Putting progress into practice for HCV care in Egypt

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Putting progress into practice

for HCV care in Egypt

Chairs: Maria Buti, Ashraf Abou-Gabal, Sami Abdel Fattah, Ali Farag, Faisal Sanai

This session has been funded by Gilead Sciences Europe The content of the programme is at the discretion of the faculty

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Session disclaimer

This is an independent programme for which Gilead Sciences Europe Ltd. (“Gilead”) provided funding;

Gilead has had no input into the content of the materials and/or presentations used during this session

This session includes reference to use of unlicensed products or unlicensed indications

The presentations express the views and opinions of the presenter which were based on information and data available at the time

Any patient cases and treatment options referred to are in the

context of contemporary knowledge and medical practice in the field; unlicensed doses and indications are included

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Cairo, 25 September 2014

Welcome

Hepatology on the Nile 2

Putting Progress into Practice

for HCV Care in Egypt

Maria Buti

Autónoma University, Barcelona;

Chief of Internal Medicine and Hepatology, Vall d’Hebron University Hospital,

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Disclosures

 Advisor: AbbVie, Boehringer Ingelheim, Bristol-Myers Squibb, Gilead Sciences, Janssen, Merck Sharp & Dohme, Novartis

 Lecturer: Bristol-Myers Squibb, Gilead Sciences, Janssen, Merck Sharp & Dohme, Novartis

 Clinical trials: Boehringer Ingelheim, Bristol-Myers Squibb,

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Programme and faculty – revised

Time Title Speaker

14.00 Welcome & introduction Maria Buti (Spain)

14.05 HCV co-infection: no longer a special population?

Karine Lacombe (France)

14.25 HCV guidelines: from paper to practice Ashley Brown (UK)

14.45 Can we take HCV out of the transplant equation?

Maria Buti (Spain)

15.05 Linking care to cure in difficult-to-reach populations

Ashley Brown (UK)

15.25 Summary Maria Buti (Spain)

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Global HCV burden and genotype distribution

 6 HCV genotypes (GT 1–6)

 GT 1 and GT 4 predominate in Egypt and Middle East

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HCV – a uniquely Egyptian epidemic

 Egypt’s HCV burden is at least 4 x greater than that of any other country

 1 in 7 sero-positive (global average 1 in 50)

 But, not only is the Egyptian HCV problem one of size,

the prevalent GT 4 is one that is not commonly found in the rest of the world

 Drug development has primarily focused on GT 1 to date Yahia M, Nature 2011:474:S12–3

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The unique Egyptian situation requires

a unique approach to HCV management

 Number of individuals with late-stage liver disease is projected to increase1

 Although Egypt now has the world’s largest HCV treatment

programme,2 _{the current treatment rate and efficacy are not sufficient}

to manage the disease burden1

 The National Treatment Programme needs to evolve with the

availability of new drugs

1. Razavi H, et al. J Viral Hepatitis 2014;21(Suppl 1):34 –59; 2. Waked I et al. Arab J Gastro. 2014;15:45–52.

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Benefits of second wave anti-HCV DAAs

 SVR rates ≥ 90%

 Pangenotypic, short treatment courses  Better adverse effect profiles

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Can we take HCV out of the transplant equation?

Hepatology on the Nile 2

Putting Progress into Practice

for HCV Care in Egypt

Maria Buti

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Disclosures

Note: This presentation includes reference to investigational agents not currently approved for use in HBV by the EMA, FDA and Egyptian MOH  Advisor: AbbVie, Boehringer Ingelheim, Bristol-Myers Squibb,

Gilead Sciences, Janssen, Merck Sharp & Dohme, Novartis

 Lecturer: Bristol-Myers Squibb, Gilead Sciences, Janssen, Merck Sharp & Dohme, Novartis

 Clinical trials: Boehringer Ingelheim, Bristol-Myers Squibb,

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Most liver transplants (LT) in Europe due to cirrhosis

are caused by hepatitis viruses

1. European liver transplant registry LTR. ww.eltr.org/spip.php?article162 (accessed September 2014); 2. EASL. The burden of liver disease in Europe.

www.easl.eu/assets/application/files/54ae845caec619f_file.pdf (accessed June 2014) Study period January 1998–December 2012

• European analysis of 55,714 transplants in Europe1

• HCV-related cirrhosis accounts for 66% of virus-related LT, therefore approximately 25% of LT are a result of HCV2

39% 33% 4% 4% 1% 8% 9% 2% Virus-related Alcoholic

Viral and alcoholic Autoimmune

Secondary biliary Unknown

Primary biliary Others

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This is also true in Egypt

Khalaf H, et al. Suez Canal Univ Med J. 2000:3;157–67

43% 3% 3% 2% 48% Virus-related Biliary Schistosomiasis Cryptogenic Mixed

• Egyptian analysis of 58 transplant candidates (12 transplanted; 46 control)

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Challenges for liver transplantation in Egypt

 Cadaveric organ donation is illegal in Egypt

 Many patients travel to America, Europe or China

 Living donor liver transplantation (LDLT) has provided the only option for patients with ESLD

 Donor must be the patient’s relative, between 20–40 years old and free of any diseases

 Concerns over organ donation for money

 In Western countries, the average waiting time for an overseas patient to receive a cadaveric graft is 18–24 months

 Significant mortality during this waiting period

1. Yosry A, et al. Transplantation Proceedings. 2008:40;1481–4;

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Decreased survival among HCV-infected

liver transplanted recipients: 1991–2000

Berenguer et al, Hepatology 2002;36:202-210

Years HCV+ HCV-1 77% 87% 3 65% 83% 5 61% 76% 7 55% 70% HCV-HCV+ 239 283 1.0 0.9 0.8 0.7 0.6 0.5 0.4 0.3 0.2 0.1 0.0 1 2 3 4 5 6 7 8 9 P=0.0001 log-rank test P ati ent s ur v iv al ( % ) Years post-transplantation

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Reduced liver-related mortality liver graft recipients

with recurrent HCV who achieve SVR

1. Picciotto et al, J. Hepatology 2007; 2. Berenguer, Am. J. of Transplant. 2008

SVR: sustained virologic response; TF: treatment failure 0.00 365 730 1095 1460 1825 2190 2555 1.0 0.8 0.6 0.4 0.2 0.0

Follow-up since treatment initiation (days)

Pa tie nt s u rv iv a l (%) Yes No Yes-censored No-censored SVR 20 30 40 50 60 10 90 80 70 60 50 40 30 20 10 Months Su rv iv al Pro ba bilit y (%)

Sustained virological responders

Patients with treatment failure Probability of survival in patients

who did not maintain SVR (n=61)1

Patient survival since treatment initiation in patients without baseline cirrhosis (n=78)2

100

0 0

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Predictors : SVR: Ciclosporin, Treatment duration,

Infections: FCH, Bilirubin; Anaemia, Thrombocytopenia

Authors DAA Pts Population GT 1a SVR12 Discontinuation

Faisal et al TVR 76 F0-F2 72% 58% 44% BOC Burton et al TVR 125 F3-F4 48% 58% 59% 20% Coilly et al TVR 79 F3-F4, FCH 78% 33% 46% 55% BOC Pungpapong et al TVR 60 F3-F4 50% FCH 8% 68% 50% 20%

Recurrent HCV treatment with TVR or BOC +

PEG-IFN/RBV: Cohort and clinical studies

Faisal et al, Ann of Hepatol 2014;13:525-32; Burton et al, J Hepatol. 2014 Sep;61:508-14; Coilly et al, J Hepatol 2014;60:78-86;

Pungpapong et al, Liver Transpl 2013;19:690-700

BOC: boceprevir; ; DAA: direct-acting antiviral FCH: fibrosing cholestatic hepatitis; GT: genotype; PEG-IFN: pegylated interferon; Pts: patients; RBV: ribavirin; TVR: telaprevir

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Clinical case 1

 Male patient, 52 years old, GT 4  Liver transplant in 2008

 Recurrence of HCV

 FCH; FibroScan® _{= 18.9 kPa; MELD = 26}

 Bilirubin: 13 mg/dL (223 µmol/L); albumin: 35 g/L (3.5 g/dL)  Treated with PEG-IFN + RBV

 Failed to respond

FCH: fibrosing cholestatic hepatitis; MELD: model for end-stage liver disease

What are his next

options?

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EASL: Recommended treatment options:

Indication for LT

 Child-Pugh A with HCC:  SOF + RBV until LT

 SOF + daclatasvir + RBV until LT probably better

 Finite (12 weeks) SOF + PEG-IFN + RBV also acceptable

 Patients with decompensated cirrhosis awaiting LT (Child-Pugh B or C)  SOF + RBV in experienced centres under close monitoring

 SOF + daclatasvir + RBV until LT probably better

 Patients with post-transplant recurrence of HCV infection should be considered for therapy

 IFN-free treatment is recommended

 No dose-adjustment is required for tacrolimus or ciclosporin with any of the available combinations

EASL Recommendations on Treatment of Hepatitis C 2014.

http://files.easl.eu/easl-recommendations-on-treatment-of-hepatitis-C.pdf. Accessed September 2014

HCC: hepatocellular carcinoma; IFN: interferon; SOF: sofosbuvir

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Safety and tolerability profiles of newly approved

DAAs: Simeprevir and sofosbuvir

Simeprevir (2nd wave PI)1

 Once-daily dosing  GT 1, 4  Main AEs  Rash including (22%)  Pruritus (22%)  Photosensitivity (5%)  Mild hyperbilirubinaemia (27%)  Due to OATP1B1/MRP2 transporter inhibition

 Resistance in treatment failures

Sofosbuvir2

 Once daily dosing  Pangenotypic

 Minimal AEs

 Headache ~20%

 No resistance detected in treatment failures

1. Janssen. OLYSIO (simeprevir). Summary of Product Characteristics, May 2014; 2. Gilead Sciences Europe. SOVALDI (sofosbuvir), Summary of Product Characteristics, January 2014

AE: adverse event; DAA: direct acting antiviral; OATP: organic anion-transporting peptide; MRP: multidrug resistant protein

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SOF + RBV for established recurrent

HCV post-LT

SOF 400 mg/d + RBV starting at 400 mg/d with dose escalation

Treatment-naïve and treatment-experienced with recurrent HCV (N=40)

Study week 0 _{No response guided therapy} 24 36 SVR12

LT ≥6 months and ≤ 150 months

MELD ≤ 17

SOF + RBV (N=40)

Male, n (%) 31 (78)

Median age, y (range) 59 (49–75)

Genotype, %:

1a / 1b / 2 /3 / 4 55/28/0/15/3

Metavir-equivalent fibrosis stage, %

F0–F2/F3/F4 38/23/40 Prior HCV treatment, % Previous PI failures, % 88 23 Immunosuppressants (%):

tacrolimus/ mycophenolate mofetil/ prednisone/ciclosporin/azathioprine

70/35/ 28/25/5

63% F3/4

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SOF + RBV for 24 weeks resulted in

high SVR rates

 Relapse was not influenced by RBV dose or exposure

 No DDI between SOF and any immunosuppressive agents in this study

 SOF + RBV in patients with recurrent HCV after LT was well tolerated

 No deaths, graft losses or episodes of rejection reported

Samuel D, et al. EASL 2014; Poster #1232

DDI: drug–drug interactions; EOT: end of therapy; LLOQ, lower limit of quantification (25 IU/mL)

100 100 73 70 70 0 20 40 60 80 100 Week 4 EOT SVR4 SVR12 SVR24 HCV R NA < LLO Q (% ) 40/40 40/40 29/40 28/40 28/40

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Compassionate use of SOF in patients with severe

recurrent HCV Including FCH following LT

SOF Compassionate Use Programme SOF + RBV ± PEG,

n=104 Severe acute hepatitis/early recurrence

(<12 mo from LT with typical

biochemical-histological findings), n=48 Post-LT compensated (F4) or decompensated cirrhosis, n=56 Completed 24-48 weeks treatment n=72 Liver transplant n=12 Death n=13

Early term due to AE n=7

Severe recurrent hepatitis C post-LT likely to have <1 yr life expectancy SOF 400 mg/d for 24-48 weeks plus RBV ± PEG-IFN

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Results: Baseline characteristics

Overall (n=104)

Age, years 55 (16–76)

Male recipient 76 (73%)

HCV RNA, log₁₀ IU/mL 8.4 (1.3–8.9)

GT, 1 / 4 vs 2 / 3 88 / 8 vs 1 / 7 Bilirubin, mg/dL 3.1 (0.4–45) Albumin, g/dL 3.1 (1.3–12.2) INR 1.3 (0.8–4.5) ALT, IU/L 71 (8–1162) MELD 15 (6–43)

Time from LT to treatment, months 17 (1–262)

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Overall, 62% of patients achieved SVR

Forns X. EASL, London 2014 0 20 40 60 80 100 EOT SVR12 HCV RNA >LLOQ Lost to follow up Death HCV RNA <LLOQ 53/85 81/93 P at ien ts ( % ) 8/93 4/93 15/85 13/85 4/85

62% SVR

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Over 79% of patients receiving at least

1 dose of SOF improved or were stable

58 21 21 0 20 40 60 80 100

Improved* Stable Worsened/deceased

60/104 22/104 22/104 79% improved or stable P at ien ts ( % )

Forns X. EASL, London 2014

All patients who received ≥1 dose of SOF are included

* Significant decrease in hepatic encephalopathy, improvement or

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Post-transplant recurrent hepatitis C

 Patients with post-transplant recurrence of HCV infection should be considered for therapy

 IFN-free treatment is recommended

 No dose adjustment is required for tacrolimus or ciclosporin with the available combinations

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Clinical case 2

 Male patient, 52 years old, GT 4 cirrhotic  HCV infection since 2001

 Treated with PEG-IFN + RBV

 Could not tolerate the full dose and only achieved a partial response  Platelet count: 60 x 103_{/µL; albumin: 3.2 g/dL (32 g/L);}

bilirubin: 4.5 mg/dL (77 µmol/L), mild ascites; MELD=15  HCC diagnosed in November 2013 and on LT waiting list

HCC: hepatocellular carcinoma; MELD: model of end-stage liver disease

What could be done before a

donor liver becomes available?

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SOF + RBV pre-LT to prevent

HCV recurrence post-LT

 Open-label, Phase 2, GT 1–6 study of SOF + RBV for the prevention of recurrent HCV infection

Curry MP, et al. ILTS 2014; Oral #137 SOF: sofosbuvir; 2o_:secondary

Liver transplant (up to 48 weeks) 12 weeks post-transplant virological response (pTVR) Time 0

No response guided therapy

SOF 400 mg/day + RBV 1000–1200 mg/day Undergoing LT for HCC 2° to HCV N=61 SOF + RBV (N=61) Male, n (%) 49 (80)

Median age, y (range) 59 (46–73)

BMI < 30 kg/m2_{, n (%)} _{43 (70)}

Genotype, %

1a/1b/2/3a/4 39/34/13/11/2

IL28B non-CC allele, n (%) 47/60 (78) CPT score, n (%)

5/6/7/8 43/30/23/5

Median MELD score, (range) 8 (6–14)

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SOF + RBV suppressed viral load and

prevented HCV recurrence post-transplant

 Of the 61 patients treated, 46 underwent LT

 SOF + RBV treatment prior to transplantation prevented HCV recurrence in most patients (70%) who were HCV RNA <LLOQ (TND) at time of LT

*3 subjects were >LLOQ at transplant; †_{1 subject has not reached pTVR12;}

BL: baseline; SD: standard deviation; TND: target not detected

Post-transplant virological response 93 70 0 20 40 60 80 100 Transplant pTVR12 43/46* 30/43*† V ira l res p o n s e r a te ( %) 0 30 60 90 120 150 180 210 240 270 300 330 360 390 420 450 480

Days with HCV RNA Continuously TND Prior to Liver Transplant

No recurrence in 24/25 (96%) of patients who maintained HCV RNA TND >30 days No Recurrence (n=30) Recurrence (n=10) >30 days TND Median days TND No recurrence: 99 Recurrence: 5.5 p <0.001

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HCV care is progressing –

and this will also be the case for LT patients

 Several IFN-free regimens are at an advanced stage of development, including:

 SOF + daclatasvir  Ledipasvir/SOF

 Paritaprevir/ritonavir/ombitasvir + dasabuvir ± RBV  MK-5172/MK-8742 ± RBV

Asunaprevir, ledipasvir, paritaprevir/ritonavir, ombitasvir, dasabuvir, MK-5172 and MK-8742 are investigational agents and not approved for use in HCV by the EMA, FDA or Egyptian MOH

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Paritaprevir/ritonavir/ombitasvir + dasabuvir + RBV in

LT recipients with recurrent GT 1

 24 weeks therapy in LT recipients with recurrent GT 1 infection; treatment-naïve; F0–2 (n=34); CNI doses adjusted for paritaprevir/r

 There were no on-treatment failures

 One patient experienced relapse (post-treatment Day 3)

 Clinically relevant DDIs seen between regimen and immunosuppressants

Kwo P. EASL 2014; oral #114

Paritaprevir/ritonavir, ombitasvir and dasabuvir are investigational agents and not approved for use in HCV by the EMA, FDA or Egyptian MOH CNI: calcineurin inhibitor; EOT: end of therapy; RVR: rapid virological response

100 100 ₉₇ ₉₆ 0 20 40 60 80 100

Week 4 (RVR) Week 24 (EOT) SVR4 SVR12

% HCV RNA unde te c ta bl e 32/33 34/34 34/34 25/26

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Ongoing clinical trials including

HCV transplant recipients

Forns et al, Digestive and Liver Disease in press; www.clinicaltrials.gov

Paritaprevir/ritonavir, ombitasvir and dasabuvir are investigational gents and not approved for use in HCV by the EMA, FDA or Egyptian MOH;

DCV: daclatasvir; LDV: ledipasvir; r: ritonavir; Wk: week

Identifier Regimen Treatment

Duration Genotype Child–Pugh class

Trial Phase

NCT01938430 LDV/SOF + RBV 12–24 wk 1, 4 Pre-LT: B, C

Post-LT: A, B, C 2

NCT02032875 DCV/SOF + RBV 12 wk 1–6 Pre- and Post-LT: A 3

NCT01938625 DCV + SMV + RBV 24 wk 1b Post LT Metavir F1–F4 (Child A) 2 NCT01782495 Paritaprevir/r/ Ombitasvir + Dasabuvir ± RBV 12 wk 1 Post LT Metavir F1–F3

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Drug–drug interactions between DAAs

and calcineurin inhibitors

1.Hulskotte et al. Hepatology 2012;56:1622-1630. 2.Coilly et al. Antimicrob Agents Chemother 2012;56:5728-5734. 3.Coilly et al. Liver Int 2013;33 Suppl 1:56-62. 4.Kwo P et al. J Hepatol 2014;60(Suppl 1):S47. 5.Ouwerkerk-Mahadevan et al. J Hepatol 2013;58(S1):S365. 6.Mathias et al. Hepatology 2012;56(Suppl 1): 1063A-1064A. 7.Fontana et al. Liver Transpl 2012;18:1053-1059

*AUC_Inf is given **AUC_Lastis given Adapted from Forns et al, Digestive and Liver Disease in press Paritaprevir is not approved for use in HCV by EMA, FDA or Egyptian MOH

DAA Ciclosporin Tacrolimus

Healthy volunteers Dose adjustment Healthy volunteers Dose adjustment

Boceprevir1,2 * _AUC↑2.7 fold ↓2 fold _AUC↑17 fold ↓5 fold

Telaprevir2,3 ** _AUC↑4.6 fold ↓4 fold _AUC↑70 fold ↓35 fold

Paritaprevir/r4 _AUC↑5.8 fold ↓5 fold _AUC↑58 fold ↓100 fold

Simeprevir5 _AUC↑19% _Under

investigation. Not recommended

AUC ↓17% Not necessary

Sofosbuvir6 _{No change} _{Not necessary} _{No change} _{Not necessary}

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Summary – taking HCV out of the transplant equation

 The future is more optimistic for patients with HCV-related ESLD  Clear evidence that re-infection post-LT can be prevented by

treating HCV before the procedure and cured afterwards with effective DAA treatment, even in those with the severest form of disease

 SOF + RBV data show promise – high efficacy and no DDIs with common immunosuppressant agents

 To put progress into practice in Egypt, a transformation in

management approach is required so that patients are cured of HCV before they require a transplant

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Meeting Close

Hepatology on the Nile 2

Putting Progress into Practice

for HCV Care in Egypt

Maria Buti

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Vision for future treatment of chronic HCV:

Putting progress into practice

1 Pill/day for 8–12 wks Simple prescribing Treatment uptake Health burden ALL PATIENTS ALL HCV GTs 1–6

including BOC/TVR failures including decompensated cirrhosis

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Putting progress into practice for HCV care in Egypt:

Summary

 Recent advances, once accessible, have the potential to transform and simplify patient management

 New potent, pangenotypic, well tolerated IFN-limiting and IFN-free treatment options of short duration are emerging

 Need to prioritise and treat now those patients with greatest need  Need to preventing the currently high rates of reinfection through

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Putting progress into practice

for HCV care in Egypt

Chairs: Maria Buti, Ashraf Abou-Gabal, Sami Abdel Fattah, Ali Farag, Faisal Sanai

This session has been funded by Gilead Sciences Europe The content of the programme is at the discretion of the faculty