BackgroundCharcot-Marie-Tooth type 1A disease (CMT1A) is a rare orphan inherited neuropathy caused by an autosomal dominant duplication of a gene encoding for the structural myelin protein PMP22, which induces abnormal Schwann cell differentiation and dysmyelination, eventually leading to axonal suffering then loss and muscle wasting. We favour the idea that diseases can be more efficiently treated when targeting multiple disease-relevant pathways. In CMT1A patients, we therefore tested the potential of PXT3003, a low-dose combination of three already approved compounds (baclofen, naltrexone and sorbitol). Our study conceptually builds on preclinical experiments highlighting a pleiotropic mechanism of action that includes downregulation of PMP22. The primary objective was to assess safety and tolerability of PXT3003. The secondary objective aimed at an exploratory analysis of efficacy of PXT3003 in CMT1A, to be used for designing next clinical development stages (Phase 2b/3).Methods80 adult patients with mild-to-moderate CMT1A received in double-blind for 1 year Placebo or one of the three increasing doses of PXT3003 tested, in four equal groups. Safety and tolerability were assessed with the incidence of related adverse events. Efficacy was assessed using the Charcot-Marie-Tooth Neuropathy Score (CMTNS) and the Overall Neuropathy Limitations Scale (ONLS) as main endpoints, as well as various clinical and electrophysiological outcomes.ResultsThis trial confirmed the safety and tolerability of PXT3003. The highest dose (HD) showed consistent evidence of improvement beyond stabilization. CMTNS and ONLS, with a significant improvement of respectively of 8% (0.4% - 16.2%) and 12.1% (2% - 23.2%) in the HD group versus the pool of all other groups, appear to be the most sensitive clinical endpoints to treatment despite their quasi-stability over one year under Placebo. Patients who did not deteriorate over one year were significantly more frequent in the HD group.ConclusionsThese results confirm that PXT3003 deserves further investigation in adults and could greatly benefit CMT1A-diagnosed children, usually less affected than adults.Trial registrationEudraCT Number: 2010-023097-40. ClinicalTrials.gov Identifier: NCT01401257. The Committee for Orphan Medicinal Products issued in February 2014 a positive opinion on the application for orphan designation for PXT3003 (EMA/OD/193/13).Electronic supplementary materialThe online version of this article (doi:10.1186/s13023-014-0199-0) contains supplementary material, which is available to authorized users.

Rationale: Excessive daytime sleepiness is a common disabling symptom in obstructive sleep apnea syndrome. Objectives: To evaluate the efficacy and safety of pitolisant, a selective histamine H3 receptor antagonist with wake-promoting effects, for the treatment of daytime sleepiness in patients with moderate to severe obstructive sleep apnea refusing continuous positive airway pressure treatment. Methods: In an international, multicenter, double-blind, randomized (3:1), placebo-controlled, parallel-design trial, pitolisant was individually titrated at up to 20 mg/d over 12 weeks. The primary endpoint was the change in the Epworth Sleepiness Scale score. Key secondary endpoints were maintenance of wakefulness assessed on the basis of the Oxford Sleep Resistance test, safety, Clinical Global Impression of severity, patient's global opinion, EuroQol quality-oflife questionnaire, and Pichot fatigue questionnaire. Measurements and Main Results: A total of 268 patients with obstructive sleep apnea (75% male; mean age, 52 yr; apnea-hypopnea index, 49/h; baseline sleepiness score, 15.7) were randomized (200 to pitolisant and 68 to placebo) and analyzed on an intention-totreat basis. The Epworth Sleepiness Scale score was reduced more with pitolisant than with placebo (22.8; 95% confidence interval, 24.0 to 21.5; P , 0.001). Wake maintenance tests were not improved. The Pichot fatigue score was reduced with pitolisant. The overall impact of pitolisant was confirmed by both physicians' and patients' questionnaires. Adverse event incidence, mainly headache, insomnia, nausea, and vertigo, was similar in the pitolisant and placebo groups (29.5% and 25.4%, respectively), with no cardiovascular or other significant safety concerns. Conclusions: Pitolisant significantly reduced self-reported daytime sleepiness and fatigue and improved patient-reported outcomes and physician disease severity assessment in sleepy patients with obstructive sleep apnea refusing or nonadherent to continuous positive airway pressure. Clinical trial registered with www.clinicaltrials.gov (NCT01072968) and EU Clinical Trials Register (EudraCT 2009-017251-94).

Alzheimer disease (AD) represents a major medical problem where mono-therapeutic interventions demonstrated only a limited efficacy so far. We explored the possibility of developing a combinational therapy that might prevent the degradation of neuronal and endothelial structures in this disease. We argued that the distorted balance between excitatory (glutamate) and inhibitory (GABA/glycine) systems constitutes a therapeutic target for such intervention. We found that a combination of two approved drugs – acamprosate and baclofen – synergistically protected neurons and endothelial structures in vitro against amyloid-beta (Aβ) oligomers. The neuroprotective effects of these drugs were mediated by modulation of targets in GABA/glycinergic and glutamatergic pathways. In vivo, the combination alleviated cognitive deficits in the acute Aβ25–35 peptide injection model and in the mouse mutant APP transgenic model. Several patterns altered in AD were also synergistically normalised. Our results open up the possibility for a promising therapeutic approach for AD by combining repurposed drugs.

Study ObjectivesTo asses the long-term safety and efficacy of pitolisant, an histamine H3-receptor antagonist, on narcolepsy.MethodsThis open-label, single-arm, pragmatic study, recruited adult patients with narcolepsy and Epworth Sleepiness Scale (ESS) score ≥12. After a titration period, patients were treated for up to 1 year with oral pitolisant once-a-day at up to 40 mg. Concomitant stimulants and anti-cataplectic agents were allowed. The primary endpoint was safety; secondary endpoints included ESS, cataplexy, and other diary parameters.ResultsPatients (n = 102, 75 with cataplexy) received pitolisant, for the first time in 73 of them. Sixty-eight patients (51 with cataplexy) completed the 12-month treatment. Common treatment-emergent adverse events were headache (11.8% of patients), insomnia (8.8%), weight gain (7.8%), anxiety (6.9%), depressive symptoms (4.9%), and nausea (4.9%). Seven patients had a serious adverse effect, unrelated to pitolisant except for a possibly related miscarriage. One-third of patients stopped pitolisant, mostly (19.6%) for insufficient benefit. ESS score decreased by 4.6 ± 0.6. Two-thirds of patients completing the treatment were responders (ESS ≤ 10 or ESS decrease ≥ 3), and one third had normalized ESS (≤10). Complete and partial cataplexy, hallucinations, sleep paralysis, and sleep attacks were reduced by 76%, 65%, 54%, 63%, and 27%, respectively. Pitolisant as monotherapy (43% of patients) was better tolerated and more efficacious on ESS than on add-on, but efficacy was maintained in this last case.ConclusionsLong-term safety and efficacy of pitolisant on daytime sleepiness, cataplexy, hallucinations, and sleep paralysis is confirmed.

Objectives To evaluate the human abuse potential of pitolisant, a selective histamine 3 (H3)-receptor antagonist/inverse agonist recently approved by the US Food and Drug Administration for the treatment of excessive daytime sleepiness in adult patients with narcolepsy. Methods Nondependent, recreational stimulant users able to distinguish phentermine HCl 60 mg from placebo in a drug discrimination test were randomized in a four-period, double-blind, crossover design to receive single doses of pitolisant 35.6 mg (therapeutic dose), pitolisant 213.6 mg (supratherapeutic dose), phentermine HCl 60 mg, and placebo. The primary endpoint was maximum effect (Emax) on the 100-point Drug Liking (“at this moment”) visual analog scale. Results In 38 study completers (73.7% male; 65.8% white; mean age, 33.3 years), mean Drug Liking Emax was significantly greater for phentermine versus pitolisant 35.6 mg (mean difference, 21.4; p < 0.0001) and pitolisant 213.6 mg (mean difference, 19.7; p < 0.0001). Drug Liking Emax was similar for pitolisant (both doses) and placebo. Similarly, for key secondary measures of Overall Drug Liking and willingness to Take Drug Again, mean Emax scores were significantly greater for phentermine versus pitolisant (both doses) and similar for pitolisant (both doses) versus placebo. The incidence of adverse events was 82.1% after phentermine HCl 60 mg, 72.5% after pitolisant 213.6 mg, 47.5% after pitolisant 35.6 mg, and 48.8% after placebo administration. Conclusions In this study, pitolisant demonstrated significantly lower potential for abuse compared with phentermine and an overall profile similar to placebo; this suggests a low risk of abuse for pitolisant. Clinical Trial Registration ClinicalTrials.gov NCT03152123. Determination of the abuse potential of pitolisant in healthy, nondependent recreational stimulant users. https://clinicaltrials.gov/ct2/show/NCT03152123.