what's now, what's next: individualizing the treatment of...

What's Now, What's Next: Individualizing the Treatment of Patients With Moderate to Severe Psoriasis for the Dermatologist

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The following is a transcript from a web-based CME-certified multimedia activity. Interactivity applies only when viewing the activity online. This activity is supported by educational grants from Celgene Corporation, Novartis Pharmaceuticals Corporation, and Lilly. For further information concerning Lilly grant funding visit www.lillygrantoffice.com.

Dr. Korman: Hello, this is Dr. Neil Korman from University Hospitals Case Medical Center in Cleveland, Ohio. Welcome to this educational activity on psoriasis. Joining me in this discussion is Dr. Mark Lebwohl from the Icahn School of Medicine at Mount Sinai in New York. After completing this activity, please access the post-test and evaluation form by clicking the red “Credit” button. I encourage you to download the slides, Practice Aids, and any other activity features that may interest you, and to participate in Ask the Faculty.


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Disclosures Course Director and Interviewee Neil J. Korman, MD, PhD, has a financial interest/relationship or affiliation in the form of: Consultant for Celgene Corporation; Lilly; and Novartis Corporation. Grant/Research Support from AbbVie Inc.; Amgen Inc; Celgene Corporation; Lilly; Pfizer Inc; and Ortho-McNeil-Janssen Pharmaceuticals, Inc. Speakers Bureau participant with AbbVie Inc. and Ortho-McNeil-Janssen Pharmaceuticals, Inc. Advisory Board for AbbVie Inc.; Celgene Corporation; Lilly; and Pfizer Inc. Interviewee Mark G. Lebwohl, MD, has a financial interest/relationship or affiliation in the form of: Consultant for AbGenomics Corporation; Amgen Inc.; Can-Fite BioPharma Ltd.; Columbia Laboratories, Inc.; Coronado Biosciences; Dermipsor Ltd.; Dermira; Eli Lilly and Company; Janssen Biotech, Inc.; LEO Pharma Inc.; Merck & Co., Inc.; Novartis Corporation; Pfizer Inc.; Thesan Pharmaceuticals Inc.; UCB, Inc.; and Valeant. Grant/Research Support from AbGenomics Corporation; Amgen Inc.; Can-Fite BioPharma Ltd.; Celgene Corporation; Coronado Biosciences; Eli Lilly and Company; Janssen Biotech, Inc.; LEO Pharma Inc.; Novartis Corporation; and Ranbaxy Inc. CME Reviewer Philip Strange, MD Assistant Professor Department of Dermatology University of New Mexico School of Medicine Health Sciences Center Albuquerque, New Mexico Philip Strange, MD, has no financial interests/relationships or affiliations in relation to this activity. Medical Director Kathryn B. Charalambous, PhD PVI, PeerView Institute for Medical Education Kathryn B. Charalambous, PhD, has no financial interests/relationships or affiliations in relation to this activity.


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Optimizing the Use of Established Therapies in Moderate to Severe Psoriasis

1. National Psoriasis Foundation. http://www.psoriasis.org/research/science-of-psoriasis/statistics. Accessed November 5, 2014.

Dr. Korman: I'd like to talk first about the impact of psoriasis. Psoriasis is, in fact, the most prevalent autoimmune disease in the United States. In terms of costs, the total, direct and indirect healthcare cost of psoriasis are calculated at over $11 billion a year, with work loss accounting for about 40% of this burden. Quality of life in psoriasis is a critical component. This is not just a cosmetic problem.


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DMARD: disease-modifying antirheumatic drug; MOA: mechanism of action; PsA: psoriatic arthritis; SEs: side effects; SubQ: subcutaneous. 1. Feldman S. http://www.uptodate.com/contents/treatment-of-psoriasis. Accessed October 28, 2014. 2. Methotrexate Prescribing Information. http://www.accessdata.fda.gov/drugsatfda_ docs/label/2011/011719s117lbl.pdf. Accessed October 28, 2014. 3. Cyclosporine Prescribing Information. https://www.pharma.us.novartis.com/product/ pi/pdf/neoral.pdf. Accessed October 28, 2014. 4. Acitretin Prescribing Information. http://www.stiefel.com/content/dam/stiefel/globals/ documents/pdf/US_Soriatane_Capsules.pdf. Accessed October 28, 2014.

Dr. Korman: So when we talk about treating patients with psoriasis, the most important point to decide is whether this patient is a candidate for topicals or systemic therapy. The location of the disease and the presence of psoriatic arthritis also affect the choice of therapy and should be taken into consideration. In terms of thinking about mild disease, limited plaque psoriasis often responds well to topical corticosteroids and emollients, but probably the biggest issue with these patients is compliance and finding a type of topical that the patient will actually use.


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When we move on to patients who need a systemic approach, we'll first approach the traditional DMARDs, and these include methotrexate, cyclosporine, and acitretin. So methotrexate, which has been around for 40-plus years, is kind of the old standard. We know that methotrexate can be a liver toxic drug, so we need to monitor baseline and ongoing liver function. You can often combine methotrexate with other biologic agents, and one of its major advantages is it's quite cheap. Cyclosporine is a very potent medication that has great short-term results in terms of efficacy, but the issue is that it has a fair amount of toxicity. The last of the old orals that have been approved is acitretin, and this is probably the least efficacious of the group of three.


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1. Apremilast Prescribing Information. http://www.otezlapro.com/prescribing-information/. Accessed October 28, 2014.

Dr. Korman: There is another oral that was just approved weeks ago actually by the FDA and it's called apremilast. This is a phosphodiesterase inhibitor molecule that we'll be discussing in the next program on what's on the horizon.


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IL: interleukin; IV: intravenous; TNF: tumor necrosis factor; URTI: upper respiratory tract infection. 1. Adalimumab Prescribing Information. http://www.rxabbvie.com/pdf/humira.pdf. Accessed October 28, 2014. 2. Etanercept Prescribing Information. http://pi.amgen.com/united_states/enbrel/derm/ enbrel_pi.pdf. Accessed October 28, 2014. 3. Infliximab Prescribing Information. http://www.remicade.com/hcp/remicade/assets/ hcp_ppi.pdf. Accessed October 28, 2014. 4. Ustekinumab Prescribing Information. http://www.stelarainfo.com/pdf/ PrescribingInformation.pdf. Accessed October 28, 2014.

Editor's Note: Since the launch of this activity, secukinumab received FDA approval for the treatment of adults with moderate to severe plaque psoriasis. Dr. Korman: This is a list of the currently approved biologics for the treatment of psoriasis. There [are] three of them that are tumor necrosis factor inhibitors, adalimumab, etanercept, and infliximab. In fact, all three of them are approved for the treatment of psoriatic arthritis as well. In terms of safety considerations, all of these agents have the


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potential for serious infections and malignancy, although the risk/benefit profile is excellent, as about 100 times more patients will receive benefits than will get harm. The other agent that's a different category is ustekinumab. This is an IL-12/23 inhibitor. It does not, in fact, have any black box warnings, but its adverse reactions are relatively similar to most other agents like this, increased risk of nasopharyngitis, upper respiratory infections, headache, and fatigue.


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DBPC: double-blind, placebo-controlled; OLE: open-label extension; PASI: Psoriasis Area and Severity Index. 1. Menter A et al. J Am Acad Dermatol. 2008;58:106-115.

Dr. Korman: First, we'll talk about adalimumab. And this is the pivotal trial that was used to get adalimumab approved. What they did here was they treated a bunch of patients with either adalimumab or placebo and at week 16 they measured the PASI score. Then over time they followed them, and [in] some of the patients they actually took drug away in order to see how these patients would respond when they came off drug and then went back onto drug.


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ADA: adalimumab; PGA: Physician’s Global Assessment. 1. Adalimumab Prescribing Information. http://www.rxabbvie.com/pdf/humira.pdf. Accessed December 4, 2014. 2. Menter A et al. J Am Acad Dermatol. 2008;58:106-115. 3. Gordon K et al. J Am Acad Dermatol. 2012;66:241-251.

Dr. Korman: At week 16, about 71% of patients reach PASI-75 and about 45% reach PASI-90. So at week 52, we have 79% of the patients reaching PASI-75. Forty-three percent of patients are maintaining PASI-75 even after they came off of adalimumab and stayed off adalimumab. So this is good to know that in the patients who got better, even if they stopped therapy, almost half of them still are maintaining PASI-75. The open-label study, the so-called OLE, found that 88% of the patients who were getting adalimumab after 160 weeks still had a PASI-75 response; excellent response showing that patients who stay on drug continue to do well and you don't lose a lot of efficacy over time.


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ETN: etanercept. 1. Leonardi CL et al. N Engl J Med. 2003;349:2014-2022. 2. Papp KA et al. Br J Dermatol. 2005;152:1304-1312. 3. Tyring S et al. Lancet. 2006;367:29-35. 4. Trying S et al. Arch Dermatol. 2007;143:719-726.

Dr. Korman: Let's move on next to another TNF inhibitor, etanercept, and this is data looking at etanercept as a monotherapy in patients with psoriasis. And those who got high-dose etanercept [50 mg twice weekly] had a PASI-75 at week 12 of about 50%. And 50% of the patients are able to maintain a PASI-75 result over a 2-year period.


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1. Kimball AB et al. J Am Acad Dermatol. 2014 Sep 25 [Epub ahead of print]. doi:10.1016/j.jaad.2014.08.050.

Dr. Korman: What about safety? Final 5-year results from an observational postmarketing safety surveillance registry of patients with etanercept showed no new safety signals when you give this drug to patients in the real world. They looked at malignancies; they looked at infections and death and injection-site reactions, and really this looks very much like the clinical trial; no new safety signals.


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1. Reich K et al. Lancet. 2005;366:1367-1374.

Dr. Korman: Let's move on to infliximab now. And in this study [EXPRESS], almost 400 patients were given either placebo or infliximab at 5 mg/kg. Then at week 24, the placebo group crossed over to infliximab induction followed by maintenance. Those who were originally given infliximab stayed on that all the way out to week 46. Basically, what we see here is the PASI scores jump up by week 10 to about 80% to 82% of patients reaching PASI-75, and then when you look out over to about week 50, people are stabilizing at 70-ish percent.


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1. Menter A et al. J Am Acad Dermatol. 2007;56:31.e1-15.

Dr. Korman: Another infliximab efficacy trial [EXPRESS II] looked at two doses—3 or 5 mg/kg of infliximab—again with the induction at week 0, 2, and 6, and then at week 14, they randomized the patients to either every 8 weeks or as needed through week 46. Basically, what this study shows is that you're getting an improved efficacy all the way out to week 10 right in the beginning, and not a whole lot of difference between 3 and 5 mg/kg in terms of efficacy. And you get excellent improvement in the PGA score.


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CHF: congestive heart failure. 1. Reich K et al. Br J Dermatol. 2013;168:1325-1334.

Dr. Korman: Let's move on now to the next slide, which talks about the safety of continuous versus intermittent infliximab. So infusion reactions—15% versus 9%. Most of the other findings, not a whole lot of difference between the two, but infusion reactions can be significantly important, and patients surely don't like them, and often means the end of your ability to use the medications. Continuous treatment is the way to go when you're using infliximab to treat patients with psoriasis.


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1. Leonardi C et al. Lancet. 2008;371:1665-1674.

Dr. Korman: Now we're going to jump to ustekinumab. There were two large studies, a total of about 2,000 patients who were treated with ustekinumab. They were given either of two doses—45 or 90 mg—or placebo. They measured the primary endpoint at week 12. And then over time, they continued to get drug, and then some of the patients actually were randomized to go onto placebo again to mimic the real-world experience of patients going off of therapy for a while. So here is the efficacy data from PHOENIX 1 showing PASI-75 jumping up at week 16 to about 75% or so, and then being maintained out to week 40. We see PASI-90 numbers as well that are quite impressive, that are increasing over time actually and getting up to 45%-50% at week 40.


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1. Papp K et al. Lancet. 2008;371:1675-1684.

Dr. Korman: PHOENIX 2 is a very similar study where some of the patients here are actually dosed every 8 weeks, and we see the same kinds of results with PASI-75 scores in the 70% to 75% [range] at the primary endpoint; PASI-90 scores in the 40% to 50% range and nice improvement rapidly over time for these patients.


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1. Griffiths C et al. N Engl J Med. 2010;362:118-128.

Dr. Korman: This was a large clinical trial that compared patients given both doses of ustekinumab, either 45 [mg] or 90 [mg], and patients given high-dose etanercept, 50 mg twice a week. Basically, what they're able to show here is that about 58% of patients given etanercept reached PASI-75, whereas about 68% of those given 45 mg of ustekinumab, and about 73% of those given higher-dose ustekinumab reached PASI-75. And both of those ustekinumab doses were statistically significantly better than etanercept. This is the first randomized controlled trial comparing two different biologics in the treatment of patients with moderate to severe psoriasis.


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DCERN: Dermatology Clinical Effectiveness Research Network; DLQI: Dermatology Life Quality Index; NB: narrow-band; PA: physician assistant; UVB: ultraviolet B. 1. Gelfand J et al. Arch Dermatol. 2012;148:487-494.

Dr. Korman: This is a cross-sectional study just published a couple of years ago whose goal was to determine the effectiveness of the commonly used systemic or phototherapy treatments for moderate to severe psoriasis. Basically, what they concluded was that although relative differences in objective response rates among therap[ies] exist, absolute differences are small and may not be clinically significant. And so you may get the same kinds of results from patient to patient. I think that's a very important finding from this practice-based, cross-sectional study.


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CeV: cerebrovascular; MACE: major adverse cardiovascular events. 1. Ryan C et al. JAMA. 2011;306:864-871.

Dr. Korman: Now I'd like to talk a little bit about some of the potential issues that we have with some of our therapies. [In] this slide we're looking at the association between anti-TNF therapy and a risk of a major adverse cardiovascular event. Was there any difference in MACE between patients given etanercept, infliximab, adalimumab, any of these agents in all these different studies? So really the answer is there is absolutely no risk difference between the TNF agents and not being treated in terms of risk of MACE.


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1. Ryan C et al. JAMA. 2011;306:864-871.

Dr. Korman: And then they looked at ustekinumab, which is an [anti–]IL-12/23 agent, as well as briakinumab, an [anti–]IL-12/23 agent that was in development, but was stopped actually because of the development, amongst other toxicities, of MACE. The 5-year data did not demonstrate any increased risk of cardiovascular disease for the ustekinumab patients, even though there was, at least in the briakinumab trials, some increased risk of major adverse cardiovascular events. So I think the conclusion is that patients might still be at risk, and it's certainly appropriate to screen patients.


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BB: broad band; CsA: cyclosporine A; MTX: methotrexate; PUVA; psoralen plus ultraviolet A. 1. Menter A et al. J Am Acad Dermatol. 2008;58:826-850.

Dr. Korman: Let's talk now about the current treatment algorithm for approaching patients with chronic plaque psoriasis. Without psoriatic arthritis, you might start with topical, but you know, I think you should jump right into a systemic approach if they have greater than 5% body surface area. And if they have ultraviolet light available, I think that makes a lot of sense. And if they don't, then all-comers between acitretin and adalimumab, cyclosporine, etanercept, infliximab, methotrexate, ustekinumab, and then apremilast as well. And then second line would be combinations. I think all of these are reasonable approaches, and individual case scenarios guide us as to what makes the most sense. It also is up to the patient. When you explain to them risks and benefits and convenience and cost and all of those other factors, we'll be able to be in a better position to make decisions. If it's women of childbearing potential using appropriate contraception, you would go to UVB first and then if UVB is not available, we have, again, first-line systemic therapy. And then we have women trying to conceive who have chronic plaque psoriasis, more


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than 5%, without arthritis. And so there UVB is probably the topline choice. And if UVB is not available, the list is a little more challenging and it has to be negotiated with the patient, with the patient's obstetrician, with everybody to talk about what medications we are, in fact, comfortable giving while the patient is trying to conceive.


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1. Menter A et al. J Am Acad Dermatol. 2008;58:826-850.

Editor's Note: Since the launch of this activity, secukinumab received FDA approval for the treatment of adults with moderate to severe plaque psoriasis. Dr. Korman: For patients who have concurrent arthritis, [we should consider] mostly the TNF inhibitors: adalimumab, etanercept, infliximab, and then one new one, golimumab. And there is actually a fifth one that was recently approved certolizumab, as well as methotrexate or the combination of any of these five TNF inhibitors plus methotrexate. And then actually second line would be reasonable to say ustekinumab alone or plus methotrexate and apremilast has also been approved for psoriatic arthritis.


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Dr. Korman: So what are the challenges associated with treating psoriasis? Probably comorbidities is far and away the largest. Our patients are often overweight, often have multiple other comorbidities, diabetes, hypertension, elevated cholesterol, hepatic disease. Selecting the right therapy for the right patient. So children and adolescents become a significant challenge and problem—very few systemic medications approved. Adherence to therapy is critical. Long-term treatment considerations—this is a lifetime disease, so you want to be able to treat people over the lifetime. Sometimes drugs work for a while and then they need to be cycled through, and we need to take people off therapies that have become ineffective over time. The management of specific areas can be definitely challenging. Identifying and then managing treatment-related adverse events can be a challenge. Patients who become resistant to therapy. These are all significant and important challenges in the treatment of patients with psoriasis.


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BSA: body surface area. 1. Armstrong A et al. JAMA Dermatol. 2013;149:1180-1185.

Dr. Korman: We know that psoriasis is undertreated. This is summary data from a study published a year or so ago demonstrating that patients are undertreated, although demonstrating some improvement over time. On the left, under the severe group in the year 2003-[2005], not quite 30% of patients were receiving no treatment, and in the year 2011 with severe disease, only 9.5% were receiving no treatment. On the right, we have who is using topicals, and we still, unfortunately, have 20% of severe patients who are using only topicals to manage their severe disease.


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1. Armstrong A et al. JAMA Dermatol. 2013;149:1180-1185.

Dr. Korman: Why do people say "I only get topicals"? This is a list of the most common reasons. They say it has fewer side effects or they say the disease is not serious. Or here is a rough one: “Doctor will not prescribe anything else.” So there are a lot of reasons why people are on only topicals.


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1. Armstrong A et al. JAMA Dermatol. 2013;149:1180-1185.

Dr. Korman: And then in terms of treatment satisfaction and reasons for stopping medication. So here we have 40% of people with mild disease are dissatisfied. Fifty percent of those with moderate disease are dissatisfied, and 40% of severe are dissatisfied. We've got a lot of room for improvement. There are a lot of reasons why people stop biologics: “Well, they don't work”; “they stop working”; “it's adverse events”; “it had a complication”; or look at the rise in time of percentage of people who had insurance issues—“insurance would not pay” or “I can't afford.”


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Dr. Korman: So we've gone through a lot in terms of the approach to a patient with psoriasis. I would like to summarize by saying that really the most important first decision point is whether or not you're seeing someone who is a candidate for a topical approach, or they're a candidate for a systemic approach. For me, it's related to how much body surface area they have and how much it's affecting their quality of life. Systemics, there are loads of them, including orals and biologics, and we need to individualize our choices based upon severity, comorbidities, cost, convenience, and patient preference. So it's very important that we talk to our patients, examine our patients, offer them what's out there. In terms of future directions, you're going to hear on the next program that this is an incredibly exciting time with more agents under development in the pipeline than ever, and those agents showing ever-improving efficacy.


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The Clinical Utility of Emerging Treatment Options for Moderate to Severe Psoriasis: An Assessment of Current Data

IL: interleukin; JAK: Janus kinase; PDE-4: phosphodiesterase 4; SubQ: subcutaneous.

Editor's Note: Since the launch of this activity, secukinumab received FDA approval for the treatment of adults with moderate to severe plaque psoriasis. Dr. Lebwohl: I'm Mark Lebwohl, and I'm very pleased to be speaking today about the treatment of moderate to severe psoriasis, because we have a rapidly expanding armamentarium of therapies for treating this condition. We have a list of agents that are in development for the treatment of psoriasis, and they're in various stages of the approval process. There are small molecules, and one of these is the phosphodiesterase inhibitor apremilast, and that is delivered orally. Apremilast was recently approved for psoriasis, and as many of you know, it was approved for psoriatic arthritis several months ago. And another is a JAK kinase inhibitor, tofacitinib, which is in testing both orally and topically for the treatment of psoriasis.


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Brodalumab blocks the IL-17 receptor. Ixekizumab and secukinumab are monoclonal antibodies that block IL-17 directly. There are also two antibodies that block IL-23: tildrakizumab and guselkumab. We'll hear about data from all of those.


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APR: apremilast; PASI: Psoriasis Area and Severity Index; sPGA: static Physician’s Global Assessment. 1. Papp K et al. 72nd Annual Meeting of the American Academy of Dermatology (AAD 2014). Abstract 8359. 2. Paul C et al. AAD 2014. Abstract 8412.

Dr. Lebwohl: Now, we’ll start out with apremilast, and the ESTEEM-1 trial. And the design of this trial is a double-blind, placebo-controlled period for the first 16 weeks, where patients received either apremilast 30 mg twice daily or placebo twice daily. After 16 weeks, the ones in the placebo group were switched over to apremilast 30 mg twice daily, and the apremilast patients were continued for another 16 weeks on the oral dose. At week 32, the patients who had achieved PASI-75 were continued on apremilast 30 mg twice daily or on placebo. So there was a re-randomization that occurred. The patients who did not achieve PASI-75 or fell below that were continued on apremilast, and topical therapies or UVB were added to that regimen. Now, in the ESTEEM-2 trial, there's a very similar design, except that at week 32, when patients were re-randomized, PASI-50 was used to allow patients to switch over to topical therapy or UVB as opposed to PASI-75 in the last trial. And this trial is going on for an extension period of 5 years.


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And you see the PASI-75 results at week 16 [for ESTEEM-1] were 33.1% of patients compared to only 5.3% of placebo patients. If you look at PASI-50, 58.7% of patients achieved that endpoint compared to 17% of placebo patients. The Physician's Global Assessment of clear or almost clear was achieved by 21.7% of active-treated patients versus 3.9% of placebo-treated patients. Looking at the ESTEEM-2 efficacy, the data is somewhat similar. PASI-75 was achieved by 28.8% of active-treated patients versus 5.8% of placebo-treated patients. PASI-50, 55.5%. And when you break down the proportion of patients that achieved PASI-75 at week 16 by prior systemic psoriasis treatment experience, it seems that systemic therapy–naïve patients do somewhat better than those who have been treated with systemic therapies in the past.


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1. Reich K et al. AAD 2014. Abstract 8296. 2. Paul C et al. AAD 2014. Abstract 8412.

Dr. Lebwohl: One of the big advantages of apremilast is the absence of side effects. And the side effects that truly emerged were diarrhea and nausea—basically, GI side effects. Those generally occurred early during the placebo-controlled period, and often improved as the drug was continued.


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DLQI: Dermatology Life Quality Index; ISS: Itch Severity Score; PROs: patient-reported outcomes; PtGA: Patient Global Assessment; SF-36: Short Form (36) Health Survey; TPSS: Target Plaque Severity Score. 1. Papp K et al. Br J Dermatol. 2012;167:668-677. 2. Mamolo C et al. J Eur Acad Dermatol Venereol. 2013 Jan 7 [Epub ahead of print]. doi:10.1111/jdv.12081. 3. Strober B et al. Br J Dermatol. 2013;169:992-999. 4. Menter A et al. J Drugs Dermatol. 2014;13:252-256. 5. Ports W et al. Br J Dermatol. 2013;169:137-145.

Dr. Lebwohl: Let's go to tofacitinib. In a phase 2b dose-ranging study, as you increase the dose, a greater proportion of patients achieve PASI-75. Now, similarly, you see a dose-related impact on the PASI-50 score and the PASI-90 score. In terms of adverse events, the numbers are very similar to placebo. There is a slight increase in adverse events as you increase the dose, going from 55.1% with 2-mg tofacitinib to 61.2% with the 15-mg dose. But the placebo rate of adverse events was 60% as well. There are several other reports of studies evaluating 15 mg of tofacitinib. So again, they do report this dose-dependent improvement in patient-reported outcomes from week 2 onwards.


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Next, in this paper by Bruce Strober, it is noted that there are some dose-dependent hematologic effects reported with tofacitinib. And in the paper by Alan Menter, it is noted that tofacitinib doses compared to placebo improve psoriasis across all four body regions measured in the PASI score.


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1. http://press.pfizer.com/press-release/pfizer-announces-detailed-results-phase-3-opt-retreatment-study-tofacitinib-adults-mod. Accessed October 30, 2014. 2. http://www.pfizer.com/news/press-release/press-release-detail/pfizer_announces_ detailed_results_of_opt_compare_phase_3_study_of_tofacitinib_5_mg_and_10_mg_ twice_daily_compared_to_high_dose_enbrel_in_adults_with_moderate_to_severe_ chronic_plaque_psoriasis. Accessed October 30, 2014.

Dr. Lebwohl: Now, there are [two] pivotal trials currently underway, and they are looking not at the 15-mg dose, but the tofacitinib 5 and 10 mg twice daily dose. And those trials have met the primary efficacy endpoints. And next, the 12-week tofacitinib 5 mg and 10 mg twice daily dose compared to etanercept 50 mg twice weekly and to placebo is a huge study enrolling over 1,100 patients. And this study did demonstrate that tofacitinib 10 mg twice daily is not inferior to the high-dose 50 mg twice a week etanercept. But tofacitinib 5 mg twice daily did not achieve that endpoint. Then there is an Extend study, which looks at the long-term evaluation of tofacitinib. And there is a Retreatment study.


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1. Langley R et al. N Engl J Med. 2014;371:326-338. 2. Blauvelt A et al. AAD 2014. Abstract P8054. 3. Paul C et al. AAD 2014. Abstract P8053. 4. Mrowietz U et al. 22nd Annual Congress of the European Academy of Dermatology and Venereology (EADV 2013). Poster. 5. http://www.novartis.com/newsroom/media-releases/en/2014/1770574.shtml. Accessed October 29, 2014.

Dr. Lebwohl: Let's move on to the next therapy, secukinumab, which is an anti–IL-17 monoclonal antibody. And the first of several studies that we'll talk about is the ERASURE study. And in that study design, patients received either 300 [mg] or 150 mg or placebo every week for the first 4 weeks and were then treated monthly. You'll notice that over 80% of patients achieved PASI-75 with the higher dose, compared to the 150-mg dose group, which also had a very dramatic improvement in psoriasis, with most of the patients achieving PASI-75. The separation between the two doses becomes much more apparent at PASI-90. The JUNCTURE study looked at the autoinjector with secukinumab, which is a very convenient way of injecting this medication. And not surprisingly, the PASI-75 level of improvement was very high, as shown here, in fact exceeding 80% with the 300-mg


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group, around 70% with the 150-mg group, and very few of the placebo patients. In terms of PASI-90, again, over 50% of the 300-mg dose group patients achieved PASI-90. Now, the FEATURE study, which looked at prefilled syringes instead, again, very high, very similar degrees of improvement. PASI-75 approaching 80%. PASI-90 exceeding 50% with the 300-mg dose group. And a little bit less in PASI-75 and PASI-90 with the 150-mg dose group. Now, in the FIXTURE study, the study went on for a full year, and it compared the two doses of secukinumab to etanercept and placebo. The placebo-controlled period was only 12 weeks, however. And as you can see, looking at the PASI-75 response here, the two doses of secukinumab were superior to etanercept numerically. And looking at the PASI-90, the same is true, as well. There are a number of additional phase 3 secukinumab trials underway. SCULPTURE is a fixed-regimen study versus retreatment upon start of relapse. So the fixed-dose regimens appear to be more effective than the as-needed regimens, and the 300-mg dosage was better than the 150-mg dosage. Yet another trial, the CLEAR trial, looks at secukinumab in comparison to ustekinumab.


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URTI: upper respiratory tract infection. 1. Langley R et al. N Engl J Med. 2014;371:326-338.

Dr. Lebwohl: If you look at adverse events in the FIXTURE study, you see that the numbers are very common between all of the groups, and not that different than placebo. There were no deaths in any of the groups. In terms of nonfatal serious adverse events, the numbers between all of the groups are very similar, one to the other. The discontinuation due to adverse events, again, fairly similar one to the other. The frequency of infections or infestations, fairly similar one to the other. The placebo group had fewer than the other groups, however.


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OLE: open-label extension. 1. Gordon K et al. J Am Acad Dermatol. 2014 Sep 19 [Epub ahead of print]. doi:10.1016/j.jaad.2014.07.048.

Dr. Lebwohl: Now, the next drug we'll talk about is ixekizumab. And what you're looking at is a 52-week open-label study. And in this study, they started with six subcutaneous doses through week 20, and at that point there was a withdrawal period. Patients were eligible to enroll in an open-label extension where they got active drug if, during that treatment-free period, their PASI score fell under 75. Of 120 patients enrolled, 103 completed 52 weeks of treatment. Now, the results are quite dramatic. You see that at virtually every dose group the proportion of patients that achieved PASI-75 is above 80%. If you look in the second set of graphs, you see that of the patients who responded at week 20, PASI-75 was maintained, PASI-90 was maintained, for the 52 weeks of the study. So not only improvement in psoriasis, but also a sustained benefit.


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1. https://investor.lilly.com/releasedetail.cfm?ReleaseID=867193. Accessed October 30, 2014.

Dr. Lebwohl: UNCOVER-1 is a comparison of ixekizumab to placebo after 12 weeks and 60 weeks of treatment. UNCOVER-2 and -3 are the comparison of ixekizumab to either placebo or etanercept for 12 weeks. And in all of those studies, ixekizumab was superior to placebo and to etanercept at the 12-week mark. Ixekizumab administered either every 4 weeks or every 2 weeks, between 78[%] and 90% of patients achieved at least a 75% reduction in PASI score at 12 weeks. So, a dramatically effective drug. In fact, between 31[%] and 41% of patients achieved PASI-100, not a single dot of psoriasis left. Of patients who were treated with etanercept, on the other hand, only 5[%] to 7% achieved PASI-100. The other point to be made from the UNCOVER studies is that high levels of response were maintained throughout 60 weeks of treatment. So not only is this a very effective treatment, but it's one that shows a sustained response.


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1. Gordon K et al. J Am Acad Dermatol. 2014 Sep 19 [Epub ahead of print]. doi:10.1016/j.jaad.2014.07.048.

Dr. Lebwohl: On the next slide, you see the adverse events, and the bottom line is that the adverse events were very uncommon. In fact, you see four patients out of 120 dropped [out] because of an adverse event. That's 3.3%. So a very low frequency of adverse events, and no clear pattern of adverse events emerging here.


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PSI: Psoriasis Symptom Inventory. 1. Papp K et al. N Engl J Med. 2012;366:1181-1189. 2. Papp K et al. AAD 2014. Abstract P8418. 3. Gordon K et al. Br J Dermatol. 2014;170:705-715.

Dr. Lebwohl: In the next slide, we're looking at the phase 2 brodalumab study that was published. If you look at the proportion of patients that achieved PASI-50, 75, 90, and 100, you see that with a 210-mg dose you actually got the best results. So we're now close to 2 years into the study, and looking at the Physician's Global Assessment of clear or almost clear, at week 96, there is a slight loss of efficacy only, but the vast majority of patients are still clear or almost clear. Notice that the mean Psoriasis Symptom Inventory and DLQI improvements correlate with the PASI improvement.


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1. Papp K et al. N Engl J Med. 2012;366:1181-1189.

Dr. Lebwohl: Now, in the next slide, we look at adverse events. They are not dose-related and not very different than placebo, and so there is no clear emergence of an adverse event attributable to brodalumab.


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1. Papp K et al. AAD 2013. Late-Breaking Abstract.

Dr. Lebwohl: Now, we move to our next drug, which is tildrakizumab, which is an anti–IL-23 drug, also known as MK-3222. Here you see again a dose-ranging study. And as you increase the dose, the proportion of patients that achieve PASI-75 increases. So we're looking at more than 70% of patients achieving PASI-75 with the 200-mg dose.


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1. Langley R et al. AAD 2014. Abstract P8056.

Dr. Lebwohl: Patients on tildrakizumab were treated over 52 weeks and maintained that improvement over 52 weeks. At week 16, the PASI-75 was significantly greater for every tildrakizumab dose compared to placebo. Following dose reduction at week 52, there was no difference when you went from 200 mg to 100 mg as compared to the response in patients who remained on 200 mg at week 16. The PASI-75 and PGA responses were generally maintained through week 72 after discontinuation of treatment at week 52, however. All of the doses were generally safe. And there is currently a phase 3 trial underway with tildrakizumab.


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1. Callis-Duffin K et al. AAD 2014. Abstract AB162.

Dr. Lebwohl: The next drug, which is in early stages of development, is guselkumab, and there are results reported from the X-PLORE trial. And here they looked at five doses of guselkumab compared with placebo and with adalimumab. And you'll notice that the proportion of patients who have minimal or no disease goes from a high of 86% with the 100-mg dose group of guselkumab to 58% with adalimumab, 7% with placebo. If you look at 75% improvement, the 50- to 200-mg dose groups all get close to 80%, compared to 70% of the adalimumab patients, 55% of the placebo patients, which is an unusual number there. In terms of 90% improvement, however, the difference is clear, with 62% of the 100-mg group getting guselkumab, and 57% of the 200-mg group achieving 90% improvement in psoriasis severity compared to 44% of adalimumab and only 2% of placebo patients.


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CIN: cervical intraepithelial neoplasia; CVA: cerebrovascular accident; MACE: major adverse cardiovascular events. 1. Callis-Duffin K et al. AAD 2014. Abstract AB162.

Dr. Lebwohl: So through week 16, 50% of patients who were receiving guselkumab, all of the doses, had some kind of adverse event, compared to 56% of those on adalimumab, 52% of those on placebo. I will point out that serious infections occurred in two patients treated with guselkumab during that 16-week placebo-controlled period. One had appendicitis, one had a lung abscess. There were no malignancies, no major adverse cardiovascular events. Through week 52, again, the proportion of patients having side effects were low and similar. There were no additional serious infection in the guselkumab groups. One guselkumab-treated patient developed cervical intraepithelial neoplasia, so that was reported as a malignancy. And there were three major adverse cardiovascular events. In terms of ongoing phase 3 trials, there is a withdrawal and retreatment study, and there is also a study comparing the use of guselkumab in patients who had an inadequate response to ustekinumab.


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Editor's Note: Since the launch of this activity, secukinumab received FDA approval for the treatment of adults with moderate to severe plaque psoriasis. Dr. Lebwohl: While we already have excellent treatments for psoriasis, we have many patients who are not treated or who don't respond to those treatments, and I believe that very early on some of the agents that are coming—and specifically the IL-17 agents secukinumab, ixekizumab, and brodalumab—will be used for the patients who have already started on other biologics and simply not done well enough. If you look at patients treated with TNF blockers and follow those patients over a few years, within 3 or 4 years the large majority of them—certainly over 50%—are no longer on the original TNF blocker that they started on. Either because of side effects or because of loss of efficacy. That is where the IL-17 drugs will emerge very quickly I predict. Then there are patients who have partial responses to some of the medicines that are out already; they will also be started on the anti–IL-17 drugs. As for apremilast, it has a very easy to use profile, it requires no laboratory monitoring, it is an oral agent so you don't have to train patients how to give injections. I believe it has


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also found a niche in the treatment of palm and sole psoriasis where it appears to work fairly well. So even though the PASI-75 scores reported with apremilast are less than those reported for most of the biologics, it has a very favorable efficacy and safety profile compared to all of the other oral agents out there. It is certainly safer than methotrexate and cyclosporine and more effective than acitretin. So I already have found a place for its use in many of my patients with psoriasis and I think the availability of these other agents as they get approved will just improve our ability to take care of psoriasis patients.


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Narrator: This activity has been jointly provided by the University of New Mexico School of Medicine, Office of Continuing Medical Education and PVI, PeerView Institute for Medical Education.

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