Biologic class differentiators

It’s an exciting time for moderate-to-severe psoriasis patients and the dermatologists treating them. Biologics are clearing skin where topicals and other therapies have failed to make a dent. The field is burgeoning with many more biologics in development or in clinical trials.

“Just a few years ago, we were using PASI [Psoriasis Area Severity Index] 75 as a benchmark, with 75 percent improvement. With our newer drugs, it’s clear that PASI 90 may be more appropriate,” says Craig L. Leonardi, M.D., adjunct professor of dermatology, Saint Louis University, and medical director of Central Dermatology, St. Louis, Mo.

But there are no guidelines or expert recommendations about which of the many biologics available today dermatologists should use and when, according to Anthony Fernandez, M.D., Ph.D., director of medical dermatology at Cleveland Clinic.

One thing that dermatologists should discuss with patients before prescribing biologics is how the medications differ in their dosing regimens, according to Anthony Fernandez, M.D., Ph.D., director of medical dermatology at Cleveland Clinic.

“Sometimes that makes a difference to patients in terms of what they prefer to try first when there are multiple options that seem to be safe for them,” Dr. Fernandez says. “For example, with etanercept, you have to give yourself an injection twice a week for the first three months, then it’s every week after that. Adalimumab is an injection every two weeks. Ustekinumab is an injection just once every three months. The IL-17 inhibitors are basically an injection once a month. Then, apremilast is a pill. For some people that makes a big difference.”

Dermatology Times asked Drs. Fernandez and Leonardi to give readers a rundown of what’s available in this space. Dr. Fernandez spoke on the topic during the Cleveland Clinic’s April 2017 Biologic Therapies VII Summit, in Cleveland. Dr. Leonardi presented on biologics at the March 2017 annual Maui Derm meeting.

TNF-alpha inhibitors

They’ve been approved to treat psoriasis the longest, according to Dr. Fernandez.

There are three tumor necrosis factor (TNF) alpha inhibitors: etanercept (Enbrel, Amgen), adalimumab (Humira, AbbVie) and infliximab (Remicade, Janssen).

“A newer [TNF inhibitor] is certolizumab pegol (Cimzia, UCB),” Dr. Leonardi says. “This drug is currently approved for psoriatic arthritis and inflammatory bowel diseases,¹ and it is in trial for psoriasis.² It’s expected to go in front of the FDA later this year. Based on results seen with the psoriasis trials, we’ll probably see them have a trouble-free submission to the FDA.”

There are differences among the three, Dr. Leonardi says.

Infliximab is given by subcutaneous infusion.³ It’s highly effective, but a complex drug to use.

“Most dermatologists don’t use infliximab because of its IV nature. It’s usually not given in the office. Administratively, it’s a tough drug to prescribe,” Dr. Leonardi says.

Dr. Leonardi calls adalimumab an amazing drug.

“With more than one million patients who are taking adalimumab for 10 different disease states, this is a tried-and-true drug. It’s a high performance skin clearing drug. And it is currently the standard of care for treating psoriatic arthritis. So, it treats the skin; it treats the joints,” Dr. Leonardi says.

Etanercept was the market leader in dermatology, but it’s falling by the wayside, Dr. Leonardi says.

“Etanercept is currently the least effective biologic drug in the entire pallet of options in dermatology,” Dr. Leonardi says. “There are some good things that have happened. Etanercept finally got approved for treating children.⁴ That’s an important thing because there are no systemic treatments of any kind that have been approved for treating children with psoriasis, until the change of heart by the FDA for etanercept.”

Other key points for dermatologists

Before prescribing TNF alpha inhibitors, dermatologists may want to consider other options for patients who have a personal history or family history of demyelinating disorders, such as multiple sclerosis.

“TNF alpha inhibitors are probably something you would not want to use in that population, given that we have so many other excellent options,” Dr. Fernandez says.

Interestingly, TNF inhibitors are associated with a reaction called TNF-alpha inhibitor-induced psoriasis. 

“Sometimes, despite our best efforts to control the reaction, it’s severe enough that we have to stop the TNF inhibitor. In those cases, we will typically choose one of the alternative medicines - either ustekinumab or one of the IL-17 inhibitors. That reaction has not been associated with those other classes of medicines,” Dr. Fernandez says.

One of the advantages of TNF alpha inhibitors is they’ve been out longer than the biologics approved for psoriasis. As a result, there’s more long-term data about the safety of these medications, in large cohorts of patients, according to Dr. Fernandez.

In a class of its own: ustekinumab

There is one p40 IL 12/23 antagonist or inhibitor, ustekinumab (Stelara, Janssen).

“One of the things we’ve learned over the years … is that the IL-23 blockage is probably the most important aspect of ustekinumab. And IL-23 blockage feeds downstream to affect IL-17 production,” Dr. Leonardi says.

IL-17 inhibitors

There are three approved IL-17 inhibitors for the treatment of psoriasis: secukinumab (Cosentyx, Novartis), ixekizumab (Taltz, Eli Lilly), and, the newest of the three, brodalumab (Siliq, Valeant).

There are some differences in the IL-17 class.

“Both ixekizumab and secukinumab bind to IL-17a. Brodalumab blocks the IL-17a receptor. So, its mechanism of action is a bit different,” Dr. Leonardi says. “Currently, all three of them are approved for psoriasis.^{5, 6, 7} Secukinumab is also approved for treating psoriatic arthritis. Ixekizumab is hot on that path now. I believe it has been submitted to the FDA for treatment of psoriatic arthritis.”

Brodalumab, while among the best efficacy-wise among biologics, is a tough one to prescribe. Its labeling includes a Boxed Warning and the drug is only available through a restricted Risk Evaluation and Mitigation Strategy (REMS) program, because of an observed risk of suicidal ideation and behavior.⁸ The REMS program requires that prescribers are certified with the program and counsel patients about risk; patients sign a Patient-Prescriber Agreement Form, understand associated risks and know they should seek appropriate medical attention when needed. Pharmacies are certified and only dispense to patients authorized to receive this drug, according to an FDA press release. (Read more in “Brodalumab prescribing regulatory hoops, page XX)

With IL-17 inhibitors, it is well known that psoriasis patients are at increased risk for developing inflammatory bowel disease, Crohns disease or ulcerative colitis.

“I’ve had a patient or two with a history of Crohns disease who was well controlled, but then began flaring on an IL-17 inhibitor. So, [dermatologists] may want to consider other options in those patients,” Dr. Fernandez says.

The only pill in the bunch

There is one small molecule inhibitor, apremilast (Otezla, Celgene), which is the only pill among approved biologics. Clinical data suggests that it is associated with minimal adverse effects.⁹

“As a result, we don’t need to follow bloodwork with apremilast,” Dr. Fernandez says. “So, it’s a good option for patients where you really need to worry about different adverse reactions that may be occurring if you give them any of the other biologics.”

Disclosures:

Dr. Fernandez is a speaker for AbbVie and Celgene. He has been a consultant and researcher for AbbVie. He also does research for the Corrona database, which collects information about patients with psoriasis and psoriatic arthritis who are on systemic medications, like biologics.

Dr. Leonardi has ties with AbbVie, Amgen, Celgene, Coherus, Dermira, Eli Lilly, Galderma, Glaxo Smith Kline, Janssen, Leo, Merck, Merck-Serono, Novartis, Pfizer, Sandoz, and Vitae. He is also a phototherapy provider and has an infusion center.

References: 

1 Cimzia [package insert]. https://www.cimzia.com/assets/pdf/Prescribing_Information.pdf Smyrna, GA: UCB, Inc ; Revised April 2016.

2 Final CIMZIA® (certolizumab pegol) Phase 3 Trial Meets Primary Efficacy Endpoint in Patients with Moderate-to-Severe Chronic Plaque Psoriasis. UCB, Inc.; https://eu.vocuspr.com/ViewAttachment.aspx?EID=hciRJLtApyzzYk8gYkD3EREuidEx9XV3VUuEXldmjyE%3d Published January 19, 2017

3 Remicade [package insert]. https://www.remicade.com/shared/product/remicade/prescribing-information.pdf Horsham, PA: Janssen Biotech, Inc.; Revised October 2015

4 FDA Approves Expanded Use Of ENBREL® (etanercept) To Treat Children With Chronic Moderate-To-Severe Plaque Psoriasis. https://www.amgen.com/media/news-releases/2016/11/fda-approves-expanded-use-of-enbrel-etanercept-to-treat-children-with-chronic-moderatetosevere-plaque-psoriasis/ Amgen. Published November 4, 2016.

5 Taltz [package insert]. http://uspl.lilly.com/taltz/taltz.html#pi Indianapolis, IN:

 Eli Lilly and Company; Revised January 2017.

6 Cosentyx [package insert]. https://www.pharma.us.novartis.com/sites/www.pharma.us.novartis.com/files/cosentyx.pdf East Hanover, NJ: Novartis Pharmaceuticals Corp.; January 2015.

7 Siliq [package insert]. https://www.accessdata.fda.gov/drugsatfda_docs/label/2017/761032lbl.pdf Bridgewater, NJ: Valeant Pharmaceuticals; February 2017.

8 FDA approves new psoriasis drug. U.S. Food and Drug Administration.  https://www.fda.gov/newsevents/newsroom/pressannouncements/ucm541981.htm Published February 15, 2017.

9 Otezla [package insert]. http://www.celgene.com/content/uploads/otezla-pi.pdf Summit, NJ: Celgene Corp.; Revised December 2015.