Biologics  Today  and  Tomorrow    

Brian G. Feagan Professor of Medicine, Epidemiology and Biostatistics, Western University,

Senior Scientific Officer, Robarts Clinical Trials Inc.

Disclosures  Grant/Research Support AbbVie Inc., Amgen Inc., AstraZeneca/MedImmune Ltd., Atlantic Pharmaceuticals

Ltd., Boehringer-Ingelheim, Celgene Corporation, Celltech, Genentech Inc/Hoffmann-La Roche Ltd., Gilead Sciences Inc., GlaxoSmithKline (GSK), Janssen Research & Development LLC., Pfizer Inc., Receptos Inc. / Celgene International, Sanofi, Santarus Inc., Takeda Development Center Americas Inc., Tillotts Pharma AG, UCB,

Consultant Abbott/AbbVie, Akebia Therapeutics, Allergan, Amgen, Applied Molecular Transport Inc., Aptevo Therapeutics, Astra Zeneca, Atlantic Pharma, Avir Pharma, Biogen Idec, BioMx Israel, Boehringer-Ingelheim, Bristol-Myers Squibb, Calypso Biotech, Celgene, Elan/Biogen, EnGene, Ferring Pharma, Roche/Genentech, Galapagos, GiCare Pharma, Gilead, Gossamer Pharma, GSK, Inception IBD Inc, JnJ/Janssen, Kyowa Kakko Kirin Co Ltd., Lexicon, Lilly, Lycera BioTech, Merck, Mesoblast Pharma, Millennium, Nestles, Nextbiotix, Novonordisk, Pfizer, Prometheus Therapeutics and Diagnostics, Progenity, Protagonist, Receptos, Salix Pharma, Shire, Sienna Biologics, Sigmoid Pharma, Sterna Biologicals, Synergy Pharma Inc., Takeda, Teva Pharma, TiGenix, Tillotts, UCB Pharma, Vertex Pharma, Vivelix Pharma, VHsquared Ltd., Zyngenia

Speakers Bureau Abbott/AbbVie, JnJ/Janssen, Lilly, Takeda, Tillotts, UCB Pharma Patent Holder Member, Scientific Advisory Board

Abbott/AbbVie, Allergan, Amgen, Astra Zeneca, Atlantic Pharma, Avaxia Biologics Inc., Boehringer-Ingelheim, Bristol-Myers Squibb, Celgene, Centocor Inc., Elan/Biogen, Galapagos, Genentech/Roche, JnJ/Janssen, Merck, Nestles, Novartis, Novonordisk, Pfizer, Prometheus Laboratories, Protagonist, Salix Pharma, Sterna Biologicals, Takeda, Teva, TiGenix, Tillotts Pharma AG, UCB Pharma

Member, Board of Directors Senior Scientific Officer – Robarts Clinical Trials Inc, London Stock Shareholder Other Financial Support Other Relationship/Affiliation

Topics  for  Discussion    

•  Today: Current treatments and their limitations

•  Tomorrow: Next generation biologics

•  Future treatment paradigms

•  Conclusions

3

Topics  for  Discussion    

•  Today: Current treatments and their limitations

•  Tomorrow: Next generation biologics

•  Future treatment paradigms

•  Conclusions

TNF  antagonist  therapy  for  CD  was  a  game  changer-­‐  but  we  are  a  long  way  from  perfect……  

. Colombel JF, et al. Gastroenterology 2007

Clinical remission Clinical response %

of P

atie

nts 60

40

20

0

p < 0.001

p < 0.001

60

40

20

0

p < 0.001

p < 0.001

60

40

20

0

p < 0.001

p < 0.001

60

40

20

0

p < 0.001

p < 0.001

Week 26

Week 56

Placebo

Adalimumab 40 mg weekly

Adalimumab 40 mg EOW

% o

f Pat

ient

s

17

40 47

12

36 41

p =NS

p = NS

p = NS

27

52 52

17

41 48

p =NS

Aminosalicylate

Corticosteroids

Anti-TNF

Aminosalicylate (UC)/ Thiopurine/MTX (CD)

Aminosalicylate

Anti-TNF Vedolizumab Thiopurine/MTX (CD, ustekinumab)

Induction Maintenance

Time

Biologics

Pre-clinical Clinical

Surgery

Stricture

Stricture

Fistula / abscess

Disease onset Diagnosis Early Disease Dig

estiv

e da

mag

e

Step-Care

SONIC  

30

45 57

0

20

40

60

80

100

Prop

ortio

n of

Pat

ient

s (%

)

AZA + placebo IFX + placebo IFX+ AZA

p<0.001

p=0.009 p=0.022

52/170 75/169 96/169

Colombel JF. et al. N Engl J Med. 2010 Apr 15;362(15):1383-95.

34.7%

27.4%

10

20

30

40

Time (months)

Hosp

italis

atio

n, s

urge

ry

or c

ompl

icat

ions

(%)

HR (95% CI) = 0.73 (0.62, 0.86), p <0.001

0 0 3 6 9 12 15 18 21 24

Conventional management Early combined immunosuppression

Khanna R. et al. The Lancet. 2015 Nov 7;386(10006):1825-34

Colombel JF. DDW 2017 [718]

CALM:  Primary  Endpoint  at  Week  48  CDEIS  <  4  and  No  Deep  UlceraMons  

Disease severity at presentation?

Severe

Moderate

Mild

Aminosalicylate

Corticosteroids

Anti-TNF

Aminosalicylate (UC)/ Thiopurine/MTX (CD)

Aminosalicylate

Vedo\Anti-TNF (UC)/ Thiopurine/MTX UST (CD)

Induction Maintenance

time

Biologics Biologic

GCS (AZA)

5-ASA

Peyrin-Biroulet L. Am J Gastroenterol 2015;110:1324-38

Treat  to  Target  in  IBD:    STRIDE  Working  Group  

Univariate

IFX use was associated with an increased incidence of serious infections (unadjusted)

Multivariate predictors of serious infection

p < 0.001

p = 0.011 p < 0.001 p < 0.001 p < 0.001

Lichtenstein, et al. DDW 2010: Abstract #T1040

Lobar  Pneumonia  with  Pneumococcus  

Mosli M et al, Drugs 2014; 74: 297-311 Feagan et al New Eng J Med 2013;396(8):699-710

Vedolizumab  Therapy  for  UC  and  CD      

UC Induction-Week 6

Prior Anti-TNF Antagonist Exposure (n=149)

Patients Without TNF Antagonist Exposure (n=224)

25.4 (5.1, 43.8) 29.7 (10.3, 47.7)

24.9 (7.1, 42.6) 27.0 (9.4, 44.6)

26.8 (12.4, 41.2) 29.0 (14.6, 43.3)

38.7 (24.0, 53.4) 29.6 (14.6, 44.6)

Clinical Remission

Durable Clinical Response

Clinical Remission

Durable Clinical Response

Patie

nts,

%

Mean Δ% vs VDZ/PBO (95% CI) VDZ/VDZ Q8W: VDZ/VDZ Q4W:

VDZ/PBO VDZ/VDZ Q8W VDZ/VDZ Q4W

Feagan, B.G. et al New Eng J Med 2013

Colombel JF et al. Gut 2017;66(5):839-851

Placebo Vedolizumab

Adverse event: Infection

UC and CD (n = 504)a UC and CD (n = 2830)d

No. of patients with

event

No. of patients with event/100 PY

(95% Cl) No. of patients

with event No. of patients

with event/100 PY (95% Cl)

Any infectione 139 82.9 (68.3-97.5) 1606 63.5 (59.6-67.3) Upper respiratory tract infections 67 34.7 (26.0-43.3) 967 28.6 (26.6-30.6)

Lower respiratory tract and lung infections

16 7.7 (3.9-11.5) 270 6.1 (5.3-6.8)

 VISIBLE  1  :  Comparison  of  s.c  and  IV  vedolizumab  to  Placebo  

Sandborn WJ, et. al. United European Gastroenterology Week 2018, LB03.

Results:  Primary  Efficacy  Endpoint-­‐Clinical  Remission  at  Week  52  

0  

10  

20  

30  

40  

50  

60  

70  

80  

%  Pa%

ents  (9

5%  CI)  

n/N:   8/56  Placebo  

49/106  SC  

23/54  IV  

46.2  42.6  

14.3  

Clinical Remission (Week 52) p<0.001  

Clinical  Remission  

GEMINI  11  

Placebo  (N=126)  

VDZ  Q8W  (N=122)  

VDZ  Q4W  (N=125)  

15.9  

***  41.8  

***  44.8  

Sandborn WJ, et. al. United European Gastroenterology Week 2018, LB03. Feagan BC, et al. N Engl J Med. 2013;22;369(8):699-710.

Louis Pasteur 1822-95

“I would rather have a general who was lucky than one who was good.”

AnM-­‐p40  Ustekinumab:  Background    

NK or T cell membrane

p40 p19

IL-23

p40 p35

IL-12

ustekinumab

No IL-12 or IL-23 intracellular signal

1 Sandborn W, et al. Oral presentation. CCFA 2015 and Rutgeerts P, et al . Oral presentation. ECCO 2016. 2 Feagan B, et al. Oral presentation. ACG and UEGW 2015.

•  IL-12 & IL-23 are key cytokines in the pathogenic immune cascade of Crohn’s disease

• Ustekinumab is a fully human IgG1k monoclonal antibody binding the p40 subunit of interleukin-12 and -23

•  Inhibits IL-12- and IL-23-mediated signaling, cellular activation, and downstream cytokine production

• Approved for moderate to severe psoriasis and psoriatic arthritis

•  Induction efficacy recently demonstrated in a broad CD population in UNITI-11 and UNITI-22

Sandborn W.J., et al. DDW 2016. Presentation 768.

Clinical  Response  and  Remission  Through  Week  8  

Clinical Remission

Clinical Response

Feagan  et  al    New  Eng  J  Med    2016.    

UNITI-2

(anti-TNF Failure)

(anti-TNF Failure)

(Conv. Failure)

(Conv. Failure)

Primary  Endpoint:  Clinical  Remission  at  Week  44  

35.9

48.8 53.1

0

20

40

60

80

100

Placebo SC* (N=131)

90 mg SC q12w (N=129)

90 mg SC q8w (N=128)

Prop

ortio

n of

Sub

ject

s (%

)

p=0.040 p=0.005

Ustekinumab

Number of Subjects in Clinical Remission**,† at Week 44; Randomized Subjects Excluding Those Enrolled Prior to Study Re-start

24

Δ 12.9% Δ 17.2%

Feagan    et  al.  New  England  J  Med  2016.    

 Risk  of  Adverse  Events  Observed  In  Ustekinumab-­‐Treated  Psoriasis  PaMents  

Papp  K,  et  al.  J  Drugs  Dermatol.  2015;14(7):706-­‐714.  

Adj

uste

d H

R [9

5%C

I]

Malignancy Major adverse cardiovascular event

Serious infection

Mortality

Independent Predictors of Time to First Event: Ustekinumab-Treated vs. Non-Biologic-Treated

Phase  3  UlceraMve  ColiMs  InducMon  Study  Design  

Sands et al. UEGW 2018, LB01

PBO  IV  UST IV 130 mg

Primary Endpoint: Clinical remission (Mayo score ≤2 with no individual subscore >1)

Clinical  Responders  at  Week  8  Randomized  to  Withdrawal  Maintenance  Study  

UST IV ~6 mg/kg†

Major Secondary Endpoints: Endoscopic Healing Clinical Response

IBDQ Mucosal Healing*

Week 0

Week 8

VISITS

Sands et al. UEGW 2018, LB01

Clinical  and  Endoscopic  Outcomes  a^er  Single  IV    Ustekinumab  Dose  in  UC  

Sands et al. UEGW 2018, LB01

5

31

14 16

51

26 16

62

27

0

20

40

60

80

100

Remission Clinical Response Endoscopic Healing

PBO UST 130 mg UST ~6 mg/kg

*  *  

Primary Endpoint

*  *  *  *  

44/319   84/320   87/322  100/319   164/320   199/322  17/319   50/319   50/322  

Frac

tion

of p

atie

nts

(%)

(Near) Future  DirecMons    •  Notwithstanding access issues, TNF antagonists will evolve to second line

agents within the next 5 years because of safety concerns

•  Vedo is likely to become the first line agent for UC, Uste for CD

•  In the interim, treatment targets will need to be re-calibrated – downwards in CD; upwards in UC (histopathology?)

•  We still have low absolute corticosteroid-free remission rates with our best therapies

•  Payors are exhausted – we need cost-effective solutions

•  How do we get there? (2 obvious solutions – WAIT FOR IT!)

Topics for Discussion

•  Today: Current treatments and their limitations

•  Tomorrow: Next generation biologics

•  Future treatment paradigms

•  Conclusions

Future Monoclonals

Newer  AnM-­‐Integrins  Therapy  

•  Leucocyte migration to the gut mucosa –  Primarily mediated by interactions between mucosal addressin cell

adhesion molecule (MAdCAM-1) and α4β7

•  Lymphocyte retention in the gut wall –  Primarily mediated by interactions between E-cadherin and αEβ7 –  1-2% of lymphocytes in the peripheral circulation express the αEβ7

integrin

•  Etrolizumab –  Is a humanized monoclonal antibody with high affinity for the Beta7

subunit of the α4β7 and the αEβ7 integrins –  In addition to blockade of α4β7-mediated activity

  Inhibition of αEβ7 binding to E-cadherin may provide improved efficacy over inhibition of trafficking alone

  Leukocyte membrane glycoproteins

  β1 and β7 subunits   Interact with endothelial

ligands VCAM-1, fibronectin, and MAdCAM-1

  Mediate leukocyte adhesion and trafficking

α4 α4

Springer TA. Cell 1994;76:301-314. Butcher EC et al. Science 1996;272:60-66

EUCALYPTUS:  Etrolizumab  in  UlceraMve  ColiMs  

Vermeire et al, Lancet 2014; 384:309

Pro

porti

on o

f pat

ient

s (%

) Clinical Remission in All Comers & by Anti-TNF status

Primary endpoint at Week 10

Primary Endpoint 95% CI (12,30) (0.2,20) p-value 0.004 0.048

95% CI (12,75) (-2,50) p-value 0.007 0.076

95% CI (-5.1,16.4) (-5.6,14.7)

Pro

porti

on o

f pat

ient

s (%

)

n=15 n=16 n=12 n=15 n=16 n=12 n=25 n=22 n=25 n=25 n=22 n=25

AnM-­‐p40  Ustekinumab:  Background    

NK or T cell membrane

p40 p19

IL-23

p40 p35

IL-12

ustekinumab

No IL-12 or IL-23 intracellular signal

1 Sandborn W, et al. Oral presentation. CCFA 2015 and Rutgeerts P, et al . Oral presentation. ECCO 2016. 2 Feagan B, et al. Oral presentation. ACG and UEGW 2015.

•  IL-12 & IL-23 are key cytokines in the pathogenic immune cascade of Crohn’s disease

• Ustekinumab is a fully human IgG1k monoclonal antibody binding the p40 subunit of interleukin-12 and -23

•  Inhibits IL-12- and IL-23-mediated signaling, cellular activation, and downstream cytokine production

• Approved for moderate to severe psoriasis and psoriatic arthritis

•  Induction efficacy recently demonstrated in a broad CD population in UNITI-11 and UNITI-22

Sandborn W.J., et al. DDW 2016. Presentation 768.

What About Blocking IL-23 Itself?

NIBRT    2015  ©    

The Evolution of Psoriasis Therapy 2000-2017

Griffiths CE. et al. N Eng J Med. 2010;362(2):118-28 Lebwohl M et al. N Eng J Med. 2015;373(14):1318-28. Papp KA, et al. N Eng J Med. 2017;376(16):1551-1560.

AnM-­‐IL  12/23  (p40)  and  AnM-­‐IL  23  (p19)  AnMbodies  

•  Anti-p40 •  Ustekinumab (Janssen) •  Briakinumab (Abbvie) – development discontinued

•  Anti-p19 •  Brazikumab (MEDI2070) (AstraZeneca / Medimmune and

Amgen, now Allergan) •  Risankizumab (BI 655066) (Boehringer Ingelheim, now

Abbvie) •  Guslekumab (Janssen) •  Mirikizumab (LY3074828) (Lilly) •  Tildrakizumab (MK 3222) (Merck, now Sun Pharma)

Background  and  ObjecMve  

•  The  IL-­‐23  pathway  has  been  implicated  in  the    pathogenesis  of  Crohn’s  disease1,2  

•  Risankizumab  is  a  humanized  mAb  that  targets  the    p19  subunit,  specific  to  IL-­‐233  

•  In  a  head-­‐to-­‐head  trial  in  subjects  with  chronic  plaque    psoriasis,  risankizumab  had  superior  efficacy    to  ustekinumab4  

•  In  a  Phase  II  proof-­‐of-­‐concept  study  in  subjects  with    Crohn’s  disease,  iv  risankizumab  was  more  effec%ve  than    placebo  for  inducing  clinical  and  endoscopic  remission    at  12  weeks5  

•  Re-­‐induc%on  therapy  with  600  mg  iv  risankizumab    increased  clinical  remission  rates  further  at  Week  26,    and  was  well  tolerated  over  26  weeks6  

ObjecMve  

•  Assessment  of  the  efficacy  and  safety  of  open-­‐label  180  mg  sc  risankizumab  maintenance  therapy  at  Week  52  

iv,  intravenous;  mAb,  monoclonal  an%body;  sc,  subcutaneous.  1.  Duerr  RH,  et  al.  Science  2006;314:1461–1463;  2.  Sandborn  WJ,  et  al.  Gastroenterology  2008;135:1130–1141;  3.  Singh  S,  et  al.  MAbs  2015;7:778–791;    4.  Papp  K,  et  al.  NEJM  2017;  376:1551–1560;  5.  Feagan  B,  et  al.  Lancet  2017;389:1699–1709;  Feagan  B,  et  al.  UEGW  2016:  Oral  presenta%on  (LB17).  

Subject  DisposiMon  

121  subjects  randomized  and  treated  

213  subjects  screened  

Risankizumab  600  mg  (n=41)  

Placebo  (n=39)  

Risankizumab  200  mg  (n=41)  

Risankizumab  600  mg  (n=34)  

Risankizumab  600  mg  (n=33)  

Risankizumab    180  mg  (n=21)  

Risankizumab    180  mg  (n=19)  

Risankizumab    180  mg  (n=22)  

Completed  (n=19)  

Completed  (n=16)  

Completed  (n=19)  

62  subjects    in  clinical  remission  entered  

Period 3 Open-label sc

maintenance therapy

Period 1 Blinded iv

induction therapy

Period 2 Open-label iv

therapy/washout

3  discon%nued  the  study:  • Protocol  viola%on  =  2  

• Withdrawal  =  1  

3  discon%nued  the  study:  • AE  =  2  

• Withdrawal  =  1  

2  discon%nued  the  study:  • Other  =  1  

• Withdrawal  =  1  

Washout  (n=5)  

Washout  (n=1)  

AE,  adverse  event;  iv,  intravenous;  sc,  subcutaneous.  

Risankizumab  600  mg  (n=34)  

12.8  

2.6  0  

26.8  

14.6  

2.4  

36.6  

19.5  

12.2  

31.7  

17.1  

7.3  

0  

5  

10  

15  

20  

25  

30  

35  

40  

Endosc.  response   Endosc.  remission   Deep  remission  

Placebo  (N=39)   200  mg  risankizumab  (N=41)   600  mg  risankizumab  (N=41)   Pooled  risankizumab  (N=82)  

*p<0.05,  **p<0.005,  ***p<0.001,  all  comparisons  versus  placebo.  FAS  was  used  for  this  analysis,  using  NRI  for  missing  values  and  stra%fied  Cochran–Mantel–Haenszel  tests.  Clinical  response  is  defined  as  a  CDAI  of  <150  points  or  a  CDAI  reduc%on  from  baseline  of  ≥100  points.  Clinical  remission  is  defined  as  a  CDAI  of  <150.  Endoscopic  response  is  defined  as  a  >50%  reduc%on  in  CDEIS  from  baseline  to  Week  12.  Endoscopic  remission  is  a  CDEIS  of  ≤4  at  Week  12  (for  subjects  with  ini%al  isolated  ilei%s,  CDEIS  score  of  ≤2).  Deep  remission  is  defined  as  clinical  remission  and  endoscopic  remission  at  Week  12.    CDAI,  Crohn's  Disease  ac%vity  index;  CDEIS,  Crohn's  Disease  endoscopic  index  of  severity;  FAS,  full  analysis  set;  NRI,  non-­‐response  imputa%on.  Feagan  B,  et  al.  Lancet  2017;389:1699–1709.  

Induction Treatment Outcome

7.7  

2.6  

15.4  

9.8  

17.1  

24.4  

19.5  

24.4  

36.6  

14.6  

20.7  

30.5  

0  

5  

10  

15  

20  

25  

30  

35  

40  

Week  4   Week  8   Week  12  

Prop

or%o

n  of  sub

jects  (%

)  

Endoscopic  endpoints  at  Week  12  

Clinical  remission  over  Mme  through  Week  12  

*  

**  

***  

*  

*  

Primary  endpoint  

*  

*  

*  

*  

*  **  

*  

*  

AnM  IL-­‐23  in  UC  

•  Dose increased in 50 and 200 mg patients at Weeks 4 and 8 if serum trough concentrations fell below 0.5 ug/ml and 2.0 ug/ml, respectively.

•  Subjects with lowest concentrations had highest dose increase based on pre-specified algorithm.

                                 Clinical  Remission  at  Week  12  

NRI: all patients who discontinued from the study at any time prior to week 12 for any reason or failed to have an adequate week 12 efficacy assessment were considered non-responders at week 12.

Oral Peptides

•  GI-restricted α4β7-specific blocker •  Small constrained peptide •  ~2.5 kDa

•  Oral, once daily dosing

•  Blood-based PD biomarkers reflect local target engagement with effects on trafficking

Briskin M, et al Am J Pathol. 1997;151:97-110

PTG-­‐100  Oral  α4β7-­‐  specific,  GI-­‐Restricted,  Targeted  Therapy  for  IBD      

Phase  2  PROPEL  Study  in  UlceraMve  ColiMs  Randomized, double-blind, placebo-controlled adaptive parallel design

300 mg QD

Placebo

900 mg QD

150 mg QD

Interim Analysis n = 65

Inte

rim A

naly

sis

Criteria Stool Frequency

Rectal Bleeding

Endo-scopy

Total Score

Score 0-1* 0 0-1 0-2

* change of one or more from baseline

Adhering to the most current and stringent definition of clinical remission

Interim futility analysis based on 1° end point of clinical remission

0  

2  

4  

6  

8  

10  

12  

14  

16  

18  

20  

Placebo  (N=17)  

 150  mg  (N=16)  

300  mg  (N=16)  

900  mg  (N=16)  

6%   6%  

13%  

19%  

%  Rem

ission

 (Re-­‐Re

ad)  

PTG-­‐100  Re-­‐Analysis  Based  on  Endoscopy  Re-­‐Reads  Interim  dataset  summary  (n  =  65)    

Sandborn WJ, et. al. United European Gastroenterology Week 2018, LB03

Defined  as  an  RHI  score  ≤  3  at  Week  12  

0

[VALUE]%

[VALUE]%

[VALUE]%

0

5

10

15

20

25

30

35

40

45

50

PBO (n=13) 150 mg (n=13) 300 mg (n=9) 900 mg (n=16)

% H

isto

logi

c R

emis

sion

Dose-­‐Dependent  Increase  in  Rates  of  Histologic  Remission  

Topics  for  Discussion    

•  Today: Current treatments and their limitations

•  Tomorrow: Next generation biologics

•  Future treatment paradigms

•  Conclusions

50

(Near) Future  DirecMons  II    •  Notwithstanding access issues, TNF antagonists will evolve to second

line agents within the next 5 years because of safety concerns

•  Vedo is likely to become the first line agent for UC, Uste for CD

•  In the interim, treatment targets will need to be re-calibrated – downwards in CD; upwards in UC (histopathology?)

•  We still have low absolute corticosteroid –free remission rates with our best therapies

•  Payors are exhausted – we need cost-effective solutions

•  How do we get there?--- Ultimately two solutions :

•  1) combination therapy a la Gilead model

•  2) clinical prediction rules to identify high risk patients for early treatment

Wang P et al. J Immunol 2016; 197:665-673

Global Airline Networks !

There is a well described path forward…

Clinical Prediction Rules

Clinical  PredicMon  Tool  for  Vedolizumab  in  CD  

Dulai  PS  et  alGastroenterology.  2018  Sep;155(3):687-­‐695.,    

Topics  for  Discussion    

•  Today: Current treatments and their limitations

•  Tomorrow: Next generation biologics

•  Future treatment paradigms

•  Conclusions

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