1. Pharmascape
Psoriasis therapy: today & tomorrow
All information herein is publically available
This document is meant only to illustrate Oliver Vit’s professional competences
and does not reflect Actelion Pharmaceuticals Ltd s corporate views
Ltd’s
3. Psoriasis therapies; EU market protection estimates
1st
Indication Use in
Parent Market Parent psoriasis Market
patent authorisation patent patent SPC exclusivity
Compound Parent patent # filing (estimated) expiry expiry (estimated) (estimated)
Enbrel EB 0418014 10-Sep-90 03-Feb-00 10-Sep-10 31-Jan-15 03-Feb-10
Remicade EP 0610201 18-Mar-92 13-Aug-99 18-Mar-12 12-Aug-14 13-Aug-09
Humira EP 0929578 10-Feb-97 08-Sep-03 10-Feb-17 16-Apr-18 08-Sep-13
Stelara
S EP 1309692 07-Aug-01
0 01 16-Jan-09
16 09 07-Aug-21
0 21 15-Jan-24
1 24 16-Jan-19
16 19
Briakinumab EP 1175446* 24-Mar-00 (Apr-11) 24-Mar-20 (24-Mar-25) (Apr-21)
* may not be granted
3 Life Cycle Management
Competitive intelligence analysis
4. Psoriasis therapies; US market protection estimates
1st
Use in Indication Use in
Parent Use in psoriasis Market Parent psoriasis PT
patent psoriasis patent authorisation patent patent extension
Compound Parent patent # filing patent # filing (estimated) expiry expiry (estimated)
Enbrel Re.36,755 10-May-90 US 5,605,690 08-Feb-95 02-Nov-98 07-Mar-12 25-Feb-14 23-Oct-12
Remicade US 6284471 04-Feb-94 24-Aug-98 04-Sep-18 none
Humira US 6090382 09-Feb-96 31-Dec-02 09-Feb-16 31-Dec-16
Stelara
St l US 6902734 01-Aug-01
01 A 01 (Oct-09)
(O t 09) 24-Jul-22
24 J l 22 (Oct-23)
(O t 23)
Briakinumab US 6914128 24-Mar-00 (Apr-11) 24-Mar-20 (Aug-23)
4 Life Cycle Management
Competitive intelligence analysis
6. Dosing regimens for adults US & EU
Rheumatoid Psoriatic Ankylosing Plaque
Arthritis* Arthritis Spondylitis Psoriasis
25 mg twice weekly
Enbrel® or
25 mg twice weekly 50 mg weekly
(etanercept)
or or
subcutaneous 50 mg weekly 50 mg twice weekly for 12 weeks
injections followed by 50 mg weekly
y g y
(max 24 weeks in EU)
Annual cost
€13,400 €19,326*
per patient $20,190 $24,848**
(ex-factory price)
Annual global sales
$3.6 bio
(2008)
* Average of FR & DE prices & based on 1 yr continuous use
** Wholesale Acquisition Cost (WAC)
6 Life Cycle Management
Competitive intelligence analysis
7. Dosing regimens for adults US & EU
Rheumatoid Psoriatic Ankylosing Crohn‘s Ulcerative Plaque
Arthritis* Arthritis Spondylitis Disease Colitis Psoriasis
3 mg/kg induction
3 mg/kg weeks 2 & 6
g g
Remicade® 5 mg/kg induction
3 mg/kg every 8
(infliximab) weeks 5 mg/kg weeks 2 & 6
Incomplete 5 mg/kg every 8 weeks
intravenous infusion responders up to
7.5mg/kg
7 5mg/kg
Annual cost per patient €17,400 €21,573*
(ex-factory price) $19,510 $21,166**
Annual global sales
$3.7 bio
(2008)
* Average of FR & DE prices & based on 1 yr continuous use
** Wholesale Acquisition Cost (WAC)
7 Life Cycle Management
Competitive intelligence analysis
8. Dosing regimens for adults US & EU
Psoriatic Ankylosing Crohn‘s Plaque
Rheumatoid Arthritis Arthritis Spondylitis Disease Psoriasis
Humira®
80 mg induction
g
(adalimumab)
( ) 80 mg induction
i d ti
40 mg every other week 40 mg at week 3
40 mg every
subcutaneous (12 week maximum exposure for Pso.Ar. & A.S.) 40 mg every other week
other week
injections
Annual cost
€14,200 €3,300 €14,700 €15,898*
per patient $18,886 $18,886 $20,339 $18,886**
(ex-factory price)
Annual global sales
$4.5 bio
(2008)
* Average of FR & DE p
g prices & based on 1 y continuous use
yr
** Wholesale Acquisition Cost (WAC)
8 Life Cycle Management
Competitive intelligence analysis
9. Prescribing paradigm
• Enbrel® i li
E b l® is licensed f chronic th
d for h i therapy i th US & ≤ 24 weeks i th EU
in the k in the
• Remicade® is licensed for chronic therapy in both the US & EU
• Humira® is licensed for chronic therapy in both the US & EU
• Stelara® is licensed for chronic therapy in the EU
• Treatment of psoriasis may vary from the label & is dependent upon
– visible efficacy
– long term side effects; both perceived & real
–d t
doctor-patient relationship
ti t l ti hi
• Awareness of malignancies & serious opportunistic infections is on the rise
9 Life Cycle Management
Competitive intelligence analysis
10. Enbrel® (etanercept)
• Dimeric fusion protein which binds TNFα and lowers the concentration of free TNFα
left in circulation
• Dosing regimens vary geographically with a 24 week maximum treatment period in
the EU and no cap in the US; yearly treatment with 50 mg weekly subcutaneous
injections is on the rise
• 34% of 25 mg twice weekly patients reached PASI 75 @ week 12 with continued
improvement to 44% @ week 24 in Study-2
• SAEs: malignancies (breast and lung carcinomas, lymphomas, non-melanoma skin
cancers), demyelinating disorders, fatal haematological reactions, fatal bacterial,
viral & fungal opportunistic infections including TB and hepatitis B reactivation
• 7% of patients tested positive for anti-etanercept antibodies after 1 year
• Contraindicated with Anakinra®, abatacept, sulfasalazine, cyclophosphoamides,
congestive heart failure, alcoholic hepatitis, Wegener‘s granulomatosis and live
vaccines
• No signals from developmental toxicity study in rats & rabbits; long term
observational pregnancy registry in place
• No head-to-head comparative trials
• Abandoned indications: idiopathic pulmonary fibrosis asthma uveitis cachexia
fibrosis, asthma, uveitis, cachexia,
myelodysplastic syndrome, congestive heart failure, Wegener‘s granulomatosis
10 Life Cycle Management
Competitive intelligence analysis
11. Enbrel® – Development overview
1997 1998 1999 2000 2001 2002 2003 2004 2005 2006 2007 2008 2009
RA PsA AS Pso
MA MA MA MA
Rheumatoid Arthritis
Study I / II / III
3 Phase III registration trials
Psoriatic Arthritis
NCT00317499
single Phase III registration
Ankylosing spondylitis
single Phase III registration
Psoriasis
Study I / II
2 Phase III registration trials
11 Life Cycle Management
Competitive intelligence analysis
12. Enbrel® – Psoriasis development
1998 1999 2000 2001 2002 2003 2004 2005 2006 2007 2008 2009 2010
Study-1
20021632
Study-2
20021639
NCT00121615
OL ext
NCT00111449
50 mg twice weekly
NCT00333034
50 mg once weekly
NCT00110981
UVB combination Tx
MAA MA Launch
12 Life Cycle Management
Competitive intelligence analysis
13. Remicade® (infliximab)
• Chimeric monoclonal antibody targeting TNFα delivered by i.v. infusion 5 mg/kg at
weeks 0, 2 & 6 followed by maintainance infusions every 8 weeks
• 80% of patients in EXPRESS I acheived PASI 75 with 5 mg/kg by week 10
sustained at 82% PASI 75 @ week 24, p<0.001;
• EXPRESS II demonstrates better efficacy of chronic over cyclical therapy
• SAEs include malignancies, serious infections (bacterial, viral, fungal) &
cardiovascular events
• Most common AEs: arthralgia, nasopharyngitis, URT infections, cough, injection site
reactions, headache
• Black box warning: serious & fatal fungal, viral & bacterial infections inclusive of TB,
and hepatosplenic T-cell lymphomas
• ~20% of patients develop infliximab antibodies and efficacy wanes over time
• Contraindicated with mild-to-severe heart failure and live vaccines
• No developmental toxicity results available; administration to pregnant women
limited by medical need
• Early development strategy was to use pivotal Phase IIb trial data in conjunction with
single Phase III trial experience with multiple label extensions per indication
• Abandoned indications: congestive heart failure asthma, COPD, sarcoidosis,
failure, asthma COPD sarcoidosis
multiple myeloma
13 Life Cycle Management
Competitive intelligence analysis
14. Remicade® – Development overview
1997 1998 1999 2000 2001 2002 2003 2004 2005 2006 2007 2008 2009
Crohn‘s RA AS PsA UC Pso
MA MA MA MA MA MA
Crohn‘s disease
ACCENT I
single Phase III registration
i l Ph i t ti
Rheumatoid Arthritis
ATTRACT
single Phase III registration
Ankylosing spondylitis
NCT00207701
single Phase III registration
Psoriatic Arthritis
NCT00051623
single Phase III registration
Ulcerative Colitis
UCI NCT00096655 & UC II NCT00036439
2 Phase III trials
Psoriasis
EXPRESS I NCT00106834
14 Life Cycle Management EXPRESS II NCT00106847
Competitive intelligence analysis 2 Phase III trials
15. Remicade® – Psoriasis development
1999 2000 2001 2002 2003 2004 2005 2006 2007 2008 2009 2010 2011
SPIRIT
Phase IIb
EXPRESS I
EXPRESS II
NCT00687401
Standard Tx & biologic Tx failures
NCT00251641
MTX head-to-head
NCT00358670
OL ext
NCT00527072
Etanercept Tx failures
NCT00833053 dose optimization
p
NCT00686595
Etanercept switch
Long term observation, registry &
cross-indication surveillance
MAA MA Launch
15 Life Cycle Management
Competitive intelligence analysis
16. Humira® (adalimumab)
• Fully humanized TNFα inhibitor
• Dosing regimen of subcutaneous injection of 40 mg every other week
• 71% of patients acheive PASI 75 by week 12 in Study Ps-I
• 28% of patients lose adequate response by week 52 as defined by a 50%
p q p y y
reduction from baseline improvement witnessed at week 33
• SAEs include malignancies, cardiovascular events & serious infections
• Most common AEs: infections, injection site reactions, headache, & rash
j
• Black box warning: TB, invasive fungal infections & other occassionally fatal
opportunistic infections
• Contraindicated with Anakinra® and live vaccines
• No signals from perinatal toxicity study in cynomolgus monkey; long term
observational pregnancy registry in place
• Development abandoned in asthma
16 Life Cycle Management
Competitive intelligence analysis
17. Humira® – Development overview
2000 2001 2002 2003 2004 2005 2006 2007 2008 2009 2010 2011 2012
RA PsA AS CD Pso JIA UC
MA MA MA MA MA MA MA
Rheumatoid Arthritis
Studies I / II / III / IV / V
5 Phase III registration trials
Psoriatic Arthritis Study
PsA-I, NCT00646386
NCT00646178
2 Phase III registration trials
Ankylosing spondylitis
NCT00085644
single Phase III registration trial
Crohn‘s Disease
CD-II, NCT00105300
CD-III, NCT00077779
2 Phase III registration trials
Psoriasis
Ps-I, NCT00237887
single Phase III registration trial
Juvenile Idiopathic Arthritis
NCT00237887
single Phase III registration trial
Ulcerative Colitis
17 Life Cycle Management NCT00408629 & NCT00385736
Competitive intelligence analysis 2 Phase III registration trials
18. Humira® – Psoriasis development
2000 2001 2002 2003 2004 2005 2006 2007 2008 2009 2010 2011 2012
NCT00646191
NCT00645905
NCT00645892
OL extention
Study Ps-II
Study Ps-I
Ps I
NCT00566722
OL in suboptimal response patients
CHAMPION
MTX & placebo controlled
NCT00195676
Phase III catch-all OL extention
NCT00735787
Hands & Feet
ESPRIT, NCT00799877
10 year post marketing safety study
MAA MA Launch
18 Life Cycle Management
Competitive intelligence analysis
19. Ustekinumab
• Fully humanized anti IL-12/23 antibody delivered by subcutaneous injection via
anti-IL
induction at weeks 0 & 4 followed by quarterly maintainance regimen
• 67% of patients in both PHOENIX trials acheived PASI 75 with 45 mg, the lower
dose, by week 12, p<0.0001; maximum effect 75% PASI 75 @ week 20 with 45 mg
y g
• SAEs include malignancies, serious infections (bacterial, viral, fungal) &
cardiovascular events
• Most common AEs: arthralgia, nasopharyngitis, URT infections, cough, injection site
reactions, headache
• Marketed as Stelara® in EU, US & CA for psoriasis
• Additional indications
– Psoriatic arthritis
– Crohn‘s disease
– previously abandoned MS
• Ustekinumab specific antibodies noted i 5% of patients
U ki b ifi ib di d in % f i
19 Life Cycle Management
Competitive intelligence analysis
20. Ustekinumab – Development overview
2005 2006 2007 2008 2009 2010 2011 2012 2013 2014 2015 2016 2017
NCT00267956
Psoriatic arthritis
x
NCT00771667
Crohn‘s disease
(pivotal IIb/III)
Crohn‘s disease
(confirmatory III)
PHOENIX I
Psoriasis
P i i
PHOENIX II
Psoriasis
MAA MA Launch MAA MA Launch
20 Life Cycle Management
Competitive intelligence analysis
21. Ustekinumab – Psoriasis development
2002 2003 2004 2005 2006 2007 2008 2009 2010 2011 2012 2013 2014
NCT00320216 x
PHOENIX I
PHOENIX II
PHOENIX 5yr OL
NCT00454584
Enbrel® controlled
x
NCT00723528 JP
NCT00747344 KR TW
MAA MA Launch
21 Life Cycle Management
Competitive intelligence analysis
22. Efficacy & median time to relapse
Half life Elimination PASI 75 Median time to relapse
(t1/2) (5 x t1/2) (50%≤PASI 50)
Enbrel 0.6 weeks 3 weeks 34% @ week 12 12 weeks1
(etanercept)
Remicade ~ 1.5 weeks ~ 7.5 weeks 80% @ week 10 >20 weeks2
(infliximab)
Humira ~ 2 weeks ~ 10 weeks 71% @ week 12 ~ 24 weeks3
(adalimumab)
Stelara ~ 3 weeks ~ 15 weeks 67% @ week 12 ~ 24 weeks4
(ustekinumab)
1 http://www.wyeth.com/news/archive?nav=display&navTo=/wyeth_html/home/news/pressreleases/2004/1145887154280.html
22 Life Cycle Management 2 SPIRIT trial, http://www.mims.co.uk/news/891873/Remicade-approved-use-psoriasis/
3 Study Ps-I, Extrapolated from graph
Competitive intelligence analysis 4 Phoenix I, trial Etrapolated from graph
23. Psoriasis therapy: competitive environment
IL-12/IL-23 inhibitor TNFα inhibitor
CNTO 1959
ART621
Briakinumab
Phase I Phase II Phase III Launched
BMS-582949
CP-690.550
R348
JAK inhibitor
p38 kinase
inhibitor
23 Life Cycle Management
Competitive intelligence analysis
24. Compounds in clinical development for psoriasis
Briakinumab, ABT874
ART621
BMS-582949
CP-690.550
R348
CNTO 1959
24 Life Cycle Management
Competitive intelligence analysis
25. Briakinumab
• Fully humanized anti-IL-12/23 antibody
anti IL 12/23
• Monthly subcutaneous injection with 200 mg induction at weeks 0 & 4 followed by
100 mg monthly maintainance regimen; t½ ~ 8- 10 days
• Positive results from 180 patient Phase IIb trial
• 90% reach PASI 75 by week 12, p<0.001 and 3 months following cessation 85%
maintain at least PASI 50 with one 200 mg injection/week for 4 weeks
• Patients were allowed to relapse in a 12 week blinded withdrawal period; 69%
regain PASI 75 within 12 weeks following retreatment
• Well tolerated; no SAEs, most common AEs: injection site reactions,
nasopharyngitis, URT infections
• Comparator trials versus Enbrel® and MTX (ongoing)
• Phase III results expected 04Q09; filing in 2010
• Additional indications
– Crohn‘s disease
– previously abandoned MS & RA programs
25 Life Cycle Management
Competitive intelligence analysis
26. Briakinumab – Psoriasis development
2002 2003 2004 2005 2006 2007 2008 2009 2010 2011 2012 2013 2014
NCT00292396
NCT00570986
NCT00691964
Enbrel® head-to-head
placebo controlled
NCT00710580
Enbrel® head-to-head
placebo controlled
NCT00679731
MTX controlled
NCT00626002
OL catch-all ext.
NCT00870948
Bioavailability for CMC process
MAA MA Launch
26 Life Cycle Management
Competitive intelligence analysis
27. ART621
• Subcutaneous anti-TNFα monoclonal antibody; i
S b t ti TNF l l tib d incorporates d
t domain i
antibodies (dAb) which being smaller improves manufacturing yield, lowers
immunogenicity and improves tissue penetration
• PoC
– factorial-design, randomised, double-blind, placebo-controlled, dose
optimisation, pharmacokinetics, safety, efficacy study
– multiple dose administration of ART621.
lti l d d i i t ti f ART621
– 1 site in NZ
– results from Mar09; well tolerated and exhibiting a safety profile
consistent with anti-TNF activity
i t t ith ti TNF ti it
• IND filed in Rheumatoid Arthritis
27 Life Cycle Management
Competitive intelligence analysis
28. BMS-582949
• Oral
O l once daily p38 mitogen-activated protein (MAP) kinase inhibitor
d il 38 it ti t d t i ki i hibit
promising to halt the inflammatory cytokine cascade
• 99 patient 12 week PoC in psoriasis completed in Apr09
• previously abandoned Eczema/dermatitis
• other p38MAP kinases abandoned due to toxicity
– Johnson & Johnson, talmapimod
p
– Vertex, VX-745
28 Life Cycle Management
Competitive intelligence analysis
29. CP-690550
• Selective oral JAK-3 inhibitor (IL-2,4,7,9,15,21 receptors only) which limits the
effects to T and NK cell development and B-cell function
B cell
• Preclinical models show efficacy
– arthritis
– asthma
– transplant
• Additional indications: Crohn‘s disease, Rheumatoid Arthritis, psoriasis,
renal t
l transplant
l t
• NK cell levels reduced with no reduction in CD4+ or CD8+ levels
Results from
58 patient PoC
29 Life Cycle Management
Competitive intelligence analysis
30. CP-690550
• Phase II trials
– Dose dependent increase in HDL & LDL levels
– Increased ALT & AST levels > 3 x ULN
– 3 sudden cardiac deaths
• 1 in 12 week study
• 2 in long term follow-up 6-12 months
– 9 serious infections in 9 patients
• Bacterial
• Viral
• Fungal
30 Life Cycle Management
Competitive intelligence analysis
31. R348
• Oral d l JAK-3 Syk inhibitor
O l dual JAK 3 & S k i hibit
• EIM Jan08; combi SAD/MAD
• Preclinical models show efficacy
– arthritic symptoms, bone destruction & swelling
– psoriasis
– transplant
p
• Planned clinical programs
– psoriasis
– Rheumatiod Arthritis
– renal transplant
– Graft vs host disease
31 Life Cycle Management
Competitive intelligence analysis
32. CNTO 1959
• Fully humanized anti-IL-12/23 antibody
F ll h i d ti IL 12/23 tib d
• EIM June 2009
– Phase I placebo-controlled trial
– 3 US sites
– 71 healthy volunteers & psoriasis patients
– evaluating the PK p
g profile and antibody development with both i.v.
y p
infusion and subcutaneous formulations
– 11 month estimated duration
32 Life Cycle Management
Competitive intelligence analysis
33. Back-ups
33 Life Cycle Management
Competitive intelligence analysis
34. Enbrel® (etanercept)
• US label
– RA
• reducing signs and symptoms, inducing major clinical response,
inhibiting the progression of structural damage, and improving physical
function in patients with moderately to severely active rheumatoid
arthritis. ENBREL can be initiated in combination with MTX or used
alone
– Polyarticular juvenile idiopathic arthritis
• reducing signs and symptoms of moderately to severely active
polyarticular juvenile idiopathic arthritis in patients ≥ 2 yrs
– Psoriatic arthritis
• reducing signs and symptoms, inhibiting the progression of structural
damage of active arthritis and improving physical function in patients
arthritis,
with psoriatic arthritis. ENBREL can be used in combination with MTX
for those patients who do not respond adequately to MTX alone
34 Competitive intelligence analysis
35. Enbrel® (etanercept)
• US label, continued
– Ankylosing spondylitis
• reducing signs and symptoms in patients with active ankylosing
spondylitis
– Plaque psoriasis
• treatment of patients ≥ 18 yrs with chronic moderate to severe plaque
psoriasis who are candidates for systemic therapy or phototherapy
35 Competitive intelligence analysis
36. Enbrel® (etanercept)
• EU label
– RA
• in combination with MTX for the treatment of moderate to severe active
rheumatoid arthritis in adults when the response to disease-modifiying
antirheumatic drugs including MTX (
g g (unless contraindicated) has been
)
inadequate
• can be given as monotherapy in case of intolerance to MTX or when
continued treatment with MTX is inappropriate
• treatment of severe, active and progressive rheumatoid arthritis in
adults not previously t t d with MTX
d lt t i l treated ith
• alone or in combination with MTX, Enbrel reduces the rate of
progression of joint damage as measured by X-ray and to improve
physical function
– Polyarticular juvenile idiopathic arthritis
• treatment of active polyarticular juvenile idiopathic arthritis in children
and adolescents ≥ 4 yrs who have had an inadequate response to, or
who have proved intolerant of, MTX. Enbrel has not been studied in
children < 4yrs
36 Competitive intelligence analysis
37. Enbrel® (etanercept)
• EU label, continued
,
– Psoriatic arthritis
• treatment of active and progressive psoriatic arthritis in adults when the
response to previous disease-modifying antirheumatic drug therapy has
been inadequate. Enbrel has been shown to improve physical function
in patients with psoriatic arthritis and to reduce the rate of progression
arthritis,
of peripheral joint damage as measured by X-ray in patients with
polyarticular symmetrical subtypes of the disease
– Plaque psoriasis
• treatment of adults with moderate to severe plaque psoriasis who failed
to
t respond t or who h
d to, h have a contraindication t or are i t l
t i di ti to, intolerant t
t to
other systemic therapy including cyclosporine, MTX and PUVA
– Paediatric plaque psoriasis
• treatment of chronic severe plaque psoriasis in children and
adolescents ≥ 8 years who are inadequately controlled by, or are
y q y y,
intolerant to, other systemic therapies or phototherapies
– Ankylosing spondylitis
• treatment of adults with severe active ankylosing spondylitis who have
has an inadequate response to conventional therapy
37 Competitive intelligence analysis
38. Remicade® (infliximab)
• US label
– Rheumatoid arthritis
• REMICADE, in combination with MTX, is indicated for reducing signs
and symptoms, inhibiting the progression of structural damage, and
improving physical function in patients with moderate to severely active
rheumatoid arthritis
h t id th iti
– Crohn‘s disease
• REMICADE is indicated for reducing signs and symptoms and inducing
and maintaining clinical remission in adult and pediatric patients with
moderately se erel acti e
moderatel to severely active Crohn‘s disease who ha e had an
ho have
inadequate response to conventional therapy
• REMICADE is indicated for reducing the number of draining
enterocutaneous and rectovaginal fistulas and maintaining fistula
closure in adult patients with fistulizing Crohn‘s disease
Crohn s
– Ankylosing spondylitis
• REMICADE is indicated for reducing signs and symptoms in patients
with active ankylosing spondylitis
38 Competitive intelligence analysis
39. Remicade® (infliximab)
• US label, continued
– Ulcerative colitis
• REMICADE is indicated for reducing signs and symptoms, inducing and
maintaining clinical remission and mucosal healing, and eliminating
corticosteroid use in patients with moderately to severely active
ulcerative colitis who have had an inadequate response to conventional
q p
therapy
– Psoriatic arthritis
• REMICADE is indicated for reducing signs and symptoms of active
arthritis, inhibiting the progression of structural damage, and improving
physical function in patients with psoriatic arthritis
– Plaque psoriasis
• REMICADE is indicated for the treatment of adult patients with chronic
severe (i.e., extensive and/or disabling) plaque psoriasis who are
candidates for systemic therapy and when other systemic therapies are
medically less appropriate REMICADE should only be administered to
appropriate.
patients who will be closely monitored and have regular follow-up visits
with a physician
39 Competitive intelligence analysis
40. Remicade® (infliximab)
• EU label
– Rheumatoid arthritis
Remicade, in combination with MTX, is indicated for:
the reduction of signs and symptoms, as well as improving physical function in:
– patients with active disease when the response to disease-modifying anti-
rheumatic drugs (DMARDs), including MTX has been inadequate
(DMARDs)
– patients with severe, active and progressive disease not previously treated
with MTX or other DMARDs
In these patient populations, a reduction in the rate of the progression of joint
damage, as measured by X-ray, has been demonstrated
– Ulcerative colitis
Remicade is indicated for:
– treatment of moderately to severely active ulcerative colitis in patients who
have had an inadequate response to conventional therapy including
corticosteroids and 6-MP or AZA, or who are intolerant to or have medical
6 MP
contraindications for such therapies
– Ankylosing spondylitis
Remicade is indicated for:
– treatment of severe, active ankylosing spondylitis, in adult patients who have
responded inadeq atel to con entional therap
inadequately conventional therapy
40 Competitive intelligence analysis
41. Remicade® (infliximab)
• EU label, continued
– Adult Crohn‘s disease
Remicade is indicated for:
– treatment of severe, active Crohn‘s disease, in patients who have not
responded despite a full and adequate course of therapy with a corticosteroid
and/or immunosuppressant; or who are intolerant to or have medical
contraindications for such therapies
– treatment of fistulising, active Crohn‘s disease, in patients who have not
responded despite a full and adequate course of therapy with conventional
treatment (including antibiotics, drainage and immunosuppressive therapy)
– Paediatric Crohn‘s disease
Crohn s
Remicade is indicated for:
– treatment of severe, active Crohn‘s disease, in paediatric patients aged 6 to
17 years, who have not responded to conventional therapy including a
corticosteroid and an immunomodulator and primary nutrition therapy; or who
are intolerant to or have contraindications for such therapy Remicade has
therapy.
been studied only in combination with conventional immunosuppressive
therapy
41 Competitive intelligence analysis
42. Remicade® (infliximab)
• EU label, continued
– Psoriasis
Remicade is indicated for:
– treatment of moderate to severe plaque psoriasis in adults who failed to
respond to, or who have a contraindication to, or are intolerant to other
systemic therapy including cyclosporine, MTX and PUVA
cyclosporine
– Psoriatic arthritis
Remicade is indicated for:
– treatment of active and progressive psoriatic arthritis in adults when the
response to previous DMARD therapy has been inadequate
Remicade should be administered
– in combination with MTX
– or alone in patients who show intolerance to MTX or for whom MTX is
contraindicated
Remicade has been shown to improve physical function in patients with psoriatic
arthritis, and to reduce the rate of progression of peripheral joint damage as
measured by X-ray in patients with polyarticular symmetrical subtypes of the
disease
42 Competitive intelligence analysis
43. Humira® (adalimumab)
H i ® ( d li b)
• US label
– Rheumatoid arthritis
• reducing signs and symptoms, including major clinical response, inhibiting
the
th progression of structural damage, and i
i f t t ld d improving physical f
i h i l function i
ti in
adult patients with moderate to severely active disease
– Juvenile idiopathic arthritis
• reducing signs and symptoms of moderately to severely active polyarticular
juvenile idiopathic arthritis in patients ≥ 4yrs
– Psoriatic arthritis
• reducing signs and symptoms of active arthritis, inhibiting the progression of
structural damage, and improving physical function
– Ankylosing spondylitis
• reducing signs and symptoms in patients with active disease
– Crohn‘s disease
• reducing signs and symptoms and inducing and maintaining clinical
remission in adult patients with moderately to severely active Crohn‘s
disease who have had an inadequate response to conventional therapy therapy.
Reducing signs and symptoms and inducing clinical remission in these
patients if they have lost response to or are intolerant to infliximab
– Plaque psoriasis
• the treatment of adult patients with moderate to severe chronic plaque
psoriasis who are candidates f systemic th
i i h did t for t i therapy or phototherapy, and
h t th d
when other systemic therapies are medically less appropriate
43 Competitive intelligence analysis
44. Humira® (adalimumab)
H i ® ( d li b)
• EU label
– Rheumatoid arthritis
• Humira in combination with MTX is indicated for:
– the treatment of moderate to severe active rheumatoid arthritis in adult
patients when the response to disease-modifying anti-rheumatic drugs
including MTX has been inadequate
– the treatment of severe, active and progressive rheumatoid arthritis in
adults not previously t t d with MTX
d lt t i l treated ith
• Humira can be given as monotherapy in case of intolerance to MTX or
when continued treatment with MTX is inappropriate
• Humira has been shown to reduce the rate of progression of joint damage
as measured by X-ray and to improve p y
y y p physical function, when g
given in
combination with MTX
bi ti ith
– Polyarticular juvenile idiopathic arthritis
• Humira in combination with MTX is indicated for the treatment of active
polyarticular juvenile idiopathic arthritis, in adolescents aged 13 to 17 years
who have had an inadequate response to one or more disease-modifying
disease modifying
ant-rheumatic drugs (DMARDs). Humira can be given as monotherapy in
case of intolerance to MTX or when continued treatment with MTX is
inappropriate
– Ankylosing spondylitis
• treatment of adults with severe active ankylosing spondylitis who have had
an inadequate response to conventional therapy
44 Competitive intelligence analysis
45. Humira® (adalimumab)
• EU label, continued
– Crohn‘s disease
Crohn s
• treatment of severe, active Crohn‘s disease, in patients who have not
responded despite a full and adequate course of therapy with a
corticosteroid and/or an immunosuppressant; or who are intolerant to or
have medical contraindications for such therapies. For induction
p
treatment, Humira should be given in combination with corticosteroids.
Humira can be given as monotherapy in case of intolerance to
corticosteroids or when continued treatment with corticosteroids is
inappropriate
– Psoriasis
• treatment of moderate to severe chronic plaque psoriasis in adult patients
who failed to respond to or who have a contraindication to, or are intolerant
to other systemic therapy including cyclosporine, MTX or PUVA
– Psoriatic arthritis
• Humira is indicated for the treatment of active and progressive psoriatic
arthritis in adults when the response to previous disease-modifying anti-
rheumatic drug therapy has been inadequate. Humira has been shown to
reduce the rate of progression of peripheral joint damage as measured by
X ray
X-ray in patients with polyarticular symmetrical subtypes of the disease
and to improve physical function
45 Competitive intelligence analysis
62. Remicade® – Clinical trials overview
• SPIRIT (NCT00230529), Study III
– 2 doses vs placebo (2:2:1)
– 1° endpoints
• Proportion of p
p patients achieving ≥PASI 75 @ week 10
g
– 2° endpoints
• Anitbodies to infliximab
• QoL: DLQI
– 249 patients
– 26 week trial
• EXPRESS I (NCT00106834), Study I
– 1 dose vs placebo (4:1)
– 1° endpoints
d i
• Proportion of patients achieving PASI 75 @ week 10
– 2° endpoints
• Proportion of patients achieving PASI 75 @ week 24
• Proportion of patients with PGA score of cleared or minimal @ week 10, 24 & 50
• Proportion of patients @ week 10, 24, & 50 acheiving:
– PASI 50
– PASI 90
– % improvement in PASI from baseline
p
– % improvement in NAPSI
– 378 moderate-to-severe patients
– 66 week trial
– 7 months recruitment
– 32 sites
– 8 countries, (AT, BE, CA, CH, DE, DK, FR, UK, US)
• EXPRESS II (NCT00106847), Study II
– 2 doses vs placebo (2:2:1)
– 1° endpoints
• Proportion of patients achieving ≥PASI 75 @ week 10
– 2° endpoints
• Efficacy of 4 maintenance regimens
• QoL: DLQI, SF-36 & Economic Questionnaire
– 835 moderate-to-severe patients
– 66 week trial
– 6 months recruitment
– 63 sites
– 4 countries, (AT, CA, FR, IT, US)
62 Competitive intelligence analysis
63. Remicade® –SPIRIT; study design
2005 New Medicines Profile
Double blind core study Follow-up period
scr x 2 6 10 26 weeks
Infliximab 3 mg/kg
Infliximab 5 mg/kg
g g
Placebo
PASI
PGA
DLQI
63 Competitive intelligence analysis
65. Remicade® –SPIRIT; baseline characteristics
2004 Gottlieb J Am Acad Dermatol
65 Competitive intelligence analysis
66. Remicade® –SPIRIT; study results
2005 New Medicines Profile
Infliximab Infliximab Placebo
3 mg/kg 5 mg/kg
PASI 75 @ week 10
(p<0.001) 72% 88% 6%
DLQI
Median ∆ from baseline* -8 -10 0
(p<0.001)
* median baseline values 11,12,14 respectively
66 Competitive intelligence analysis
67. Remicade® –SPIRIT; study results
2004 Gottlieb J Am Acad Dermatol
67 Competitive intelligence analysis
68. Remicade® –SPIRIT; study results
2004 Gottlieb J Am Acad Dermatol
68 Competitive intelligence analysis
69. Remicade® –SPIRIT; study results
2004 Gottlieb J Am Acad Dermatol
69 Competitive intelligence analysis
70. Remicade® –SPIRIT; safety & tolerability
2004 Gottlieb J Am Acad Dermatol
70 Competitive intelligence analysis
71. Remicade® – EXPRESS I; study design
2005 Lancet, Infliximab induction and maintenance therapy
Double blind core study Follow-up period
scr x 2 6 10 14 22 24 26 30 38 46 50 66 weeks
Infliximab 5 mg/kg x x x x x x x x x x x
Placebo x x x x x x
PASI
PGA
NAPSI
[Infliximab
serum]
Infliximab antibodies
Anti-nuclear & anti-double
stranded DNA antibodies
71 Competitive intelligence analysis x 5 mg/kg adminsitration
79. Remicade® – EXPRESS I; antibody development
2005 Lancet, Infliximab induction and maintenance therapy
79 Competitive intelligence analysis
80. Remicade® – EXPRESS II; study design
2005 FDA website, Clinical Study Report
Double blind core study Follow-up
period
scr x 2 6 10 14 16 18 22 30 38 46 50 66 weeks
x x x x
Infliximab 3 mg/kg x x x x
x x x x
Infliximab 5 mg/kg x x x x x x x x x x
Placebo x x x
PASI
PGA
Infliximab antibodies
Anti-nuclear anti double
Anti nuclear & anti-double stranded DNA antibodies
80 Competitive intelligence analysis x 3 or 5 mg/kg group adminsitration
x placebo re-rand. group adminsitration
81. Remicade® – EXPRESS II; study results
2005 FDA website, Clinical Study Report
Infliximab Infliximab Placebo
3 mg/kg 5 mg/kg
≥ PASI 75 @ week 10
(p<0.001)
(p<0 001) 71% 76% 2%
PASI 90 @ week 10
(p 0 00 )
(p<0.001) 37% 45% 0.5%
0 5%
PGA score of excellent
or cleared @ week 10 70% 76% 1%
DLQI
Median ∆ from baseline
baseline* -9
9 -9
9 0
(p<0.001)
81 Competitive intelligence analysis * median baseline value 12
113. Ustekinumab – Clinical trials overview
• PHOENIX I (NCT00267969)
– 2 doses vs placebo (1:1:1)
– 1° endpoints
• Proportion of patients achieving PASI 75 @ week 12
– 2° endpoints
• Proportion of patients with PGA score of cleared or minimal @ week 12
• ∆ dermatology QoL @ week 12
• Time to loss of PASI 75 response following randomized withdrawal
– 766 moderate-to-severe patients
– 76 week trial
– 9 months recruitment
– 48 sites
– 3 countries (US, CA, BE)
• PHOENIX II (NCT00307437)
– 2 doses vs placebo (1:1:1)
– 1° endpoints
• Proportion of patients achieving PASI 75 @ week 12
– 2° endpoints
• Proportion of p
p patients with PGA score of cleared or minimal @ week 12
• ∆ dermatology QoL @ week 12
• # of visits with PASI 75 response between weeks 40 and 52 in the intensified groups compared to maintained dosing
– 1230 moderate-to-severe patients
– 6 months recruitment
– 70 sites
– 7 countries, (AT, CA, CH, DE, FR, UK, US)
113 Competitive intelligence analysis
114. Ustekinumab – PHOENIX I; study design
2008 Lancet, Efficacy and safety of ustekinumab
114 Competitive intelligence analysis
115. Ustekinumab – PHOENIX I; patient flow
2008 Lancet, Efficacy and safety of ustekinumab
115 Competitive intelligence analysis
116. Ustekinumab of ustekinumab
2008 Lancet, Efficacy and safety
– PHOENIX I; baseline characteristics
116 Competitive intelligence analysis
117. Ustekinumab of ustekinumab
2008 Lancet, Efficacy and safety
– PHOENIX I; endpoints & results
• Efficacy endpoints
– 1° endpoints
67% of patients achieving PASI 75 @ week 12 with 45 mg
f ti t hi i k ith
66% of patients achieving PASI 75 @ week 12 with 90 mg
76% of patients achieving PASI 75 @ week 24 with 45 mg
85% of patients achieving PASI 75 @ week 24 with 90 mg
85%
– 2° endpoints
Sustained improved PGA score of cleared or minimal @ week 12
Sustained improved ∆ dermatology QoL @ week 12
Median time to loss of PASI 75 response following randomized withdrawal
was 15 weeks
met x not met ~trend
117 Competitive intelligence analysis
122. Ustekinumab of ustekinumab
2008 Lancet, Efficacy and safety
– PHOENIX I; safety & tolerability
122 Competitive intelligence analysis
123. Ustekinumab – PHOENIX II; study design
2008 Lancet, Efficacy and safety of ustekinumab
123 Competitive intelligence analysis
124. Ustekinumab – PHOENIX II; patient flow
2008 Lancet, Efficacy and safety of ustekinumab
124 Competitive intelligence analysis
125. Ustekinumab – PHOENIX II; baseline characteristics
2008 Lancet, Efficacy and safety of ustekinumab
125 Competitive intelligence analysis
126. Ustekinumab of ustekinumab
2008 Lancet, Efficacy and safety
– PHOENIX II; endpoints & results
• Efficacy endpoints
– 1° endpoints
67% of patients achieving PASI 75 @ week 12 with 45 mg
76% of patients achieving PASI 75 @ week 12 with 90 mg
– 2° endpoints
Sustained improved PGA score of cleared or minimal @ week 12
Sustained improved ∆ dermatology QoL @ week 12
90 mg every 8 weeks was the only group to show an advantage with
intensified dosing
• Further analysis
• 75% of patients acheiving PASI 75 @ week 20 with 45 mg
• 84% of patients acheiving PASI 75 @ week 20 with 90 mg
• only 5-7% of all patients with less than PASI 50 @ week 28
t x not met ~trend
met t t t d
126 Competitive intelligence analysis
134. Briakinumab – Clinical trials overview
• Phase IIb NCT00292396
– 5 doses vs placebo (1:1:1:1:1:1)
– 1° endpoints
• Proportion of patients achieving PASI 75 @ week 12
– 180 patients
– 48 week trial
• Phase III NCT00570986
– 2 doses vs placebo (1:1:1)
– 1° endpoints
• Proportion of patients achieving PASI 75 @ week 12
• Proportion of p
p patients with PGA score of cleared or minimal @ week 12
• Proportion of patients maintaining PGA score of cleared or minimal @ week 52
– 2° endpoints
• ∆ DLQI score between baseline & week 12
• ∆ NAPSI score between baseline & week 12
• Proportion of patients achieving PASI 90 & 100 @ week 12
– 1465 moderate-to-severe patients
p
– 52 week trial
– 122 sites
– 2 countries, (CA, US)
134 Competitive intelligence analysis
135. Briakinumab – Clinical trials overview
• Phase III NCT00691964
– 1 dose vs Enbrel® vs placebo (1:1:1)
– 1° endpoints
• Proportion of patients achieving PASI 75 @ week 12
• Proportion of patients with PGA score of cleared or minimal @ week 12
– 2° endpoints
• Proportion of patients achieving PASI 100 @ week 12
– 347 patients
– 12 week trial
– 33 sites
– US only
• Phase III NCT00710580
– 1 dose vs Enbrel® vs placebo (1:1:1)
– 1° endpoints
• Proportion of patients achieving PASI 75 @ week 12
• Proportion of patients with PGA score of cleared or minimal @ week 12
– 2° endpoints
• Proportion of patients achieving PASI 100 @ week 12
– 350 patients
– 12 week trial
– 41 sites
– US only
• Phase III NCT00679731
– 1 dose vs MTX (1:1)
– 1° endpoints
• Proportion of patients achieving PASI 75 @ week 12
• Proportion of patients with PGA score of cleared or minimal @ week 12
• Proportion of patients achieving PASI 75 @ week 52
P i f i hi i k 2
• Proportion of patients with PGA score of cleared or minimal @ week 52
– 2° endpoints
• Proportion of patients achieving PASI 100 @ week 24
• ∆ DLQI from baseline @ week 24
• Proportion of patients achieving PASI 100 @ week 52
• ∆ DLQI from baseline @ week 52
– 317 patients
– 52 week trial
– 44 sites
– 14 countries (AT, BE, CA, CH, DE, DK, ES, FI, FR, GR, IT, NL, SE, UK)
135 Competitive intelligence analysis
136. Competitors in development
• Rejected for lack of efficacy or an unsuitable safety & tolerability profile
136 Competitive intelligence analysis
137. Golimumab
• Never assessed in plaque psoriasis
• Marketed as Simponi® for Rheumatoid Arthritis, Psoriatic Arthritis &
Ankolysing Spondylitis in the US & CA
• Clinical trials in Ulcerative Colitis ongoing
• previously abandoned Uveitis, Crohn‘s Disease, chronic asthma
137 Competitive intelligence analysis
138. Cimzia® (Certolizumab pegol)
• PEGylated Fc free anti-TNFα antagonist delivered by subcutaneous
Fc-free anti TNFα
injection; t½ ~ 2 weeks
• PoC
– 200 or 400 mg vs placebo every 2 weeks for 12 weeks
– 176 patients (1:1:1)
– 75% and 83% acheived PASI 75 respectively at week 12, p<0.001
– placebo like tolerability
• Registered in the US & CA for Crohn‘s Disease and Rheumatoid Arthritis
• EMEA rejected the MAA for Crohn‘s Disease citing low & potentially waning
efficacy and safety concerns of long-term immunosuppression;
opportunistic infections and malignancy
t i ti i f ti d li
• Phase III program in psoriasis terminated; UCB product pipeline lists
Crohn‘s Disease and Rheumatoid Arthritis in the EU only
• previously abandoned A k l i S
i l b d d Ankylosing Spondylitis, P i ti A th iti
d liti Psoriatic Arthritis
138 Competitive intelligence analysis
139. Cimzia® (Certolizumab pegol)
• US label
– Crohn‘s disease
• CIMZIA is a tumor necrosis factor (TNF) blocker indicated for:
– Reducing signs and symptoms of Crohn‘s disease and maintaining
clinical response in adult patients with moderately to severely active
disease who have had an inadequate response to conventional
therapy
– Rheumatoid arthritis
in combination with methotrexate (MTX), for the treatment of moderate to
severe active rheumatoid arthritis (RA) in adult patients when the
response to disease-modifying antirheumatic drugs (DMARDs)
disease modifying (DMARDs),
including MTX, has been inadequate. In these patients, Cimzia(R) can
be given as monotherapy in case of intolerance to MTX or when
continued treatment with MTX is inappropriate. Cimzia(R) has been
shown to reduce the rate of progression of joint damage as measured
by X-ray and to improve physical function, when given in combination
X ray
with MTX.
139 Competitive intelligence analysis
140. Apremilast
• Oral twice daily phosphodiesterase IV inhibitor promising to halt the
inflammatory cytokine cascade
• POC
– 260 patients, 20 mg BID vs placebo
– 24.4% reach PASI 75 at week 12 (p=0.023)
– 57% reach PASI 50 at week 12 (p<0.001)
– Placebo-like tolerability profile
• no SAE
SAEs
• most common AEs nausea, nasopharyngitis, headache and diarrhea
• Phase IIb
– 348 patients,10, 20, 30 mg BID vs placebo
patients 10 20
– exploring the % of patients reaching PASI 75 at week 16
– 10 sites, US only
– 6 month treatment period; study duration Sep08 – Sep09
140 Competitive intelligence analysis
141. Apremilast
• additional indications
– Psoriatic Arthritis; phase II
– Bechet‘s Syndrome; phase II
• IIS
– Discoid cutaneous lupus erythematosus
– Uveitis
– Chronic prostatitis & chronic pelvic syndrome
– Chronic cutaneous sarcoidosis
– Vulvodynia
– P i nodularis
Prurigo d l i
• previously abandoned asthma
141 Competitive intelligence analysis
142. Voclosporin
• Twice day
T i a d oral C l i
l Calcineurin i hibit promises superior efficacy th
i inhibitor; i i ffi than
cyclosporin-A with less toxicity
• Phase III psoriasis program completed in CA & EU Oct06; no registration
• Additional indications
– renal transplant
– Uveitis
142 Competitive intelligence analysis
143. Bimosiamose
• Subcutaneous i j ti of cell adhesion molecule (CAM) inhibitor which
S b t injection f ll dh i l l i hibit hi h
prevents the signaling leukocyte tethering to the vascular endothelial cells
• PoC ongoing
• No listing of the compound in Pfizer‘s pipeline
143 Competitive intelligence analysis
144. SCH 527123
• Once daily oral CXCR2/IL 8β G protein coupled receptor inhibitor
CXCR2/IL-8β G-protein
• Psoriasis development halted with Phase II; results available in Oct07,
however Product Pipeline Apr 09 mentions only COPD
144 Competitive intelligence analysis