Hi Histor orical al outcome p parameters u used ed in PBC and - PowerPoint PPT Presentation

Hi Histor orical al outcome p parameters u used ed in PBC and the s e sea earch f for poten enti tial alter ernatives es EMA MA stakeho eholde der i interaction o n on the d dev evelopm pmen ent o of medicinal p produc ducts f for ch chronic n c non-infectious l liver er di dise sease ses ( s (PBC, P , PSC, N NAS ASH) 3 3 De December 2018 2018 Bettina E Hansen IHPME, University of Toronto Toronto Center for Liver Disease, UHN Gastro & Hepatology, Erasmus MC, The Netherlands

Definition of of T True ue E Endpoint • Meet criteria recognized by academia/ guidelines • Meet requirements from regulatory True Disease agencies: Endpoint • a clinical event relevant to the patient • measures directly how a patient feels, functions or survives Intervention

Lon Long t ter erm ou outcome f for P PBC True endpoint • Death (all-cause) • Liver transplantation • Decompensation of cirrhosis (variceal bleed, encephalopathy, spontaneous bacterial peritonitis, uncontrolled ascites) • MELD score ≥ 15 (above specific threshold ) Reflection paper on regulatory requirements for the development of medicinal products for chronic non- infectious liver diseases (PBC, PSC, NASH); 2018 • Hepatocellular carcinoma ? • Rotterdam Severe Disease Stage ? (abnormal bilirubin AND abnormal albumin)

Lon Long t ter erm ou outcome f for P PBC PROS CONS • Requires large population and often • Measures direct benefit/harm long follow-up • No potential bias • trial duration 8-15 years • Event may be confounded by competing risks • Event may be effected by cross over of therapies or subsequent therapies • Does not capture symptom benefit • Ethical unacceptable

Inter ermed ediate e e endpoi oint = t = surrog ogate e endpoint An acceptable regulatory strategy in case of unmet need is to consider intermediate endpoints: • A validated substitute for the true endpoint: changes observed in the surrogate endpoint is expected to reflect changes in the true endpoint • Requires confirmation of efficacy (and safety) of the compound after approval Reflection paper on regulatory requirements for the development of medicinal products for chronic non-infectious liver diseases (PBC, PSC, NASH); 2018; Prentice, Stat in Med; 1989

Surrogate E Endpoin int PROS CONS • Time and Care • Measurements may be subject to bias • a new intervention is quicker available • Validation needed for the patient in need • Various definitions: cut points, combined • the benefit/harm of an intervention is endpoints observed quicker • Benefit for design of a new trial • Depends on mode of action of intervention • Influence on sample-size calculation • Shorter duration of study • Influence of recruitment and participation enthusiasm • Endpoint not effected by cross over of therapies or subsequent therapies

Phase 3 3 cu current t intermedia iate en endpoin ints Duration: 1 year POISE 1 – trial Inclusion : ALP>1.67 OR abnormal bilirubin, but bilirubin < 3xULN Response: ALP<= 1.67 AND min. 15 % reduction compared to baseline AND normal bilirubin BEZURSO 2 - trial Inclusion: Non-responder according to Paris I Response: normal bilirubin, normal ALP, AST, ALT, albumin and PT 1 Nevens et al ; NEJM 2016; 2 Corpechot at al; NEJM 2018

Inter ermed ediate e e endpoi oint = t = surrog ogate e endpoint EMA advocates a more stringent definition of response and duration of study: • Duration of study 1 - 2 years add on to SOC (UDCA) • Intermediate endpoint: • ALP < 1.5xULN AND • 40% reduction compared to baseline AND • normal bilirubin  Impacts sample size calculation  ALP baseline = 1.5  ALP 1yr < 0.9  ALP baseline = 2  ALP 1yr < 1.2 Reflection paper on regulatory requirements for the development of medicinal products for chronic non-infectious liver diseases (PBC, PSC, NASH); 2018; Prentice, Stat in Med; 1989

Histor orical B Bioc ochemical R Respon onse e Criteria Group Year of Number of Response Criteria assessed at 1 or 2 years publication patients Barcelona 1 2006 192 ALP >40% decrease from baseline or normalization ALP ≤ 3 x ULN and AST ≤ 2 x ULN and bilirubin ≤ 1 Paris 1 2 2008 292 mg/dl Rotterdam 3 2009 375 Normalization of albumin and/or bilirubin ALP ≤ 1.67 ULN Toronto 4 2010 69 ALP ≤ 1.5 x ULN and AST ≤ 1.5 x ULN and bilirubin Paris 2 5 2011 165 ≤ 1 mg/dl Japan 6 2011 138 GGT normalization or > 70% reduction 1 Parés, Gastroenterology, 2006. 2 Corpechot, Hepatology, 2008. 3 Kuiper, Gastroenterology, 2009. 4 Kumagi, the American Journal of Gastroenterology, 2010. 5 Corpechot, Journal of Hepatology, 2011 6 Azamoto, Hepatology Research, 2011

Databan Da banks Global PBC Study Group UK PBC • individual patient data • individual patient data • N >6000 PBC patients, 30.000 patient • from all UK centers visits, >20 years follow-up • N >6000 PBC patients • 21 sites in Europe, North America, Asia • genetic data, prospective lifestyle data f from to a rare disease gigantic databases

Bioch chem emical r respon onse c e criter eria a associated w with improved l liver er t transplantati tion f free ee s survival Barcelona Paris1 Rotterdam Responders Non- responders HR = Hazard Ratio (HR) = HR = 4.0 (3.3-5.0) 1.6 (1.4-1.9) 4.1 (3.5-5.0) C-stat = 0.75 C-stat = 0.67 C-stat = 0.77 GGT 70% reduction Paris2 Toronto 100 90 80 70 Cum Survival (%) 60 50 40 HR = HR = HR = 2.3 30 2.8 (2.3-3.4) 2.7 (2.3-3.4) 20 GGT, N = 1700 10 C-stat = 0.71 C-stat = 0.72 0 0 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 FU years - 1 year Hansen, Data Global PBC Study Group

What Makes a a Goo ood S Surrogate E Endpoin int? • Frequently observed • Assessed within a short timeframe • Easy to measure • Preferably non-invasive and at low costs • Epidemiology/clincal studies demonstrates that surrogate endpoints is linked to clinical outcomes • Clinical trials demonstrate that treatment effects on the surrogate endpoint correspond to effects on the clinical outcome Boissel JP et al. Eur J Clin Pharm 1992;43:235-44 Espeland MA et al. Current controlled trials in Cardiovascular Med 2005;6:3-6

Biomarker er endpoints Bilirubin Key diagnostic variable for liver detoriation Numerous studies showing prognostic significance of bilirubin Component of established prognostic models: • Mayo model • MELD score • Child-Pugh score Alkaline phosphatase Key diagnostic variable Mutiple studies indicating prognostic significance Component of Paris I & II, Barcelona, Toronto established criteria Useful as surrogate endpoint?

Challe llenges in asses essin ing d drug effic ficacy cy b by uti tiliz lizin ing biomarker e r endpoints i s in clinical s studies • Biomarker often continuous : ALP < 1.67 • threshold ? • magnitude of efficacy ? Normal ALP ≥ 1.67 • % difference ? bilirubin • Biomarker response measured at one fixed time point Abnormal ALP < 1.67 bilirubin • which time point ? ALP ≥ 1.67 • durability/sustainable response ? • What is the impact on the true endpoint • in the natural history of disease ? Lammers et al, Gastroenterology 2014 • association and mechanism of action? • Is ‘biomarker response’ = level 3 ‘surrogate’ endpoint ? • influence independent of therapies (depends on mode of action) • biomarker endpoint influenced through other pathways

Hi Higher ALP LP and b bilir lirubin v values a are a associa ociated w with th higher hazard of of l liver tr transpla lantatio ion/d /death Bilirubin Alkaline phosphatase (ALP) 6 6 0.80 Bilirubin ALP: lower is better 1.67xULN <1xULN threshold 0.75 Hazard ratio Hazard ratio 4 c-statistics 4 0.70 2 2 0.65 0 0 0.60 0 1 2 3 4 0 1 2 3 4 1.0 1.5 2.0 2.5 3.0 ALP (xULN) values after 1 year follow-up Bili (xULN) values after 1 year follow-up ALP (xULN) values after 1 year follow-up Lammers et al., Gastroenterology 2014

Zoomin ing i in on A ALP LP belo elow 2 2 and n nor ormal b l bilir lirubin in Alkaline phosphatase (ALP) Bilirubin tra n s p la n ta tio n o r d e a th (9 5 % C I) T im e 0 c o h o rt tra n s p la n ta tio n o r d e a th (9 5 % C I) 6 4 Abnormal 5 H a z a rd ra tio fo r H a z a rd ra tio fo r 3 4 3 2 2 1 1 0 0 0 1 1.67 2 3 0 .0 0 .5 0 .7 1 1 .0 1 .5 A lk a lin e p h o s p h a ta s e ( × U L N ) B iliru b in ( × U L N ) ALP: lower is better Bilirubin: > 0.6 - 0.7 at higher risk Murillo et al., AASLD 2017; Murillo et al., AASLD 2018

Des esign of of Risk S Scores: c : com ombinatio ion o of biomarkers

Des esign of of Risk S Scores: G : Globe s scor ore These patients could potentially benefit of additional therapies HR globe score > threshold = 4.5 C-stat = 0.82 50 th percentile 0 100 Lammers et al., Gastroenterology 2015 http://globalpbc.com/globe

Globe-scor ore f e for PBC – use a e as dynamic ic r risk s scor ore Regulatory Agencies HR time dependent = 3.5 (2.9-4.1) C-stat > 0.81 Patient example • 67 years at start of UDCA • Bilirubin&albumin normal at 0 and 12 months • GLOBE score threshold passed at 7 years Mobile App • † (liver-related) after 11.5 years follow-up Goet et al. JHep 2017