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    New systemic psoriasis treatments keep raising bar

    Dr. LeonardiThe ongoing rush of safe, highly effective systemic agents for psoriasis has created a new era in which substantial numbers of patients may achieve complete clearance, said an expert at the American Academy of Dermatology 75th Annual Meeting, held here.

    In the year 2000, said Craig Leonardi, M.D., two authors called complete skin clearance an unrealistic expectation for patients with psoriasis.1

    “The fact is that right now, we have many drugs that are so far different from what we used to use even five years ago that complete clearance is a realistic possibility in many of our patients,” says Dr. Leonardi. He is adjunct professor of dermatology at St. Louis University and a St. Louis, Missouri-based dermatologist in private practice.

    As a reference point, he says, “Finally, we have numbers for how methotrexate performs in modern measurement systems.” In a well-designed 120-patient trial with modest dose escalation, 41% of patients achieved psoriasis area and severity index (PASI) 75, and 66% achieved PASI 50 at week 16.2 “This settles the issue of how well methotrexate indeed performs,” Dr. Leonardi says. Although no study patients developed pancytopenia, “It’s always an issue in the back of my mind. At any one time I’ll have hundreds of patients on methotrexate.” Based on research in rheumatoid arthritis, he says, risk factors include renal disease, hypoalbuminemia, infection, age and concomitant medication use.

    New targets

    Since the demise of T-cell inhibitors such as alefacept and efalizumab, Dr. Leonardi says, “We’ve been concentrating on cytokines and cytokine inhibitors. And it’s been a very busy time in the pharmaceutical industry and for those of us who do this research.”

    Among tumor necrosis factor alpha (TNFa) inhibitors that dermatologists may not have heard much about, “Certolizumab is one you should definitely remember. It is a pegylated TNF-alpha inhibitor, not a monoclonal antibody. In trials, it is a high-performance skin-clearing drug.” In phase 3 testing, 81% and 82% in separate cohorts achieved PASI 75.3 “That’s functionally equivalent to infliximab. This is a drug you might be able to reach for. You can prescribe it currently for psoriatic arthritis – it’s approved.” And based on phase 3 results in psoriasis, “We expect it to sail through the approval process.”

    Recent approvals in the TNF inhibitor category include biosimilar versions of infliximab, etanercept and adalimumab. “And there are others in the pipeline.”

    New indications for existing drugs include hidradenitis suppurativa and uveitis (adalimumab) and pediatric psoriasis (etanercept). Physicians use golimumab mainly for psoriatic and rheumatoid arthritis, he says. “It offers very modest results in psoriasis.”

    “We know that psoriasis is a significant cardiovascular risk factor. Patients with severe psoriasis have a marked increased relative risk of myocardial infarction (MI) compared to mild psoriasis4 and, in another analysis, control subjects.”

    More recently, research analyzing cardiovascular risk in various treatment groups has shown that TNF inhibitors and methotrexate reduce risk of MI around 50%.5 “This is the first time we are seeing evidence that treatments can reduce the risk of myocardial infarction,” Dr. Leonardi says.

    Additionally, an analysis of cardiovascular risk in patients on TNF inhibitors showed a statistically significant, marked decrease of MI risk, starting at around month 12 and lasting several months thereafter, versus patients on methotrexate.6 “Even more amazing, cumulative use of TNF antagonists serially reduced the risk of myocardial infarction.” Predicted hazard rate reductions at one, two and three years were 21%, 38% and 51%. “And there’s probably more to be gained beyond three years. What a wonderful story. We’re treating their skin and joints and giving them an increased benefit from a cardiovascular risk perspective,” he says.

    Among interleukin (IL)-23 inhibitors, he says, a straightforward phase 3 study of tildrakizumab (two doses, versus placebo or etanercept) showed that the higher dose outperforms the lower dose — 66% versus 61% — in terms of both PASI 75 and physician assessments, without noteworthy safety issues.7 “With regard to severe infections, malignancies, major adverse cardiovascular events and drug hypersensitivity reactions, all of these issues are comparable to placebo or to etanercept. This drug appears to be safe and well tolerated. ”

    The phase 3 study of guselkumab did not even consider PASI 75 a primary endpoint, Dr. Leonardi says. Rather, 73% of patients reached PASI 90 at 16 weeks, versus 2.9% of placebo-treated patients.8 “This is a significant drug. It distinguishes itself quite clearly from adalimumab” in terms of efficacy, with comparable safety findings.

    In phase 2 testing, a single dose of risankizumab allowed 87% of patients to reach PASI 75, and 58% to reach PASI 90, at 12 weeks.9 “And one-third of these patients remained clear for more than 66 weeks.” James Krueger, M.D., Ph.D., has called the drug and immunologic disruptor, says Dr. Leonardi, because its pharmacodynamic effect far exceeds its pharmacokinetic effect. Dr. Krueger is D. Martin Carter Professor in Clinical Investigation at Rockefeller University.

    IL-17 inhibitors

    In secukinumab four-year data, “Efficacy — whether it’s PASI 75 (88.5%), PASI 90 (66.4%) or PASI 100 (43.5%) —  seems to be maintained.10 The caveat is that this is an as-observed analysis. In other words, the denominator is dropping” over time as patients achieving lesser efficacy and tolerability drop out. For most patients, “It’s not surprising that the efficacy should seem stable over time. It would have been a real problem if we saw efficacy dropping off.” Regarding serious adverse events, he adds, “There are a lot of zeros in the table, including for Crohn’s disease. There were two cases of ulcerative colitis. This issue of ulcerative colitis and its association with IL-17 antagonists is ongoing, and we’re going to have to see how that plays out. It’s a rare event – less than one in 1000 patients” in the secukinumab data.

    Unpublished five-year data for ixekizumab, in an analysis which accounted for dropouts over time, shows stable PASI 75, 90 and 100 results (approximately 80%, 70% and 47%, respectively), he says. As for AEs that led to drug discontinuation (13), “There were many one-off events that don’t seem to have any pattern.” All adverse events also appear uncommon and stable over time, he added.

    The IL-17 receptor antagonist brodalimumab showed efficacy similar to that of ixekizumab in phase 3 trials (86%/85% PASI75, and 37%/44% PASI 100).11 But early in these trials, he says, concerns for depression, suicidal ideation and behavior appeared. “There were six suicides in these trials — four in the skin trials and two in psoriatic arthritis trials. The FDA remarked that this was an unprecedented collection of serious issues for any psoriasis trial to date. I would take that to heart.”

    Amgen abandoned the product’s development in 2015, and Valeant took it to an FDA hearing in July 2016, at which all 18 FDA reviewers recommended approval — although 14 advised implementing a strong risk management program. “So this drug has a boxed warning for depression and suicide coming out of the gate,” and a risk-management system reminiscent of iPLEDGE, he said.

    “We must wait and see how our specialty reacts to this, how onerous this will be in our offices and whether or not this drug will gain any traction” given that equally efficacious drugs with fewer hassles already exist. Moreover, Dr. Leonardi noted that patients with psoriasis have elevated baseline levels of suicidal ideation and depression versus the general population.12

    Development of tofacitinib in dermatology has stopped, said Dr. Leonardi. “The FDA has returned the application to Pfizer. The problem with this drug is that patients needed a big dose —15 mg twice a day — to have outstanding efficacy. But there was a hard safety signal that occurred much earlier at lower doses.” FDA officials noted that in rheumatoid arthritis trials, 14 of the 15 patients who died were on tofacitinib. “And there were 34 opportunistic infections,” he added, “all in tofacitinib-treated patients. In the psoriasis trials, there were more than 1,000 cases of herpes zoster.”

    However, he said, tofacitinib can be useful off-label for indications including alopecia areata, alopecia-associated nail dystrophy, vitiligo and severe atopic dermatitis. When he prescribed 5 mg of tofacitinib twice-daily for a patient with a 15-year history of alopecia universalis and steroid induced adrenal suppression, “One year later, she had more hair than I did.” ƒ

    Disclosures: Dr. Leonardi has been a consultant, researcher and/or speaker for Abbvie, Amgen, Celgene, Coherus, Dermira, Eli Lilly, Galderma, GlaxoSmithKline, Janssen, Leo, Merck, Merck-Serono, Novartis, Pfizer, Sandoz and Vitae. He also provides phototherapy and has an infusion center.

    References

    1. Al-Suwaidan SN, Feldman SR. Clearance is not a realistic expectation of psoriasis treatment. J Am Acad Dermatol. 2000;42(5 Pt 1):796-802.

    2. Warren RB, Mrowietz U, von Kiedrowski R, et al. An intensified dosing schedule of subcutaneous methotrexate in patients with moderate to severe plaque-type psoriasis (METOP): a 52 week, multicentre, randomised, double-blind, placebo-controlled, phase 3 trial. Lancet. 2017; 389(10068):528-537.

    3. http://www.ucb.com/stories-media/press-releases/article/CIMZIA-certolizu... http://www.ucb.com/stories-media/press-releases/article/CIMZIA-certolizu.... Published October 3, 2016. Accessed April 7, 2017.

    4. Gelfand JM, Neimann AL, Shin DB, Wang X, Margolis DJ, Troxel AB. Risk of myocardial infarction in patients with psoriasis. JAMA. 2006;296(14):1735-41.

    5. Wu JJ, Poon KY, Channual JC, Shen AY. Association between tumor necrosis factor inhibitor therapy and myocardial infarction risk in patients with psoriasis. Arch Dermatol. 2012;148(11):1244-50.

    6. Wu JJ, Guérin A, Sundaram M, Dea K, Cloutier M, Mulani P. Cardiovascular event risk assessment in psoriasis patients treated with tumor necrosis factor-α inhibitors versus methotrexate. J Am Acad Dermatol. 2017;76(1):81-90.

    7. Reich K, et al. Tildrakizumab, selective IL-23p19 antibody, in the treatment of chronic plaque psoriasis: results from two randomized, controlled, Phase 3 trials (reSURFACE 1 and reSURFACE 2) [abstract]. Presented as a late breaking abstract at the European Academy of Dermatology and Venereology 2016. October 1, 2016.

    8. Blauvelt A, Papp KA, Griffiths CE,  et al. Efficacy and safety of guselkumab, an anti-interleukin-23 monoclonal antibody, compared with adalimumab for the continuous treatment of patients with moderate to severe psoriasis: Results from the phase III, double-blinded, placebo- and active comparator-controlled VOYAGE 1 trial. J Am Acad Dermatol. 2017;76(3):405-417.

    9. Krueger JG, Ferris LK, Menter A, et al. Anti-IL-23A mAb BI 655066 for treatment of moderate-to-severe psoriasis: safety, efficacy, pharmacokinetics, and biomarker results of a single-rising-dose, randomized, double-blind, placebocontrolled trial. J Allergy Clin Immunol. 2015;136(1):116–124; e117. 29.

    10. Bissonnette R, et al. Secukinumab maintains high levels of efficacy through 4 years of treatments: Results from an extension to a phase 3 study (SCULPTURE). Paper presented at: European Academy of Dermatology and Venereology Annual Meeting.; October 01, 2016; Vienna, Austria.

    11. Lebwohl M, Strober B, Menter A, et al. Phase 3 studies comparing brodalumab with ustekinumab in psoriasis. N Engl J Med. 2015;373(14):1318-28.

    12. Gupta MA, Schork NJ, Gupta AK, Kirkby S, Ellis CN. Suicidal ideation in psoriasis. Int J Dermatol. 1993;32(3):188-90.

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