Practical Insights on the Changing Spectrum of Biologic Agents for the Treatment of Patients With Psoriatic Disease

AJMC®: How would you characterize the patient experience of psoriatic disease from a quality-of-life standpoint?

Bagel: Let’s imagine that 12 years ago, in June 1, an 18-year-old boy comes into your office with bad psoriasis. Most likely, 3 months later, that 18-year-old boy is going to matriculate to college, and that moderate-to-severe psoriasis will have a major impact on his quality of life for the next 4 years, increasing his amount of anxiety, depression, and probably ability to focus in school. It will interfere with having good interpersonal relationships, and with his sexual activity and development. Flash forward to 2020, and that same person comes into my office on June 1. Now, with the availability of an interleukin (IL)-17 agent, there is a 50% chance that he will go to school clear, totally clear, and have a 90% chance that his quality of life will not be impacted during the course of his 4 years at college. He will be able to develop like other kids, without a skin disorder. That’s just one aspect in which the quality of life has improved significantly for patients with the advent of the highly efficacious IL-17 biologic agents.

AJMC®: What is the prevalence of overlap among disease states that fall under psoriatic disease? What implications does this have for treatment with biologic agents?

Bagel: With psoriasis, to start, we have plaque psoriasis; scalp psoriasis, which is very difficult to treat with topical therapy; palmar plantar psoriasis, which is very difficult to treat with some older biologic agents; and psoriatic arthritis (PsA). In addition, there’s psoriasis of the nails; people who have 8% of body surface area significant in psoriatic nail involvement have a quality of life just as poor as that of somebody with 15% body surface area involvement and no nail involvement.

The IL-17 drug class has had a major impact in improving these conditions. For instance, 50% of an individual’s scalp can be clear within 12 weeks of beginning a biologic agent. We can have a significant improvement in PsA, comparable to the efficacy of tumor necrosis factor (TNF) inhibitors; data show an inhibition of radiographic progression of joint destruction with both TNF inhibitors and IL-17s. In addition, in the past, maybe 25% of people could improve palmar plantar disease, but now about 50% of people can get clear or almost clear with the worst palmar plantar disease. We can get almost clear nails in more than 50% of people, as well.

Also, it is worth considering that patients with psoriatic disease are at an increased risk of metabolic disease, ie, an increase in obesity, diabetes. These may be related to the disease itself. Some data have shown that by decreasing the amount of proinflammatory markers that worsen psoriasis as well as cardiovascular disease, you can get psoriasis down and the inflammation down, and you probably can decrease cardiovascular events like heart attacks and stroke as well.

AJMC®: How does the term “psoriatic disease” influence your understanding of disease states as part of the spectrum?

Bagel: We understand psoriasis as a multisystemic disease. It can involve an increase of TNF in the skin, an increase of ILs in the skin as well as in the cerebral spinal fluid of people who are depressed and anxious. There could be a correlation among the physical manifestations of the disease and the anxiety, depression, and even suicidal ideations that goes along with the disease state. And data have shown that [when] psoriasis [improves physically, that] can lead to better anxiety and depression scores. Thus, we can deal with patients’ psychological and emotional health by helping their psoriatic skin.

AJMC®: As biological therapies have proliferated, how has your approach to treating patients with psoriatic disease changed?

Bagel: First, we began using less ultraviolet light and more biologic agents, because we realized that coming in for phototherapy 3 times a week for 12 weeks is inconvenient and we had better outcomes with the biologic agents. I think a greater change was recognizing that most of these biologic agents were FDA-approved for PsA, and that phototherapy, topical therapy, and even methotrexate and cyclosporine did not have the impact on preventing joint destruction as the new biologic agents did. So, our first question after looking at someone with skin involvement was about their joints: stiffness in fingers or toes, swelling of joints, dactylitis, swelling of an entire digit. We started asking about these symptoms to try to determine the best way to go in terms of treatment.

If patients have PsA, certain biologics would be better. Even now, with ustekinumab, which is FDA approved for psoriasis and PsA, 1 shot can be given every 12 weeks and it really helps about 45% to 50% of people. Plus, it doesn’t seem like there is any cumulative toxicity, which is what we are finding with most biologic agents. In long-term safety data at year 1, year 2, year 3, year 4, year 5, we don’t see an increase in serious infections, and when they are used as a monotherapy, the malignancy rate seems to be pretty comparable to that of patients who are not on biologic agents.

AJMC®: What are some factors you consider during treatment selection?

Bagel: If a patient has a history of recurring infections—such as upper respiratory infection, bronchitis, pneumonia, urinary tract infections—they might not be a great candidate for biologic agents. The reason is that biologics are immunosuppressive, which increases the risk of infection. Similarly, I wouldn’t put somebody who has a history or a family history of demyelination, or of congestive heart failure, on TNF inhibitors. Analogously, there seems to be some controversy about inflammatory valve disease with IL-17 inhibition, so if somebody has a personal or family history of ulcerative colitis or Crohn disease, an IL-17 agent would clearly not be my first choice. However, if someone has had a malignancy, it is worth noting that investigators did allow people in clinical trials who had malignancies 5 years ago or more. So, some data show that you can put people with malignancies on an IL-17 agent, whereas with TNF inhibitors or ustekinumab, no one enrolled in clinical trials had malignancies, other than a basal cell or squamous cell carcinoma.

AJMC®: To what extent does benefits design affect treatment selection regarding the use of biologic therapies in patients with psoriatic disease?

Bagel: Many patients on Medicare do not have access to biologic agents, and I find that prejudicial against the elderly population. Outside of Medicare, some prescription plans require utilizing one drug versus the other, and sometimes it’s OK and sometimes it’s not. If it’s not OK, clinicians should talk to the medical director of the insurance plan about why they need one biologic over the other. Some insurance plans require that people fail either phototherapy or acitretin or methotrexate or cyclosporine prior to going on biologics, so certain barriers are associated with access to biologic therapy. The problem is that most drugs that you use first work best, so if you didn’t use the best drug first, it’s not going to work as well. Why wouldn’t you want to use the best drug first, to get the best benefit for the long term, so that you don’t have to switch and start over with a new loading dose that is more expensive? For instance, ustekinumab works 71% of the time in biologic-naïve individuals and 62% of the time in biologic-experienced individuals. I do believe that with a more highly efficacious drug, you’re best off using it first instead of waiting around to see if maybe they’ll work in the second round.

AJMC®: How would you characterize IL-17 inhibitors compared with TNF inhibitors and other biologic agents with different mechanisms?

Bagel: When you look at the PsA data about the TNF inhibitor adalimumab and the IL-17 inhibitor ixekizumab, the efficacy data are comparable. If you look at the psoriasis efficacy data, izekizumab is probably 50% to 60% more effective. Regarding adverse effects, with ixekizumab comes concerns regarding inflammatory bowel disease, whereas with adalimumab concerns should be for demyelination and congestive heart failure; they both are associated with increased risk of infections. So, looking at the data, the IL-17 therapies do trump the TNF inhibitors as far as efficacy, and they are rather comparable on safety.

IL-23 inhibitors are given less frequently and have comparable efficacy with TNF inhibitors in psoriasis. However, they are not approved for PsA. Guselkumab is currently under investigation for PsA and so far the phase 2 data look good, although they are still trying to figure out the exact dose. Ustekinumab, which is an IL-12/23 inhibitor, is approved for PsA but it is not as effective as IL-17 agents. IL-23 inhibitors are also not very effective for palmar plantar and nail psoriasis, whereas IL-17 agents have good efficacy in these and other difficult-to-treat areas. Another benefit of IL-17 agents is the time to response. Specifically, IL-17 inhibitors have a higher loading dose than other IL-based agents and may yield a quicker response.

AJMC®: What variables do you weigh when selecting among agents in the IL-17 class?

Bagel: Dosing is often very important for patients. For example, secukinumab is 2 shots at week 0, week 1, week 3, and week 4, then 2 shots every 4 weeks. Ixekizumab involves 2 shots at week 0, and 1 shot every other week for 12 weeks, then 1 shot every 4 weeks. Ixekizumab means fewer shots. Efficacy, of course, must also be considered. If you look at brodalumab, although the dosing is every other week, the efficacy is also very high. Plus, the mechanism of action of brodalumab is unique, in that it’s a receptor binder. I think brodalumab and ixekizumab have comparable efficacies. I know that with brodalumab, we have to look for inflammatory bowel disease, which brodalumab may bring on, but also for depression and suicidal ideations. I now have to ask all my patients about these topics. [That said,] I think people with psoriasis are more at risk for suicidal ideation.

Another variable worth considering is duration of efficacy. With secukinumab, for instance, data show that roughly 75% of patients who are doing well after 1 year of treatment maintain that efficacy over 4 to 5 years. Ixekizumab may lose a little bit of efficacy over time. The reason is that there are neutralizing antibodies with secukinumab or brodalumab or guselkumab, so that’s another thing to keep in mind. Psoriasis is not a 12-week disease, so agents with staying power—such as secukinumab, brodalumab, and guselkumab—are noteworthy.

AJMC®: With the treatment landscape for psoriatic disease expanding and drug costs rising, can you share your perspective about the evolving managed care spectrum with respect to biologic therapies?

Bagel: Since secukinumab came to market, various pharmaceutical companies have developed certain plans that allow patients on commercial insurance to receive the drugs for a small monthly payment. This allows patients to be on the drug until the insurance company starts paying for the biologic agent. This increases the amount of people on the drug, and then insurance companies feel that they have to get that drug and keep it on a higher tier of the formulary. Now, it’s still easier to get people on adalimumab in general then it is to get them on other biologic agents. That said, often these policies are very regional.

One potential way of addressing costs is with biosimilars. Although 8 biosimilars have been FDA approved for psoriasis, none of them have been used yet in the United States. I did have a recent opportunity to teach and see patients in Italy, where they were starting to use etanercept biosimilars, and they were very disappointed in the efficacy. I worry that if biosimilars are introduced and they are not as efficacious, that could be an issue; as I noted before, if [a certain] biologic is used first and it doesn’t work as well [as you’d hoped], then the better ones might not work as well when [trying them as a later line of therapy]. So that’s something that I’m concerned about. When it comes to the amount of money spent on biologic therapies, the costs that payers and patients assume is unsustainable.

Another challenge that will need to be addressed is body surface area (BSA). Ultimately, all of our patients deserve to be clear. But what is the price of getting a patient with 3% BSA involvement fully clear? Are these patients at an increased risk for heart attack, stroke, depression and other conditions associated with psoriatic disease? We’re still trying to figure the percentage of affected BSA that the vast majority of people can accept as “minimal” and livable and that is associated with no impact on the rest of their health. We’re going to need to figure that out.