Download The Next Wave of Psoriasis Drug Programs: Targeting IL

The Next Wave of Psoriasis
Drug Programs: Targeting
IL-17 and IL-23
PAMELA SPICER
ANALYST, CNS, AUTOIMMUNE/INFLAMMATION,
OPHTHALMOLOGY
2
Psoriasis is a chronic inflammatory condition that primarily
affects the skin but may also result in systemic inflammation
and related adverse consequences on a patient’s overall
health1. The disease affects between 1% and 5% of the global
population2. Mild forms of psoriasis may be treated with topical
therapies or phototherapy, but as disease severity increases,
systemic medications are prescribed in addition to topical
treatment. Many of the topicals have been met with a lack
of compliance among patients due to insufficient tolerability
and the requirement for daily application. Because traditional
oral systemic therapies have not proven to be as efficacious
as is necessary, anti-tumor necrosis factor (TNF) injectables
have been developed as label expansions from other inflammatory diseases. Despite the availability of these different
treatment options, many patients still do not respond fully
or are dissatisfied with these therapies3.
Recently, biological drugs targeting interleukin (IL)-23 and IL-17 have emerged for the
treatment of psoriasis. Stelara, which targets both IL-12 and IL-23, was first launched in
Europe in early 2009. Most recently, the anti-IL-17 drug Cosentyx was approved in Japan
in December 2014 and subsequently in the US and EU in January 2015. Currently, there
are two novel drugs in Phase III development that specifically block IL-23, tildrakizumab
and guselkumab. Additionally, two novel IL-17 targeting biologics are also in Phase III,
ixekizumab and brodalumab. This analysis explores strategies these novel drug programs
employ to leverage various aspects of their Phase III design in order to distinguish
themselves from one another, to outshine approved biologics, and to carve out a niche
in the highly competitive psoriasis market.
1 Chiricozzi A. and Krueger J.G. (2013) IL-17 targeted therapies for psoriasis. Expert Opin Investig Drugs. 2013
Aug;22(8):993-1005
2 Hudson V. (2014) Datamonitor Healthcare Report: Psoriasis Treatment, Reference: DMKC0046055
3 Brown G., Malakouti M., Wang E., Koo J.Y., Levin E. (2015) Anti-IL-17 phase II data for psoriasis:
A review. J Dermatolog Treat. 2015 Feb;26(1):32-6
3
Recently approved and pipeline IL-23 and IL-17
antagonists for psoriasis
Table 1. Phase III and Marketed IL-17 or IL-23 Targeting Psoriasis Drugs
COMPANIES
PHASE III INITIATION
MAJOR MARKET
LAUNCH DATE
TARGET
Stelara
(ustekinumab)
J&J
Q4 2005
Q1 2009 (Europe)
Q3 2009 (US)
Q1 2011 (Japan)
IL-12/IL-23
Cosentyx
(secukinumab)
Novartis
Q1 2011
Q4 2014 (Japan)
Q1 2015 (US &
Europe)
IL-17
ixekizumab
Lilly
Q4 2011
H1 2016 (US
predicted)
IL-17
brodalumab
Amgen/AZ/
Kyowa Hakko Kirin
Q3 2012
2016 (US predicted)
IL-17 receptor
tildrakizumab
Merck/Sun Pharma
Q4 2012
H2 2016 (US
predicted)
IL-23
guselkumab
J&J/MorphoSys
Q4 2014
2018 (US predicted)
IL-23
DRUG
Source: Citeline’s Trialtrove, Citeline’s Pharmaprojects, and Sagient Research Systems’ BioMedTracker (data accessed February 2015)
Since the approval of Stelara in 2008 five novel biologics have entered the global competition, as profiled
in Table 1. Eli Lilly’s ixekizumab program was the first of the current pipeline biologics to initiate Phase III
trials in psoriasis in late 2011. Retaining full rights to the IL-17 inhibitor, Eli Lilly has completed three large
Phase III UNCOVER trials. The Phase III trials for anti-IL-17 brodalumab began in late 2012, with Amgen
leading the global development and commercialization in collaboration with AstraZeneca. Amgen and
AstraZeneca have also successfully completed three Phase III trials in psoriasis as part of the AMAGINE
program, while Kyowa Hakko Kirin has rights to develop and market brodalumab in Asian markets.
Although Phase III development of anti-IL-23 tildrakizumab was initiated by Merck & Co. only a few months
after brodalumab’s Phase III program started in 2012, the two Phase III reSURFACE trials are still ongoing.
The program may have been delayed while agreements were forged for a partnership. Merck & Co.
granted Sun Pharmaceutical Industries (Sun Pharma) global rights to the monoclonal antibody in
September 2014, but continues to be responsible for development activities. Guselkumab, a monoclonal
antibody developed by MorphoSys that targets IL-23, is the most recent drug to initiate a Phase III
program. All Phase III trials are currently open to enrollment and are sponsored by Johnson & Johnson’s
Janssen subsidiaries, in accordance with a MorphoSys partnership agreement.
4
Study design: higher bars for trial outcomes
Predominantly, the primary endpoints used in plaque psoriasis trials are the Psoriasis Area and Severity
Index (PASI) and the Physician’s Global Assessment (PGA) scale. The PASI evaluates disease severity on
various regions of the body while accounting for the percentage of body surface area involvement4. In the
pivotal psoriasis trials for anti-TNF biologics that were run in the mid-2000s, PASI 75, or 75% improvement
in disease severity, was used as the standard primary outcome. Since then, psoriasis trials of biologics have
increasingly included PGA as a second co-primary outcome. Although European healthcare systems may
use PASI, the index is not commonly used in US clinical practice and has demonstrated inconsistent
reproducibility5. Both the EMA and FDA have recognized these limitations and there has been an ongoing
push from the FDA to move away from using PASI and toward PGA.
Primary endpoints, depicted in Figure 1, illustrate the current trends in study designs. The pivotal trials for
the first targeted IL-12/IL-23 biologic, Stelara, evaluated only PASI 75, which was in keeping with the design
of the earlier anti-TNF label expansion trials. However, the use of co-primary endpoints, PASI and PGA, in
each of the more recent programs is now observed. Of note, the addition of co-primary endpoints has not
impacted the primary outcome timeframes. The guselkumab program is also exploring improvement in
PGA as the single primary endpoint in the NAVIGATE trial, taking the next big step in the movement away
from PASI as the primary endpoint. Also of note, a planned ixekizumab study will evaluate the early onset
of clinical improvement by change in Patient’s, rather than Physician’s, Global Assessment of disease
severity score as the primary outcome.
The bar has also been raised for the degree of disease improvement required to meet these primary
endpoints. For example, the guselkumab program has replaced PASI 75 with PASI 90, as the co-primary
endpoint in the two VOYAGE trials. In addition, the brodalumab program included a third primary
endpoint in its AMAGINE-2 and -3 studies to evaluate PASI 100 (total skin clearance). The evolution of
primary endpoints for these biologics may reflect their necessity to outperform currently approved drugs
in order to penetrate an increasingly saturated market as well as a shift towards the use of outcomes that
will translate into the clinic.
4 Hudson V. (2014) Datamonitor Healthcare Report: Psoriasis Pipeline, Reference: DMKC0046055
5 Langley R.G., Feldman S.R., Nyirady J., van de Kerkhof P., Papavassilis C. (2015) The 5-point Investigator’s Global
Assessment (IGA) Scale: A modified tool for evaluating plaque psoriasis severity in clinical trials. J Dermatolog Treat.
2015 Feb;26(1):23-31
5
Figure 1. Primary Endpoints for IL-17 and IL-23 Antagonist Phase III Psoriasis Trials
tyx )
sen umab
o
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uk
sec
(us Stel
tek ara
inu
ma
b
)
(
PGA
ixekizumab
PGA
PASI 75
SI 7
PA
PG
A
I 90
PAS
5
PASI 75
tildrakizumab
5
PA
SI 7
SI 7
PA
5
PGA
PG
A
PGA
PAS
I 100
bro
da
lum
ab
ab
um
lk
use
g
Source: Citeline’s Trialtrove (data accessed February 2015)
The Phase III trials included are: ACCEPT, PHOENIX 1, and 2 for Stelara; ERASURE, FIXTURE, and
SCULPTURE for Cosentyx; UNCOVER-1, -2, and -3 for ixekizumab; AMAGINE-1, -2, and -3 for brodalumab;
reSURFACE-10 and -11 for tildrakizumab; and NAVIGATE, VOYAGE 1, and 2 for guselkumab. The Psoriasis
Area and Severity Index (PASI) is evaluated by percentage improvement in disease severity, for example
75%, 90%, or total clearance at 100%. The PGA measures the Physician’s Global Assessment scale.
6
Study design: active comparator selections
Another important distinguishing factor for pipeline biologics is how well they compare to established
biologic psoriasis treatments, which include Enbrel, Humira, Remicade, and Stelara. Figure 2 profiles the
active comparator trials for these biologics and highlights their outcomes (or current status). To date, none
of these programs have run trials comparing to Remicade, despite its high efficacy6. This may be due to
Remicade’s intravenous route of administration and its more limited approval for adult patients with
chronic severe plaque psoriasis.
Figure 2. Active Comparator Trials for IL-17 and IL-23 Antagonists in Psoriasis
5
4
Cosentyx
(secukinumab)
# of Trials
3
2
Cosentyx
(secukinumab)
UNCOVER-2
May 2012
(1,225 pts)
Superior
ixekizumab
1
tildrakizumab
0
FIXTURE
Jun 2011
1,307 pts
Superior
Enbrel
UNCOVER-3
Jul 2012
(1,225 pts)
Superior
reSURFACE-11
Feb 2013
(1,050 pts)
Closed
brodalumab
guselkumab
CLEAR
Feb 2014
679 pts
Superior
AMAGINE-2
Aug 2012
1,831 pts
140 mg - Failed
210 mg - Superior
VOYAGE 1
Nov 2014
(750 pts)
Open
AMAGINE-3
Sep 2012
1,881 pts
Superior
VOYAGE 2
Nov 2014
(1,000 pts)
Open
guselkumab
NAVIGATE
Oct 2014
(800 pts)
Open
Stelara
X-PLORE
Nov 2011
293 pts
+ vs pbo
Humira
Source: Citeline’s Trialtrove (data accessed February 2015)
Active comparators: Enbrel, Stelara, and Humira. Programs: IL-17 antagonists Cosentyx, ixekizumab, and
brodalumab; and IL-23 antagonists tildrakizumab and guselkumab. Protocol ID, start date, accrual, and
status or outcomes are provided from available information. Target accrual is represented in parentheses.
It is interesting to note that the Cosentyx program is the only IL-17 antagonist to have run active
comparator trials to both Enbrel and Stelara, two biologics with molecular targets distinct from its own.
In the FIXTURE and CLEAR studies, Cosentyx was demonstrated to be superior to both approved drugs.
The guselkumab program is the only one to use Humira as an active comparator in three trials (VOYAGE-1, -2
and X-PLORE) and is running an active comparator study with Stelara (NAVIGATE). As a result, guselkumab’s
VOYAGE 1 and 2 trials are reporting primary outcomes at 16 weeks, following Humira’s pivotal trials, rather
than the 12 week time point that the other programs are using in order to track with Enbrel and Stelara’s
primary outcome timeframes. While most of the guselkumab trials are currently still enrolling patients,
Johnson & Johnson reported that higher doses of guselkumab compared well against Humira in the
completed Phase II X-PLORE study, although this trial was not powered to demonstrate non-inferiority 7.
6 Hudson V. (2014) Datamonitor Healthcare Report: Psoriasis Marketed Drugs, Reference: DMKC0046514
7 BioMedTracker: Phase II - X-PLORE, Trial Data - Top-Line Results, data accessed February 2015
7
The recently completed programs for IL-17 antagonists, ixekizumab and brodalumab, ran active comparator
trials with only one of the approved biologics, Enbrel or Stelara, respectively. Eli Lilly reported that both
the UNCOVER-2 and -3 trials demonstrated ixekizumab superiority to Enbrel. Interestingly, ixekizumab’s
three Phase III UNCOVER trials were initiated sequentially over the course of eight months, but Eli Lilly
reported results from all three studies in a single press release that provided few details for the positive
results. In contrast, Amgen and AstraZeneca’s three large AMAGINE trials, which initiated over a twomonth period, reported positive results in separate press releases, each with detailed descriptions of
the efficacy outcomes. These reports revealed that in the AMAGINE-3 study, superiority was achieved
in PASI 100 and for the AMAGINE-2 study that PASI 100 outcomes for brodalumab dosed at 140 mg
were numerically higher, but not statistically superior, to Stelara. Considering that the Cosentyx program
included active comparator studies to both Enbrel and Stelara, it will be interesting to see the full clinical
results from the ixekizumab and brodalumab programs in order to gauge how they will be positioned in
the market relative to Cosentyx.
Scale and geographic scope of the phase III
psoriasis programs
An avid focus on developing targeted biologics for psoriasis therapies began with Johnson & Johnson’s
Stelara program and has continued with competition by other top 20 pharmaceutical sponsors, Novartis, Eli
Lilly, Amgen, AstraZeneca and Merck & Co. Considering the complexity of the study design for these trials,
it is interesting to look at which factors might dictate sizes of these large trials and their overall programs.
Figure 3 captures the size of various plaque psoriasis trials for the IL-17 and IL-23 antagonist programs.
The actual accrual is provided from available sources and the target patient accrual is provided for the
ixekizumab, tildrakizumab, and guselkumab trials.
Figure 3. Key Phase III Plaque Psoriasis Trials by Number of Patients
4500
AMAGINE-1
4000
UNCOVER-A
3500
JUNCTURE
FEATURE
3000
UNCOVER-1
# of Patients
AMAGINE-2
2500
ACCEPT
SCULPTURE
NAVIGATE
2000
1500
UNCOVER-2
PHOENIX 1
reSURFACE-10
FIXTURE
1000
500
0
8
VOYAGE 1
AMAGINE-3
PHOENIX 2
UNCOVER-3
ERASURE
Stelara
(ustekinumab)
Cosentyx
(secukinumab)
ixekizumab
brodalumab
Source: Citeline’s Trialtrove (data accessed February 2015)
reSURFACE-11
VOYAGE 2
tildrakizumab
guselkumab
The two largest programs, by number of participants in key Phase III trials, are currently brodalumab
and ixekizumab. Active comparator studies for each of these programs have thus far only run against a
single approved biologic, as shown in Figure 2. The two largest trials, brodalumab’s AMAGINE-2 and
AMAGINE-3, with an actual accrual of 1,831 and 1,881 patients, respectively, are the only trials to evaluate
a third primary efficacy endpoint. These two studies alone enrolled almost the same number of patients as
ixekizumab’s UNCOVER-1, -2, and -3 studies, whose accrual numbers are comparable to other programs
that also evaluated only two primary outcomes.
It is noteworthy that most of these large trials are enrolling around 300 patients per study arm, regardless
of whether or not an active comparator arm is included. This suggests that inclusion of active comparator
arms alone does not explain the scale of these studies and that the use of additional co-primary endpoints
may dictate larger patient accruals per trial.
Other factors contributing to the size of these programs include additional smaller trials run for several
programs, including Cosentyx’ (FEATURE and JUNCTURE) and ixekizumab’s (UNCOVER-A) trials to evaluate
the pre-filled syringe or auto-injector delivery systems. In addition, guselkumab’s NAVIGATE trial evaluates
patients with inadequate response to Stelara at week 16 who are then either switched to guselkumab
treatment or remain on Stelara. Moreover, the SCULPTURE trial examined the maintenance of fixed-interval
compared to retreatment-as-needed regimens of Cosentyx in PASI 75 responders at week 12.
The geographic scope of these psoriasis programs is also impressive. Figure 4 profiles the global regions
where each of the programs for recently approved and the pipeline biologics have run or are running
plaque psoriasis trials.
Figure 4. Global Scale and Country Count for Phase III Plaque Psoriasis Trials of IL-17 and IL-23 Targeting Biologics
30
Stelara
Cosentyx
ixekizumab
brodalumab
tildrakizumab
guselkumab
25
# of Countries
20
15
10
5
0
Europe
North America
South/Central
America &
Caribbean
Asia
Australia
Middle East &
North Africa
Source: Citeline’s Trialtrove (data accessed February 2015)
9
In Europe, where the number of individual countries is high, all of these programs are represented.
Likewise, all programs have run trials in North America, but only the Cosentyx and ixekizumab programs
include sites in all three countries: the US; Canada; and Mexico. All programs have enrolled at sites in Asia
and have run at least one trial in Japan. Cosentyx and ixekizumab are the only programs running trials in
South/Central America & the Caribbean regions and only Cosentyx is represented in Brazil. Inclusion of
sites in the Middle East & North African region is less common, as seen from the fact that only the
Cosentyx, Stelara, and tildrakizumab programs have a presence in just a few countries there.
The geographic scope of these programs likely reflects planned regulatory filings in these regions. In
the EU, the central agency (the EMA) approves drugs for many countries; however, individual countries
determine their own prescribing and compensation guidelines for approved drugs. Therefore, local
experience with the drug is likely to improve its chances in that market. In contrast, South American
countries each approve drugs separately; therefore, Cosentyx and ixekizumab may have better leverage
in this region, possibly providing an edge over Stelara which is not yet approved in those markets. Stelara
is the only drug program to have run trials in China, which may reflect an attempt to gain Chinese approval
after major market approvals were achieved.
The top 20 pharmaceutical companies sponsoring these psoriasis studies have taken alternative
approaches to gaining approval in the challenging Japanese regulatory market. Johnson & Johnson
ran separate studies exclusively in Japan for Stelara approval and is following the same approach now
for their guselkumab program. Novartis, Eli Lilly, and Merck & Co./Sun Pharma have taken the alternative
approach of including Japanese sites in their global pivotal studies. Kyowa Hakko Kirin, the Asian
development partner for brodalumab, has one closed and one completed Phase III plaque psoriasis trial,
both run exclusively in Japan. Running global trials could synchronize the regulatory submission timelines
for programs, while running separate studies for only Japanese patients leverages Johnson & Johnson’s
and Amgen/AstraZeneca’s partnerships and local experience in that market.
Summary and conclusions
The initial development of targeted biologics specifically for psoriasis brought first-to-market drugs in their
classes, Stelara (IL-23 antagonists) and Cosentyx (IL-17 antagonists). The field of competitors has expanded
remarkably in recent years and the various factors that each program leveraged to carve out a niche have
been evaluated in this analysis. Figure 5 highlights some of the key distinguishing features for each of the
pipeline stage drugs.
Ixekizumab was the first IL-17 antagonist to follow Cosentyx into Phase III and has run a similar global
program in terms of scope and primary endpoints evaluated. Both drugs have developed a pre-filled,
self-injection delivery device. Ixekizumab was not as broadly compared to approved biologics as Cosentyx
(Figure 2) and was evaluated in fewer countries in several regions, which might pose challenges in these
competitive markets.
Amgen/AstraZeneca sponsored brodalumab trials enrolled the highest number of patients in their
ex-Japan studies, but in fewer geographic locations. Having the ambitious PASI 100 primary endpoint,
the largest number of patients evaluated in Phase III, and the different target (IL-17 receptor) could be
distinguishing factors for brodalumab. However, like the ixekizumab program, this program evaluated only
one active comparator (Stelara), which gives Cosentyx a competitive edge in both geographic presence
and demonstrated efficacy as compared with approved biologics.
10
Merck & Co./Sun Pharma’s ongoing Phase III tildrakizumab program evaluates primary endpoints PGA
and PASI 75 and includes a single active comparator study (versus Enbrel). A 12-week dosing frequency is
currently being studied, which is an attractive feature for a biologic treatment of a chronic disease. Should
this drug prove efficacious and safe in this treatment regimen, it would be dosed similarly to Stelara but is
more specific to the molecular target, IL-23.
The guselkumab program currently has included the most active comparator trials, a primary endpoint of
PASI 90, and a co-primary endpoint, PGA. Should the ongoing trials return positive results, these factors
might be leveraged to gain market share compared with Stelara. The geographic footprint of the program
is currently smaller than the other programs, however, Johnson & Johnson’s global presence could kick this
program into a higher gear if future results are encouraging.
BioMedTracker’s likelihood of approval methodology can be used to directly compare these drugs to one
another at a point in time. As of February 2015, ixekizumab’s likelihood of approval in the US is 64%, which
is 5% above the average. For brodalumab, BioMedTracker estimates a 72% likelihood of approval, which is
13% above what would be expected based on its phase and indication. BioMedTracker also predicts that
the US approval dates for both Eli Lilly’s ixekizumab and Amgen/AstraZeneca’s brodalumab are expected
to be in 2016, with brodalumab’s date range narrowed to the first half of the year. Guselkumab’s likelihood
of approval is currently 62%, which moved to 3% above the average after the X-PLORE study results were
presented in 2014. With these near-term timelines, it will not take long before the competition heats up for
IL-17 antagonists in the psoriasis market. The timelines for the next IL-23 antagonists are further down the
road, giving Stelara a bit more mechanistic exclusivity in the market.
Figure 5. Distinguishing Features (Pipeline or Registered) for IL-17 (Blue) and IL-23 (Green)
Antagonists as Psoriasis Therapeutics
IXEKIZUMAB
• 1st of the current pipeline Phase III programs
to start
• PFS and auto-injector PK study being explored
TILDRAKIZUMAB
• Quarterly dosing schedule
• 1 trial in the Middle East (Israel)
• Highest number of countries relative to trials
• Phase III studies in South/Central America
and the Caribbean
• Superior to Enbrel in 2 studies
• 5% above average likelihood of approval
BRODALUMAB
GUSELKUMAB
• Targets the IL-17 receptor
• Newest Phase III program
• Most patients studied
• Highest number of active comparator trials
• Addition of PASI 100 as 3rd efficacy primary
endpoint
• Co-primary endpoint of PASI 90 and 1 trial with
PGA as sole primary endpoint
• Superior to Stelara in 1 study, 2nd study showed
1 dose was superior
• Only drug to compare against Humira
• 3% above average likelihood of approval
• 13% above average likelihood of approval
Source: Citeline’s Trialtrove and BioMedTracker (data accessed February 2015)
11
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