A randomised, placebo-controlled clinical trial with the α2/3/5 subunit selective GABAA positive allosteric modulator PF-06372865 in patients with chronic low back pain.

The effect of PF-06372865, a subtype-selective positive allosteric modulator of the γ-aminobutyric acid type A (GABAA) receptor, on chronic low back pain was investigated in a randomised, placebo- and active-controlled phase 2 clinical trial. The parallel treatment group trial consisted of a 1-week single-blind placebo run in the phase, followed by 4-week double-blind treatment. Patients were randomised to receive either PF-06372865, naproxen, or placebo twice a day for 4 weeks. The primary end point was the numerical rating score of low back pain intensity after 4 weeks of active treatment. Secondary end points included the Roland Morris Disability Questionnaire and the Hopkins Verbal Learning Test-Revised. The trial had predefined decision rules based on the probability that PF-06372865 was better than placebo. The study was stopped at the interim analysis for futility. At this time, a total of 222 patients were randomised and the mean PF-06372865 4-week response on the low back pain intensity was 0.16 units higher (worse) than placebo (90% confidence interval -0.28 to 0.60). There were small, statistically significant reductions in the delayed recall test score with PF-06372865, as measured by Hopkins Verbal Learning Test-Revised. The effects of naproxen were in line with expectations. PF-06372865 was well tolerated. The most common treatment-related adverse events in the PF-06372865 arm were somnolence (5 mild and 4 moderate), dizziness (2 mild and 3 moderate), and nausea (2 mild). Although the reason for the lack of analgesic effect is not completely clear, it may be a result of not achieving sufficient receptor occupancy to drive efficacy.

Apixaban compared to heparin/vitamin K antagonist in patients with atrial fibrillation scheduled for cardioversion: the EMANATE trial.

Aim: The primary objective was to compare apixaban to heparin/vitamin K antagonist (VKA) in patients with atrial fibrillation (AF) and ≤48 h anticoagulation prior to randomization undergoing cardioversion. Methods: One thousand five hundred patients were randomized. The apixaban dose of 5 mg b.i.d. was reduced to 2.5 mg b.i.d. in patients with two of the following: age ≥ 80 years, weight ≤ 60 kg, or serum creatinine ≥ 133 µmol/L. To expedite cardioversion, at the discretion of the investigator, imaging and/or a loading dose of 10 mg (down-titrated to 5 mg) was allowed. The endpoints for efficacy were stroke, systemic embolism (SE), and death. The endpoints for safety were major bleeding and clinically relevant non-major (CRNM) bleeding. Results: There were 1038 active and 300 spontaneous cardioversions; 162 patients were not cardioverted. Imaging was performed in 855 patients, and 342 received a loading dose of apixaban. Comparing apixaban to heparin/VKA in the full analysis set, there were 0/753 vs. 6/747 strokes [relative risk (RR) 0; 95% confidence interval (95% CI) 0-0.64; nominal P = 0.015], no SE, and 2 vs. 1 deaths (RR 1.98; 95% CI 0.19-54.00; nominal P > 0.999). In the safety population, there were 3/735 vs. 6/721 major (RR 0.49; 95% CI 0.10-2.07; nominal P = 0.338) and 11 vs. 13 CRNM bleeding events (RR 0.83; 95% CI 0.34-1.89; nominal P = 0.685). On imaging, 60/61 with thrombi continued randomized treatment; all (61) were without outcome events. Conclusions: Rates of strokes, systemic emboli, deaths, and bleeds were low for both apixaban and heparin/VKA treated AF patients undergoing cardioversion. Clinical Trials.gov number: NCT02100228.

Acute kidney injury observed during phase 1 clinical trials of a novel xanthine oxidase/URAT1 dual inhibitor PF-06743649.

The objective of these clinical studies was to assess the safety and urate lowering activity of a novel urate transporter 1 (URAT1)/ xanthine oxidase (XO) inhibitor PF-06743649 in healthy subjects and gout patients. Escalating doses of PF-06743649 or placebo were given to healthy young subjects, healthy elderly subjects and gout patients. Serum uric acid (sUA) and urinary pharmacodynamic markers were assayed, and safety was assessed by collection of adverse events and assessment of safety labs, ECGs and vital signs. Administration of PF-06743649 led to rapid decrease in sUA in all cohorts; in gout patients, a change from baseline of 69 % was observed for the 40 mg dose. Urinary and serum biomarkers were consistent with inhibition of both URAT1 and XO. Although dosing was otherwise well tolerated, two subjects experienced serious adverse events of acute kidney injury. Both subjects exhibited increased serum creatinine and blood urea nitrogen in the first 3 days post first dose and were hospitalised. One subject exhibited oliguria for the first 24 h. Both subjects made a complete recovery with minimal intervention. PF-06743649 was effective at rapidly lowering sUA, but further development was terminated for an identified renal safety risk.

Safety and tolerability of LBR-101, a humanized monoclonal antibody that blocks the binding of CGRP to its receptor: Results of the Phase 1 program.

BACKGROUND: LBR-101 is a fully humanized monoclonal antibody that binds to calcitonin gene-related peptide. OBJECTIVE: The objective of this article is to characterize the safety and tolerability of LBR-101 when administered intravenously to healthy volunteers, by presenting the pooled results of the Phase 1 program. METHODS: LBR-101 was administered to 94 subjects, while 45 received placebo. Doses ranged from 0.2 mg to 2000 mg given once (Day 1), as a single IV infusion, or up to 300 mg given twice (Day 1 and Day 14). RESULTS: Subjects receiving placebo reported an average of 1.3 treatment-emerging adverse events vs 1.4 per subject among those receiving any dose of LBR-101, and 1.6 in those receiving 1000 mg or higher. Treatment-related adverse events occurred in 21.2% of subjects receiving LBR-101, compared to 17.7% in those receiving placebo. LBR-101 was not associated with any clinically relevant patterns of change in vital signs, ECG parameters, or laboratory findings. The only serious adverse event consisted of "thoracic aortic aneurysm" in a participant later found to have an unreported history of Ehlers-Danlos syndrome. CONCLUSION: Single IV doses of LBR-101 ranging from 0.2 mg up to 2000 mg and multiple IV doses up to 300 mg were well tolerated. Overt safety concerns have not emerged. A maximally tolerated dose has not been identified.

Influence of sildenafil on genital engorgement in women with female sexual arousal disorder.

INTRODUCTION: We previously described dynamic, noncontrast magnetic resonance imaging (MRI) of the female genitalia as a reproducible, nonintrusive, objective means of quantifying sexual arousal response in women without sexual difficulties. These studies showed an increase in clitoral engorgement ranging from 50 to 300% in healthy women during sexual arousal. AIM: This study sought to evaluate the genital arousal response in women with female sexual arousal disorder (FSAD) after administration of sildenafil and placebo. We performed a multicenter, double-blind, placebo-controlled, cross-over study to assess the clitoral engorgement response using dynamic MRI in women with FSAD after administering sildenafil and placebo followed by audiovisual sexual stimulation (AVSS). METHODS: Nineteen premenopausal women with FSAD underwent two MRI sessions. Subjects were randomized to receive either (i) sildenafil 100 mg during the first session followed by placebo during the second session, or (ii) placebo followed by sildenafil. During each session, baseline MR images were obtained while subjects viewed a neutral video. Subjects then ingested sildenafil or placebo. After 30 minutes, a series of MRIs were obtained at 3-minute intervals for 10 time points while subjects viewed AVSS. MAIN OUTCOME MEASURES: A positive sexual arousal response was achieved if clitoral volume increased ≥50% from baseline. RESULTS: Thirteen of 19 (68%) subjects achieved a ≥50% increase in clitoral engorgement from baseline when administered sildenafil or placebo 30 minutes after dose administration. At 60 minutes after administration, 17/19 (89%) subjects receiving sildenafil and 16/19 (84%) subjects receiving placebo had responded (P value 0.3173). CONCLUSIONS: Sildenafil did not augment the genital response in women with FSAD. Secondarily, a majority of women in this study did not have impaired clitoral engorgement as measured by MRI, suggesting that FSAD is not predominantly a disorder of genital engorgement.

Discovery of a selective small-molecule melanocortin-4 receptor agonist with efficacy in a pilot study of sexual dysfunction in humans.

The relevance of the melanocortin system to sexual activity is well established, and nonselective peptide agonists of the melanocortin receptors have shown evidence of efficacy in human sexual dysfunction. The role of the MC4 receptor subtype has received particular scrutiny, but the sufficiency of its selective activation in potentiating sexual response has remained uncertain owing to conflicting data from studies in preclinical species. We describe here the discovery of a novel series of small-molecule MC4 receptor agonists derived from library hit 2. The addition of methyl substituents at C3 and C5 of the 4-phenylpiperidin-4-ol ring was found to be markedly potency-enhancing, enabling the combination of low nanomolar potencies with full rule-of-five compliance. In general, the series shows only micromolar activity at other melanocortin receptors. Our preferred compound 40a provided significant systemic exposure in humans on both sublingual and oral administration and was safe and well tolerated up to the maximum tested dose. In a pilot clinical study of male erectile dysfunction, the highest dose of 40a tested (200 mg) provided a similar level of efficacy to sildenafil.

I. Slow oscillations in vaginal blood flow: alterations during sexual arousal in rodents and humans.

PURPOSE: This study investigated slow oscillatory rhythms in vaginal blood flow as a physiological marker of female sexual arousal in rodents, human healthy volunteers, and women with female sexual arousal disorder (FSAD). MATERIALS AND METHODS: Vaginal blood flow was measured in urethane-anesthetized rodents using laser Doppler flowmetry, while in humans, vaginal photoplethysmography was used. Acquired data were filtered for frequency analysis in the range of 0.013-2.5 Hz in rodents and 0.01-0.5 Hz in humans. Rodents were assessed for changes in a high frequency range (HF = 0.6-2.5 Hz), and a low frequency range (LF = 0.013-0.6 Hz). Human data were assessed for total spectral power in the entire frequency range. RESULTS: During naturally induced arousal (exposure to male), oscillatory rhythms in vaginal blood flow from rodents demonstrated an increase in the ratio of LF oscillations to HF oscillations (LF/HF ratio). Drugs known to induce sexual arousal (apomorphine and melanotan II) were tested in anesthetized rodents. Both compounds induced an increase in the LF/HF ratio. In humans, visual sexual stimulation induced an increase in the total power of slow oscillatory activity in vaginal blood flow in healthy human volunteers. No such increase was observed in women with FSAD. CONCLUSIONS: This study demonstrated that slow oscillations in vaginal blood flow are correlated with subjective physiological arousal and display diminished responsiveness in women with FSAD. Slow oscillations in vaginal blood flow are entirely independent of vaginal vasocongestion as women with FSAD demonstrated a normal vasocongestion response to visual sexual stimulation. In conditions where rodents would be expected to be sexually aroused, slow oscillations in vaginal blood flow showed a shift from HFs to LFs. This technique will greatly enhance the investigation of female sexual function both clinically and preclinically.