Joëlle Micallef

Orphandev, French Clinical Trials Network dedicated to Orphan drugs and therapeutics development for rare diseases

Though rare diseases affect fewer patients than common diseases, developing drugs for them is subject to the same principles. But constructing and leading rare diseases clinical trials means also facing numerous difficulties which are more important in this field (methodology, little knowledge of the disease’s evolution, choice of the judgment’s criteria, small population’s size, logistical matters...) However during the last decade, France led several initiatives to improve the burden of rare diseases. Centres of Expertise were identified, ability centres have been appointed and a National Plan for rare diseases was developed. Nevertheless, in spite of the great dynamic created by France, development and availability of orphan therapeutics remain problematic regarding rare diseases specificities. In this context, it is important to gather skills and strengths to make patients benefit from fundamental research’s results and accelerate clinical trials. Orphandev is a French Clinical Trials Network based on a strong collaboration principle with all actors involved (academics, industries and patients) dedicated to orphan drugs development. It was created by academics to help academics but also others actors involved in rare diseases’ research. The Network’ skills have already been dedicated to orphan drugs’ trials: Charcot Marie Tooth (2004), Rett (2006) and Progeria (2008). Orphandev has intervened according to the mutualisation and translational research concepts from the experimental phase (in vitro and animals’ tests) to the results’ valorisation with every single actor involved in the study. With the experience gained and the successful results, we have developed an organisational concept in order to capitalise on the lessons learnt and optimise the trials process. In a time of great therapeutics development with solutions coming from gene breakthroughs but not only, Orphandev allows for further improvement of the interface between fundamental research, clinical research and drug developments in rare diseases in a more operational way.

Cannabis Use: Signal of Increasing Risk of Serious Cardiovascular Disorders

Background Cannabis is known to be associated with neuropsychiatric problems, but less is known about complications affecting other specified body systems. We report and analyze 35 recent remarkable cardiovascular complications following cannabis use. Methods and Results In France, serious cases of abuse and dependence in response to the use of psychoactive substances must be reported to the national system of the French Addictovigilance Network. We identified all spontaneous reports of cardiovascular complications related to cannabis use collected by the French Addictovigilance Network from 2006 to 2010. We described the clinical characteristics of these cases and their evolution: 1.8% of all cannabis‐related reports (35/1979) were cardiovascular complications, with patients being mostly men (85.7%) and of an average age of 34.3 years. There were 22 cardiac complications (20 acute coronary syndromes), 10 peripheral complications (lower limb or juvenile arteriopathies and Buerger‐like diseases), and 3 cerebral complications (acute cerebral angiopathy, transient cortical blindness, and spasm of cerebral artery). In 9 cases, the event led to patient death. Conclusions Increased reporting of cardiovascular complications related to cannabis and their extreme seriousness (with a death rate of 25.6%) indicate cannabis as a possible risk factor for cardiovascular disease in young adults, in line with previous findings. Given that cannabis is perceived to be harmless by the general public and that legalization of its use is debated, data concerning its danger must be widely disseminated. Practitioners should be aware that cannabis may be a potential triggering factor for cardiovascular complications in young people.

Neurobiology and clinical pharmacology of obsessive-compulsive disorder

Obsessive-compulsive disorder (OCD) is a brain disorder with recognizable periods of onset, course, familial occurrence, epidemiology, phenomenology, and treatment response. Several manifestations of pathophysiology are beginning to be defined, although they may represent intermediate pathophysiology rather than primary etiology. Positron emission tomography studies have consistently identified hypermetabolism in the orbitofrontal cortex, caudate nucleus, and, sometimes, anterior cingulate cortex. Neuropsychologic testing frequently identifies abnormalities in visuospatial function. Abnormal levels of cerebrospinal fluid neurotransmitters and neuromodulators are identifiable in untreated patients with OCD and return toward normal levels after effective treatment. The most consistent pathophysiologic finding in OCD points toward an abnormality in serotonin neurotransmission. Therapeutic response to selective serotonin reuptake inhibitors and the absence of improvement with norepinephrine reuptake inhibitors and dopamine antagonists argue strongly for a role of serotonin in the pathophysiology and treatment of OCD. Despite this clear indication from treatment trials, probes and manipulations of the serotonin system and its specific receptors have not provided a useful understanding of specific abnormalities. Clomipramine or potent selective serotonin reuptake inhibitors are the pharmacotherapy of choice for OCD, with a more limited role reserved for monoamine oxidase inhibitors. If one selective serotonin reuptake inhibitor is ineffective, others may be beneficial, in addition to the different proserotonergic and nonserotonergic augmentation strategies that could be useful in treatment of resistant OCD patients. Nondrug therapies are also important in OCD: behavioral therapy is frequently helpful and neurosurgery is sometimes helpful when other treatments fail.

A longitudinal study of the evolution of cognitive function and affective state in patients with amyotrophic lateral sclerosis.

OBJECTIVES: The study aimed to evaluate cognitive function and emotional reactivity in 18 patients with ALS, compared to19 matched controls, and assess their evolution over a 12‐month period. METHODS: 18 ALS patients and 19 matched controls were included, and assessed at inclusion, six months and twelve months later. Depression was evaluated with the Geriatric Depression Scale, and cognitive function with the Folstein Mini Mental State. A battery of psychometric tests (Wisconsin Card Sorting Test (WCST), the numerical Empan test, the Trail‐making test, the Boston Naming Test, the 15‐word Rey memory test, the Benton visual retention test and the Raven Progressive Matrix) was used to measure frontal processing and non‐frontal function. Emotional reactivity was measured with the film‐evoked emotions test. RESULTS: ALS patients were significantly more depressed than controls, as measured on the Geriatric Depression Scale, and depression increased over the study period. There was a very mild defect in cognitive function, and a performance deficit in the Trail‐making test, a measure of frontal processing. These deficits, unlike neuromuscular function and depression, did not aggravate over the 12 months of the study. There was no observable change in non‐frontal function. Emotional reactivity did not differ significantly between ALS patients and controls. CONCLUSIONS: This study provides further evidence for a mild defect in frontal cognitive processing in ALS patients that evolves only slowly, if at all, with time.

Observation of Psychoactive Substance Consumption: Methods and Results of the French OPPIDUM Programme

This study presents a French programme designed to observe and evaluate psychoactive substance dependence and abuse. Annual surveys lasting 4 weeks are performed with drug users in drug centres. Its usefulness is discussed using examples from the study: potential for antidepressant dependence (amineptine), monitoring benzodiazepine use and consumption associated with maintenance treatments. Flunitrazepam is the most consumed benzodiazepine and often got by deal (29%). There are important differences between buprenorphine consumption in a maintenance treatment context (9/10) and beyond this context (1/10). The main methodology problems encountered are representativeness and validity of data. The limits of the programme and its role in the French health care system are discussed.

Patterns of methylphenidate use and assessment of its abuse and diversion in two French administrative areas using a proxy of deviant behaviour determined from a reimbursement database: main trends from 2005 to 2008.

AbstractBackground: Methylphenidate is a psychostimulant drug indicated for the treatment of attention-deficit hyperactivity disorder (ADHD). Its abuse and diversion have been previously described in specific populations, such as students; however, few studies investigating abuse and diversion among the overall population are available. Objectives: The aim of this study was to describe patterns of methylphenidate use and to explore the magnitude of its abuse and diversion in two French administrative areas using data from a reimbursement database. A proxy of ‘deviant behaviour’ was used for the abuse and diversion of methylphenidate, defined using the following parameters: total number of defined daily doses (DDDs) of methylphenidate dispensed; number of different pharmacies seen for dispensing of methylphenidate; number of prescribers consulted for a prescription of methylphenidate; and number of dispensings of methylphenidate. Data from the reimbursement database were analysed by clustering methods. These data were assessed from 2005 to 2008. Method: The French General Health Insurance System (GHIS) database was used to obtain data on methylphenidate use in two French administrative areas. Individuals affiliated to the GHIS who had a prescription for methylphenidate reimbursed between 1 January and 31 March of 4 selected years (2005, 2006, 2007 and 2008) were included. After the first dispensing of methylphenidate for these individuals, all their dispensings (including methylphenidate and other psychoactive drugs) were monitored over a 9-month period. Following a descriptive analysis, a clustering method was used to identify different subgroups of subjects according to the methylphenidate consumer profile characteristics. Results: With regard to the number of patients who had a dispensing for methylphenidate during the first quarter of the year, an 84% increase was observed between 2005 (n = 640) and 2008 (n= 1175). The clustering method identified two subgroups. One of them was characterized by a higher number of dispensings, different prescribers and pharmacies and a greater total dispensed quantity, suggesting a deviant behaviour and, thus, possible abuse and diversion of methylphenidate. These subjects were older (aged 35.4 ± 11.3 years) and were more frequently patients receiving benzodiazepines, antidepressants, antipsychotics and maintenance opioid treatment. The proportion of subjects with a deviant behaviour increased from 0.5% in 2005 to 2% in 2007 and then decreased to 1.2% in 2008. Conclusion: This method was able to assess the magnitude of methylphenidate abuse liability and to follow its evolution. The decrease in methylphenidate abuse and diversion seen between 2007 and 2008 can be explained by the enactment in April 2008 of specific regulations for prescription drugs (such as methylphenidate) that are deemed by the French government to have the potential for misuse; these regulations require the establishment of a ‘contract of care’ between the GHIS, prescriber and patient.

An exploratory randomised double-blind and placebo-controlled phase 2 study of a combination of baclofen, naltrexone and sorbitol (PXT3003) in patients with Charcot-Marie-Tooth disease type 1A

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).

OPPIDUM surveillance program: 20 years of information on drug abuse in France.

It is important to assess drug abuse liability in ‘real life’ using different surveillance systems. Some are based on specific population surveys, such as individuals with drug abuse or dependence, or under opiate maintenance treatment, because this population is very familiar with drugs and is more likely to divert or abuse them. In France, an original surveillance system based on this specific population and called ‘Observation of illegal drugs and misuse of psychotropic medications (OPPIDUM) survey’ was set up in 1990 as the first of its kind. The aim of this article is to describe this precursor of French drug abuse surveillance using different examples, to demonstrate its ability to effectively give health authorities and physicians interesting data on drug abuse. OPPIDUM is an annual, cross‐sectional survey that anonymously collects information on abuse and dependence observed in patients recruited in specialized care centers dedicated to drug dependence. From 1990 to 2010, a total of 50 734 patients were included with descriptions of 102 631 psychoactive substance consumptions. These data have outlined emergent behaviors such as the misuse of buprenorphine by intravenous or nasal administration. It has contributed to assess abuse liability of emergent drugs such as clonazepam or methylphenidate. This surveillance system was also able to detect the decrease of flunitrazepam abuse following implementation of regulatory measures. OPPIDUMs twenty years of experience clearly demonstrate that collection of valid and useful data on drug abuse is possible and can provide helpful information for physicians and health authorities.

Recent evolution in opiate dependence in France during generalisation of maintenance treatments

Two maintenance drugs had been used in France since 1996, methadone and high-dosage buprenorphine. This study aimed to examine changes in drug use from observations gathered between 1995 and 1997, within the framework of the French program for the monitoring of drug dependence (OPPIDUM). This annual survey studies psychoactive substances consumed by drug addicts attending specialised drug care centres. During the last three surveys, 16 centres collected a total of 1597 patient-files. This study shows an increase in the number of patients undergoing maintenance treatment (from 14 to 69%), a reduction in the number of intravenous drug users (from 55 to 22%) and a reduction in consumption of psychoactive substances. However, poly-drug addiction behaviour continues and high-dose buprenorphine subjects frequently use the substance intravenously and in association with benzodiazepines.

Which indicators can public health authorities use to monitor prescription drug abuse and evaluate the impact of regulatory measures? Controlling High Dosage Buprenorphine abuse

BACKGROUND Two methods have been recently developed from a drug reimbursement database to provide useful indicators for public health authorities concerning the abuse potential of psychotropic drugs. The doctor-shopping indicator (DSI) measures the proportion of the drug obtained by doctor shopping among the overall quantity of the drug reimbursed and the clustering method reveals subgroups of deviant patients. OBJECTIVE The objective of the study was to analyze and compare indicators resulting from these two methods, applied to High Dosage Buprenorphine (HDB) (a product well-known to be diverted in France), in order to determine which public health authorities needs they answer. DATA ANALYSIS The patients with reimbursed HDB were grouped using the clustering method in terms of drug dispensations characteristics over a nine month period. The characteristics of the resulting subgroups, including their DSI, were then compared. RESULTS 4787 Patients (73.4%) had no measurable doctor-shopping behaviour. But the comparison of the two methods demonstrated that the more a patients profile was characterized by deviant behavior, the higher was the DSI: from 0.4% in a subgroup with a median profile to 72% in a subgroup with a deviant profile. CONCLUSION These two methods are useful surveillance tools for public health authorities: the clustering method may help devise pertinent intervention strategies to reduce prescription drug abuse while the DSI method provides quantitative information demonstrating whether these strategies are useful. We discuss the advantages and disadvantages of using these two methods as useful indicators for public health authorities.