Targeting Tumor Angiogenesis with the Selective VEGFR-3 Inhibitor EVT801 in Combination with Cancer Immunotherapy.

The receptor tyrosine kinase VEGFR-3 plays a crucial role in cancer-induced angiogenesis and lymphangiogenesis, promoting tumor development and metastasis. Here, we report the novel VEGFR-3 inhibitor EVT801 that presents a more selective and less toxic profile than two major inhibitors of VEGFRs (i.e., sorafenib and pazopanib). As monotherapy, EVT801 showed a potent antitumor effect in VEGFR-3-positive tumors, and in tumors with VEGFR-3-positive microenvironments. EVT801 suppressed VEGF-C-induced human endothelial cell proliferation in vitro and tumor (lymph)angiogenesis in different tumor mouse models. In addition to reduced tumor growth, EVT801 decreased tumor hypoxia, favored sustained tumor blood vessel homogenization (i.e., leaving fewer and overall larger vessels), and reduced important immunosuppressive cytokines (CCL4, CCL5) and myeloid-derived suppressor cells (MDSC) in circulation. Furthermore, in carcinoma mouse models, the combination of EVT801 with immune checkpoint therapy (ICT) yielded superior outcomes to either single treatment. Moreover, tumor growth inhibition was inversely correlated with levels of CCL4, CCL5, and MDSCs after treatment with EVT801, either alone or combined with ICT. Taken together, EVT801 represents a promising anti(lymph)angiogenic drug for improving ICT response rates in patients with VEGFR-3 positive tumors. Significance: The VEGFR-3 inhibitor EVT801 demonstrates superior selectivity and toxicity profile than other VEGFR-3 tyrosine kinase inhibitors. EVT801 showed potent antitumor effects in VEGFR-3-positive tumors, and tumors with VEGFR-3-positive microenvironments through blood vessel homogenization, and reduction of tumor hypoxia and limited immunosuppression. EVT801 increases immune checkpoint inhibitors' antitumor effects.

A selective reversible monoamine oxidase B inhibitor in smoking cessation: effects on its own and in association with transdermal nicotine patch.

RATIONALE: Monoamine oxidase B (MAO-B) activity is reduced in smokers. A MAO-B inhibitor alone or co-administered with nicotine may mimic the effects of smoking and be a candidate drug for smoking cessation. OBJECTIVE: This study aims to determine the efficacy and safety of EVT302, a selective reversible MAO-B inhibitor, alone and on top of nicotine patch (NP) in smoking cessation. METHODS: This was a randomised, double blind, placebo-controlled phase II, multicentre trial. Smokers (≥10 cigarettes/day) received either EVT302 (N = 145) or placebo (N = 145), or EVT302 (N = 61) or placebo (N = 61) on top of open label NP 21 mg/day for 8 weeks. The main comparison was between EVT302 and placebo without NP. The primary outcome measure was end-of-treatment 4-week continuous abstinence rate (CAR). SECONDARY OUTCOME MEASURES: point prevalence abstinence rate, saliva cotinine concentrations in the groups without NP, urge to smoke, nicotine withdrawal symptoms and assessment of subjective effects of cigarettes. RESULTS: The 4-week CAR was 15.2 % in the placebo, 17.2 % in the EVT302, 26.8 % in the NP + placebo and 32.8 % in the NP + EVT302 groups, respectively. There was no difference between EVT302 and placebo either alone (adjusted OR: 1.45, 95 % CI: 0.65-3.26) or when co-administered with NP. No statistically significant difference occurred for the secondary outcome measures. CONCLUSIONS: The selective, reversible MAO-B inhibitor EVT302 was not superior to placebo in helping smokers quit, in line with data with selegiline and confirms that MAO-B inhibitors are not effective in smoking cessation. Co-administration of NP does not provide a supplementary benefit.

Treatment of elderly primary insomnia patients with EVT 201 improves sleep initiation, sleep maintenance, and daytime sleepiness.

OBJECTIVE: Two doses of EVT 201, a partial positive allosteric modulator of the GABA(A) system, were evaluated in elderly primary insomnia patients with daytime sleepiness. PATIENTS AND METHODS: Participants were 149 elderly patients with DSM-IV primary insomnia including evidence of daytime sleepiness (53 males, 96 females; mean age 71.3yrs, range 65-86yrs). A randomized, multicentre, double-blind, placebo-controlled, parallel-group design was used to assess the hypnotic efficacy of EVT 201 1.5 and 2.5mg during seven consecutive nights. Polysomnography (PSG) was performed on nights 1, 6 and 7 of treatment. Daytime assessments on Day 8 included the multiple sleep latency test (MSLT), Rey Auditory Verbal Learning Test (RAVLT), Psychomotor Vigilance Task (PVT) and the Karolinska Sleepiness Scale (KSS). The primary endpoint was total sleep time (TST) and the key secondary endpoint was mean MSLT latency. RESULTS: Compared to placebo, EVT 201 1.5 and 2.5mg increased TST (30.9, 56.4min, respectively; p=0.0001, p<0.0001); reduced wake after sleep onset (WASO; -15.2, -36.1min, respectively; p=0.014, p<0.0001); reduced latency to persistent sleep (LPS; -15.9, -19.9min, respectively; p=0.009, p=0.001). The 2.5mg dose also reduced WASO in hours 5-8 (-16.3min, p=0.001). Both doses also improved subjective sleep quality and usual subjective efficacy measures. A significantly longer mean MSLT latency was observed on Day 8 with both doses, compared to placebo (2min increase; p=0.03, both doses). The PVT, RAVLT, and POMS did not differ among treatment groups. No serious or unexpected treatment emergent adverse events were noted. CONCLUSION: EVT 201 improved PSG measures of sleep onset and sleep maintenance and significantly reduced daytime physiological sleep tendency. These findings suggest that treatment of primary insomnia in older patients has the potential to improve daytime sleepiness as well as sleep.

The partial positive allosteric GABA(A) receptor modulator EVT 201 is efficacious and safe in the treatment of adult primary insomnia patients.

OBJECTIVE: To evaluate polysomnographic (PSG) and self-reported measures of the efficacy and safety of EVT 201 in patients with primary insomnia. PATIENTS AND METHODS: Following clinical and PSG screening, 75 patients (mean age: 45.1+/-11.2 y; 50 f, 25 m) meeting DSM-IV criteria for primary insomnia entered this crossover study and were randomly assigned to double-blind treatment sequences of 1.5 mg or 2.5 mg EVT 201, or placebo using a balanced Latin square design. For each study condition study medication was administered on two consecutive nights and PSG and self-reported data were collected. Safety assessments included physical examination, clinical laboratory measures, electrocardiogram, documentation of adverse events, and the digit symbol substitution test (DSST) and self-reported sleepiness/alertness ratings to detect residual sedation. Data were collected at five US sleep laboratories. Efficacy analyses were performed for the 67 patients completing the study. Safety analyses included all 75 randomized patients. RESULTS: On PSG measures compared to placebo, EVT 201 1.5 mg and 2.5 mg increased total sleep time (TST; 33.1, 45.0 min; both p<0.0001), reduced wake after sleep onset (WASO; -16.7, -25.7 min; both p<0.0001), reduced latency to persistent sleep (LPS; -17.0, -20.7 min; both p<0.0001), and reduced the number of awakenings (-1.2, -2.6; both p<0.0001). Significant reduction of wake time was seen with 1.5 mg during each of the first three quarters of the night (p<0.0001-0.002), and with 2.5 mg in all four quarters (p<0.0001-0.0005). Both doses also improved all key self-reported measures of sleep including total sleep time (rTST; 51.9, 51.1 min; both p<0.0001), wake after sleep onset (rWASO; -29.3, -29.6 min; both p<0.0001), sleep latency (rSL; -24.0 min, p<0.004; -25.1 min, p<0.0002), and number of awakenings (rNAW; -1.1, -1.2; both p<0.0001). Sleep quality was also improved by both doses. Self-rated sleepiness in the morning did not differ from placebo for either dose; however, there was a small negative effect on the DSST for both doses. Both doses had similar effects on sleep architecture including an increase in Stage 2 sleep and REM latency and a small, but significant decrease in REM (REM -5.7, -8.3 min; p=0.0175, p=0.0006). No effect on other sleep architecture parameters, including SWS, was seen. EVT 201 was well tolerated. No serious or unexpected adverse events were reported. CONCLUSION: This first study of EVT 201 in adult patients with primary insomnia demonstrated improved measures of sleep onset and sleep maintenance, including during the third and fourth quarters of the night. Adverse events were infrequent and all were mild to moderate in severity.