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French Institute of Petroleum, Proteus and French National Center for Scientific Research | Date: 2017-04-26

The present invention relates to the expression and optimisation of enzymes involved in the breakdown of lignocellulosic biomass. The present invention specifically relates to variants of the exoglucanase 2 of Trichoderma reesei, as well as to the use of said variants with improved efficiency in methods for breaking down cellulose and for producing biofuel.


BURLINGTON, Mass.--(BUSINESS WIRE)--ArQule, Inc. (Nasdaq: ARQL) today announced that preclinical data for ARQ 531 in diffuse large B-cell lymphoma (DLBCL) in vitro and in vivo tumor models will be presented on June 23, 2017 at EHA Congress in Madrid, Spain. The data supports clinical trials with ARQ 531 in the ibrutinib resistant patient population. A phase 1 trial with ARQ 531 in patients with B-cell malignancies refractory to other therapeutic options, including ibrutinib, is planned to commence by the third quarter of 2017. ARQ 531 is an investigational, orally bioavailable, potent and reversible inhibitor of both wild type and C481S-mutant Bruton’s tyrosine kinase (BTK). ARQ 531 Abstract E1400 ARQ 531, a reversible BTK inhibitor, demonstrates potent anti-tumor activity in ABC-DLBCL and GCB-DLBCL E-poster Screens Time: 9:30 AM CET ARQ 531 is an investigational, orally bioavailable, potent and reversible Bruton’s tyrosine kinase (BTK) inhibitor. Biochemical and cellular studies have shown that ARQ 531 inhibits both the wild type and C481S-mutant forms of BTK. The C481S mutation is a known emerging resistance mechanism for first generation irreversible BTK inhibitors. In preclinical studies ARQ 531 has demonstrated high oral bioavailability as well as good ADME, pharmacokinetic and metabolic properties. The company plans to initiate a phase 1 trial by the third quarter of 2017. BTK is a therapeutic target that has been clinically proven to inhibit B-cell receptor signaling in blood cancers. ArQule is a biopharmaceutical company engaged in the research and development of targeted therapeutics to treat cancers and rare diseases. ArQule’s mission is to discover, develop and commercialize novel small molecule drugs in areas of high unmet need that will dramatically extend and improve the lives of our patients. Our clinical-stage pipeline consists of four drug candidates, all of which are in targeted, biomarker-defined patient populations, making ArQule a leader among companies our size in precision medicine. ArQule’s proprietary pipeline includes: ARQ 087, a multi-kinase inhibitor designed to preferentially inhibit the fibroblast growth factor receptor (FGFR) family, in phase 2 for iCCA and in phase 1b for multiple oncology indications; ARQ 092, a selective inhibitor of the AKT serine/threonine kinase, in phase 1/2 company sponsored study for Overgrowth Diseases, in phase 1 for ultra-rare Proteus syndrome conducted by the National Institutes of Health (NIH), as well as in multiple oncology indications; ARQ 751, a next generation AKT inhibitor, in phase 1 for patients with AKT1 and PI3K mutations; and ARQ 761, a β-lapachone analog being evaluated as a promoter of NQO1-mediated programmed cancer cell necrosis, in phase 1/2 in multiple oncology indications in partnership with the University of Texas Southwestern Medical Center. In addition, we have advanced ARQ 531, an investigational, orally bioavailable, potent and reversible inhibitor of both wild type and C481S-mutant BTK, through toxicology testing and plan to initiate a phase 1 trial by the third quarter of 2017. ArQule’s current discovery efforts are focused on the identification and development of novel kinase inhibitors, leveraging the Company’s proprietary library of compounds. You can follow us on Twitter and LinkedIn. This press release contains forward-looking statements regarding preclinical experiments and planned clinical trials with ARQ 531. These statements are based on the Company’s current beliefs and expectations, and are subject to risks and uncertainties that could cause actual results to differ materially. Positive information about pre-clinical results does not ensure that clinical trials will be successful. For example, ARQ 531 may not demonstrate promising therapeutic effect in man; in addition, it may not exhibit an adequate safety profile in planned or later stage or larger scale clinical trials as a result of known or as yet unanticipated side effects. The results achieved in later stage trials may not be sufficient to meet applicable regulatory standards or to justify further development. Problems or delays may arise during clinical trials or in the course of developing, testing or manufacturing ARQ 531 that could lead the Company to discontinue development. Even if later stage clinical trials are successful, unexpected concerns may arise from subsequent analysis of data or from additional data. Obstacles may arise or issues may be identified in connection with review of clinical data with regulatory authorities. Regulatory authorities may disagree with the Company’s view of the data or require additional data or information or additional studies. Drug development involves a high degree of risk. Only a small number of research and development programs result in the commercialization of a product. For more detailed information on the risks and uncertainties associated with the Company’s drug development and other activities, see the Company’s periodic reports filed with the Securities and Exchange Commission. The Company does not undertake any obligation to publicly update any forward-looking statements.


BURLINGTON, Mass.--(BUSINESS WIRE)--ArQule, Inc. (Nasdaq: ARQL) today announced that data from the phase 1/2 trial in intrahepatic cholangiocarcinoma (iCCA) with fibroblast growth factor receptor (FGFR) inhibitor, ARQ 087, will be presented on June 3, 2017 at the 2017 ASCO Annual Meeting in Chicago, Illinois. The presentation will include an analysis of iCCA patients with FGFR2 fusions. ARQ 087 is a multi-kinase inhibitor designed to preferentially inhibit the fibroblast growth factor receptor (FGFR) family. A registrational phase 3 trial with ARQ 087 in second-line iCCA FGFR2 fusion positive patients is planned to begin in the third quarter of 2017. The company has been granted orphan drug designation by the U.S. Food and Drug Administration and European Medicines Agency for ARQ 087 in this indication. The company will also present at ASCO final data from the completed Tivantinib METIV-HCC phase 3 trial for hepatocellular carcinoma. Data will also be presented for the company sponsored ARQ 092 phase 1b trial in combination with carboplatin plus paclitaxel for oncology, and for the University of Texas Southwest sponsored ARQ 761 phase 1 trial cancer for cell necrosis. ARQ 087 Abstract 4017/Poster Board: #9 ARQ 087, an oral pan-Fibroblast Growth Factor Receptor (FGFR) inhibitor, in patients (pts) with advanced intrahepatic cholangiocarcinoma (iCCA) with FGFR2 genetic aberrations. Poster Session Location: Hall A, 8:00 AM - 11:30 AM CT Poster Discussion Session Location: Hall D2, 4:45 PM - 6:00 PM CT Tivantinib (ARQ 197) Abstract 4000 Second-line tivantinib (ARQ 197) vs placebo in patients (Pts) with MET-high hepatocellular carcinoma (HCC): Results of the METIV-HCC phase III trial. Oral Abstract Session Location: Hall D2, 8:00 AM - 8:12 AM CT ARQ 092 Abstract 2524/Poster Board #16 Results of a phase Ib study of ARQ 092 in combination with carboplatin (C) plus paclitaxel (P), or with P in patients (pts) with solid tumors. Poster Session Location: Hall A, 8:00 AM - 11:30 AM CT ARQ 761 Abstract 2517/ Poster Board #9 Phase 1 study of ARQ 761, a β-lapachone analog that promotes NQO1-mediated programmed cancer cell necrosis. Poster Session Location: Hall A, 8:00 AM - 11:30 AM CT Poster Discussion Session Location: Arie Crown Theater, 11:30 AM - 12:45 PM CT Cholangiocarcinoma (CCA) is the most common biliary malignancy and the second most common hepatic malignancy after hepatocellular carcinoma (HCC)1. Depending on the anatomic location, CCA is classified as intrahepatic (iCCA), perihilar (pCCA), and extrahepatic (eCCA). iCCA originates from the intrahepatic biliary ductal system and forms an intrahepatic mass. The average age adjusted incidence rate for iCCA is approximately one in 100,000 per year in the United States and Europe2,3. ARQ 087 is a multi-kinase inhibitor designed to preferentially inhibit the fibroblast growth factor receptor (“FGFR”) family with demonstrated efficacy in FGFR2 genetic alterations. The FGFR pathway is disrupted in several ways in human cancer, thus providing numerous therapeutic targets for an inhibitor of this pathway. ARQ 087 has demonstrated in vivo inhibition of tumor growth and downstream signaling in tumors whose growth is driven by FGFR targets. Signals of single agent activity with this drug were observed in phase 1a testing. Phase 1b expansion cohorts with ARQ 087 include patients with cholangiocarcinoma and adrenocortical tumors, as well as those with FGFR translocations, amplifications and mutations. Clinical development of ARQ 087 advanced into phase 2 for intrahepatic cholangiocarcinoma (iCCA) in patients with FGFR2 fusions following the observation of two confirmed responses in this patient population in the phase 1 portion of the program, and a phase 3 registrational trial is planned to begin in the third quarter of 2017 in this same patient population. About the AKT Pathway and ARQ 092 ARQ 092 is an orally bioavailable, selective small molecule inhibitor of the AKT kinases. The AKT pathway when abnormally activated is implicated in multiple oncogenic processes such as cell proliferation and apoptosis. This pathway has emerged as a target of potential therapeutic relevance for compounds that inhibit its activity, which has been linked to a variety of cancers as well as to select non-oncology indications. Dysregulation of AKT is also a driver of certain rare proliferative disorders. For example, the E17K mutation of AKT1 causes Proteus syndrome, a rare non-cancerous segmental overgrowth disorder, and the analogous PIK3CA-Related Overgrowth Spectrum (PROS) is caused by genetic alterations in the PI3K pathway. ARQ 092 has been shown preclinically and clinically to inhibit AKT and PI3K cell signaling and therefore may provide the potential for much-needed treatment options for patients with these diseases. ARQ 092, the lead compound in ArQule’s AKT program, has completed phase 1a clinical testing and has advanced into phase 1b expansion testing in cohorts of patients with endometrial cancer, lymphomas and tumors harboring either AKT or PI3K mutations. A company sponsored phase 1/2 trial is being conducted in the U.S. and E.U. for Overgrowth Diseases, including PROS and Proteus syndrome. ARQ 092 is also in a phase 1 trial being conducted by the NIH for Proteus syndrome. Collaborators are exploring in preclinical testing other indications for ARQ 092, including sickle cell disease. ArQule is a biopharmaceutical company engaged in the research and development of targeted therapeutics to treat cancers and rare diseases. ArQule’s mission is to discover, develop and commercialize novel small molecule drugs in areas of high unmet need that will dramatically extend and improve the lives of our patients. Our clinical-stage pipeline consists of four drug candidates, all of which are in targeted, biomarker-defined patient populations, making ArQule a leader among companies our size in precision medicine. ArQule’s proprietary pipeline includes: ARQ 087, a multi-kinase inhibitor designed to preferentially inhibit the fibroblast growth factor receptor (FGFR) family, in phase 2 for iCCA and in phase 1b for multiple oncology indications; ARQ 092, a selective inhibitor of the AKT serine/threonine kinase, in phase 1/2 company sponsored study for Overgrowth Diseases, in phase 1 for ultra-rare Proteus syndrome conducted by the National Institutes of Health (NIH), as well as in multiple oncology indications; ARQ 751, a next generation AKT inhibitor, in phase 1 for patients with AKT1 and PI3K mutations; and ARQ 761, a β-lapachone analog being evaluated as a promoter of NQO1-mediated programmed cancer cell necrosis, in phase 1/2 in multiple oncology indications in partnership with the University of Texas Southwestern Medical Center. In addition, we have advanced ARQ 531, an investigational, orally bioavailable, potent and reversible inhibitor of both wild type and C481S-mutant BTK, through toxicology testing and plan to initiate a phase 1 trial by the third quarter of 2017. ArQule’s current discovery efforts are focused on the identification and development of novel kinase inhibitors, leveraging the Company’s proprietary library of compounds. You can follow us on Twitter and LinkedIn. This press release contains forward-looking statements regarding the Company’s clinical trials with ARQ 087 and ARQ 092. These statements are based on the Company’s current beliefs and expectations, and are subject to risks and uncertainties that could cause actual results to differ materially. Positive information about pre-clinical and early stage clinical trial results does not ensure that later stage or larger scale clinical trials will be successful. For example, ARQ 087 and ARQ 092 may not demonstrate promising therapeutic effect; in addition, these drugs may not demonstrate appropriate safety profiles in current or later stage or larger scale clinical trials as a result of known or as yet unanticipated side effects. The results achieved in later stage trials may not be sufficient to meet applicable regulatory standards or to justify further development. Problems or delays may arise during clinical trials or in the course of developing, testing or manufacturing these compounds that could lead the Company to discontinue development. Even if later stage clinical trials are successful, unexpected concerns may arise from subsequent analysis of data or from additional data. Obstacles may arise or issues may be identified in connection with review of clinical data with regulatory authorities. Regulatory authorities may disagree with the Company’s view of the data or require additional data or information or additional studies. In addition, we plan to develop and use a companion diagnostic to identify patients with FGFR2 and possibly other fusions for our future ARQ 087 clinical trials. We intend to outsource the development of such companion diagnostics to one or more third party collaborators. There can be no assurance that we will successfully enter into an agreement or agreements with any such collaborators; in addition, any such collaborator may encounter difficulties in developing and obtaining approval for such companion diagnostic, including issues relating to selectivity/specificity, analytical validation, reproducibility, concordance or clinical validation. Any delay or failure to develop or obtain regulatory approval of such companion diagnostic could delay or prevent approval of ARQ 087. Drug development involves a high degree of risk. Only a small number of research and development programs result in the commercialization of a product. Furthermore, ArQule may not have the financial or human resources to successfully pursue drug discovery in the future. For more detailed information on the risks and uncertainties associated with the Company’s drug development and other activities, see the Company’s periodic reports filed with the Securities and Exchange Commission. The Company does not undertake any obligation to publicly update any forward-looking statements. 1 Welzel TM, et al. Impact of classification of hilar cholangiocarcinomas (Klatskin tumors) on the incidence of intra- and extrahepatic cholangiocarcinoma in the United States. J Natl Cancer Inst. 2006; 98(12),873–875. 2 National Cancer Institute: Surveillance, Epidemiology, and End Results 3 rarecarenet.eu


News Article | May 19, 2017
Site: www.theengineer.co.uk

An automobile designed with a target speed of 500mph in mind Donald Campbell’s pursuit of speed records is the stuff of legend, and the vehicle that embodies his attempts on land is the Bluebird CN7. In the planning stages since 1956 – at which point Campbell was chasing records exclusively on the water – the CN7 was almost ready for action by the time it featured in the May 1960 issue of The Engineer. The land speed record (LSR) stood at 394mph, set by John Cobb in the Railton Mobil Special. Campbell, in collaboration with his engineering partners Norris Brothers, planned to obliterate that number, and Bluebird was designed with a target of 500mph in mind. To achieve this, the CN7 would incorporate a host of groundbreaking technology. The four-wheel-drive monocoque Bluebird was the first LSR contender to be powered by a gas turbine engine, a Bristol-Siddeley ‘Proteus’ 705 with an output of 4,250bhp. According to this magazine, “the use of a ‘Proteus’ dictated other important characteristics of the design; since it has, in effect, a ring of air intakes around the centre section,  a plenum chamber installation was virtually mandatory, so that the steel-tube-frame construction of the Norris-designed ‘Bluebird’ hydroplane was forsaken for an ‘egg-box’ design.” The ‘egg-box’ construction was apparently selected in order to sustain the pressure differential of around 3lb per square inch expected in the engine bay. To accommodate this, the team used an aluminium alloy, the stiffness of which “was obtained by using ‘sandwich panels’ with stabilising cores of ‘Aeroweb’ honeycomb”. Sandwiched honeycomb structures are common today in the aerospace industry, but their use for lightweighting in a motor vehicle was, at the time, revolutionary. According to our predecessors, the primary driver of the lightweighting was the split-rim design wheels and – more specifically – 52in diameter tyres, which were manufactured by Dunlop. “During the design of the car it proved that the one component whose capability limited the performance and dictated alterations to the design was the tyre. Weight saving and even drag reduction are prosecuted solely to lighten the duty of the tyres.” Tyre performance at speeds in excess of 420mph was so vital that Dunlop built an entirely new test rig on which to trial Bluebird’s custom boots. They would see their first action at Goodwood in July 1960 at the vehicle’s public launch, and would propel Campbell and the CN7 to a speed just shy of 400mph at Utah’s Bonneville Salt Flat two months later. Shortly after, on 16 September 1960, Campbell suffered a high-speed crash in Bluebird, fracturing his skull. It was 1963 before he was back at the wheel of the CN7 attempting to break the record, this time at the salt flats of Lake Eyre in South Australia. Having not seen rain in 20 years, the dried salt lake witnessed torrential downpours in May, and Campbell had to abandon his efforts. He returned a year later, however, setting an official FIA LSR of 403.10mph on 17 July 1964. But rains that year also prevented Bluebird from reaching its full potential, and Campbell was disappointed not to have posted a speed in excess of 450mph. His frustration was compounded by American Craig Breedlove having already exceeded Campbell’s speed, although this was not officially recognised by the FIA, as Breedlove’s Spirit of America was not wheel-driven by its jet engine. Bluebird was actually the last wheel-driven vehicle to hold the official record, as the FIA subsequently relaxed its technical rules. Campbell’s legendary status was cemented later in 1964 when he broke the water speed record (WSR) on the last day of the year, hitting a speed of 276.33mph in the Bluebird K7 hydroplane. He remains the only person to set land and water speed records in the same calendar year. Just over two years later, on 4 January 1967, Campbell was killed attempting to set an eighth WSR. On Coniston Water, in the Lake District, a heavily modified K7 broke up at speeds in excess of 300mph, killing its pilot instantly. Between them, Donald Campbell and his father, Sir Malcolm, set a total of 11 speed records on water and 10 on land.


TOKYO & REDWOOD CITY, Calif.--(BUSINESS WIRE)--Otsuka Pharmaceutical Co., Ltd. (Otsuka) and Proteus Digital Health® (Proteus) today announce that the United States Food and Drug Administration (FDA) has acknowledged receipt of the New Drug Application (NDA) resubmission for the drug-device combination product of ABILIFY® (aripiprazole) embedded with a Proteus ingestible sensor in a single tablet. The NDA resubmission will now be reviewed by the FDA, with an anticipated action date by the agency in the fourth quarter of 2017. The FDA requested additional information, including further human factors investigations. The goal of human factors testing is to evaluate use-related risks and confirm that individuals can use the system safely and effectively.2 If approved, this Digital Medicine would securely measure patient medication-taking patterns, as well as select physiological data and self-reported behavioral information. This information would help enable individuals along with their healthcare professional team to better manage their serious mental illness. With the patient’s consent, this information could be shared with their healthcare professional team and selected family and friends, with the goal of allowing physicians to be more informed in making treatment decisions that are specific to the patient's needs. This Digital Medicine would be used in the treatment of adults with schizophrenia, acute treatment of manic and mixed episodes associated with bipolar I disorder, and as adjunctive therapy for the treatment of major depressive disorder. This Digital Medicine is comprised of FDA-approved ABILIFY with the only FDA-cleared ingestible sensor, the size of a grain of sand, embedded inside a single tablet at the point of manufacture.3 The Proteus ingestible sensor activates when it reaches stomach fluids and communicates with the patch, which is a wearable sensor that detects and records the ingestion of the ABILIFY tablet, and select physiological data, such as activity level. A mobile patient application, or medical app, displays the data collected by the patch to allow individuals to review their objective medication intake and activity level, as well as enter self-reported measures of rest and mood. A web-based portal for healthcare professionals and selected family and friends displays this information for the duration of treatment. Discovered by Otsuka Pharmaceutical Co., Ltd., ABILIFY was the first available dopamine partial agonist and is indicated for the treatment of schizophrenia in adults, for the acute treatment of manic or mixed episodes associated with Bipolar I Disorder as monotherapy and as an adjunct to lithium or valproate in adults, and for use as an adjunctive therapy to antidepressants in adults with Major Depressive Disorder who have had an inadequate response to antidepressant therapy. ABILIFY tablets are available in 2 mg, 5 mg, 10 mg, 15 mg, 20 mg and 30 mg strengths. About the Proteus Digital Health® Ingestible Sensor and Wearable Sensor Patch The Proteus ingestible sensor and wearable sensor patch have been cleared by the Food and Drug Administration (FDA) for use in the United States, CE marked per the Medical Device Directive for use in the European Union and approved by the CFDA for use in China. More information is available at www.proteus.com. ABILIFY is indicated for: Elderly patients with dementia-related psychosis treated with antipsychotic drugs are at an increased risk (1.6 to 1.7 times) of death compared to placebo (4.5% vs 2.6%, respectively). Although the causes of death were varied, most of the deaths appeared to be cardiovascular (e.g., heart failure, sudden death) or infectious (e.g., pneumonia) in nature. ABILIFY is not approved for the treatment of patients with dementia-related psychosis. Antidepressants increased the risk compared to placebo of suicidal thinking and behavior (suicidality) in children, adolescents, and young adults in short-term studies of Major Depressive Disorder (MDD) and other psychiatric disorders. Anyone considering the use of adjunctive ABILIFY or another antidepressant in a child, adolescent, or young adult must balance this risk with the clinical need. Short-term studies did not show an increased risk of suicidality in adults beyond age 24. Depression and certain other psychiatric disorders are themselves associated with increases in the risk of suicide. Patients of all ages who are started on antidepressant therapy should be monitored appropriately and observed closely for clinical worsening, suicidality, or unusual changes in behavior. Families and caregivers should be advised of the need for close observation and communication with the prescriber. ABILIFY is not approved for use in pediatric patients with depression. Contraindication – Known hypersensitivity reaction to ABILIFY. Reactions have ranged from pruritus/urticaria to anaphylaxis. Cerebrovascular Adverse Events, Including Stroke – Increased incidence of cerebrovascular adverse events (e.g., stroke, transient ischemic attack), including fatalities, have been reported in clinical trials of elderly patients with dementia-related psychosis treated with ABILIFY. Neuroleptic Malignant Syndrome (NMS) – A potentially fatal symptom complex sometimes referred to as NMS may occur with administration of antipsychotic drugs, including ABILIFY. Rare cases of NMS occurred during ABILIFY treatment. Signs and symptoms of NMS include hyperpyrexia, muscle rigidity, altered mental status, and evidence of autonomic instability (e.g., irregular pulse or blood pressure, tachycardia, diaphoresis, and cardiac dysrhythmia). Additional signs may include elevated creatinine phosphokinase, myoglobinuria (rhabdomyolysis), and acute renal failure. The management of NMS should include: 1) immediate discontinuation of antipsychotic drugs and other drugs not essential to concurrent therapy; 2) intensive symptomatic treatment and medical monitoring; and 3) treatment of any concomitant serious medical problems for which specific treatments are available. Tardive Dyskinesia (TD) – The risk of developing TD (a syndrome of abnormal, involuntary movements) and the potential for it to become irreversible are believed to increase as the duration of treatment and the total cumulative dose of antipsychotic increase. The syndrome can develop, although much less commonly, after relatively brief treatment periods at low doses. Prescribing should be consistent with the need to minimize TD. There is no known treatment for established TD, although the syndrome may remit, partially or completely, if antipsychotic treatment is withdrawn. Metabolic Changes – Atypical antipsychotic drugs have been associated with metabolic changes that include: Pathological Gambling and Other Compulsive Behaviors – Intense urges, particularly for gambling, and the inability to control these urges have been reported while taking ABILIFY. Other compulsive urges (e.g., eating, sexual, or shopping) have been reported less frequently. Prescribers should ask patients or their caregivers specifically about, and closely monitor for, the development of new or intense compulsive urges. Consider dose reduction or stopping ABILIFY, if such urges develop. Orthostatic Hypotension – ABILIFY may cause orthostatic hypotension and should be used with caution in patients with known cardiovascular disease, cerebrovascular disease, or conditions which would predispose them to hypotension. Falls – Antipsychotics may cause somnolence, postural hypotension, motor and sensory instability, which may lead to falls causing fractures or other injuries. For patients with diseases, conditions, or medications that could exacerbate these effects, complete fall risk assessments when initiating treatment and recurrently during therapy. Leukopenia, Neutropenia, and Agranulocytosis – Leukopenia, neutropenia, and agranulocytosis have been reported. In patients with a history of clinically significant low white blood cell count (WBC)/absolute neutrophil count (ANC) or history of drug-induced leukopenia/neutropenia, perform a complete blood count (CBC) frequently during the first few months of therapy. Consider discontinuing ABILIFY at the first sign of a clinically significant decline in WBC in the absence of other causative factors. Monitor patients with clinically significant neutropenia for fever or other symptoms or signs of infection and treat promptly if such symptoms or signs occur. Discontinue ABILIFY in patients with severe neutropenia (ANC <1000/mm3) and follow their WBC counts until recovery. Seizures/Convulsions – ABILIFY should be used with caution in patients with a history of seizures or with conditions that lower the seizure threshold. Potential for Cognitive and Motor Impairment – ABILIFY may impair judgment, thinking, or motor skills. Instruct patients to avoid operating hazardous machinery, including automobiles, until they are certain ABILIFY does not affect them adversely. Body Temperature Regulation – Disruption of the body’s ability to reduce core body temperature has been attributed to antipsychotic agents. Advise patients regarding appropriate care in avoiding overheating and dehydration. Appropriate care is advised for patients who may exercise strenuously, may be exposed to extreme heat, receive concomitant medication with anticholinergic activity, or are subject to dehydration. Suicide – The possibility of a suicide attempt is inherent in psychotic illnesses, Bipolar Disorder, and Major Depressive Disorder. Close supervision of high-risk patients should accompany drug therapy. Prescriptions should be written for the smallest quantity consistent with good patient management in order to reduce the risk of overdose. Dysphagia – Esophageal dysmotility and aspiration have been associated with antipsychotic drug use, including ABILIFY; use caution in patients at risk for aspiration pneumonia. Aspiration pneumonia is a common cause of morbidity and mortality in elderly patients, in particular those with advanced Alzheimer’s dementia. Concomitant Medication – Dosage adjustments are recommended in patients who are CYP2D6 poor metabolizers and in patients taking concomitant CYP3A4 inhibitors or CYP2D6 inhibitors or strong CYP3A4 inducers. When the coadministered drug is withdrawn from the combination therapy, ABILIFY dosage should then be adjusted to its original level. When the coadministered CYP3A4 inducer is withdrawn, ABILIFY dosage should be reduced to the original level over 1 to 2 weeks. For patients who are known CYP2D6 poor metabolizers, administer half of usual dose. For patients who are known CYP2D6 poor metabolizers taking concomitant strong CYP3A4 inhibitors (e.g., itraconazole, clarithromycin), administer a quarter of usual dose. For patients taking strong CYP2D6 (e.g., quinidine, fluoxetine, paroxetine) or CYP3A4 inhibitors (e.g., itraconazole, clarithromycin), administer half of usual dose. For patients taking strong CYP2D6 and CYP3A4 inhibitors, administer a quarter of usual dose. For patients taking strong CYP3A4 inducers (e.g., carbamazepine, rifampin), double usual dose over 1 to 2 weeks. Commonly observed adverse reactions: (≥5% incidence and at least twice the rate of placebo for ABILIFY vs placebo, respectively): Dystonia – Symptoms of dystonia may occur in susceptible individuals during the first days of treatment and at low doses. Pregnancy – Neonates exposed to antipsychotic drugs, including ABILIFY, during the third trimester of pregnancy are at risk for extrapyramidal and/or withdrawal symptoms. These complications have varied in severity, from being self-limited to requiring intensive care and prolonged hospitalization. ABILIFY should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus. Nursing Mothers – ABILIFY is present in human breast milk. A decision should be made whether to discontinue nursing or to discontinue the drug, taking into account the importance of the drug to the mother and any potential risks to the infant. To report SUSPECTED ADVERSE REACTIONS, contact Otsuka America Pharmaceutical, Inc. at 1-800-438-9927 or FDA at 1-800-FDA-1088 (www.fda.gov/medwatch). About Otsuka Pharmaceutical Co., Ltd. Otsuka Pharmaceutical is a global healthcare company with the corporate philosophy: “Otsuka-people creating new products for better health worldwide.” Otsuka researches, develops, manufactures and markets innovative products, with a focus on pharmaceutical products for the treatment of diseases and nutraceutical products for the maintenance of everyday health. In pharmaceuticals, Otsuka is a leader in the challenging area of mental health and also has research programs on several under-addressed diseases including tuberculosis, a significant global public health issue. These commitments illustrate how Otsuka is a “big venture” company at heart, applying a youthful spirit of creativity in everything it does. Otsuka Pharmaceutical is a subsidiary of Otsuka Holdings Co., Ltd. headquartered in Tokyo, Japan. The Otsuka group of companies employed 45,000 people worldwide and had consolidated sales of approximately USD 11 billion (€ 9.9 billion) in 2016. All Otsuka stories start by taking the road less travelled. Learn more about Otsuka Pharmaceutical Company on its global website at https://www.otsuka.co.jp/en. Learn more about Otsuka in the U.S. at www.otsuka-us.com and connect with us on Twitter at @OtsukaUS. Headquartered in Redwood City, Calif., Proteus is privately held and funded by leading institutional and corporate investors, including: Novartis, Otsuka, Medtronic and Kaiser Permanente. For more information, visit www.proteus.com. Connect with us on Twitter @ProteusDH. 1 Rohatagi S et al. Optimization of a Digital Medicine System in Psychiatry. J Clin Psychiatry 2016;77(9):e1101-1107. 2 U.S. Food & Drug Administration. Premarket Information - Device Design and Documentation Processes. https://www.fda.gov/MedicalDevices/DeviceRegulationandGuidance/HumanFactors/ucm119190.htm. Updated 9/15/2016. Accessed April 11, 2017. 3 U.S. Food & Drug Administration. 510(k) Premarket Notification. https://www.accessdata.fda.gov/scripts/cdrh/cfdocs/cfpmn/pmn.cfm?ID=K133263. Accessed April 21, 2017.


Patent
French Institute of Petroleum, Proteus and French National Center for Scientific Research | Date: 2015-06-12

The present invention relates to the expression and optimisation of enzymes involved in the breakdown of lignocellulosic biomass. The present invention specifically relates to variants of the exoglucanase 1 of Trichoderma reesei, as well as to the use of said variants with improved efficiency in methods for breaking down cellulose and for producing biofuel.


Patent
French Institute of Petroleum, Proteus and French National Center for Scientific Research | Date: 2015-06-12

The present invention relates to the expression and optimisation of enzymes involved in the breakdown of lignocellulosic biomass. The present invention specially relates to variants of the exoglucanase 2 of Trichoderma reesei, as well as to the use of said variants with improved efficiency in methods for breaking down cellulose and for producing biofuel.


Grant
Agency: European Commission | Branch: H2020 | Program: RIA | Phase: BIOTEC-1-2014 | Award Amount: 7.06M | Year: 2015

P4SB is about the utilization of the conceptual and material tools of contemporary Synthetic Biology to bring about the sustainable and environmentally friendly bioconversion of oil-based plastic waste into fully biodegradable counterparts by means of deeply engineered, whole-cell bacterial catalysts. These tools will be used to design tailor-made enzymes for the bio-depolymerization of PET (polyethylene terephthalate) and PU (polyurethane), but also for the custom design of a Pseudomonas putida Cell Factory capable of metabolizing the resulting monomers. Pseudomonas putida will undergo deep metabolic surgery to channel these diverse substrates efficiently into the production of polyhydroxyalkanoates (PHA) and derivatives. In addition, synthetic downstream processing modules based on the programmed non-lytic secretion of PHA will facilitate the release and recovery of the bioplastic from the bacterial biomass. These industry driven objectives will help to address the market need for novel routes to valorise the gigantic plastic waste streams in the European Union and beyond, with direct opportunities for SME partners of P4SB spanning the entire value chain from plastic waste via Synthetic Biology to biodegradable plastic. As a result we anticipate a completely biobased process reducing the environmental impact of plastic waste by establishing it as a novel bulk second generation carbon source for industrial biotechnology, while at the same time opening new opportunities for the European plastic recycling industry and helping to achieve the ambitious recycling targets set by the European Union for 2020.


Patent
Proteus, French Institute of Petroleum and French National Center for Scientific Research | Date: 2013-09-04

The invention relates to a polypeptide which has enhanced beta-glucosidase activity at a temperature of between about 30 C. and about 35 C.


The invention provides for methods of generating modified polynucleotide libraries by inserting and/or deleting at least three nucleotide residues in polynucleotide sequences. Theses methods may be used with other methods of gene modification such as gene shuffling. The invention further provides methods of directed molecular evolution using the modified polynucleotide libraries produced by these methods.

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