2013-02-21 00:00 Source: Dingxiang Garden Author: Stinging Insect Font SizeDermatology Department, Guangdong Dermatology Hospital Wu Tieqiang-|+ Newer drugs hold wonderful promise for patients with severe psoriasis, but what are the treatment options for more patients with relatively less severe disease? In a recent article published online in Nature, Australian science writer James Mitchell Crow provides exciting answers through an overview of recent breakout psoriasis biologic therapies and small molecule drugs. Kim Papp, a clinical researcher at the Probity Medical Research Institute in Canada, believes that this is an extraordinary time. Most exciting is the creation of new drugs in the anti-interleukin (IL)-17 class. Anti-IL-17 has been shown to be effective. Over the past decade, Papp has managed more than 100 clinical trial studies of new treatments for psoriasis. Not only are these drugs effective, but they are also safe as of today. All of these treatments have been well tolerated and continue to be effective given what we have seen in the current phase II clinic. There is a strong need for new treatments for psoriasis. A National Psoriasis Foundation survey showed that 40% of patients in a Portland patient group suffered from psoriasis due to inadequate recent treatment. However, most psoriasis patients will not benefit from expensive biologics such as anti-IL-17 classes. For most psoriasis patients, antibody-based biologics will not be widely available in the near term. This difference is likely to spawn another class of psoriasis treatment drugs that are quietly making their way through clinical trials. The first new biologic agent for psoriasis was Alfaxet, an anti-T-cell drug approved by the U.S. Food and Drug Administration (FDA) in 2003. Five more drugs were subsequently approved, the last one being uteconazole (utekinumab) in 2009. These drugs target different signaling molecules or cytokine targets in the immune system that cause the keratinization of skin cells characteristic of psoriasis. This drug has now become the yardstick for testing the efficacy of new psoriasis biologics. The efficacy of psoriasis is judged by the Psoriasis Area and Severity Index (PASI)75; that is, at least 75% remission as judged by the PASI. At 12 weeks of treatment, Uteno achieved a 67% PASI75 remission. As with other drugs that suppress the immune system, the main concern with utekinol is the risk of serious side effects. As with briakinumab, a biologic agent with the same mechanism of action, clinical trials were stopped due to the occurrence of serious major cardiovascular events. No serious adverse events have been associated with utekinol to date. If the safety confidence level increases, the safety-related requirements may be further enhanced. However serious adverse reactions may also manifest years later. 2009 saw the withdrawal of a biologic called efalizumab, approved six years earlier, after three cases of progressive multifocal white matter encephalopathy. Utenol is now competing in phase III clinical trials with three anti-IL-17 drugs: brodalumab, ixekizumab and secukinumab, all of which have proven highly effective, according to Christopher Griffiths, a dermatologist specializing in psoriasis-related research at the University of Manchester in the United Kingdom. About half of the participants in the high-dose phase II trials of anti-IL-17 drugs achieved PASI100 remission, a complete cure of psoriasis. This is comparable to the percentage of patients now receiving first-line biologics who achieved PASI75 remission. Indeed, the efficacy of these drugs is surprisingly good. Animal tests suggest that the upstream blocker euthyroxine is more effective than blocking IL-17, the only molecule that can develop psoriasis-type lesions when injected into the skin of mice. This led Merck to develop a new blocker, MK-3222, which specifically targets IL-23 in order to reduce the unnecessary risks and side effects associated with targeting IL-12. Why the anti-IL-17 class performs so well is unclear. However, research on IL-17 is still in its early stages and there are still many unknowns. Genetic studies give clues. While the clinical efficacy of the anti-IL-17 class is impressive, what is more surprising is the genetic alteration in psoriatic lesions. Even though IL-17 is an upstream regulator, these drugs were able to downregulate the expression of every important cytokine in psoriasis. The expression on psoriasis-related genes was quite strong and even more effective than euthyroxine. Despite this strong efficacy, the application of anti-IL-17 analogs is as limited as that of utekinol and other biologics: they are currently allowed only for patients with severe psoriasis. The severity of psoriasis is characteristically determined by the percentage of the patient’s damaged skin surface area (BSA). 3-10% of BSA is considered moderate, but traditionally 10% is considered severe. Patients with a BSA of 9% cannot be treated with biologics, partly due to cost and partly due to safety concerns. In the UK, these medications can cost up to £11,000 ($17,500) per person. This is beyond the reach of Medicare and the health care system. The risk/benefit ratio must also be considered. As with the withdrawal of efalizumab, it takes several years to demonstrate the appearance of serious side effects. For moderate patients, the risks outweigh the benefits. Approximately 90% of patients with mild and moderate psoriasis do not have a novel biologic agent available to them. Therefore, as of today, most patients with psoriasis lack new treatments. There are two drugs now in Phase III clinical trials that may benefit patients with moderate psoriasis. They are Pfizer’s tofacitinib, or tofacitinib citrate, approved by the FDA in November 2012 for rheumatoid arthritis, and SelGen Pharmaceuticals’ apremilast, both of which are small-molecule chemotherapy drugs and therefore less expensive than biologics. Tofacitinib is a molecule of tyrosine kinases (JAKs). Knockdown of JAKs means that no psoriasis-associated cytokine receptor sites are produced. Papp hopes that these small molecules will be available in oral or topical dosage forms for the treatment of patients with non-severe psoriasis. Phase II clinical data for these two drugs are not as impressive as those for biologics. In the study data for tofacitinib, 67% of patients achieved PASI 75 remission, compared with 41% for aprmilast. However, because neither drug showed significant side effects, it can be used in the treatment of patients with non-severe psoriasis. Apremilast, in particular, is particularly suitable for the treatment of patients with moderately active psoriasis. apremilast may well be a dark horse. Although apremilast does not have the same efficacy as biologics, it has a very good safety profile. Although the long-term safety profile of JAK blockers is unclear, eventually this drug may also have a place in the treatment of moderate psoriasis. However, for most psoriasis patients, their disease is too mild to be treated systemically. For them, the new small-molecule ointments are good news. For example, Pfizer has made tofacitinib available in a topical form with encouraging results. While SelGen has no plans to develop a topical form of apremilast, Anacor Pharmaceuticals is developing a topically applied PDE4 blocker. Both therapies are in Phase II clinical trials. The cream appears to be the most logical vehicle medium for treating psoriasis, but this dosage form has its own unique problems. It is difficult to develop a medium that will allow drug penetration into the skin barrier sufficient for efficacy. Therefore, developing a cream is much more difficult than developing a pill. Once safety is confirmed, anti-IL-17 classes could become available as prescription drugs for the treatment of moderate psoriasis. Biologics have already qualified as such in other diseases, but this will take time. Whether the disease is mild or severe, we need to work to develop treatments that are effective for all patients with psoriasis; this is a great and respectable shift in psoriasis drug development. Starting with the approval of Utechnol, psoriasis drug therapy ended the history of relying overwhelmingly on organ transplant immunosuppression and transplant applications of drugs for rheumatoid arthritis treatment. Not only that, but new small molecule therapeutics are rising to the occasion. For physicians, psoriasis itself is a very good clinical research subject, and his research studies are now at the leading edge.