“The landscape of biologics and biosimilars is changing rapidly, and for the better,” says Mark Lebwohl, M.D. Biologics have given patients the possibility of complete psoriasis clearance and control of their psoriatic arthritis (PsA), which were not options 20 years ago, adds Alice Gottlieb, M.D., Ph.D.
“The landscape of biologics and biosimilars is changing rapidly, and for the better,” says Mark Lebwohl, M.D. (Nikkikii - stock.adobe.com)
Treatments in development for psoriasis
FDA-approved agents for psoriasis, psoriatic arthritis
Although legal wrangling has largely sidelined biosimilars for psoriasis in the United States, new drugs targeting interleukin (IL)-17 and IL-23 provide potent new options. Meanwhile, dozens of biologic and biosimilar candidates pack the psoriasis pipeline.
“The landscape of biologics and biosimilars is changing rapidly, and for the better,” says Mark Lebwohl, M.D. He is the Waldman Professor and Chairman, Kimberly and Eric J. Waldman department of dermatology, Icahn School of Medicine at Mount Sinai, New York.
Biologics have given patients the possibility of complete psoriasis clearance and control of their psoriatic arthritis (PsA), which were not options 20 years ago, says Alice Gottlieb, M.D., Ph.D. She is clinical professor, department of dermatology, Icahn School of Medicine at Mount Sinai, and medical director at Mount Sinai-Union Square in New York City.
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“Assuming my patients don’t have complicating health issues preventing me from using the complete treatment repertoire,” she says, “I can tell them that I have a greater than 90% chance of clearing you. I tell them they can run around naked and no one will know they have psoriasis.”
For patients with PsA, Dr. Gottlieb says she can offer a high probability of having a normal quality of life, inhibiting radiographic progression and controlling their signs and symptoms.
“And I can do so safely,” she says.
Dr. Gottlieb’s investigator-initiated study showing that Remicade (infliximab, Janssen) monotherapy cleared psoriasis1 got the biologic ball rolling in dermatology.
“This was the first double-blinded, placebo-controlled experiment in psoriasis with a biologic,” she says.
Delayed era makes strides
“Psoriasis was fairly late to the biologic era,” says M. Alan Menter, M.D., professor and program director of dermatology at Baylor Scott & White Health, Dallas.
All the TNF-alpha inhibitors were first approved in rheumatology or gastroenterology.
“But that’s changed completely over the last five years,” he says.
With four TNF-alpha agents, the IL 12/23 inhibitor ustekinumab (Stelara, Janssen), three IL-17 drugs and three IL-23 agents, he says, dermatology has more biologics available than does gastroenterology or rheumatology.
Newer biologics, moreover, offer unprecedented efficacy. Whereas inhibitors of TNF-alpha and IL-12/23 offer PASI 75 rates of 70% to 75%, says Dr. Menter, blockers of IL-17 and IL-23 provide PASI 75 scores in the 90% range - and PASI 90 rates of 60% to 70%.
IL-17 inhibitors and IL-23 inhibitors also provide lengthy remissions. In a phase 1 trial of risankizumab (Skyrizi, AbbVie), six of nine patients given a high dose maintained PASI 100 for 40 to 66 weeks after a single treatment,2 Dr. Lebwohl says.
“Imagine, not a dot of psoriasis in two-thirds of patients a year later,” he says.
Experts believe that when these drugs block IL-23, the Th17 cell that makes IL-17 disappears.
“It takes a while to reconstitute the Th17 cell, and that’s why the disease stays away for so long,” he explains. “Patients stay clear for months, which is why we can get away with dosing only every two or three months.”
Among IL-17 inhibitors, secukinumab (Cosentyx, Novartis) and ixekizumab (Taltz, Lilly) block IL-17A directly, while brodalumab (Siliq, Valeant Pharmaceuticals) blocks the IL-17 receptor.
“They’re incredibly effective. They actually work faster than the IL- 23 drugs, but they need more injections,” Dr. Lebwohl says. Secukinumab’s loading dose, for example, is two injections weekly for five weeks, followed by two injections monthly thereafter.
“Ixekizumab is every two weeks for three months, and then every month,” he says.
Now in FDA phase 3, bimekizumab (UCB4940, UCB), which blocks IL-17A and IL-17F, will probably be available in late 2021, Dr. Lebwohl says. Along with working quickly, he says, it offers the highest efficacy rates to date for psoriasis and psoriatic arthritis (PsA).
Side effect profiles for the IL-17 and IL-23 blockers are identical, he adds, except for a warning about suicides with brodalumab, which may not be drug-related. Beyond that, Dr. Lebwohl says the only commonly occurring side effect of newer biologics is yeast infections.
Still, Dr. Menter says, the new biologic categories must prove long-term safety. Because rare adverse events can accumulate once a drug reaches the market, he says, it normally takes up to five to seven years after clinical trials to establish long-term safety.
“Clinical trial patients do not equal clinical practice patients,” he says. A three-year continuous dosing study of efalizumab (Raptiva, Genentech) that Dr. Menter co-authored showed no serious adverse events.3 Yet the next year, three cases of leukoencephalopathy resulted in the drug’s withdrawal from the U.S. market.
“I still have hundreds of patients totally clear on the TNF-alpha drugs,” Dr. Menter adds. And these drugs have a 15-year safety record. “The important issue that remains for all the TNF-alpha drugs is that they still do not have any evidence to show - and it may take up to three to five years - that using a biologic will reduce the incidence of cardiovascular disease in our psoriasis population.”
Many TNF-alpha inhibitors seem to lose their efficacy over time, Dr. Lebwohl says, as patients commonly must switch to other biologics in less than five years. But ustekinumab’s drop-off rate is lower, he says.
With secukinumab, Dr. Lebwohl says clinical trials showed very little loss of efficacy. However, a recent Danish registry study suggested that patients come off secukinumab frequently - approximately 15% of secukinumab treatments were switched to another biologic within 12 months.10
“If you look at the numbers,” Dr. Lebwohl says, “you can cherry-pick to make a point. But then you’re missing the big picture. These drugs actually are quite durable.”
Drug switches in clinical practice could be explained by insurance changes or other factors unrelated to the drug,11 he says.
Formulary penetration for the IL-17 and IL-23 blockers has been good, say Drs. Menter and Lebwohl. However, Dr. Menter’s practice has had trouble with Medicare because many of its patients lack secondary insurance.
“So it’s sometimes very difficult to get an expensive biologic drug approved for a Medicare patient,” he says. Even for those who have secondary insurance but need to switch to another biologic, getting approval is a constant struggle, he says.
Dr. Gottlieb, whose patient population is predominantly on Medicare or Medicaid, says that her Medicare patients have the toughest time accessing biologic drugs as well. Once a drug is approved for a patient on Medicaid, she explains, the patient pays virtually nothing. But, when a Medicare patient gets approval for a biologic drug, the patient typically must pay a higher percentage of the cost as coinsurance.
“Even if it’s 20%, it’s still prohibitive for many Medicare patients,” she says.
The IL-23 blockers have a buy-and-bill model: A doctor or hospital buys and bills for the drug, which is attributed to the patient’s medical - not pharmacy - benefit. This approach relieves Medicare patients of the high coinsurance burden, Dr. Gottlieb says. But it puts doctors and hospitals at significant risk if insurers don’t pay for the drugs they have purchased.
Dr. Menter says that the only drawback to having the new, highly targeted biologics is that no test can determine which drug will work best for which patient.
“Many of the choices are not driven by what we or patients want, but by what third-party payers have as number one and number two on their formulary list,” he says.
Dr. Lebwohl says, “We still don’t have a drug that achieves PASI 100 in the majority of patients long-term.”
Bimekizumab is the first drug to spark serious conversations about achieving American College of Rheumatology (ACR) 50 or ACR70 in PsA, he adds.
The story of biologic drugs in psoriasis and PsA is so positive, says Dr. Gottlieb, that efficacy and safety are no longer her top concerns.
“Patients have lots of choices. The biggest challenge with biosimilars and branded drugs is the high cost. Access is the major issue,” she says. DT
Dr. Lebwohl is a paid consultant to Boehringer-Ingelheim. He is also an unpaid investigator for most other companies making biologics for psoriasis (Mount Sinai receives payment from these companies).
Dr. Gottlieb is a consultant and/or advisory board member for AbbVie, Allergan, Avotres Therapeutics, Beiersdorf, Boehringer-Ingelheim, Bristol-Myers Squibb, Celgene, Dermira, Eli Lilly, Incyte, Janssen, LEO Pharma, Novartis, Dr. Reddy’s Laboratories, Sun Pharmaceutical, UCB, Valeant (Ortho Dermatologics) and XBiotech. She has also received research/educational grants from Boehringer-Ingelheim, Incyte, Janssen, Novartis, XBiotech and UCB.
Dr. Elewski has been a clinical researcher (with funds going to UAB) for AbbVie, AnaptysBio, Boehringer-Ingelheim, Bristol-Myers Squibb, Celgene, Eli Lilly, Incyte, LEO Pharma, Merck, Menlo, Novartis, Pfizer, Regeneron, Sun Pharmaceuticals, Valeant (Ortho Dermatologics) and Vanda. She has also been a consultant (honoraria) for Boehringer-Ingelheim, Celgene, Eli Lilly, LEO Pharma, Menlo, Novartis, Pfizer, Sun Pharmaceuticals, Valeant (Ortho Dermatologics) and Verrica.
Dr. Menter has been a paid investigator and consultant for all companies making biologics for psoriasis, but he owns no stock in any of these companies.
1. Chaudhari U, Romano P, Mulcahy LD, Dooley LT, Baker DG, Gottlieb AB. Efficacy and safety of infliximab monotherapy for plaque-type psoriasis: a randomised trial. Lancet. 2001;357:1842-1847.
2. Krueger JG, Ferris LK, Menter A, et al. Anti-IL-23A mAb BI 655066 for treatment of moderate-to-severe psoriasis: safety, efficacy, pharmacokinetics, and biomarker results of a single-rising-dose, randomized, double-blind, placebo-controlled trial. J Allergy Clin Immunol. 2015 Jul;136(1):116-124.e7.
3. Leonardi C, Menter A, Hamilton T, Caro I, Xing B, Gottlieb AB. Efalizumab: results of a 3-year continuous dosing study for the long-term control of psoriasis. Br J Dermatol. 2008;158:1107- 1116.
4. Egeberg A, Bryld LE, Skov L. Drug survival of secukinumab and ixekizumab for moderate-to-severe plaque psoriasis. J Am Acad Dermatol. 2019 Mar 23. pii: S0190-9622(19)30466-9. doi: 10.1016/j.jaad.2019.03.048. [Epub ahead of print]
5. Lebwohl MG. Letter in response to Egeberg A, Bryld LE, Skov L, Drug survival of secukinumab and ixekizumab for moderate-to-severe plaque psoriasis. J Am Acad Dermatol. 2019 Jun 1. pii: S0190-9622(19)30885-0. doi: 10.1016/j.jaad.2019.05.081. [Epub ahead of print]