Emerging Therapies

Craig Leonardi, MD

Dr Leonardi began this session with an update on what’s new in the first quarter of 2013 with regards to biologic therapy. So, where have we been? Our first set of drugs was T-cell inhibitors. This was a wonderful rationale, but since then these drugs have fallen by the wayside for a number of reasons. For example, alefacept (withdrawn from market in 2012) was probably one of the least efficacious drugs approved. Efalizumab had serious infections (PML) and was taken off the market in 2009.  Our attention then drifted over to cytokines and cytokine inhibitors for the treatment of chronic inflammation. Our 2^nd generation biologics are what Dr Leonardi characterizes as the TNF-alpha inhibitors.

Etanercept, in its usually approved dose, achieves a 45-50% PASI 75 response and you can get even more improvement with the double dose. Infliximab, three infusions in the first six weeks, will carry patients up to about 82% PASI 75, and then you will see a slow loss of response over time; however, still about 65% PASI 75 responders over the long term. Adalimumab achieves a 71% PASI 75 at week 16.

Third generation drugs include ustekinumab and briakinumab (withdrawn). Phase III data on Ustekinumab was positive in both the PHOENIX 1 and PHOENIX 2 studies, and demonstrates that it is a high performance drug blocking IL-12 and IL-23 showing a sustained PASI 75 response of over 80% as compared to placebo. Ustekinumab also has a nice, durable effect.

What about breakthrough early on with ustekinumab? It’s very common to see patients who have some return of disease, but just encourage patients to continue and hold on to see the positive effects.

Ustekinumab Safety Data

The 5 year safety data show that over time, adverse events on ustekinumab such infections are low and stable over time, and SAEs that lead to discontinuation seem to be low and stable as well. One caveat to keep in mind is that in any long-term safety signal monitoring study like this, patients are coming out of the trial because they either are not responding or are not tolerating the drug well.

New Development Efforts

There are several new drugs currently in development of the treatment of psoriasis. These therapies target IL-12, IL-23, and IL-17.

Ixekizumab, an IL-17 inhibitor, appears to be a very promising drug in the pipeline with almost 50 percent of patients in the studies achieving a PASI 100. As far as adverse events (AEs) are concerned, there were no serious AEs and this is extremely comforting.

The IL-17 receptor blocker, brodalumab, was studied in a variety of different dosing strategies. Brodalumab showed about an 80 percent PASI score, demonstrating a very high performance. There were a couple of serious adverse events (four), but they seemed to be unrelated to medication and no serious infections or cancers were reported.

The data on secukinumab is  difficult to explain as the studies are rather disjointed, in that, as a dermatologist, you have to look past the published data. The higher dose of secukinumab (150mg) was selected for the phase III trials because of its PASI response of approximately 81%. There were no serious adverse events with secukinumab.

Conclusions

• We have seen an explosion of biologic drugs that are mostly targeting the IL-23 pathway
• There are a variety of novel small molecules that are under investigation
• JAK inhibitor may be a new topical approach
• Short and long-term safety issues exist for therapy
• Assess benefit/risk ratios when deciding on appropriate treatment strategies

Small Molecules For Psoriasis

Kenneth Gordon, MD

Small molecules were the mainstay for systemic psoriasis therapy for about forty years. Many patients would say that they prefer small molecules to a shot and, in fact, sometimes physicians feel more comfortable with a pill as well. In the last decade; however, all attention with regards to the treatment of psoriasis has been given to the biologics.

How will these small molecules impact our practice?

Methotrexate (MTX) is the small molecule standard and, for the most part, well tolerated. Unfortunately, some of the first studies for MTX were conducted poorly. Overall, we can expect to achieve a PASI 75 of about 40 percent with relatively aggressive MTX dosing when compared to biologics.

Apremilast

Apremilast, an inhibitor of PDE4, is currently under development for the treatment of psoriasis. In Phase II studies, apremilast (30 mg  PO BID) has achieved a PASI 75 score of about 41 percent. More than 96 percent of adverse events (AEs) were not serious. The early phase III results have not yet been released, yet a recent press release said that the studies met their clinical endpoints. Overall, apremilast seems to be well tolerated, but we don’t have the results to date.

The JAK/STAT Pathway

Tofacitinib is a novel, oral JAK inhibitor currently being investigated as a treatment for psoriasis among other indications. Although tofacitinib is a small molecule that binds to a specific area, it may have a wide range of effects; therefore, targeting various phases of the inflammatory process.

The phase II data on tofacitinib (15mg BID and 5 mg BID) demonstrate a PASI 75 response of 67 percent and 40 percent at week twelve, respectively; therefore, showing that this could be quite effective for the management of psoriasis. The issue that we have with this therapy is the overall tolerance of this medication.

When looking at some of the data that we have in rheumatoid arthritis, we see changes in baseline in hemoglobin and also lymphocyte changes. An FDA briefing document states that as the dose of tofacitinib increases, as does the risk of malignancies, this also seems to be true for lymphoma and infection. While this medication has a broader immunosuppressive effect, there may be more issues with side effects and that is something, as dermatologists, that needs to be considered.

Conclusions

• Small molecules are again being developed for systemic psoriasis therapy
• While they have exciting mechanisms of action, it remains to be seen if efficacy will be superior to methotrexate
• Small molecules, since they work on multiple areas of the immune system, can have a very significant effect on the immune system