New TKI toward highly targeted therapies - Moodle

New TKI toward highly targeted therapies - Moodle

TYROSINE KINASE INHIBITO RS Alice RENARD Julie TELLIEZ Valentin LEGROS Oussama KAMAL TKI taking off d ra t e e n e al g inases: n g i k S G FR ugh

D o P r h n t , the R F EG F I R ST S HT INSIG INIB AT OF IM Bcr-Abl EGFR VEGFR Others 2

Kinase Signalisation Basis 1. Molecular level Nobel Price E. Fischer & E. Krebs (1992) 2. Celullar level 3. Phenotype Deregulation Cancer, inflammation, level immunological and neurological diseases 3 Signaling Pathways Normal (wild type) Abnormalities

MODULATION INHIBITION JAK, Syk Bcr-Abl, EGFR Inflammatio n, Autoimmuni ty Companion Diagnosis + Cancer 4 Signalling Pathways Normal pathways

Abnormalities MODULATION INHIBITION JAK, Syk Bcr-Abl, EGFR Inflammatio n,Autoimmu nity Companion Diagnostics + Cancer 5 THE LONG ROAD TO IMATINIB 6

Birth of Targeted Therapies Oncogene addiction Beginning (dependency of the on a single biology oncogenic science at protein or a pathway) molecular Side level effects+ lack of activity of cancer treatment and chemotherapy radiations

Targeted therapies to enhance sensitivity: PROTEIN KINASE INHIBITION 7 Drug Discovery 8 From random screening to understanding Bcr-Abl: the first interesting target for selective chemotherapy Imatinib: a break-through in oncology (96.6% responders in IRIS) 9

A challenged discovery Imatinib paved the way to a whole new era of tumor treatment : Orally, targeted therapies BUT ?... Competition with intracellular millimolar ATP concentration Selective, but not exclusive Resistance mecanism (31%) - Missense mutations within the Abl kinase domain - Over-expression of Bcr-Abl 10 Overcoming Resistances Dealing with mutations the 2nd generation Bcr-Abl inhibitors Bosutinib Bosutinib FDA approval 2001

2007 2006 2012 10 100 times more potent than imatinib 11 2nd generation Bcr-Abl TKI Imatinib (1st generation) Binding of the ABL-TK Nilotinib Dasatinib Bosutinib Inactive Inactive Active Active

conformation conformation conformation conformation Inhibitor type 2 (DFG out) 2 1 Selectivit y Bcr-Abl, PDGFR, cKit ~ imatinib Pan-TKI Every common mutation

Insensitive Spectrum Limited Every common mutation T315I gatekeep er mutation Insensitive Insensitive 1 Bcr-Abl + KIT + Src Even broader

than the others Insensitive 12 2nd generation Bcr-Abl TKI Avantages Solve nearly all the mutations-related resistance problems Faster response rates Deeper responses + lower rate of progression compared to imatinib Drawbacks Not active against T315I gatekeeper mutation This mutation : threonine -> isoleucine (T315I) emergence as a common pathway to failure of both first &

second line treatments 13 3rd generation Bcr-Abl TKI Targeting the T315I mutation 14 Gefitinib IRESSA 15 Gefitinib Indication - Gefitinib has been the first EGFR-TKI approved in NSCLC - Gefitinib is indicated for locally advanced or metastatic non-small cell lung cancer (NSCLC) in adult patients. -

It targets EGFR-TK, which enable the development of the tumor. 16 Gefitinib Development 1.0 1.0 0.8 0.8 Proportion without treatment failure Proportion surviving - The two first studies ISEL and INTEREST were unselected trials in pre-treated settings. 0.6

0.4 IRESSA Placebo 0.2 ISEL Study 20032005 0.6 0.4 0.2 0.0 0.0 0 1 2

3 4 5 6 7 8 9 10 11 12 13 14 15 16 0 1 2 3 4 5

6 7 8 9 10 11 12 13 14 15 16 Months Months Objective Response Rate 8.0% vs 1.3%, p<0.0001 Thatcher 2005 17 Gefitinib Development - After the results of the INTEREST study, FDA has restricted labelling of Iressa in 2005. 1. 0

1. 0 IRESSA Docetaxel 0. 8 0. 6 0. 6 0. 4 0. 4 0. 2 0. 2

0. 0 0 IRESSA Docetaxel 0. 8 Probability of progression-free survival Probability of survival INTEREST Study 2004- 2008 4 8 12

16 20 24 Months 28 32 36 40 0. 0 0 4 8 12

16 20 24 28 32 36 40 Months ORR [EFR population]: 9.1% IRESSA, 7.6% Docetaxel; p=0.3257 Kim 2008 18 Gefitinib Development -

In 2004, discovery of the relation between EGFR mutations and the response to Gefitinib. - In 2006 : start of IPASS study, with clinically selected trial in first line setting. IRESSA EGFR M+ (n=132) - Probability 2009 : Gefitinib approved for the treatment of clinically advanced or metastatic 1.0 Carboplatin / paclitaxel EGFR M+ ofNSCLC PFS with EGFR activating mutations in second line therapy. Associated with (n=129) EGFR mutation test Cobas from Roche 0.8 EGFR M+

HR=0.48, 95% CI 0.36, 0.64 p<0.0001 0.6 0.4 Objective response rate 71.2% vs 47.3% p=0.0001 0.2 0.0 0 M+, mutation positive 4 8 12 16 Time from randomisation (months) 20

24 Mok 2009 19 Erlotinib - Tarceva 20 Erlotinib Indication - Erlotinib is the first drug specifically approved for the treatment of EGFR activating mutations in NSCLC. - Erlotinib is indicated for locally advanced or metastatic non-small cell lung cancer (NSCLC) with EGFR activating mutations in adult patients in first line of treatment. - It has been developed with EGFR mutation test Roche cobas.

21 Erlotinib Development EURTAC phase III clinical trial Erlotinib (n = 86) Chemotherapy (n = 87) HR = 0.37 Log-rank p < 0.0001 22 Erlotinib Development - 2004 : Erlotinib is approved by the FDA for initial treatment of metastatic NSCLC for patients with particular mutations of EGFR, that can be detected with an FDA approved test. - 2010 : Approved for maintenance of treatment for patients with metastatic NSCLC and no progression after four cycles of platinium based chemotherapy. -

2013 : Erlotinib is approved in first line of treatment for locally advanced or metastatic NSCLC with EGFR activating mutations. - The first line has been approved with the Roche Cobas test to detect EGFR mutations. 23 Roche Cobas EGFR test - Cobas tests are realised in a real-time PCR system : Cobas 4800 V 2.0. - Cobas EGFR test detects exon 19 deletion and exon 21 substitution before treating patients with Erlotinb. - This test is also used with Gefitinib and for dectecting BRAF V600E mutation for the treatment of melanoma with this mutation.

24 Dabrafenib - Tafinlar 25 Dabrafenib Indication - Dabrafenib is indicated for the treatment of unresectable or metastatic melanoma with BRAF mutation V600E. - BRAF V600E mutation is the most common mutation with a prevalence of 90%. BRAF mutations are present approximately in 60% of advanced melanomas. - Dabrafenib activity has been confirmed by suppressing ERK-P and decreasing cell proliferation. - It has been developed with a detection test from bioMrieux : THxID BRAF.

26 Dabrafenib Development - Dabrafenib has been approved by the FDA and the EMA in 2013 as a NME. - It has a major activity on BRAF V600E but also on BRAF V600K mutation. - It has been developed with a detection test from bioMrieux : THxID BRAF that detects both V600E and V600K mutations. 27 THxID BRAF test - THxID BRAF has been developed through the collaboration of bioMrieux and GSK.

- The test is approved by the FDA since may 2013 and is CE marked. - It has the same detection mechanism of BRAF mutations than Cobas : a real time PCR system, but has been developed only for detecting BRAF mutations. 28 Summary --tinib Gefitinib 2002 Unspecific development and clinical trials Erlotinib 2004

Specific development and clinical trials without companion diagnostic Gefitinib Dabrafenib 2009 2013 Specific clinical trials to have a specific indication Specific development and clinical trials with a

companion diagnostic 2013 29 Regulatory Landscape Ensuring the safe and effective delivery of molecularly targeted agents Status : IVD July 14th, 2011 draft guidance : Targeted oncology agents would only gain approval if reviewed in parallel with companion diagnostic Status : IVD IVD directive 98/79/EC : Certification process (CE) by

an EU Notified Body. IVD directive is currently being re-written. Classe C rating. 30 Regulatory Landscape 31 CDx Perspective Historical perspective : Most of CDx developed after companion drug with a retrospective validation. Draft Guidance : In most circumstances, if use of an in vitro companion diagnostic device is essential for the safe and effective use of a therpeutic product, the IVD companion diagnostic device and therapeutic product should be approved or cleared contemporaneously by FDA for the use indicated in the therapeutic product labeling ZELBORAF :

Advanced Melanoma Approved in 2011 XALKORI : NSCLC Apporved in 2011 32 CDx Perspective 33 Co-development Value

Stake Holder Benefit BioPharma Reduce drug development costs Companies Improve efficacy-safety profile of drug Increase cost-effectiveness profile Accelerate approval

Premium pricing for targeted drug Premium reimbursement CDx New market opportunities Companies New partnership Biopharma-CDx companies Premium pricing for CDx 34

l CDx Market 35 Global Diagnostic Market Key Players $45 Bn in 2012 +5% of growth to $62 Bn in 2016 Key Market Players : Roche : $7.5 Bn 52.45% Siemens : $5.2 Bn Danaher : $4.4 Bn Abbott : $4.3 Bn 16.67% 11.55%

Roche Siemens Danaher Abbott Others 9.78% 9.55% 36 Global CDx Market $22 Bn of companion drugs sales Key Market Players : Roche Laboratories Novartis Pfizer. Sales Revenue 4.00% Other Diagnostics

96.00% Companion Diagnostics 62% of the companion drugs market. $1.8Bn of CDx sales US market : 40% of global CDx market. Annual Growth 21.6% 37 New Pharmaceutical Landscape Emergence of a Life Science Majors (Roche, Abbott) : Roche : Integrate the 3 key of the CDx-drug Market ( Drug development, Diagnostics, Devices). Business Model : In-house development. Co-development Drug-CDx. 4 Business Models :

In-house Dx division Dx Business Unit Pharma Dx development group Life sciences research division. Strong strategic Partnerships : Manage complex development projects. New strategic partnerships : Pharma-Academic R&D (focused on biomarker discovery). 38 Perspectives Short Term < 3 years Medium Term 3-10 years Long Term > 10 years

Oncology Diabetes Metabolic Solid and blood cancer Thrombosis Stroke Depression Autoimmunity Inflammation Chronic Pain Dementia 39 l

CDx Perspectives 40 CDx development Hurdles Financial and economic risk of co-development drugCD : early development failure. The co-development drug-CD process is complex. Small targeted market. Impact on the Pharma business model. Global regulatory landscape : Heterogeneous and continually changing. Heterogeneous HealthCare/Reimbursement System in the EU. 41 Signaling Pathways Normal pathways Abnormalities MODULATION

INHIBITION JAK, Syk Bcr-Abl, EGFR Inflammatio n, Autoimmuni ty Companion Diagnostics Cancer 42 Rheumatoid understanding of ArthritisGreater inflammatory signalling cascades JAK Tofacitin

ib Sy k Fostamati nib 43 Rheumatoid Arthritis Context Painful, systemic, chronic inflammatory disease damage to the joints, connective tissues, muscles, tendons Inflammatory cytokines (IL, IFN, GF) activation of Janus Kinases (JAKs) JAK 1 & 3 expression in the synovium of patients with RA First to be tested

jakinib Tofacitinib 44 Tofacitinib Mechanism of action JAK1 & JAK3 potent antagonist JAK3 c family cytokines JAK1 c cytokines, IF, IL-6 inhibits innate immune responses : macrophages, proinflammatory cytokines, potent effects on lymphocytes inflammation 45 Tofacitinib Approval First oral Kinase Inhibitor approved for the treatment of rheumatoid arthritis : FDA approval in 2012 : treatment of adult patients with moderately to

severely active rheumatoid arthritis who have had an inadequate response or intolerance to methotrexate Studies to evaluate efficacy in other inflammatory immune-mediated disease : - Phase III : Psoriasis , Ulcerative colitis - Phase II : Crohns disease - Phase I : Juvenile Idiopathic Arthrosis 46 Tofacitini b Superiority VS placebo, non-inferiority VS adalimumab Oral agents many patients do not respond to biologic therapies Clinical trials in psoriasis, ulcerative colitis, Crohns disease potentially attractive Blockage of cytokines involved in the pathogenosis of systemic lupus erythematosus could reprensent another setting

FDA warning box for serious infections and malignancies FDA approval with a Risk Evaluation and Mitigation Strategy (REMS) Long-term, large-scale and high-quality postmarketing research is necessary to further verify the conclusion Not approved by the EMA : concerns about 47 safety profile : Other JAK inhibitors in RA Baricitinib Ruxolitinib JAK 1 & 2 inhibitor JAK 1 & 2 inhibitor

Phase III clinical trials RA FDA approval myelofibrosis polycythaemia vera Phase II diabetic nephropathy psoriasis Phase II clinical trials RA, psoriasis, essential thrombocythaemia, acute leukaemia, lymphoma, multiple myeloma, prostate cancer, breast cancer 48 Rheumatoid understanding of ArthritisGreater inflammatory signalling cascades JAK

Tofacitin ib Sy k Fostamati nib 49 Fostamatinib : a promising Syk inhibitor Syk important mediator of immunoreceptor (Fc) signalling in macrophages, neutrophils, mast cells, and B cells also present in the synovium of patients with Rheumatoid Arthritis

critical roles in the mechanisms of immunity and inflammation 50 Fostamatinib development Phase II trials : 2010 : Phase III trials : fostamatinib therapy was generally well tolerated Partnership with AstraZeneca (potential as a first-in-class oral alternative to current injectable RA drugs)

OSKIRA 1 : VS placebo in patients responding inadequately to Methotrexate => one of the two primary endpoints reached OSKIRA 2 : VS placebo in patients responding inadequately to DMARDs* => significant improvements OSKIRA 3 : VS placebo in patients responding inadequately to TNF antagonist therapy => significant improvements in one group of two OSKIRA 4 : VS placebo (superiority) : significant improvements in one group of tw VS adalimumab (non inferiority) : failed to match the efficacy of adalimumab * DMARDs: Disease Modifying Anti-Rheumatoid Drugs 51 Fostamatinib : an end in failure ? Failure in clinical trials AstraZeneca handing rights for the drug back to Rigel Rigel has now given up completely on the development of fostamatinib for the treatment of RA insufficient efficacy findings

competitive landscape New opportunities Phase II clinical study in Immune Thrombocytopenic Purpura (ITP) showed positive results in patients Phase III study in the first half of 2014 Phase II study for Immunoglobulin A Nephropathy (IgAN) in spring 2014 52 New Indications TKI Tofacitinib Baricitinib (Ph III) Rheumatoid Arthritis JAK Idiopathic

Pulmonar y Fibrosis PDGF, VEGF, FGF Immune Thrombocytope nic Purpura Syk Fostamatinib (Ph III) JAK Tofacitinib (Ph III) Psoriasis Nintedanib (Ph III)

53 New indications TKI : far from being a success Waiting for Very first Success clinical steps results Rheumatoi d Arthritis Idiopathic Pulmonary Fibrosis Psoriasis Immune Thrombocytopenic Purpura Alzheimer s Disease Diabetic

Nephropathy Lupus Systematic Erythematosu Juvenile s Idiopat hic Arthrosi Glauco ma s Allergic Allergic Asthma Rhiniti 54 Conclusion Birth of targeted therapies : Imatinib -> TKI development Targeting more precisely the mutations : Companion Diagnostics Cancer and Inflammation : Interlinked pathways Cance r

Inflammatio n 55 References Zhang, J., Yang, P. L., & Gray, N. S. (2009). Targeting cancer with small molecule kinase inhibitors. Nature reviews. Cancer, 9(1), 2839. Liu, Y., & Gray, N. S. (2006). Rational design of inhibitors that bind to inactive kinase conformations. Nature chem bio, 2(7), 35864. Lamontanara, A. J., Gencer, E. B., Kuzyk, O., & Hantschel, O. (2013). Bioch et Biophys Acta. Mechanisms of resistance to BCR-ABL and other kinase inhibitors. BBA - Proteins and Proteomics, 1834(7), 14491459. Tsai, C.-J., & Nussinov, R. (2013). The molecular basis of targeting protein kinases in cancer therapeutics. Seminars in Cancer Biology, 23(4), 23542. Boutayeb, S., Zakkouri, F. Z. et al. (2012). [Protein tyrosine kinase inhibitors in cancer therapy]. Pathologie-Biologie, 60(4), 22933 Coiteux, V. (2012). Inhibiteurs de tyrosine-kinase de 2e gnration et associations: perspectives. Oncologie, 14(10-11), 601605. Fava, C., Kantarjian, H., & Cortes, J. (2012). Molecular resistance: an early indicator for treatment change? Clin Lymph, Myel & Leukemia, 12(2), 7987 Lemmon, M. a, & Schlessinger, J. (2010). Cell signaling by receptor tyrosine kinases. Cell, 141(7), 111734. Rosenzweig, S. a. (2012). Acquired resistance to drugs targeting receptor tyrosine kinases. Biochemical Pharmacology, 83(8), 10418 Sherbenou, D. W., & Druker, B. J. (2007). Review series Applying the discovery of the Philadelphia chromosome, 117(8), 20672074 Arora, A., & Scholar, E. M. (2005). Role of Tyrosine Kinase Inhibitors in Cancer Therapy, 315(3), 971979. Biarc, J., Chalkley, R. J. et al. (2011). Receptor tyrosine kinase signaling--a proteomic perspective. Advances in Enzyme Regulation, 51(1), 293305. Danilov, A. V. (2013). Targeted therapy in chronic lymphocytic leukemia: past, present, and future. Clinical Therapeutics, 35(9), 125870. Etienne, G. (2012). Traitement par inhibiteurs de tyrosine-kinase de 2e gnration chez les patients en chec de limatinib. Oncologie, 14(10-11), 589 595. Fabbro, D. et al. (2002). Protein kinases as targets for anticancer agents: from inhibitors to useful drugs. Pharmacology & Therapeutics, 93(2-3), 7998 Grant, S. K. (2009). Therapeutic protein kinase inhibitors. Cellular and Molecular Life Sciences : CMLS, 66(7), Hunter, T. (2007). Review series Treatment for chronic myelogenous leukemia : the long road to imatinib, 117(8).

Noble, M. E. M., Endicott, J. a, & Johnson, L. N. (2004). Protein kinase inhibitors: insights into drug design from structure. Science, 303(5665), 18005. OHare, T. et al.(2012). Pushing the limits of targeted therapy in chronic myeloid leukaemia. Nature Reviews. Cancer, 12(8), 51326. Shchemelinin, I., efc, L., & Neas, E. (2006). Protein Kinase Inhibitors, 148, 137148. Stegmeier, F. et al. (2010). Targeted cancer therapies in the twenty-first century: lessons from imatinib. Clin Pharmacol and Therap, 87(5), 54352. Turner, J. G., Dawson, J., & Sullivan (2012). Nuclear export of proteins and drug resistance in cancer. Biochemical Pharmacology, 83(8), 102132. 56 References - Drug development to overcome resistance to EGFR inhibitors in lung and colorectal cancer Rodrigo Dienstmanna,*, Sara De Dossob, Enriqueta Felipa, Josep Taberneroa Molecular Oncology 6 (2012) 15e2 6 - Cellular Targets of Gefitinib Dirk Brehmer,1 Zoltan Greff,2 Klaus Godl,1 Stephanie Blencke,1 Alexander Kurtenbach,1 Martina Weber,1 Stefan Muller,1 Bert Klebl,1 Matt Cotten,1 Gyorgy Keri,2,3 Josef Wissing,1 and Henrik Daub1Cancer Res 2005; 65(2): 379-82. - Cobas EGFR mutation Test. - CHUGAI PHARMACEUTICAL CO., LTD. Lifecycle Leader (Tarceva) Oncology Disease Area Dept. Strategic Marketing Unit Koh Sato 2005.12.16 - Anne De Bock Portfolio Leader, Oncology/Infection European Regulatory Affairs AstraZeneca - Dabrafenib RCP - EMA 57 References http://www.ariis.fr/wp-content/uploads/2011/03/biomarqueurs-etude-version-c omplete-130-slides.pdf

http://www.ddw-online.com/personalised-medicine/p92845-overview-of-compa nion-diagnostics-in-the-pharmaceutical-industry.spring-10.html http://www.fiercemedicaldevices.com/story/roche-bets-big-companion-diagnosti cs/2012-09-05 http://www.medscape.com/viewarticle/804156 http://www.reportlinker.com/p01361266/Companion-Diagnostics-Market.html# utm_source=prnewswire&utm_medium=pr&utm_campaign=Diagnostics http://www.fdanews.com/articles/149287-ema-to-wait-for-more-experience-bef ore-issuing-guidance-on-companion-diagnostics http://www.ema.europa.eu/ema/ http://www.fda.gov/ 58 References Back to the future: oral targeted therapy for RA and other autoimmune diseases, OShea, J. J. et al. Nat. Rev. Rheumatol. 9, 173182 (2013); published online 19 February 2013; doi:10.1038/nrrheum.2013.7 Tofacitinib for acute rheumatoid arthritis patients who have had an inadequate response to disease-modifying antirheumatic drug (DMARD): a systematic review and meta-analysis, Xingming Zhang et al, Clin Rheumatol 2014 DOI 10.1007/s10067-013-2452-7

Tofacitinib for acute rheumatoid arthritis patients who have had an inadequate response to disease-modifying antirheumatic drug (DMARD): a systematic review and meta-analysis, Xingming Zhang & Fuxiang Liang & Xiaoxue Yin & Xiaojuan Xiao & Peiyu Shi & Dang Wei & Liang Yao & Qi Wang & Yaolong Chen, Clin Rheumatol (2014) 33:165173 DOI 10.1007/s10067-013-2452-7 http://www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/ucm327152.htm http://www.ema.europa.eu/ema/index.jsp?curl=pages/medicines/human/medicines/002542/smops/Negative/human_smop_000501.jsp&mid=WC0b01ac0580 01d127 An Oral Spleen Tyrosine Kinase (Syk) Inhibitor for Rheumatoid Arthritis, Weinblatt ME, Kavanaugh A, Genovese MC, Musser TK, Grossbard EB, Magilavy DB., N Engl J Med. 2010 Sep 30;363(14):1303-12. doi: 10.1056/NEJMoa1000500. Epub 2010 Sep 22. A1.72 Baricitinib, an oral janus kinase inhibitor, in the treatment of rheumatoid arthritis: safety and efficacy in an open-label, long-term extension study1, Taylor P, Genovese M, Keystone E, Schlichting D, Beattie S, Macias W. Ann Rheum Dis. 2014 Mar 1;73 Suppl 1:A31. doi: 10.1136/annrheumdis-2013-205124.71.

Reducing lung function decline in patientswith idiopathic pulmonary fibrosis:potential of nintedanib, Hannah V Woodcock, Philip L Molyneaux, Toby M Maher, Drug Design, Development and Therapy 2013:7 503510 Inhibition of Src kinase blocks high glucose-induced EGFR transactivation and collagen synthesis in mesangial cells and prevents diabetic nephropathy in mice. Taniguchi K, Xia L, Goldberg HJ, Lee KW et al, Diabetes. 2013 Nov;62(11):3874-86. doi: 10.2337/db12-1010. Epub 2013 Aug 13. Inhibition of Src kinase activity attenuates amyloid associated microgliosis in a murine model of Alzheimer's disease, Dhawan G, Combs CK, J Neuroinflammation. 2012 Jul 2;9:117. doi: 10.1186/1742-2094-9-117. Novel ocular antihypertensive compounds in clinical trials, June Chen,1 Stephen A Runyan,1 and Michael R Robinson2, Clin Ophthalmol. 2011; 5: 667677. Inhibitors of switch kinase 'spleen tyrosine kinase' in inflammation and immune-mediated disorders: a review, Kaur M, Singh M, Silakari O, Eur J Med Chem. 2013 Sep;67:434-46. doi: 10.1016/j.ejmech.2013.04.070. Epub 2013 Jul 12. 59 Back up

60 Back up 61 Back up Essais cliniques de phase III randomiss : 717 patients ayant reu pralablement du Methotrexate(3), rpartis en 4 groupes qui ont reu respectivement : - le Tofacitinib 5mg - le Tofacitinib 10mg - lAdalimumab (2) - un placebo En termes defficacit, le tofacitinib dmontre une supriorit significative par rapport au placebo et une non-infriorit par rapport ladalimumab.

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