Molecule called IL-17 could unlock more psoriasis treatments
By Tamara Miller
Editor's note: As of May 2015, Amgen has stopped developing brodalumab, due to reports of suicidal thoughts and behavior in patients taking the drug in clinical trials.
Scientists usually tend toward caution when faced with promising discoveries, but a new crop of biologic drugs in clinical trials is showing unprecedented success in clearing moderate to severe plaque psoriasis—and that is making a lot of people in the field of psoriasis research positively excited.
Amgen, Eli Lilly and Novartis each are in the midst of testing biologics that target a critical molecule in the immune system called IL-17 that has been linked to the skin inflammation of psoriasis. In each case, the drug so far is performing very well. About 80 percent of Phase II clinical trial patients achieved PASI (Psoriasis Area Severity Index) 75 percent, or their psoriasis has cleared by 75 percent in 12 weeks. As many as 60 percent of patients are completely clear in three months.
"That's quite an accomplishment," said Dr. Jerry Bagel, associate clinical professor of dermatology for Columbia University's College of Physicians. "We haven't seen that before. That's a high number of people who are clear. That's pretty good stuff."
How they work
IL-17 is a cytokine, which is a protein that controls cells and activates inflammation. To understand how IL-17 works, imagine the chemical processes that keep skin healthy as a stream of molecules heading back and forth from the skin's surface. In someone without psoriasis, these molecules serve a usually healthy purpose—they move the body's immune system into action when there is a cut or a scrape, sending cells to the surface to fight infection and heal a wound.
In someone with psoriasis, those signals can be faulty. The body will overreact to an injury in the skin, or the immune system will mobilize for an unknown reason. People with psoriasis lesions, in particular, have 30 times more IL-17 than people without lesions, according to an article Bagel published in the August 2012 issue of Practical Dermatology. Conversely, studies show that stopping IL-17, or reducing it, can help clear psoriasis.
Brodalumab (Amgen), secukinumab (Novartis) and ixekizumab (Eli Lilly) all work by interfering with the IL-17 pathway. Secukinumab and ixekizumab target IL-17, while brodalumab targets a specific receptor that binds to the IL-17 cytokine.
These latest drugs more specifically target molecules in the immune system connected to psoriasis than biologics currently on the market. That may have a lot to do with their success, Bagel said.
Dr. Subhashis Banerjee, medical director for ixekizumab, said patients in Phase II clinical trials started seeing significant results as early as week two. Additionally, patients with psoriasis in particularly difficult-to-treat areas such as the scalp and nails saw improvement.
The IL-17 inhibitors build upon the design of Stelara (Ustekinumab), said Dr. Andy Blauvelt, a dermatologist and researcher with Oregon Health & Science University. Stelara attacks psoriasis by interfering with different, but related, cytokines, IL-12 and IL-23.
To understand the relationship between Stelara and these newer drugs, Blauvelt also uses the stream comparison to describe the immunological pathway involved in psoriasis. At the top of the stream are the IL-12/23 cytokines, proteins in the immune system that trigger human cells. Stelara works by inhibiting the IL-12/23 cytokines, preventing them from creating the inflammatory IL-17 cytokine. Novartis and Eli Lilly's new biologics aim midstream, acting directly on IL-17. Amgen's is a little farther downstream than that, acting specifically on the IL-17 receptor.
Similar to other biologics, IL-17 inhibitors could have far-reaching effects. Novartis has seen reasonable success in alleviating the brain lesions associated with multiple sclerosis in a small clinical trial. Amgen is in the process of evaluating the efficacy of its drug for psoriatic arthritis, ankylosing spondylitis and rheumatoid arthritis. Eli Lilly has plans for Phase III clinical trials for psoriatic arthritis.
There are still several unanswered questions about IL-17 inhibitors. It's unknown exactly how much of each drug or how often it needs to be given to achieve the best results, Bagel said. Additionally, it's too early to tell how safe IL-17 inhibitors are. So far, the drugs have been used in relatively short clinical trials and without serious side effects other than the risk of a reaction at the injection site (all three drugs are injected) and an increased risk of an infection typical of immunosuppressive drugs.
Genentech's efalizumab, marketed as Raptiva, also seemed very effective in clinical trials and was approved by the FDA in 2003. However, Genentech pulled Raptiva from the market in 2009 after it was discovered the drug was associated with an increased risk of developing a rare and potentially fatal disease of the central nervous system.
Raptiva's target was T cells, which are proteins high up in the immunological pathway. In theory, the farther upstream a drug targets, the greater the likelihood of side effects, Blauvelt said. So far there have been few safety concerns about longterm use of Stelara. If the theory holds correct, the outlook for IL-17 inhibitors is optimistic.
"These drugs are the hottest thing in psoriasis right now," Blauvelt said.