Psoriasis Update 2013: Emerging Therapies

Craig Leonardi, MD

It is crucial that dermatologists recognize the major advances in the management of psoriasis. Psoriasis affects approximately one to two percent of the general population in the United States, plaque psoriasis being the most common form accounting for approximately 90 percent of all cases.

It is important to look at where dermatologists have been with the use of biologics over the last decade. The first set of drugs were the T-cell inhibitors. T-cell inhibitors work by blocking T-cell activation; it is a multi-step process. The primary signal was the presentation of antigen; the secondary signal was that of the binding of accessory ligand pairs; therefore, forming immunologic “synapse.” According to Dr Leonardi, 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 For example, alefacept (withdrawn from market in 2012) was probably one of the least efficacious drugs approved.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 (i.e., progressive multifocal leucoencephalopathy (PML)) and was taken off the market in 2009. From that point, attention then drifted over to cytokines and cytokine inhibitors for the treatment of chronic inflammation.

Screen Shot 2013-11-27 at 4.47.30 AM

 

The 2nd generation biologics are what Dr Leonardi characterizes as the TNF-alpha inhibitors.  Etanercept, in its usually approved dose of 50 mg once weekly, achieves a 45-50% PASI 75 response and you can see even more improvement with the double dose of 50 mg twice weekly.

Screen Shot 2013-11-27 at 4.47.40 AM

 

Infliximab, three infusions in the first six weeks, will carry patients up to about an 80% PASI 75 achievement rate, and then you will see a slow loss of response over time; however, there will still be about 60% PASI 75 achievement rate over the long term.

Screen Shot 2013-11-27 at 4.47.51 AM

 

Adalimumab achieves a 71% PASI 75 at week 16.

Screen Shot 2013-11-27 at 4.48.04 AM

 

Third generation biologics include ustekinumab and briakinumab (which never completed the FDA-approval process for psoriasis). 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 approximately 67-75% (depending on dose) as compared to placebo. Ustekinumab also has a nice, durable effect.

Screen Shot 2013-11-27 at 4.48.13 AM

 

What about breakthrough early on with ustekinumab? In between doses of ustekinumab it’s very common to see patients who have some return of disease prior to their next dose, but Dr Leonardi urges clinicians to encourage patients to continue and hold on to see the positive effects.

Ustekinumab Safety Data

Over time, adverse events on ustekinumab are coming down, 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 analysis like this, patients are coming out of the trial because they either are not responding or are not tolerating the drug well. From this perspective, long-term safety data from open label extension studies usually looks favorable.

New Development Efforts

Screen Shot 2013-11-27 at 4.48.24 AM

There are several new drugs currently in development of the treatment of psoriasis. These therapies target IL-23 (without targeting IL-12) 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 75 achievement rate, 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, another inhibitor of IL-17, is difficult to explain as the studies are rather disjointed, in that, as a dermatologist, one has to look past the published data. The higher dose of secukinumab (150mg) was selected for the phase III trials because of its PASI 75 response rate of approximately 81%. There were no serious adverse events with secukinumab.

Conclusions
  • Dermatologists have seen an explosion of biologic drugs that are mostly targeting the IL-17 and 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 will depend on the results of the ongoing phase III studies and subsequent post-marketing data capture.
  • Assess benefit/risk ratios when deciding on appropriate treatment strategies