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Psoriasis Therapy: Breakthroughs in Pharmacogenomics or in Pharmacology?

  • Mark Lebwohl
    Correspondence
    Correspondence: Mark Lebwohl, Department of Dermatology, Mount Sinai School of Medicine, 5 East 98th Street, New York, New York 10029, USA.
    Affiliations
    Department of Dermatology, Icahn School of Medicine at Mount Sinai, New York, New York, USA
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      As the cost of psoriasis therapies skyrockets, it becomes increasingly important to find biomarkers that predict which patients will respond to expensive medications. The ability to predict response to a specific therapy is particularly important for medications that are effective in only a small portion of the population. As we develop medications that clear most patients, the need for a predictive biomarker diminishes. Nevertheless, the importance of pharmacogenomics is likely to increase as the cost of drugs continues to rise.
      In an era of personalized medicine, the ability to identify genetic markers that predict response to medications is certainly valuable, but the value is clearly greatest when the overall response rate is low.
      • Li K.
      • Huang C.C.
      • Randazzo B.
      • Li S.
      • Szapary P.
      • Curran M.
      • et al.
      HLA-C*06:02 allele and response to IL-12/23 inhibition: results from the ustekinumab phase 3 psoriasis program.
      have published an intriguing study that suggests that the presence of HLA-CW6 allele may predict patients who will respond better to ustekinumab therapy. In the pivotal studies of ustekinumab, 86% of HLA-C*06:02 positive patients achieved psoriasis area and severity index (PASI) 75 compared with 76% of HLA-C*06:02 negative patients at week 24. Looking at multiple end points and time points, the authors were able to identify the largest difference in PASI 75 at week 12 (17.9% more HLA-C*06:02 positive patients achieved that end point than negative patients). There was an 11.8% difference in PASI 90 end points at week 24 and a 10.2% difference in PASI 100 at week 28 favoring the allele-positive patients compared with the negative patients. The authors correctly point out that these differences are modest.
      The first biologic approved for psoriasis was alefacept. In the pivotal trials for that drug, only 33% of patients achieved PASI 75 at any point during the trial. Moreover, the drug had to be administered by intramuscular injection in the physician’s office for 12 consecutive weeks, and the peak response did not occur until several weeks later (
      • Lebwohl M.
      • Christophers E.
      • Langley R.
      • Ortonne J.P.
      • Roberts J.
      • Griffiths C.E.
      Alefacept Clinical Study Group. An international, randomized, double-blind, placebo-controlled phase 3 trial of intramuscular alefacept in patients with chronic plaque psoriasis.
      ). A biomarker to predict which patients would achieve PASI 75 would certainly have been helpful for that drug. In patients who responded to alefacept and were then treated with repeated courses, response rates on retreatment of responders were higher, suggesting that responders might be a genetically distinct group that could be identified (
      • Goffe B.
      • Papp K.
      • Gratton D.
      • Krueger G.G.
      • Darif M.
      • Lee S.
      • et al.
      An integrated analysis of thirteen trials summarizing the long-term safety of alefacept in psoriasis patients who have received up to nine courses of therapy.
      ). Unfortunately, no genetic differences, biomarkers, or phenotypic differences were ever identified that could predict response to alefacept.
      Although biomarkers would certainly have been valuable for older therapies that did not perform as well, the need for biomarkers diminishes as the drugs approved for psoriasis achieve consistently better results. Between 70 and 80% of patients achieved PASI 75 with ustekinumab, and even higher numbers of patients achieved PASI 75 with our newest drugs, secukinumab, ixekizumab, and brodalumab. For the latter drugs, simply having plaque psoriasis predicts response to IL-17 blockade in more than 80% of patients.
      Will we need biomarkers to identify PASI 90 or PASI 100 responders with some of these new drugs? Although an inexpensive, reliable, biomarker would certainly be welcome before starting patients on very expensive medications, such a test would have to add value by predicting improvements in quality of life before starting on expensive therapies. If major improvements in quality of life occur in achieving PASI 75, will insurers pay for expensive drugs just to get to PASI 90 or PASI 100, even if those levels of improvement have been associated with greater quality of life improvements?
      And, are there other factors, such as environmental factors or phenotypic factors, that should be considered along with biomarkers to predict responders? For example, are obese patients more or less likely to respond? Trials with most drugs would suggest that low body weight improves the likelihood of response.
      In an era of personalized medicine, the ability to identify genetic markers that predict response to medications is certainly valuable, but the value might be even greater for drugs that do not achieve such high response rates. Acitretin, methotrexate, and apremilast, for example, require months of treatment before achieving optimal benefit, and the proportion of PASI 75 responders in those three groups is less than 50%. A biomarker to predict response to any of those drugs would certainly be welcome.
      As the treatment options for psoriasis increase, the availability of biomarkers would certainly be welcome, but we all hope to see the day when we have a completely safe medication that allows 100% of patients to achieve PASI 100. At that point, we will not need a genetic marker to predict response.

      Conflict of Interest

      ML is an employee of the Mount Sinai Medical Center that receives research funds from AbGenomics, Amgen, Anacor, Boehringer Ingleheim, Celgene, Ferndale, Lilly, Janssen Biotech, Kadmon, LEO Pharmaceuticals, Medimmune, Novartis, Pfizer, Sun Pharmaceuticals, and Valeant.

      References

        • Goffe B.
        • Papp K.
        • Gratton D.
        • Krueger G.G.
        • Darif M.
        • Lee S.
        • et al.
        An integrated analysis of thirteen trials summarizing the long-term safety of alefacept in psoriasis patients who have received up to nine courses of therapy.
        Clin Ther. 2005; 27: 1912-1921
        • Lebwohl M.
        • Christophers E.
        • Langley R.
        • Ortonne J.P.
        • Roberts J.
        • Griffiths C.E.
        Alefacept Clinical Study Group. An international, randomized, double-blind, placebo-controlled phase 3 trial of intramuscular alefacept in patients with chronic plaque psoriasis.
        Arch Dermatol. 2003; 139: 719-727
        • Li K.
        • Huang C.C.
        • Randazzo B.
        • Li S.
        • Szapary P.
        • Curran M.
        • et al.
        HLA-C*06:02 allele and response to IL-12/23 inhibition: results from the ustekinumab phase 3 psoriasis program.
        J Invest Dermatol. 2016; 136: 2364-2371

      Linked Article

      • HLA-C*06:02 Allele and Response to IL-12/23 Inhibition: Results from the Ustekinumab Phase 3 Psoriasis Program
        Journal of Investigative DermatologyVol. 136Issue 12
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          Several small studies suggest that the presence of the human leukocyte antigen (HLA)-Cw6 (C*06:02) allele may be a predictor of improved response to ustekinumab. This study was designed to assess the association of the HLA-C*06:02 allele with response to ustekinumab in large cohorts of patients from the phase 3 studies of ustekinumab in moderate-to-severe psoriasis. In this retrospective study, both HLA-C*06:02-positive and -negative patients demonstrated good responses to ustekinumab (86% vs. 76%, respectively, achieved at least a 75% improvement from baseline in Psoriasis Area and Severity Index [PASI 75] at week 24).
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