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News Article | January 20, 2016
Site: www.nature.com

Clinical-trial death Five people were hospitalized and one has died after a French clinical trial went disastrously wrong. The phase I trial — designed to test the safety of new treatments in healthy people — involved a drug made by the company Bial near Porto, Portugal, and was conducted by a French contract-research organization, Biotrial, in Rennes. Neither the French authorities nor Biotrial has identified the drug, but Bial says that it was an inhibitor of the enzyme FAAH (fatty acid amide hydrolase). See page 263 for more. Ebola returns Health officials confirmed on 15 January that a 22-year-old woman in Sierra Leone had died of Ebola. The announcement comes two months after the World Health Organization declared that the disease had stopped spreading in Sierra Leone, and less than a day after it was announced that a similar resurgence of the virus in Liberia had ended. The source of the latest case is being investigated; other flare-ups have been traced to survivors who still harboured the virus in semen and other bodily fluids. Launch was a success, landing less so A joint US–European satellite that will track the surface height of the oceans was launched into orbit on 17 January. The oceanography mission Jason-3 will provide data for weather, climate and ocean researchers. But the Falcon 9 rocket that delivered the satellite into orbit had a less happy outcome. It was supposed to touch down on an ocean barge, but instead toppled over and was destroyed on landing. Turkish arrests Twenty-seven Turkish academics were arrested, and later released, on 15 January for signing a petition calling on their government to end violence in Turkey’s southeast, where government forces have been fighting Kurdish separatists. The researchers face prosecution for alleged defamation of the state and spreading of terrorist propaganda. Around 2,000 scientists from about 90 Turkish universities have signed the petition. Several of the universities have launched investigations into signatories in their faculty. See go.nature.com/gpcarv for more. Zika virus The US Centers for Disease Control and Prevention has issued a travel alert over the ongoing transmission of Zika virus in 14 countries in the Caribbean and in Central and South America. The alert — issued on 15 January — recommends that pregnant women consider postponing travel to any areas where Zika infection is occurring. It comes after evidence emerged that, since October, around 3,530 babies have been born in Brazil with unusually small heads and brains — a disorder called microcephaly. That is ten times more than the country usually sees in a year, and cases are concentrated in regions with Zika outbreaks. NASA spaceplane Starting in 2019, NASA will gain a third commercial partner for flying cargo to and from the International Space Station. The space agency announced on 14 January that it will use a miniature spaceplane owned by the Sierra Nevada Corporation in Sparks, Nevada, for a minimum of six missions by 2024. The craft can transport both pressurized and unpressurized loads, and lands on a runway back on Earth, improving NASA’s options for delivering and returning fragile scientific equipment. NASA also uses spacecraft from Orbital ATK in Dulles, Virginia, which burn up on re-entry, and from SpaceX in Hawthorne, California, which splash down into the ocean. Vaccine deal Gavi, the international vaccine alliance, announced on 20 January that it has paid US$5 million to Merck, manufacturer of the first Ebola vaccine shown to protect against the virus in a human clinical trial. The deal marks the first time that the public-health organization has moved to purchase a vaccine before it has been licensed. In return for the payment, Merck promises that it will seek to have the vaccine approved by a regulatory agency by 2017. See go.nature.com/ujcirz for more. Taiwanese election An epidemiologist famed for his work on the 2003 outbreak of severe acute respiratory syndrome (SARS) and for his studies on the health burden of arsenic and hepatitis is to become Taiwan’s vice-president. Chen Chien-Jen (pictured) assumes the role after Tsai Ing-Wen, his running mate, won the 16 January election. Chen is widely respected for his work as health minister in Taiwan during the SARS epidemic, and was vice-president of the nation’s premier research organization, the Academia Sinica. See go.nature.com/wwrrwn for more. Sentence upheld A former biomedical researcher at Iowa State University has failed to reduce his prison sentence for making false statements on successful funding applications to the US National Institutes of Health. On 11 January, a federal appeals court ruled against reducing the sentence of Dong Pyou Han, who pleaded guilty in 2015. At the time, Han was sentenced to 57 months in prison, but he appealed against the sentence two weeks later and argued that its length was unreasonable given his remorse and lawful past. The appeals court disagreed and upheld the sentence. Perpetrator named Nature and other sources confirmed last week that the faculty member suspended by the California Institute of Technology for harassing two female graduate students is theoretical astrophysicist Christian Ott. Caltech, in Pasadena, announced on 4 January that it had suspended an unnamed faculty member without pay for an academic year. Meanwhile, in a 12 January statement to the US House of Representatives, Congresswoman Jackie Speier (Democrat, California) highlighted sexual harassment in astronomy. She has called for universities to share information with each other on the outcome of harassment investigations. See go.nature.com/mnwdim for more. US coal pause The United States has halted any new coal mining on federal land as it begins a major review of the coal industry. Interior secretary Sally Jewell announced the review on 15 January and said it would ensure that the federal coal programme took into account the impact of the industry on climate change. Coal power is one of the most greenhouse-gas-intensive forms of electricity generation. The halt on new leases applies while the comprehensive review — which Jewell says is the first in 30 years — is under way. Iran sanctions The United States and the European Union lifted a broad array of sanctions against Iran on 16 January after it was confirmed that the country had taken steps to impair its ability to produce plutonium and enriched uranium, which are used in atomic bombs. The lifting of restrictions came within hours of confirmation by the International Atomic Energy Agency that Iran was in compliance with the deal it struck with six world powers in July over its nuclear programme. Sanctions have crippled Iran’s economy and contributed to the international isolation of its scientists. EU reprimand The ombudsman for the European Union (EU), Emily O’Reilly, has ruled that delays by the European Commission in dealing with 20 authorization applications for genetically modified (GM) foods and feedstuffs were a “systemic problem” and “constituted maladministration”. The ombudsman, who investigates complaints about EU bodies, said on 15 January that the commission had consistently failed to make decisions on the applications within the three-month deadline required by law. A review of EU decision-making on GM foods and feedstuffs is under way, and so O’Reilly did not make a recommendation related to the case. But she said that the commission should comply with current requirements until the review is complete. Reproducibility call A coalition representing more than 100,000 experimental biologists has released recommendations for enhancing the reproducibility of research. The Federation of American Societies for Experimental Biology, which includes 30 scientific groups, wants to see better characterization of antibodies, easier reporting of negative results, better training for graduate students and established scientists, and fuller descriptions of animal models. See page 256 for more. As the number of scientists and engineers in the United States jumped between 2003 and 2013, so too did the proportion of immigrants. A report from the US National Science Foundation (see go.nature.com/9hhf15) shows that immigrants made up just 15% of the 21.6-million-strong science workforce in 2003, rising to 18% of 29 million people in 2013. Asia remains the most likely region of birth for the immigrants; the number of Indian-born scientists nearly doubled, from 515,000 in 2003 to 960,000 in 2013. Annual amount needed to fight pandemics, says a group convened by the US National Academy of Medicine. Source: Commission on a Global Health Risk Framework for the Future


Bruderer S.,Actelion Pharmaceuticals | Aanismaa P.,Actelion Pharmaceuticals | Homery M.-C.,BIOTRIAL | Hausler S.,Actelion Pharmaceuticals | And 4 more authors.
AAPS Journal | Year: 2012

Macitentan is a dual endothelin receptor antagonist under phase 3 investigation in pulmonary arterial hypertension. We investigated the effect of cyclosporine (Cs) and rifampin on the pharmacokinetics of macitentan and its metabolites ACT-132577 and ACT-373898 in healthy male subjects. In addition, in vitro studies were performed to investigate interactions between macitentan and its active metabolite ACT-132577 with human organic anion-transporting polypeptides (OATPs). The clinical study (AC-055-111) was conducted as a two-part, one-sequence, crossover study. Ten subjects in each part received multiple-dose macitentan followed by multiple-dose co-administration of Cs (part A) or rifampin (part B). In the presence of Cs, steady-state area under the plasma concentration-time profiles during a dose interval (AUC τ) for macitentan and ACT-373898 increased 10% and 7%, respectively, and decreased 3% for ACT-132577. Steady-state AUC τ of macitentan and ACT-373898 in the presence of rifampin decreased 79% and 64%, respectively. For ACT-132577, no relevant difference in AUC τ between the two treatments was observed. Macitentan co-administered with Cs or rifampin was well tolerated. The complementary in vitro studies demonstrated no marked differences in uptake rates of macitentan and ACT-132577 between the wild-type and OATP over-expressing cells over the concentration range tested. Concomitant treatment with Cs did not have any clinically relevant effect on the exposure to macitentan or its metabolites, at steady-state. Concomitant treatment with rifampin reduced significantly the exposure to macitentan and its metabolite ACT-373898 at steady-state but did not affect the exposure to the active metabolite ACT-132577 to a clinically relevant extent. © 2011 The Author(s).


News Article | January 16, 2016
Site: motherboard.vice.com

On Friday several French agencies opened an investigation into a clinical drug trial that has hospitalized six men in the last week, leaving one permanently brain dead and three in critical condition, likely with permanent brain damage. At a press conference held Friday afternoon at the University Hospital of Rennes, where the six victims are currently being treated, the French Minister of Health, Marisol Touraine, vowed to “get to the bottom of this…tragic incident.” She also denied reports that the experimental drug contained cannabis or cannabis derivatives, as some French media agencies had originally reported. When the story of the hospitalizations broke, several French media agencies erroneously reported that a “cannabis based product was in question” and i-Télé reported that a cannabis-based pain killing drug was being injected into the trial participants. This assertion was categorically denied by Touraine during her press conference. “Contrary to what I've heard, this drug does not contain cannabis and is not a cannabis derivative,” said Touraine. “It acts on the endo-cannabinoid system.” The confusion likely stems from the use of the word ‘cannabinoid,’ the term for a wide variety of compounds which act on the cannabinoid receptors in the brain. These cannabinoid receptors are part of the endocannabinoid system, which is found in a wide variety of mammals and is responsible for helping regulate everything from memory and pain to appetite and mood. There are three major types of cannabinoids: endocannabinoids (produced naturally in humans and animals), synthetic cannabinoids (manufactured artificially) and phytocannabinoids (which are found naturally in some plants, such as cannabis). Although tetrahydrocannabinol (also known as THC, the main psychoactive compound in cannabis) is perhaps the most well-known cannabinoid, it is not a part of the drug that was being tested in Rennes. Just which molecule was being tested is not known for sure: a press release from Bial, the Portuguese pharmaceutical company that produced the drug in question, described the molecule as a type of pain medication known as an FAAH enzyme inhibitor. There is a chance the molecule was BIA 10-2474, an experimental drug for “neurological and psychiatric pathologies” and one of two substances listed on Bial’s website as in the first phase of clinical trials. The clinical trial for the molecule that has left six men, ages 28-49, with varying degrees of neural complications (one brain dead, three in critical condition, one with neurological problems and one under close observation) began last year in July. It has been executed by Biotrial, a research company operating on behalf of Bial. So far the molecule has been administered to a total 90 participants, although the six hospitalized last week were the first to show such severe adverse effects. The six men began taking the molecule on January 7, and by January 10 the first man was hospitalized and his condition rapidly deteriorated until he was declared to be brain dead by Gilles Edan, the chief neuroscientist at the Rennes hospital. According to Edan, there is no known antidote to the compound. This calamitous occurrence is a first for France, which maintains strict national and international regulations for carrying out drug testing on humans. Typically, a drug undergoing a clinical trial goes through three phases. In Phase I, the drug is administered to healthy patients in incremental doses—the first patients will receive a single dose while latter patients will receive multiple doses over several days. In Phase II, experimental drugs are given to patients with relevant conditions to see if the drug helps them. In Phase III, the drug is tested against a placebo and compared with existing treatments to gauge its effectiveness. The six hospitalized participants were participating in the first phase of the clinical trials for this molecule and were all declared healthy prior to beginning the study. According to Bial’s press release, the company had the clinical trial approved by the French Regulatory Authorities as well as the French Ethics committee in accordance with the guidelines laid out in Good Clinical Practices and Declaration of Helsinki. The trials related to the Bial drug have been suspended as of January 11 and at her press conference Touraine promised a full scale investigation into the trial spearheaded by the French General Inspectorate of Social Affairs. The Health Minister said she expected a final report on the occurrence by the end of March at the latest.


News Article | January 19, 2016
Site: cen.acs.org

The clinical trial, conducted by the company Biotrial on behalf of the Portuguese pharmaceutical firm Bial, was evaluating a pain relief drug candidate that inhibits fatty acid amide hydrolase (FAAH) enzymes. Blocking these enzymes prevents them from breaking down cannabinoids in the brain, a family of compounds that includes the euphoria-inducing neurotransmitter anandamide and Δ9-tetrahydrocannabinol, the major psychoactive component of marijuana. Phase I clinical trials are conducted to check a drug candidate’s safety profile in healthy, paid volunteers. In this case, the drug caused hemorrhagic and necrotic brain lesions in five out of six men in a group who received the highest doses of the drug, said Gilles Edan, a neurologist at the University Hospital Center of Rennes, during a press conference on Friday. All six men were hospitalized by Sunday, Jan. 10, and the clinical trial was stopped the next day. The most severely affected man was pronounced brain dead after hospitalization and then died on Jan. 17. Prior to these serious adverse reactions, 84 people had taken lower doses of the candidate drug without complications, a hospital press release stated. Over the weekend, ten of those 84 individuals were given MRI scans. The hospital reported that none of the brain anomalies seen in the hospitalized patients were observed in these low-dose trial participants. A spokesperson for the European Medicines Agency told C&EN that “since 2007, approximately 12,500 Phase I clinical trials have been conducted in the European Union without any major incidents being reported.” The last major Phase I clinical trial catastrophe took place in London in 2006, when six healthy men suffered permanent organ damage, including loss of fingers, during a trial for an immunotherapy drug candidate called TGN1412. In the case of TGN1412, within minutes of being given the putative arthritis and cancer drug, the volunteers suffered from unanticipated and severe immune reactions. An analysis of the 2006 tragedy concluded that “drugs showing safety and efficacy in preclinical animal models may show very different pharmacological properties when administered to humans. Development of proper preclinical models which can efficiently predict drug behavior in humans is very essential prior to testing a drug in a human subject” (J. Young Pharma 2010, DOI: 10.4103/0975-1483.66810). French authorities have now launched several investigations to determine whether the Bial clinical trial was conducted properly and whether there were problems with the manufacture or transport of the drug candidate. In a press release, Bial officials noted that the clinical trial “has been conducted since the beginning in accordance with all the good international practices guidelines, with the completion of tests and pre-clinical trials, particularly in the area of toxicology.” Multiple pharmaceutical companies, including Merck & Co. and Pfizer, have evaluated FAAH inhibitors as possible treatments for pain, anxiety, and insomnia, among other applications. Until the current tragedy in France, there have been no reports of extreme adverse reactions for FAAH inhibitors. A Phase II clinical trial conducted by Pfizer to evaluate an FAAH inhibitor for post-traumatic stress disorder, for example, was terminated “based on Pfizer portfolio prioritization and not due to safety and/or efficacy concern,” noted an entry on clinicaltrials.gov. As the news of the clinical trial broke, the online chemical community exploded with speculation about the nature of the putative drug. To date, the company has reported only that it is an FAAH inhibitor developed for pain remedy. Many observers, however, believe the compound’s name is BIA 10-2474. That’s because the company’s website lists two drug candidates in Phase I clinical trials. One candidate is for pulmonary arterial hypertension—a drug that likely targets the lungs instead of the brain and is therefore unlikely to be an FAAH inhibitor. The second Bial candidate—BIA 10-2474—is listed for “neurological and psychiatric pathologies,” and is thus more likely to be involved in the tragedy. Additional support for BIA 10-2474 being the compound’s name comes from an e-mail forwarded to the French news outlet Breizh-info.com from a man who had tried to enlist in the trial but was denied entry. Southan has mined the patent literature and thinks he may have figured out the drug candidate’s structure. He says the trick is to look at secondary patent filings. Companies tend to protect a whole series of molecules in their first patent filings without naming their most promising lead compound, Southan explains. In subsequent patents for processing, synthesis, or crystallization techniques, though, it’s possible to surmise which compound is destined for the clinic, he says. In this case, Southan found a 2014 patent in Bial’s portfolio that he thinks is a “best guess” for the lead compound involved in this clinical trial. Minutes before he posted a blog post reporting his patent mining for BIA 10-2474, Southan says an anonymous Wikipedia editor posted the same structure in the online encyclopedia, giving him confidence that he was on the right track. Others in the online chemical community have since evaluated the structure proposed by Southan and the anonymous Wikipedia editor for binding partners in the body other than FAAH enzymes. If the drug candidate hits “off target” partners, it might help explain what went wrong with this trial. For example, computational chemist Sean Ekins, from Collaborative Chemistry, inputted the putative structure for BIA 10-2474 into an in silico screening app called PolyPharma that searches for possible biological targets of a submitted molecule. He also ran the molecule through another ligand-protein modeling program called SEA, developed independently by Brian Shoichet at the University of California, San Francisco.


News Article | January 20, 2016
Site: www.nature.com

One person died, and five others were hospitalized, after a clinical trial of an experimental drug in France went tragically wrong. But days after the first public acknowledgement of the incidents on 15 January, a lack of official information has left outside experts and the public largely in the dark as to what happened. “The French authorities have not been very rapid nor transparent in their response,” says Catherine Hill, a specialist in clinical-trial design and a former member of the scientific advisory board of France’s National Agency for Medicines and Health Products Safety (ANSM). She adds that French investigations into other medical accidents have often been opaque. The trial was a ‘first-in-human’ phase I trial to test the drug’s safety in healthy people (see ‘Basic facts about the trial’). The Portuguese company Bial produced the drug, which was aimed at treating anxiety and motor disorders associated with Parkinson’s disease, and chronic pain in people with cancer and other conditions. Biotrial, a French contract-research organization, conducted the trial at its facilities in Rennes. But many key questions remain unanswered, says Marc Rodwin, a biomedical-law specialist at Suffolk University Law School in Boston, Massachusetts. This includes how the participants’ injuries came about — magnetic-resonance-imaging scans showed dying and bleeding tissue deep in the brain — and whether the trials were conducted properly. In particular, neither the French authorities nor Biotrial has disclosed the identity of the molecule administered in the trials. Bial did say that the drug was an FAAH (fatty acid amide hydrolase) inhibitor; FAAH is an enzyme produced in the brain and elsewhere in the body that breaks down neurotransmitters known as endocannabinoids. By blocking these enzymes, FAAH inhibitors cause endocannabinoids — which activate the same neural receptors as the active chemical in cannabis, and might have painkilling properties — to accumulate in the body. Some scientists scrambled over the weekend to try to establish the identity of the drug. Among them were Steve Alexander, a molecular pharmacologist at the University of Nottingham Medical School, UK, who has worked on FAAH for 15 years, and his colleague Christopher Southan, a curator for the Guide to Pharmacology database at the University of Edinburgh, UK. Together, the pair examined an online list of drugs in Bial’s research pipeline. The search revealed just two molecules in phase I trials, one of which fitted the therapeutic profile mentioned by Bial, although it was referred to only by a codename, BIA 10-2474. A French newspaper also published a recruitment form given to a volunteer in the trial that mentioned a drug with the same codename. “As best as we can make out, this compound has not been described in the [scientific] literature,” says Alexander. “So we’re working in the dark.” It is common in the pharmaceutical industry not to reveal the structure of a molecule this early in development — although the practice has been criticized by researchers. “They declare codenames of candidates in development and hide the structure,” says Southan. “I think it’s time they stopped.” That lack of information left researchers trying to guess the structure from published Bial patents over the weekend, Southan adds. He also says that there seems to be no entry for the trial in clinical-trial registries. Numerous companies have developed FAAH inhibitors. There is none on the market, because most clinical trials have shown them to be ineffective — but the ones that were previously tested in people proved safe. Many researchers believe that BIA 10-2474 is acting ‘off target’ — in other words, inhibiting a protein other than an FAAH. To investigate, researchers could radioactively label the compound and test it on brain tissue from cadavers to ‘fish out’ the proteins it binds to. Knowing the drug’s molecular structure would also enable scientists to run computer predictions of this and other mechanisms that might result in toxicity. “There’s a whole gamut of sophisticated computation analysis to predict anything you like,” says Southan. Other researchers studying the FAAH pathway will probably look more closely at the potential for inhibitors to strike other proteins, Alexander says. “I think it’s very likely that both private industry and academic institutions will be looking very hard as to what this off-target affect might be.” The lack of transparency is typical of French investigations, which tend to favour secrecy until firm conclusions are established, says a French health-law specialist who requested anonymity. He notes that the country’s rules governing research on human subjects are strong and guarantee substantial protection of trial participants. He adds that safety incidents in clinical trials are almost unheard of in the country, with the price often being delays in the approval of trial applications. In recent years, there have been two major changes to French laws affecting the approval of drugs in clinical trials. France strengthened its medical-safety laws following the 2009 withdrawal of a diabetes drug that was suspected of causing hundreds of deaths: a 2011 law, in particular, tightened rules on conflicts of interest for people involved in the country’s drug-approval process, as well as giving authorities more power to demand safety tests of medications after they are approved. Then, in 2012, the government passed a separate law intended to streamline the rules for research involving humans, to speed up therapeutic progress and to make France a more attractive place for companies to carry out clinical trials. One possible safety issue in the trial of BIA 10-2474, notes trial-design specialist Hill, is that all six participants seem to have been administered the doses simultaneously, rather than one receiving a test dose and being checked for adverse effects before others were given it. Simultaneous rather than sequential administration was identified as problematic in a disastrous UK clinical trial in 2006 that caused multiple organ failure in six participants. “From the 2006 catastrophe in London, I had concluded that treating several individuals with the same dose on the same day in a phase I trial was a big mistake,” says Hill. Jean-Marc Gandon, the president and chief executive of Biotrial, says that he cannot immediately respond to queries from Nature, that he is focused on trying to save the patients and that the company will respond later. Bial spokeswoman Susana Vasconcelos says that the trial had been conducted “in accordance with all the good international practices guidelines, with the completion of tests and preclinical trials” and that the company “is committed to determine thoroughly and exhaustively the causes which are at the origin of this situation”.


News Article | January 15, 2016
Site: www.biosciencetechnology.com

Six medical volunteers have been hospitalized - one in a state of brain death - after taking part in a botched drug test at a clinic in western France, the Health Ministry said Friday. The prosecutor's office has opened an investigation into what the ministry called a "serious accident during a clinical test" in Rennes. It did not name the clinic. However, the Rennes-based lab Biotrial said its CEO, Jean-Marc Gandon, would join Health Minister Marisol Touraine. The minister went to Rennes on Friday after ordering an investigation into the organization and how it conducts clinical tests. The ministry statement said those who fell ill had taken an oral medication in the first phase of testing, which was studying safe usage, tolerance and other measures on healthy volunteers. It was not immediately clear whether the six were among a larger group of volunteers involved in the tests or what dose they had been given. The statement did not name the type of medication being tested. Biotrial, with headquarters in Rennes and offices in London and Newark, New Jersey, says on its website it has over 25 years of experience in clinical trials and uses "state-of-the-art facilities." In France, adults volunteering for Biotrial tests can earn between 100 euros and 4,500 euros ($110 to $4,922). It is rare for volunteers to fall seriously ill when testing new drugs. Researchers generally start with the lowest possible dose for humans after extensive drug tests in animals. But there was a similar incident in Britain in 2006, when six previously healthy men were treated for organ failure only hours after being given an experimental drug targeting the immune system. That prompted a review of procedures and resulted in the U.K. regulatory agency imposing new testing standards, including recommendations to use the lowest possible dose and to test new drugs only in one person at a time. The six men in Britain now apparently have a higher risk of cancer and autoimmune diseases tied to their exposure to the experimental drug. Dr. Ben Whalley, a neuropharmacology professor at Britain's University of Reading, said standardized regulations for clinical trials are "largely the same" throughout Europe. "However, like any safeguard, these minimize risk rather than abolish it," Whalley said in a statement. "There is an inherent risk in exposing people to any new compound."


News Article | January 22, 2016
Site: cen.acs.org

One man is dead and five men were hospitalized after participating in a Phase I clinical trial in Rennes, France. The clinical trial, conducted by the company Biotrial on behalf of the Portuguese pharmaceutical firm Bial, was evaluating a pain relief drug candidate called BIA 10-2474 that inhibits fatty acid amide hydrolase (FAAH) enzymes. Blocking these enzymes prevents them from breaking down cannabinoids in the brain, a family of compounds that includes the euphoria-inducing neurotransmitter anandamide and Δ9-tetrahydrocannabinol, the major psychoactive component of marijuana. Phase I clinical trials are conducted to check a drug candidate’s safety profile in healthy, paid volunteers. In this case, the drug caused hemorrhagic and necrotic brain lesions in five out of six men in a group who received the highest doses of the drug, said Gilles Edan, a neurologist at the University Hospital Center of Rennes. The most severely affected man was pronounced brain-dead after hospitalization and then died on Jan. 17. Four men remain in the hospital in stable condition. The only man in the high-dose group who had no adverse symptoms has been released from the hospital. Prior to the hospitalizations, 84 people had taken lower doses of BIA 10-2474 in the clinical trial without complications. A spokesperson for the European Medicines Agency told C&EN that, “since 2007, approximately 12,500 Phase I clinical trials have been conducted in the European Union without any major incidents being reported.” The last major Phase I clinical trial catastrophe took place in London in 2006, when six healthy men suffered permanent organ damage, and the loss of fingers, from unanticipated severe immune reactions during testing of an arthritis and cancer drug candidate called TGN1412. Multiple pharmaceutical companies, including Merck & Co. and Pfizer, have evaluated FAAH inhibitors as possible treatments for pain, mood disorders, and insomnia, among other applications, with no reports of significant adverse reactions until the Bial clinical trial. After the events in Rennes, Janssen, part of Johnson & Johnson Pharmaceutical Research & Development, voluntarily suspended a Phase II clinical trial of an FAAH inhibitor; no adverse events have been reported, the company noted in a press release, so it was a precautionary step . As news of the clinical trial tragedy broke, the online chemical community exploded with speculation about the nature of the putative drug. “What everybody wants to know now is its structure,” says Christopher Southan, a senior curator for the University of Edinburgh-based Guide to Pharmacology database. As C&EN went to press, Le Figaro posted a 96-page clinical study protocol for BIA 10-2474 that the French newspaper procured from an unnamed source. BIA 10-2474 “is designed to act as a long-active and reversible inhibitor of brain and peripheral FAAH,” notes the protocol. The compound “increases anandamide levels in the central nervous system and in peripheral tissues.” The clinical trial protocol also notes that the company tested BIA 10-2474 on mice, rats, dogs, and monkeys for effects on the heart, kidneys, and gastrointestinal tract, among other pharmacological and toxicological evaluations.


Bertaina-Anglade V.,Biotrial | Drieu-La-Rochelle C.,Biotrial | Mocaer E.,Pleiades | Seguin L.,Pleiades
Pharmacology Biochemistry and Behavior | Year: 2011

The aim of the present study was to evaluate the effects of agomelatine, an antidepressant with melatonergic agonist and 5-HT2C antagonist properties, in the rat novel object recognition (NOR) task, a model of short-term episodic memory. To assess the potential involvement of its chronobiotic activity, single intraperitoneal administration of agomelatine and NOR testing were performed either in the evening or in the morning. In both conditions, using a 24 h retention interval, vehicle-treated rats did not discriminate between the novel and the familiar object (recognition index was not different from chance performance) while object memory performance of rats treated with agomelatine either in the evening (10 and 40 mg/kg) or in the morning (2.5, 10, and 40 mg/kg) was significantly improved. Moreover, the selective 5-HT2C antagonist SB 242,084 (0.63, 2.5, and 10 mg/kg) and melatonin (2.5, 10, and 40 mg/kg) displayed also memory facilitating effects in both administration conditions. Finally, thioperamide used as positive reference compound to validate the experimental conditions, demonstrated a memory facilitating effect. In conclusion, agomelatine was shown to possess memory facilitating effects in the rat NOR task and both melatonergic agonist and 5-HT2C antagonist properties could be involved in these effects. © 2011 Elsevier Inc. All rights reserved.


Dingemanse J.,Actelion Pharmaceuticals | Van Giersbergen P.L.M.,Actelion Pharmaceuticals | Patat A.,Biotrial | Nilsson P.N.,Actelion Pharmaceuticals
Antiviral Therapy | Year: 2010

Background: We aimed to investigate the extent of pharmacokinetic drug interactions between bosentan and a fixed combination of lopinavir/ritonavir. Methods: This was a three-way crossover study in 12 healthy male participants treated with bosentan (125 mg twice daily) and lopinavir/ritonavir (400/100 mg twice daily) alone or in combination for 9.5 days. Results: Combination treatment resulted in slightly lower area under the concentration-time curve during the 12 h dosing interval under steady-state conditions (AUC τ,ss) values of both lopinavir and ritonavir with geometric mean ratios (GMRs: 90% confidence intervals [Cls]) of 0.86 (0.74-0.99) for lopinavir and 0.83 (0.76-0.92) for ritonavir. The maximum concentration in steady state (Cmax,ss) of lopinavir and ritonavir remained unchanged with a GMR of 0.95 and 1.01, respectively, and the 90% Cls were within the range of 0.8-1.25. The observed effects of bosentan on lopinavir and ritonavir pharmacokinetics were considered to be not clinically relevant. The pharmacokinetics of bosentan were strongly affected by coadministration. Bosentan concentration increased up to 48-fold during the first 4 days of coadministration with lopinavir/ritonavir. At steady state, the GMR for AUCτss was 5.22 (3.84-7.10) and for Cmax,ss was 6.12 (4.24-8.82). The increased exposure to bosentan was reflected in an increase in adverse events attributed to bosentan, that is, mainly headache, but not in liver enzyme abnormalities. Conclusions: Bosentan does not affect lopinavir and ritonavir exposure to a clinically relevant extent, but tolerability of bosentan should be monitored in HIV patients under antiretroviral therapy with lopinavir/ritonavir. It is anticipated that all ritonavir-boosted protease inhibitors will have a similar effect on bosentan pharmacokinetics.


Wilson F.J.,Medical Imaging and Physiological Measurements Consultant | Danjou P.,Biotrial
Neuropsychobiology | Year: 2016

The pharmaceutical industry has been suffering from low clinical success rates of new drugs for some time with particularly high attrition in early clinical development, especially for drugs aimed at central targets. Both pharmaco-electroencephalography (EEG) and pharmaco-sleep, along with other biomarker techniques, have significant potential to assist with this problem by enabling early decisions to be made about the likelihood of a compound proving successful in the clinic. This paper discusses the role and points of application of biomarker techniques in early drug development. It proposes a framework for the use of pharmaco-EEG and pharmaco-sleep in drug development that (i) relies on the combination of preclinical data and an understanding of translatability to generate robust hypotheses for testing in early clinical studies and (ii) is backed up by a clear decision-making process. The areas that need further development before this framework can be put fully into practice are discussed, along with some possible routes by which this could be achieved through precompetitive co-operation within the industry. © 2016 S. Karger AG, Basel. Copyright: All rights reserved.

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