JORNADAS 2011 DE ACTUALIZACIÓN EN ATENCIÓN FARMACÉUTICA AL PACIENTE CON PATOLOGÍAS VÍRICAS. SOCIEDAD ESPAÑOLA DE FARMACIA HOSPITALARIA Madrid, 13 de mayo.

Presentación del tema: "JORNADAS 2011 DE ACTUALIZACIÓN EN ATENCIÓN FARMACÉUTICA AL PACIENTE CON PATOLOGÍAS VÍRICAS. SOCIEDAD ESPAÑOLA DE FARMACIA HOSPITALARIA Madrid, 13 de mayo."— Transcripción de la presentación:

1 JORNADAS 2011 DE ACTUALIZACIÓN EN ATENCIÓN FARMACÉUTICA AL PACIENTE CON PATOLOGÍAS VÍRICAS. SOCIEDAD ESPAÑOLA DE FARMACIA HOSPITALARIA Madrid, 13 de mayo de 2011 JORNADAS 2011 DE ACTUALIZACIÓN EN ATENCIÓN FARMACÉUTICA AL PACIENTE CON PATOLOGÍAS VÍRICAS. SOCIEDAD ESPAÑOLA DE FARMACIA HOSPITALARIA Madrid, 13 de mayo de 2011 Actualización en nuevas terapias para la hepatitis C Actualización en nuevas terapias para la hepatitis C Javier García-Samaniego Unidad de Hepatología Hospital Carlos III. CIBERehd Madrid Javier García-Samaniego Unidad de Hepatología Hospital Carlos III. CIBERehd Madrid

2 Evolución del tratamiento de la hepatitis C Descubrimiento del genoma del VHC La combinación IFN + RBV mejora la respuesta Peg-IFN alfa más RBV terapia de referencia Tratamiento con IFN alfa 3 veces/sem durante 24 ó 48 sem. Resultados pobres Desarrollo de Peg-IFN en monoterapia 20111989 Terapia basada en la respuesta viral Desarrollo de nuevos antivirales

3 Evolución de la tasa de respuesta 0 10 20 30 40 50 60 70 100 90 80 RVS (%) 66% 19% 41% 39% 6% 2005 7 1998 48 sem 2 1998 1,2 2000 3 1997 24 s 1 1. McHutchison J, et al. N Engl J Med 1998; 339: 1485 2. Poynard T, et al. Lancet 1998; 352: 1426 3. Zeuzem S, et al. N Engl J Med 2000; 343: 1666 4. Lindsay K, et al. Hepatology 2001; 34: 395 5. Manns M, et al. Lancet 2001; 358: 958 6. Fried M, et al. N Engl J Med 2002; 347: 975 7. Zeuzem S, et al. J Hepatol 2005; 43: 250 54% 2001 5 Todos los genotipos 23% 56% 2001 4 2002 6 Peg-IFN  -2b (12KD) + RBV Peg-IFN  -2 a (48KD) + RBV Peg-IFN  -2b (12KD) Peg-IFN  -2a IFN  + RBV IFN 

4 Respuesta virológica: definiciones Respuesta fin de tratamiento (RFT) Niveles indetectables de ARN-VHC al final del tratamiento (24 semanas para genotipo 2/3 del VHC, 48 semanas para genotipo 1 del VHC) Respuesta virológica sostenida (RVS) Niveles indetectables de ARN-VHC al final del seguimiento (24 semanas después de terminado el tratamiento) No respuesta Disminución de ARN-VHC < 2 logs en el tercer mes y/o ARN- VHC (+) en el 6º mes de tratamiento Recaída ARN-VHC negativo al final del tratamiento, pero de nuevo positivo durante el período de seguimiento

5 Definiciones de respuesta viral rápida y temprana RespuestaDefinición RVR*RNA VHC negativo (<15 IU/mL) en la semana 4 RVT** – Completa (RVTc) No RVR pero RNA VHC negativo (<15 IU/mL) en la semana 12 – Parcial (RVTp) No RVR, RNA VHC positivo en la semana 12 pero con descenso  2 log 10 No-RVTDescenso RNA VHC <2 log 10 en la semana 12 * RVR = respuesta viral rápida ** RVT = respuesta viral temprana

6 HCV Treatment: A Lexicon of Acronyms DAAs: direct antiviral agents IL28B: IL28B polymorphism (rs12979860) genotype test NA: nucleoside analog polymerase inhibitors NNI: nonnucleoside polymerase inhibitors PI: protease inhibitors MV: minority variants UDPS: ultradeep pyrosequencing vBT: viral breakthrough RGT: response-guided therapy eRVR: extended rapid virological response DRM: drug-resistant mutations

7 Genetics Predict Response: IL28B Genotype C/C Confers Higher SVR Rates SVR (%) Gt 1Gt 2/3Gt 4 T/TT/CC/CT/CT/CT/TC/CT/TC/C 29791047481145122 n = C/C* T/C* T/T* *Genotype of rs12979860 on chromosome 19 (Ge D et al. Nature. 2009;461:399-401). Strättermayer A et al. EASL 2010.

8 Hepatitis C: escenario en 2011 Aprobación de los primeros DAAs: telaprevir y boceprevir Amplia utilización de estos medicamentos en la UE y EE UU Incremento de la RVS hasta el 75% en pacientes naïves G1 Problemas potenciales con el uso de estos nuevos fármacos: –Selección adecuada de los pacientes –Control y monitorización inapropiados –Manejo de los efectos adversos –Resistencias

9 Tratamiento de la hepatitis C Tratamiento actual (PEG-IFN + Riba) Nuevos tratamientos –Standard of care en 2012 Naïves No respondedores –Nuevos antivirales Nuevos IFNs Inhibidores de la proteasa Inhibidores de la polimerasa Combinaciones “libres” de IFN

10 Select DAAs in Clinical Development Phase IPhase IIPhase III Protease InhibitorsABT-450 ACH-1625 GS 9451 MK-5172 VX-985 BMS-650032 CTS-1027 Danoprevir GS 9256 IDX320 Vaniprevir BI 201335 Boceprevir Telaprevir TMC435 Nonnucleoside polymerase inhibitors BI 207127 IDX375 ABT-333 ABT-072 ANA598 BMS-791325 Filibuvir Tegobuvir VX-759 VX-222 Nucleoside polymerase inhibitors IDX184 PSI-7977 RG7128-Mericitabine NS5A inhibitorsA-831 PPI-461 BMS-790052 BMS-824393 CF102

11 Anti-HCV drugs in development

12 New treatments in AASLD 2010 & EASL 2011 36 Drugs 15 Protease Inhibitors 10 Polymerase Inhibitors 9 Other 240 Abstracts

13 Antiviral Activity of DAA Vary Among and Within Classes NS3 protease inhibitorsNS5A inhibitors BCP, boceprevir; TVP, telaprevir. *Clinical development stopped. Sarrazin C, Zeuzem S. Gastroenterology. 2010;138:447-62. BOC ITMN191 BI-201335 TVR TMC435 MK7009 Narlaprevir * BMS-650032 PHX1766 BI 207 127 Filibuvir VCH-222 ANA598 GS9190 ABT-333 VCH-759 VCH-916 BMS-790052 R7128 PSI-7851 IDX184 non-nucleoside inhibitors Median or Mean HCV RNA Decline (log IU/mL) nucleos/tide inhibitors 3-14 day monotherapy in genotype 1 patients

14 . Type of drugsGenetic Barrier/ AV EfficacyOther Protease InhibitorsLow/ HighGenotype 1 Polymerase Inhibitors Nucleoside Analogs High / Low-Medium Few in develop All genotypes Polymerase Inhibitors Non Nucleoside Low/ MediumGenotype 1 Ciclofilin InhibitorsNo/ LowAll? NS5A InhibitorsHigh/Medium-HighAll? Efficacy & Genetic Barrier

15 Telaprevir o Boceprevir Ribavirina PegIFN-α Standard of care en 2012

16 Boceprevir and Telaprevir Boceprevir, a potent inhibitor of HCV NS3/4A protease Telaprevir, a potent inhibitor of HCV NS3/4A protease Both being tested in combination with standard-of- care pegIFN alfa-2/RBV in phase III studies in chronic HCV infection Boceprevir –SPRINT-2: naive GT1 patients –RESPOND-2: nonresponder GT1 patients (partial responders and relapsers) Telaprevir –ADVANCE: naive GT1 patients –ILLUMINATE: response- guided therapy in naive GT1 paitents –REALIZE: nonresponder GT1 patients (null responders, partial responders, relapsers)

17 N = 350 Telaprevir 750 mg q8h + Peg-IFN  2a + RBV Follow-up Telaprevir Phase 3 Trial: ADVANCE – GT1 Naïve Telaprevir 750 mg q8h + Peg-IFN  2a + RBV Peg-IFN  2a + RBV Peg-IFN  2a + RBV Follow-up Peg-IFN  2a + RBV Follow-up no eRVR Peg-IFN  2a + RBV Follow-up Peg-IFN  2a + RBV Follow-up no eRVR *eRVR = undetectable HCV RNA at week 4 and week 12 Telaprevir patients who achieve extended EVR (i.e., RVR + EVR) stop treatment after 24 weeks. 8 Weeks on therapy 1212 2424 3636 4848 6060 7272 0

18 ADVANCE: SVR rates SVR 75 69 44 P<0.0001 271/363250/364158/361n/N = Percent of patients with SVR 0 10 20 30 40 50 60 70 80 90 100 T12PRT8PRPR Jacobson I, et al. AASLD 2010: Abstract 211.

19 Jacobson IM, et al. AASLD 2010. Abstract 211. Outcome, %8-Wk TVR/PR + 16/40-Wk PR (n = 364) 12-Wk TVR/PR + 12/36-Wk PR (n = 363) 48-Wk PR (n = 361) Discontinuation of TVR/placebo due to rash 7111 Discontinuation of all drugs due to AEs874  Anemia3.30.80.6 Telaprevir: Discontinuations Discontinuations due to adverse events in Phase III ADVANCE:

20 N = 500 Telaprevir 750 mg q8h + Peg-IFN  2a + RBV Telaprevir Ph3 Trial: ILLUMINATE – GT1 Naïve Peg-IFN  2a + RBV eRVR Follow-up Peg-IFN  2a + RBV Follow-up Peg-IFN  2a + RBV No eRVR Weeks on therapy 1212 2424 3636 4848 6060 7272 0 * eRVR = undetectable HCV RNA at week 4 and week 12 Non-inferiority trial requested by the FDA to specifically demonstrate that treating GT1 Naïve patients for 24 weeks was not a disadvantage compared to treating them for 48 weeks

21 ILLUMINATE: Undetectable HCV RNA over time – ITT Population 389/540352/540 n/N= RVReRVR Patients with Undetectable HCV RNA levels (%) 72 65 469/540 EOT 87 388/540 SVR 72 Sherman KE, et al. AASLD 2010: Abstract LB-2.

22 ILLUMINATE SVR Rates - Noninferiority of 24-week Regimen  4.5% (2-sided 95% CI = -2.1% to +11.1%) Patients with SVR (%) T12PR24T12PR48 149/162140/160n/N= 92 88 Sherman KE, et al. AASLD, 2010: Abstract LB-2.

23 Resumen de los estudios Advance 1 e Illuminate 2 (Telaprevir-Fase III pacientes naïve Gt 1) El tratamiento “guiado” por la respuesta viral (RGT) durante 24 semanas es igual de eficaz que el de 48 semanas de duración en pacientes con eRVR (semanas 4-12). La RGT es posible en 2/3 de los pacientes La duración más corta del tratamiento facilita el cumplimiento y la tolerancia, y reduce los efectos secundarios. La duración óptima del tratamiento con TVR es de12 semanas 1. Jacobson IM, McHutchison JG,Dusheiko GM, et al. AASLD 2010: Abstract 211. 2. Sherman KE, Flamm SL, Afdhal NH, et al. AASLD 2010:LB-2.

24 REALIZE Study Design (N=662)* 48 4 16012 8 Weeks 24 72 T12/PR48 Peg-IFN + RBV TVR + Peg-IFN + RBV Pbo + Peg-IFN + RBV n=266 Follow-up SVR assessment TVR+ Peg-IFN + RBV Peg-IFN + RBV T12(DS)/ PR48 n=264 Follow-up Pbo + Peg-IFN + RBV *Randomization stratified by viral load and prior response; stopping rules applied for TVR (Weeks 4, 6, and 8) and Peg-IFN/RBV (Weeks 12, 24, and 36) Peg-IFN = 180μg/week; RBV 1000–1200mg/day; TVR = 750mg every 8 hours ClinicalTrials.gov identifier: NCT00703118 Pbo = placebo; DS = delayed start Pbo/PR48 ( control ) Pbo + Peg-IFN + RBV Peg-IFN + RBV n=132 Follow-up Zeuzem, et al. EASL 2011

25 PR48 Patients with SVR (%) SVR by Treatment Arms (ITT Analysis) 100 80 60 40 20 0 TVR12/PR48 (pooled TVR arms) Zeuzem EASL 2011 Overall (n= 662) 86% P < 0.01 Relapsers (n=354) 24% 65% 17% Partial Reponders (n=124) 57% 15% P < 0.01 Null Reponders (n= 184) 31% 5% P < 0.01

26 −5 −4 −3 −2 −1 0 Day 15 HCV-RNA Log Reduction Gt 2Gt 3 −6 TP/RT/P/R Telaprevir in Genotype non-1 (C209) P, Peg-IFNα-2a 180 μg/wk; R, ribavirin 800 mg/d; T, telaprevir q8h. Foster G et al. EASL 2010. −5.5 −3.7 −4.83 −4.85 −4.72 −0.54

27 Week 4 Week 48 PR + Placebo Follow-up PR lead-in PR + Boceprevir Week 28 Week 72 TW 8-24 HCV-RNA Undetectable TW 8-24 HCV-RNA Detectable PR + Placebo Follow-up SPRINT 2: Study Design Control 48 P/R N = 363 BOC RGT N = 368 Peginterferon (P) administered subcutaneously at 1.5 μg/kg once weekly, plus ribavirin (R) using weight based dosing of 600-1400 mg/day in a divided daily dose. BOC 800 mg 3 times daily 1 Poordad F, et al. N Engl J Med 2011; 364: 1195-206. PR + Boceprevir Follow-up BOC/ PR48 N = 366 PR lead-in PR lead-in

28 SPRINT 2: SVR and Relapse Rates (ITT) p < 0.0001 Non-Black Patients p = 0.044 p =0.004 Black Patients SVR* Relapse Rate 12 52 22 52 29 55 2/14 3/25 6 35 125 311 211 316 213 311 37 162 21/232 18/230 *SVR was defined as undetectable HCV RNA at the end of the follow-up period. The 12-week post-treatment HCV RNA level was used if the 24-week post- treatment level was missing (as specified in the protocol). A sensitivity analysis was performed counting only patients with undetectable HCV RNA documented at 24 weeks post-treatment and the SVR rates for Arms 1, 2 and 3 in Cohort 1 were 39% (122/311), 66% (207/316) and 68% (210/311), respectively and in Cohort 2 were 21% (11/52), 42% (22/52) and 51% (28/55), respectively. Poordad et al. NEJM 2011

29 Boceprevir: Adverse Events and Discontinuations 1. Poordad F, et al. NEJM 2011. Anemia and dysgeusia reported more frequently in BOC arms vs control in SPRINT-2 [1-2] Outcome4-Wk PR + Response- Guided BOC/PR (n = 368) 4-Wk PR + 44-Wk BOC/PR (n = 366) 48-Wk PR (n = 363) Adverse event, %  Anemia [1] 49 29 EPO use414621  Dysgeusia [2] 374318 Discontinuations due to adverse events, % [1] 1216  Anemia [1] 221

30 Week 4 Week 48 PR + Placebo Follow-up PR lead-in PR + Boceprevir PR lead-in Week 36 Week 72 TW 8 HCV-RNA Undetectable TW 8 HCV-RNA Detectable/ TW 12 Undetectable PR + placebo Follow-up RESPOND-2 Study Arms and Dosing Regimen Control 48 P/R N = 80 BOC RGT N = 162 Peginterferon ( P) administered subcutaneously at 1.5 μg/kg once weekly, plus Ribavirin (R) using weight based dosing of 600-1400 mg/day in a divided daily dose Boceprevir dose of 800 mg thrice daily Bacon et al. N Engl J Med 2011; 364: 1217-17. PR + Boceprevir PR lead-in Follow-up BOC/ PR48 N = 161 HCV-RNA measured by the Cobas TaqMan assay (Roche). Patients with detectable HCV-RNA (LLD=9.3 IU/mL) at week 12 were considered treatment failures. Week 12 futility

31 8 25 95 162 RESPOND-2 SVR and Relapse Rates Intention to treat population p < 0.0001 SVR Relapse Rate 17 80 107 161 17 111 14 121 12-week HCV RNA level used if 24-week post-treatment level was missing. A sensitivity analysis where missing data was considered as non-responder, SVR rates for Arms 1, 2 and 3 were 21% (17/80), 58% (94/162) and 66% (106/161), respectively. SVR rates in BOC RGT and BOC/PR48 arm not statistically different (OR, 1.4; 95% CI [0.9, 2.2]) % of Patients PR 48 BOC RGT BOC/PR48

32 Las pautas de tratamiento con BOC requieren un periodo de 4 semanas de lead-in (LI) con PEGIFN+RBV La RGT (viremia C indetectable en las semanas 8 y 24) es posible en la mitad de los pacientes naïve Se requiere un mínimo de 24 semanas de BOC para la respuesta viral óptima en pacientes naïve Se requiere LI + un periodo mínimo de 32 semanas de tratamiento con BOC/PEGIFN/RBV para los pacientes con fallo a un tratamiento previo con PEGIFN/RBV 1.Poordad F, et al. NEJM 2011; 364: 1195-206. 2.Bacon B et al. NEJM 2011; 364: 1207-17 Resumen de los estudios Sprint-2 1 y Respond-2 2

33 Similarities and Differences in Phase III Studies of TVR and BOC in GT1 Naive Pts ParameterTVR [1] BOC [2] PR lead-in?NoYes: 4 wks PegIFN alfa formulation2a2b PI dosing requirements TID; administer with fatty meal TID Duration of PI triple therapy 8-12 wks followed by 12-40 wks PR 24-44 wks after 4 wks PR lead-in Qualification for shortened therapy (response guided) Undetectable HCV RNA until Wk 12 of triple therapy Undetectable HCV RNA until Wk 24 of triple therapy Qualified for shortened therapy, %58 (24 wks)44 (28 wks) SVR, %69-7563-66 Relapse, %99 Adverse events more frequent in PI arms Rash, anemia, pruritus, nausea Anemia, dysgeusia Jacobson IM, et al. AASLD 2010. Abstract 211. 2. Poordad F, et al. N Engl J Med 2011; 364: 1195-206.

34 Tratamiento de la hepatitis C Tratamiento actual (PEG-IFN + Riba) Nuevos tratamientos (DAA) –Standard of care en 2012 Naïves No respondedores –Nuevos antivirales Nuevos IFNs Inhibidores de la proteasa Inhibidores de la polimerasa Combinaciones “libres” de IFN

35 Interferons in Development  Albinterferon alfa-2b (albIFN; HGS - Novartis): Every-2-week injections (phase 3 completed; clinical development stopped in EU and USA) Every-4-week injections (phase 2; clinical development stopped in EU and USA))  Locteron (Biolex, Octoplus): phase 2b  Omega IFN (Intarcia): phase 2  Peginterferon Lambda (IL-29; ZymoGenetics/BMS): phase 2 Type III IFN binding to unique receptor

36 Second-Generation Protease Inhibitors -TMC435: Tibotec -Danoprevir: ITM/Roche - BI-201335: Boehringer Ingelheim - Vaniprevir: Merck

37 Activity of Other Protease Inhibitors Combined With PR in Phase II Studies Protease InhibitorTrial, PhasePatients Meeting Efficacy Measure, % (SOC) BI 201335-NR [1] SILEN-C2, IIeEVR: 42-47 (NO) SVR12: 32-47 (NO) Danoprevir-NR [2] IIRVR: 37*-87** (NO) cEVR: 50*-77** (NO) TMC435-NR [3] ASPIRE, IIbRVR: 40-68-93 (NO) eEVR: 75-90-97 (NO) Vaniprevir (MK-7009) [4] Protocol 007, IIaRVR: 67-84 (5)* cEVR: 74-85 (47)* SVR: 61-84 (63). 11. Sulkowski M, et al. EASL 2011. 2. Rouzier, et al. EASL 2011. *G1a. **G1b 3. Zeuzem,et al. EASL 2011. Abstract LB.. 4. Manns MP, et al. AASLD 2010. Abstract 82. *Significant

38 Cross-resistance of NS3 Protease Inhibitors V36A/M R155K/T/Q/P V55A A156/V/T V170A/T/L D168A/V/T/H T54S/A *Mutations associated with in vitro resistance but not described in patients. Susser S et al. Hepatology. 2009;50:1709-18; Sarrazin C, Zeuzem S. Gastroenterology. 2010;138:447-62. A156S Q80R/K * * * * * Telaprevir Narlaprevir ITMN-191 TMC 435 BI 201335 MK-7009 Boceprevir Linear Macrocyclic 38

39 What Do We Currently Know About Resistance to Protease Inhibitors? Minor resistant populations preexist at baseline in virtually all HCV- infected patients [1] Resistant variants rapidly selected with monotherapy [2] –R155K requires 1 nucleotide change in GT1a but 2 nucleotide changes in GT1b; virtually all resistance has been seen in GT1a [3] Emergence of resistance reduced when protease inhibitor combined with potent antivirals without cross-resistance, such as pegIFN, or pegIFN plus RBV [3,4] Failure to achieve SVR during triple-combination therapy associated with selection of resistant HCV variants [3] Boceprevir mutations can persist at least 3 yrs after exposure. However, telaprevir resistance mutations undetectable 2 yrs after treatment discontinuation in 89% of patients in EXTEND study [4] 1. Bartenschlager R, et al. J Gen Virol. 2000;81:1631-1648. 2. Ozeki I. J Hepatol. 2009;50:S350. 3. McHutchison JG, et al. N Engl J Med. 2009;360:1827-1838. 4. Zeuzem S AASLD 2010.

40 Polymerase Inhibitors: Main Characteristics SummaryAdvantagesDisadvantages Nucleoside Inhibitors (Mericitabine; IDX 184) Analogs of natural substrates Binds active site of NS5B, terminates viral RNA chain generation High genetic barrier for resistance Equally active in all genotypes Relatively lower antiviral efficacy Few in pipeline Non- nucleoside Inhibitors (GS 9190; BI 207127; filibuvir) Binds to various allosteric sites, inducing conformational changes in polymerase Multiple target sites identified Low-to-medium antiviral efficacy Low genetic barrier HCV genotype/subtype dependent Efficacy influenced by polymorphisms? Sarrazin C, Zeuzem S. Gastroenterology. 2010;138:447-62.

41 JUMP-C – Mericitabine + PEGASYS ® + RBV in Naïve G1/4 Patients Randomization Study Weeks 48 0 CHC, naïve, G1/4, n=166 24 Mericitabine 1000 mg bid plus PEGASYS ® plus RBV PEGASYS ® plus RBV * eRVR (HCV RNA <15 IU/mL from weeks 4-22) STOP Pts with eRVR * Pts without eRVR * Pockros et al, EASL 2011, late-breaker oral

42 51/81 12/85 49/8111/8574/81 53/85 Pockros et al, EASL 2011, late-breaker oral JUMP-C – Virological Response – On Treatment Interim Results

43 Other strategies: PI + Polymerase Inhibitor. Potent Antiviral Activity in HCV G1 Interferon-Naïve and Null Responders with a BID Regimen of RG7128 + Danoprevir: INFORM-1 50 25 0 10 20 30 40 50 60 70 80 90 100 <LLOQ<LLOD 88 63 Nulls Naïves RG7128 1000 mg BID + RG7227 (Danoprevir) 900 mg BID Days 135791113 Limit of Detection Median Log 10 HCV RNA (IU/mL) 1 2 3 4 5 6 7 TF - Nulls Naïves LLOD: Lower limit of detection LLOQ: Lower limit of quantification Gane EJ, et al. Lancet 2010. EOT HCV RNA < LLOQ or LLOD (%)

44 Combination Therapies with 2 or More DAAs Presented at AASLD 2010 DRUG COMBOS CLASSCOMPANYPHASEABSTRACT BMS-650032+ BMS-790052 PI+NS5a BMS2aLB-8 Danoprevir (RG7227)+ RG7128 PI+NIRoche/ Genetech 2b32, 81 GS-9190+ GS-92568 PI+NNI Gilead2aLB-1 BI-201335+ BI-207127 PI+NNIBoehringer Ingelheim 2aLB-7

45 IFN RBV DAA RBV? DAA IFN RBV ¿Podremos curar la hepatitis C sin IFN?

46 “A theory is something nobody believes, except the person who made it. An experiment is something everybody believes, except the person who made it” Albert Einstein