The Next Wave of Psoriasis Drug Programs: Targeting IL-17 and IL-23 PAMELA SPICER ANALYST, CNS, AUTOIMMUNE/INFLAMMATION, OPHTHALMOLOGY

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1 The Next Wave of Psoriasis Drug Programs: Targeting IL-17 and IL-23 PAMELA SPICER ANALYST, CNS, AUTOIMMUNE/INFLAMMATION, OPHTHALMOLOGY

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3 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 health 1. The disease affects between 1% and 5% of the global population 2. 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 therapies 3. 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 Most recently, the anti-il-17 drug Cosentyx was approved in Japan in December 2014 and subsequently in the US and EU in January 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 Aug;22(8): Hudson V. (2014) Datamonitor Healthcare Report: Psoriasis Treatment, Reference: DMKC 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 Feb;26(1):32-6 3

4 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 DRUG COMPANIES PHASE III INITIATION MAJOR MARKET LAUNCH DATE TARGET Stelara (ustekinumab) J&J Q Q (Europe) Q (US) Q (Japan) IL-12/IL-23 Cosentyx (secukinumab) Novartis Q Q (Japan) Q (US & Europe) IL-17 ixekizumab Lilly Q H (US predicted) IL-17 brodalumab Amgen/AZ/ Kyowa Hakko Kirin Q (US predicted) IL-17 receptor tildrakizumab Merck/Sun Pharma Q H (US predicted) IL-23 guselkumab J&J/MorphoSys Q (US predicted) IL-23 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 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

5 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 involvement 4. 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 reproducibility 5. 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: DMKC 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 Feb;26(1):

6 Figure 1. Primary Endpoints for IL-17 and IL-23 Antagonist Phase III Psoriasis Trials Cosentyx (secukinumab) Stelara (ustekinumab) PGA ixekizumab PGA PASI 75 PASI 75 PASI 75 PASI 75 PGA tildrakizumab PASI 75 PASI 90 PGA PGA PGA brodalumab PASI 100 guselkumab 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

7 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 efficacy 6. 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) FIXTURE Jun ,307 pts Superior Cosentyx (secukinumab) CLEAR Feb pts Superior # of Trials 3 2 ixekizumab UNCOVER-2 May 2012 (1,225 pts) Superior UNCOVER-3 Jul 2012 (1,225 pts) Superior brodalumab AMAGINE-2 Aug ,831 pts 140 mg - Failed 210 mg - Superior AMAGINE-3 Sep ,881 pts Superior guselkumab VOYAGE 1 Nov 2014 (750 pts) Open VOYAGE 2 Nov 2014 (1,000 pts) Open 1 tildrakizumab resurface-11 Feb 2013 (1,050 pts) Closed guselkumab NAVIGATE Oct 2014 (800 pts) Open X-PLORE Nov pts + vs pbo 0 Enbrel Stelara 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: DMKC BioMedTracker: Phase II - X-PLORE, Trial Data - Top-Line Results, data accessed February

8 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 UNCOVER-A AMAGINE JUNCTURE FEATURE UNCOVER-1 AMAGINE-2 # of Patients ACCEPT PHOENIX 1 SCULPTURE FIXTURE UNCOVER-2 resurface-10 NAVIGATE VOYAGE AMAGINE PHOENIX 2 ERASURE UNCOVER-3 resurface-11 VOYAGE 2 0 Stelara (ustekinumab) Cosentyx (secukinumab) ixekizumab brodalumab tildrakizumab guselkumab 8 Source: Citeline s Trialtrove (data accessed February 2015)

9 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 # of Countries Europe North America South/Central America & Caribbean Asia Australia Middle East & North Africa Source: Citeline s Trialtrove (data accessed February 2015) 9

10 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

11 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 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 TILDRAKIZUMAB 1st of the current pipeline Phase III programs to start PFS and auto-injector PK study being explored Phase III studies in South/Central America and the Caribbean Superior to Enbrel in 2 studies 5% above average likelihood of approval Quarterly dosing schedule 1 trial in the Middle East (Israel) Highest number of countries relative to trials BRODALUMAB GUSELKUMAB Targets the IL-17 receptor Most patients studied Addition of PASI 100 as 3rd efficacy primary endpoint Superior to Stelara in 1 study, 2nd study showed 1 dose was superior 13% above average likelihood of approval Newest Phase III program Highest number of active comparator trials Co-primary endpoint of PASI 90 and 1 trial with PGA as sole primary endpoint Only drug to compare against Humira 3% above average likelihood of approval Source: Citeline s Trialtrove and BioMedTracker (data accessed February 2015) 11

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