Small Molecules for Psoriasis: A New Frontier?
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, i.e., a pill 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 the dermatology practice?
Methotrexate (MTX) is the small molecule standard and, for the most part, well-tolerated. Most countries require the use of MTX before trying a more expensive medication. Unfortunately, some of the first studies for MTX were conducted poorly. Overall, you 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 III studies, apremilast (30 mg BID) has achieved a PASI 75 achievement rate of 33%. The majority of adverse events (AEs) were not serious. The phase III results (ESTEEM I and II) demonstrate greater improvements from baseline Dermatology Quality of Life Index versus placebo and a greater proportion of patients reported improvements in the MCID versus placebo. Apremilast seems to be well tolerated in patients with moderate to severe psoriasis, with mild and infrequent gastrointestinal side effects (nausea and diarrhea).
The JAK/STAT Pathway
Tofacitinib, a novel, oral JAK inhibitor recently approved for the treatment of rheumatoid arthritis, is 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 achievement rate 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 safety 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.
In conclusion, you can see that small molecules are again being developed for systemic psoriasis therapy. While they have exciting mechanisms of action, it remains to be seen if they will be superior to methotrexate in both efficacy and safety, especially with regards to the immune system. Pricing and prior authorization requirements will be critical when it comes to treating patients.
