2.2 biologics today and tomorrow feagan · 11/2/2018 · anm;p40!ustekinumab:!background!! nk or t...
TRANSCRIPT
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
57