neutralizing monoclonal antibodies attenuate lymphoma growth by targeting heparanase in the tumor microenvironment.

A Phase I study of the novel immunomodulatory agent PG545 (pixatimod) in subjects with advanced solid tumours.

BACKGROUND: PG545 (pixatimod) is a novel immunomodulatory agent, which has been demonstrated to stimulate innate immune responses against tumours in preclinical cancer models. METHODS: This Phase I study investigated the safety, tolerability, pharmacokinetics, pharmacodynamics and preliminary efficacy of PG545 monotherapy. Escalating doses of PG545 were administered to patients with advanced solid malignancies as a weekly 1-h intravenous infusion. RESULTS: Twenty-three subjects were enrolled across four cohorts (25, 50, 100 and 150 mg). Three dose-limiting toxicities (DLTs)-hypertension (2), epistaxis (1)-occurred in the 150 mg cohort. No DLTs were noted in the 100 mg cohort, which was identified as the maximum-tolerated dose. No objective responses were reported. Best response was stable disease up to 24 weeks, with the disease control rate in evaluable subjects of 38%. Exposure was proportional up to 100 mg and mean half-life was 141 h. The pharmacodynamic data revealed increases in innate immune cell activation, plasma IFNγ, TNFα, IP-10 and MCP-1. CONCLUSION: PG545 demonstrated a tolerable safety profile, proportional PK, evidence of immune cell stimulation and disease control in some subjects. Taken together, these data support the proposed mechanism of action, which represents a promising approach for use in combination with existing therapies.

Persistent CSF but not plasma HIV RNA is associated with increased risk of new-onset moderate-to-severe depressive symptoms; a prospective cohort study.

Major depressive disorder is the most common neuropsychiatric complication in human immunodeficiency virus (HIV) infections and is associated with worse clinical outcomes. We determined if detectable cerebrospinal fluid (CSF) HIV ribonucleic acid (RNA) at threshold ≥50 copies/ml is associated with increased risk of depression. The CNS HIV Anti-Retroviral Therapy Effects Research (CHARTER) cohort is a six-center US-based prospective cohort with bi-annual follow-up of 674 participants. We fit linear mixed models (N = 233) and discrete-time survival models (N = 154; 832 observations) to evaluate trajectories of Beck Depression Inventory (BDI) II scores and the incidence of new-onset moderate-to-severe depressive symptoms (BDI ≥ 17) among participants on combination antiretroviral therapy (cART), who were free of depression at study entry and received a minimum of three CSF examinations over 2496 person-months follow-up. Detectable CSF HIV RNA (threshold ≥50 copies/ml) at any visit was associated with a 4.7-fold increase in new-onset depression at subsequent visits adjusted for plasma HIV RNA and treatment adherence; hazard ratio (HR) = 4.76, (95 % CI 1.58-14.3); P = 0.006. Depression (BDI) scores were 2.53 points higher (95 % CI 0.47-4.60; P = 0.02) over 6 months if CSF HIV RNA was detectable at a prior study visit in fully adjusted models including age, sex, race, education, plasma HIV RNA, duration and adherence of CART, and lifetime depression diagnosis by Diagnostic Statistical Manual (DSM-IV) criteria. Persistent CSF but not plasma HIV RNA is associated with an increased risk for new-onset depression. Further research evaluating the role of immune activation and inflammatory markers may improve our understanding of this association.

Cocaine Use May be Associated with Increased Depression in Persons Infected with HIV.

HIV infection, depression, and cocaine use are independently associated with increased inflammatory signal production. There is increasing evidence about the role of inflammation in depression. In HIV disease, cocaine use may increase disease progression as well as alter T cell functioning resulting in cytokine activation and thereby increasing susceptibility to depression. We examined the association between cocaine use and depression among 447 African American persons infected with HIV who were frequent cocaine users or non-users, enrolled in an observational study in Baltimore, Maryland, between August 2003 and December 2012. The overall prevalence of depression was 40.9 % (183 of 447) participants. Among persons who were depressed, the prevalence of cocaine use was 81.4 % (149 of 183), compared to 69.3 % among persons who were not depressed (183 of 264), P = 0.004. Cocaine use was associated with nearly twofold increased odds of depression, unadjusted odds ratio (OR) 1.94, (95 % CI 1.23, 3.06); P = 0.004, compared to never using cocaine, and OR 1.02, (95 % CI 1.10, 1.05); P = 0.04 in adjusted analysis. A dose-response relationship between increasing duration of cocaine use and depression was observed. Frequency and duration of cocaine use may be associated with depression. We speculate that depression among cocaine users with HIV may involve an inflammatory component that needs further examination.

Functional Donor Site Morbidity After Vascularized Toe Transfer Procedures: A Review of the Literature and Biomechanical Consideration for Surgical Site Selection.

BACKGROUND: The purpose of this study was to conduct a systematic review and pooled analysis of vascularized toe-to-hand transfer to determine functional donor site morbidity among different techniques. METHODS: Pubmed MEDLINE, EMBASE, and Cochrane databases search yielded 302 citations, with 56 meeting inclusion criteria. Pooled outcomes and analysis are reported based on donor site morbidity, specific toe transferred, technique used, and foot biomechanical changes. RESULTS: A total of 802 digit transfers (418 isolated great toe transfers, 324 isolated second toe transfers, and 153 toes classified as "other") were included for analysis. Sex was reported in 510 patients (80.2 % men, 19.8% women). The mean patient age was 28.5 ± 8.4 years. Functional impairment analysis found 23.7% (97 digit transfers) experienced gait impairment. Great toe transfer versus second toe transfer versus the "other" group demonstrated morbidity rates of 21.8%, 14.5%, and 23% (P = 0.001), respectively. Donor site reoperative intervention occurred in 11.8% of cases (95 digits): 4.5%, 16.6%, and 16.0% (P < 0.001), respectively. Mean follow-up time was 62.6 months. CONCLUSIONS: Functional foot impairment can occur after various toe transfer procedures due to altered biomechanics of weight distribution and gait. Rigorous biomechanical foot evaluation of this subset of patients is lacking. Great toe transfer appears to have the highest morbidity rate, but lower reoperative intervention as compared to second toe transfer. Preserving ray projection does not prevent biomechanical changes to the foot, but may delay functional impairment leading to favorable functional interpretation by patients and surgeons.

Development and evaluation of a clinical staging system for amyotrophic lateral sclerosis.

BACKGROUND: Staging of disease severity is useful for prognosis, decision-making and resource planning. However, no commonly used, validated staging system exists for amyotrophic lateral sclerosis (ALS). Our purpose was to develop an ALS staging system (ALS Milano-Torino Staging) that captures the observed progressive loss of independence and function. METHODS: Clinical milestones in ALS progression were defined by loss of independence in four key domains on the ALS Functional Rating Scale (ALSFRS): swallowing, walking/self-care, communicating and breathing. Stages were defined as follows: stage 0, functional involvement but no loss of independence on any domain; stages 1-4, number of domains in which independence was lost; and stage 5, death. Staging criteria were applied to patients enrolled in a Quality of Care in ALS (QOC) study; endpoints included function (ALSFRS), quality of life (QOL; Short Form-36) and health service costs. Between-stage transition probabilities were assessed in the QOC study and in a second clinical study of lithium carbonate in ALS. RESULTS: 70/118 (59.3%) participants in the QOC study progressed to higher stages of disease at 12 months compared with their baseline stage. Functional (ALSFRS) and QOL measures were inversely related to disease stage. Health service costs were directly related to increasing disease stages from 0 to 4 (p<0.001). Probabilities for transitioning from a given stage at baseline in both studies were usually greatest for the next highest stage. CONCLUSIONS: The proposed ALS Milano-Torino Staging system correlates well with assessments of function, QOL and health service costs. Further studies are warranted to validate this system.

The cerebrospinal fluid HIV risk score for assessing central nervous system activity in persons with HIV.

Detectable human immunodeficiency virus (HIV) RNA in the cerebrospinal fluid (CSF) is associated with central nervous system (CNS) complications. We developed the CSF HIV risk score through prediction modeling to estimate the risk of detectable CSF HIV RNA (threshold >50 copies/mL) to help identify persons who might benefit most from CSF monitoring. We used baseline data from 1,053 participants receiving combination antiretroviral therapy who were enrolled in the 6-center, US-based CNS HIV Antiretroviral Therapy Effects Research (CHARTER) prospective cohort in 2004-2007. Plasma HIV RNA, CNS penetration effectiveness, duration of combination antiretroviral therapy, medication adherence, race, and depression status were retained correlates of CSF HIV RNA, displaying good discrimination (C statistic = 0.90, 95% confidence interval (CI): 0.87, 0.93) and calibration (Hosmer-Lemeshow P = 0.85). The CSF HIV risk score ranges from 0 to 42 points, with a mean of 15.4 (standard deviation, 7.3) points. At risk scores greater than 25, the probability of detecting CSF HIV RNA was at least 42.9% (95% CI: 36.6, 49.6). For each 1-point increase, the odds of detecting CSF HIV RNA increased by 26% (odds ratio = 1.26, 95% CI: 1.21, 1.31; P < 0.01). The risk score correlates with detection of CSF HIV RNA. It represents an advance in HIV management and monitoring of CNS effects, providing a potentially useful tool for clinicians.

Bone mass in individuals with chronic spinal cord injury: associations with activity-based therapy, neurologic and functional status, a retrospective study.

OBJECTIVE: To describe the prevalence of osteoporosis and its association with functional electrical stimulation (FES) use in individuals with spinal cord injury (SCI)-related paralysis. DESIGN: Retrospective cross-sectional evaluation. SETTING: Clinic. PARTICIPANTS: Consecutive persons with SCI (N=364; 115 women, 249 men) aged between 18 and 80 years who underwent dual-energy x-ray absorptiometry (DXA) examinations. INTERVENTIONS: Not applicable. MAIN OUTCOME MEASURE: Prevalence of osteoporosis defined as DXA T score ≤-2.5. RESULTS: The prevalence of osteoporosis was 34.9% (n=127). Use of FES was associated with 31.2% prevalence of osteoporosis compared with 39.5% among persons not using FES. In multivariate adjusted logistic regression analysis, FES use was associated with 42% decreased odds of osteoporosis after adjusting for sex, age, body mass index, type and duration of injury, Lower Extremity Motor Scores, ambulation, previous bone fractures, and use of calcium, vitamin D, and anticonvulsant; (adjusted odds ratio [OR]=.58; 95% confidence interval [CI], .35-.99; P=.039). Duration of injury >1 year was associated with a 3-fold increase in odds of osteoporosis compared with individuals with injury <1 year; (adjusted OR=3.02; 95% CI, 1.60-5.68; P=.001). CONCLUSIONS: FES cycling ergometry may be associated with a decreased loss of bone mass after paralysis. Further prospective examination of the role of FES in preserving bone mass will improve our understanding of this association.

Population-Based Characterization of the Pharmacokinetics and Food Effect of ANAVEX3-71, a Novel Sigma-1 Receptor and Allosteric M1 Muscarinic Receptor Agonist in Development for Treatment of Frontotemporal Dementia, Schizophrenia, and Alzheimer Disease.

Pharmacokinetic (PK) data from 28 subjects who received 5-200-mg single ascending doses of ANAVEX3-71, formerly AF710B, were analyzed to characterize the PK of ANAVEX3-71 and its M8 metabolite. PK data from 12 subjects who received 160 mg ANAVEX3-71 under fed and fasted conditions were analyzed to characterize the effect of food on the PK of the drug and its M8 metabolite. PK was characterized using the standard 2-stage approach and the nonlinear mixed-effects modeling approach. Dose proportionality was determined using the power model. Two- and 3-compartment linear PK models were tested for the characterization of the PK of ANAVEX3-71 and its M8 metabolite. The PK of ANAVEX3-71 is linear, dose proportional, and time invariant. The drug is rapidly eliminated with a mean (standard deviation) apparent terminal elimination half-life of 3.56 (4.09) hours, while the M8 metabolite was eliminated with a mean (standard deviation) apparent terminal elimination half-life of 6.59 (1.64) hours. The population PK model was used to investigate the effects of covariates on the PK of ANAVEX3-71 and M8. Age, weight, and creatinine clearance were not explanatory of the variability in apparent clearance and apparent volume of the central compartment of ANAVEX3-71. Food had no effect on the PK of ANAVEX3-71 and its M8 metabolite.

Older individuals with HIV infection have greater memory deficits than younger individuals.

The prevalence of HIV-associated neurocognitive disorder (HAND) remains persistently high in the era of combination antiretroviral therapy. We aimed to characterize the pattern of neurocognitive dysfunction in older subjects with HAND in particular amnestic versus non-amnestic impairment. One hundred six subjects from the Johns Hopkins University NIMH Clinical Outcomes cohort underwent standardized neuropsychological (NP) testing between November 2006 and June 2010. We examined performance in seven cognitive domains (memory, attention, speed of processing,visuospatial, language, motor, and executive). Older subjects were defined as age >50 years at the time of NP testing.Subjects were diagnosed with HAND according to established criteria and dichotomized into amnestic cognitive impairment or non-amnestic cognitive impairment with deficit defined as z scores <−1.5 for the verbal and nonverbal memory domains.There were 32 older subjects with a mean age (SD) of 54.2 (2.8) years and 74 younger subjects, 43.7 (4.3) years. Older age was associated with a 4.8-fold higher odds of memory deficits adjusted for potential confounders (p =0.035) identified a priori. With age modeled as a continuous covariate,every 1 year increase in age was associated with a 1.11-fold higher odds of memory deficit (p =0.05). There was a higher proportion of amnestic cognitive impairment among older subjects than younger subjects with HIV infection. Neurodegenerative processes other than those directly due to HIV maybe increasingly important as individuals with chronic HIV infection and HAND survive into older age.

Ictal adiponectin levels in episodic migraineurs: a randomized pilot trial.

OBJECTIVE: To assess ictal adiponectin (ADP) levels before and after acute abortive treatment in women episodic migraineurs. METHODS: Peripheral blood specimens were collected from women episodic migraineurs before and after acute abortive treatment with sumatriptan/naproxen sodium vs placebo. Univariate and multivariate models were utilized to examine the relationship between serum total ADP (T-ADP), ADP oligomers (high molecular weight [HMW], middle molecular weight, and low molecular weight [LMW]-ADP), and ADP ratio levels and pain severity. Paired t-tests and random intercept longitudinal models were utilized to assess the mean changes in T-ADP, ADP oligomers, and ratios over time in treatment responders and nonresponders. RESULTS: Twenty participants (11 responders, 9 nonresponders) have been studied to date. In all participants, increases in the HMW : LMW ADP ratio were associated with an increase in pain severity. For every 1 point increase in the HMW : LMW ratio, pain severity increased by 0.22 (Confidence Interval [CI]: 0.07, 0.37; P = .004). In contrast, for every 0.25 µg/mL increase in LMW-ADP, pain severity decreased by 0.20 (CI: -0.41, -0.002; P = .047). In treatment responders, T-ADP levels were reduced at 30 minutes (12.52 ± 3.4; P = .03), 60 minutes (12.32 ± 3.2; P = .017), and 120 minutes (12.65 ± 3.2; P = .016) after treatment as compared with onset (13.48 ± 3.8). Additionally, in responders, the HMW : LMW ratio level was greater at pain onset (3.70 ± 1.9 µg/mL) as compared with nonresponders (2.29 ± 0.71 µg/mL), P = .050. Responders also showed a decrease in the HMW : LMW ratio at 60 minutes (2.37 ± 1.1; P = .002) and 120 minutes (2.76 ± 1.4; P = .02) after treatment as compared with onset (3.70 ± 1.9). These changes in responders remained significant after adjusting for covariates, including measured body mass index (m-BMI). Although nonresponders showed no significant changes in unadjusted T-ADP or ADP oligomer or ratio levels, the HMW : LMW ratio was increased in nonresponders after adjustments (P = .025). CONCLUSION: In this pilot study of women episodic migraineurs, the HMW : LMW ADP ratio level was associated with migraine severity and predictive of acute treatment response. ADP and the HMW : LMW ratio of ADP represent potential novel biomarkers and drug targets for episodic migraine.

Lower extremity functional electrical stimulation cycling promotes physical and functional recovery in chronic spinal cord injury.

OBJECTIVE: To examine the effect of long-term lower extremity functional electrical stimulation (FES) cycling on the physical integrity and functional recovery in people with chronic spinal cord injury (SCI). DESIGN: Retrospective cohort, mean follow-up 29.1 months, and cross-sectional evaluation. SETTING: Washington University Spinal Cord Injury Neurorehabilitation Center, referral center. PARTICIPANTS: Twenty-five people with chronic SCI who received FES during cycling were matched by age, gender, injury level, and severity, and duration of injury to 20 people with SCI who received range of motion and stretching. INTERVENTION: Lower extremity FES during cycling as part of an activity-based restorative treatment regimen. MAIN OUTCOME MEASURE: Change in neurological function: motor, sensory, and combined motor-sensory scores (CMSS) assessed by the American Spinal Injury Association Impairment scale. Response was defined as ≥ 1 point improvement. RESULTS: FES was associated with an 80% CMSS responder rate compared to 40% in controls. An average 9.6 CMSS point loss among controls was offset by an average 20-point gain among FES subjects. Quadriceps muscle mass was on average 36% higher and intra/inter-muscular fat 44% lower, in the FES group. Hamstring and quadriceps muscle strength was 30 and 35% greater, respectively, in the FES group. Quality of life and daily function measures were significantly higher in FES group. CONCLUSION: FES during cycling in chronic SCI may provide substantial physical integrity benefits, including enhanced neurological and functional performance, increased muscle size and force-generation potential, reduced spasticity, and improved quality of life.

An Enzymatic Activity Assay for Heparanase That Is Useful for Evaluating Clinically Relevant Inhibitors and Studying Kinetics.

The enzyme heparanase cleaves heparan sulfate and is involved in a range of human diseases including cancer, inflammation, diabetes, and viral infection. There is a need for a simple and reliable enzymatic assay to allow for the screening of compounds to find inhibitors of heparanase. We have developed an assay that uses the heparinoid fondaparinux as enzyme substrate and detects one of the products of catalysis, which contains a newly formed reducing terminus, with the tetrazolium salt WST-1. Due to the homogenous substrate and single point of cleavage therein, this assay allows for more systematic kinetic analysis of heparanase inhibitors. Here, we provide a detailed method for conducting this assay and also provide information to assist researchers in evaluating whether the assay is performing properly in their laboratories.

Concentration-QTc Relationship from a Single Ascending Dose Study of ANAVEX3-71, a Novel Sigma-1 Receptor and Allosteric M1 Muscarinic Receptor Agonist in Development for the Treatment of Frontotemporal Dementia, Schizophrenia, and Alzheimer's Disease.

This is the cardiodynamic evaluation of a single ascending dose study in healthy participants with the primary objective of assessing the effect of ANAVEX3-71, formerly AF710B, on ECG parameters. Twelve-lead ECGs were obtained at 3 time points within 1 hour prior to dosing to establish a baseline and then serially postdose. Concentration-QTc analysis of plasma concentrations of ANAVEX3-71 and metabolite M8 was conducted. ANAVEX3-71 at the studied doses did not have a clinically relevant effect on heart rate or on the PR and QRS intervals. ANAVEX3-71 alone was retained in the primary model due to small fit differences between models which included the metabolite M8. The estimated population slope of the concentration-QTcF relationship was small and slightly negative: -0.017 ms per µg/L, with a small treatment effect-specific intercept of -0.49 ms. An effect on the placebo-corrected, change-from-baseline QTc exceeding 10 ms can be excluded within the full observed ranges of plasma concentrations of ANAVEX3-71 and M8 up to ∼996 and ∼58 µg/L, respectively. The results from this cardiodynamic evaluation demonstrated that ANAVEX3-71 at single ascending doses of 5-200 mg had no clinically relevant effects on any of the studied ECG parameters.

PG545 sensitizes ovarian cancer cells to PARP inhibitors through modulation of RAD51-DEK interaction.

PG545 (Pixatimod) is a highly sulfated small molecule known for its ability to inhibit heparanase and disrupt signaling mediated by heparan-binding-growth factors (HB-GF). Previous studies indicated that PG545 inhibits growth factor-mediated signaling in ovarian cancer (OC) to enhance response to chemotherapy. Here we investigated the previously unidentified mechanisms by which PG545 induces DNA damage in OC cells and found that PG545 induces DNA single- and double-strand breaks, reduces RAD51 expression in an autophagy-dependent manner and inhibits homologous recombination repair (HRR). These changes accompanied the ability of PG545 to inhibit endocytosis of the heparan-sulfate proteoglycan interacting DNA repair protein, DEK, leading to DEK sequestration in the tumor microenvironment (TME) and loss of nuclear DEK needed for HRR. As a result, PG545 synergized with poly (ADP-ribose) polymerase inhibitors (PARPis) in OC cell lines in vitro and in 55% of primary cultures of patient-derived ascites samples ex vivo. Moreover, PG545/PARPi synergy was observed in OC cells exhibiting either de novo or acquired resistance to PARPi monotherapy. PG545 in combination with rucaparib also generated increased DNA damage, increased antitumor effects and increased survival of mice bearing HRR proficient OVCAR5 xenografts compared to monotherapy treatment in vivo. Synergistic antitumor activity of the PG545/rucaparib combination was likewise observed in an immunocompetent syngeneic ID8F3 OC model. Collectively, these results suggest that targeting DEK-HSPG interactions in the TME through the use of PG545 may be a novel method of inhibiting DNA repair and sensitizing cells to PARPis.