Improvement of fatigue in generalised myasthenia gravis with zilucoplan.

BACKGROUND: Fatigue is a debilitating symptom of myasthenia gravis (MG). The impact of fatigue on MG can be assessed by Quality of Life in Neurological Disorders (Neuro-QoL) Short Form Fatigue scale. Transformation of raw Neuro-QoL fatigue scores to T-scores is a known approach for facilitating clinical interpretation of clinically meaningful and fatigue severity thresholds. METHODS: In the Phase 3, double-blind, placebo-controlled RAISE study (NCT04115293), adults with acetylcholine receptor autoantibody-positive generalised MG (MG Foundation of America Disease Class II-IV) were randomised 1:1 to daily subcutaneous zilucoplan 0.3 mg/kg or placebo for 12 weeks. Patients completing RAISE could opt to receive zilucoplan 0.3 mg/kg in an ongoing, open-label extension study, RAISE-XT (NCT04225871). In this post-hoc analysis, we evaluated the long-term effect of zilucoplan on fatigue in RAISE patients who entered RAISE-XT. We report change in Neuro-QoL Short Form Fatigue T-scores and fatigue severity levels from RAISE baseline to Week 60. RESULTS: Mean Neuro-QoL Short Form Fatigue T-scores improved from baseline to Week 12 in the zilucoplan group (n = 86) with a clinically meaningful difference versus placebo (n = 88; least squares mean difference: - 3.61 (nominal p-value = 0.0060]), and these improvements continued further to Week 60. At Week 12, more patients on zilucoplan (n = 34, 47.2%) experienced improvements in ≥ 1 fatigue severity level from baseline versus placebo (n = 23, 28.4%; p = 0.017). At Week 60, most (n = 55, 65.5%) patients had mild fatigue or none. CONCLUSION: Treatment with zilucoplan demonstrated statistical and clinically meaningful improvements in fatigue scores and severity versus placebo during RAISE, which were sustained to Week 60 in RAISE-XT.

Efficacy of testosterone combined with a PDE5 inhibitor and testosterone combined with a serotonin (1A) receptor agonist in women with SSRI-induced sexual dysfunction. A preliminary study.

Selective serotonin reuptake inhibitors (SSRIs) are known to cause sexual dysfunction, such as decreased sexual motivation, desire, arousal, and orgasm difficulties. These SSRI-induced sexual complaints have a high prevalence rate, while there is no approved pharmacological treatment for SSRI-induced sexual dysfunction. It is hypothesized that a polymorphisms in the androgen receptor gene, encoded by the nucleotides cysteine, adenine, and guanine (CAG), influence the effect of testosterone on sexual functioning. In an explorative, randomized, double-blind, placebo-controlled, crossover study we investigated the possible effects of sublingual testosterone combined with a serotonin (5-HT)1A receptor agonist, and of sublingual testosterone combined with a phosphodiesterase type 5 inhibitor (PDE5-i) on sexual functioning in women with SSRI-induced sexual dysfunction. Furthermore, we did an exploratory analysis to assess if the CAG polymorphism influences this effect. 21 pre- and postmenopausal women with SSRI-induced sexual dysfunction participated and underwent the following interventions: a combination of testosterone (0.5 mg) sublingually and the PDE5-i sildenafil (50 mg) and a combination of testosterone (0.5 mg) sublingually and the 5-HT1A receptor agonist buspirone (10 mg). The results show that women who use a low dose of SSRI and have relatively long CAG repeats report a marked improvement in sexual function in response to both treatments compared to placebo. This explorative study and preliminary results indicate that in women with SSRI-induced sexual dysfunction, a combination of testosterone sublingually and a PDE5-i or testosterone sublingually and a 5-HT1A receptor agonist might be promising treatments for certain subgroups of women with this condition.

Toward personalized sexual medicine (part 1): integrating the "dual control model" into differential drug treatments for hypoactive sexual desire disorder and female sexual arousal disorder.

In three related manuscripts we describe our drug development program for the treatment of Hypoactive Sexual Desire Disorder (HSDD). In this first theoretical article we will defend the hypothesis that different causal mechanisms are responsible for the emergence of HSDD: low sexual desire in women (with HSDD) could be due to either a relative insensitive brain system for sexual cues or to enhanced activity of sexual inhibitory mechanisms. This distinction in etiological background was taken into account when designing and developing new pharmacotherapies for this disorder. Irrespective of circulating plasma levels of testosterone, administration of sublingual 0.5 mg testosterone increases the sensitivity of the brain to sexual cues. The effects of an increase in sexual sensitivity of the brain depend on the motivational state of an individual. It might activate sexual excitatory mechanisms in low sensitive women, while it could evoke (or strengthen) sexual inhibitory mechanisms in women prone to sexual inhibition. Sexual stimulation in the brain is necessary for phosphodiesterase type 5 inhibitor (PDE5i)-mediated increase in genital sexual response. Accordingly, a single dose of T+PDE5i might enhance sexual responsiveness, especially in women with low sensitivity to sexual cues. In other women sexual stimulation might elicit a prefrontal cortex (PFC)-mediated phasic increase in sexual inhibition, in which activity of 5-hydroxytryptamine (5-HT, serotonin) is involved. We hypothesize that a single dose of 5-hydroxytryptamine receptor agonist (5-HT(1A)ra) will reduce the sexual-stimulation-induced PFC-mediated sexual inhibition during a short period after administration. Consequently, treatment with T+5-HT(1A)ra will be more effective, in particular in women exhibiting sexual inhibition. Based on the results of our efficacy studies described in parts 2 and 3 of the series, we conclude that tailoring on-demand therapeutics to different underlying etiologies might be a useful approach to treat common symptoms in subgroups of women with HSDD.

Pharmacokinetics of three doses of sublingual testosterone in healthy premenopausal women.

CONTEXT: Sublingual testosterone is a single-dose treatment often used in studies regarding social, cognitive and sexual behavior. It is hypothesized that an increase in the ratio of free to total testosterone (free fraction) is indirectly, via genomic effects, responsible for the behavioral effects after sublingual testosterone administration. OBJECTIVE: To characterize the pharmacokinetics of three doses sublingual testosterone in premenopausal women. Also, to investigate the SHBG saturation threshold influencing the free level and free fraction of testosterone. DESIGN: We conducted an investigator-blind, randomized, cross-over placebo controlled study. SETTING: This study was undertaken at the research and development department of a scientific company for research regarding female sexual dysfunction. PARTICIPANTS: 16 healthy premenopausal women (mean age 27.3±5.3 years). INTERVENTIONS: Sublingual testosterone solution; 0.25, 0.50 and 0.75 mg. MAIN OUTCOMES MEASURE: The pharmacokinetics of three single doses sublingual testosterone solution; the influence of SHBG levels on free and total levels of testosterone. RESULTS: After sublingual testosterone administration, serum free and total testosterone levels peaked at 15 min and reached baseline levels within 150 min. The AUCs and C(max) of free and total testosterone differed significantly between the three doses (p<0.0001) and increased dose-dependently. A dose-dependent increase in free fraction of testosterone was found in women with low SHBG levels, but not in women with high SHBG levels. CONCLUSIONS: The three doses sublingual testosterone are rapidly absorbed and quickly metabolized in premenopausal women. These data demonstrate the influence of SHBG levels on the treatment induced alterations in plasma free testosterone.