Lisette Hilton is president of Words Come Alive, based in Boca Raton, Florida.
As research advances understanding of psoriasis, drug development evolves to address various pathways to disease. A number of possibilities, now in clinical trials, appear safe, effective and promising with improved long-term clearance rates.
There are about eleven Injectable drugs in the phase 2 and 3 trial pipeline for psoriasis, according to the National Psoriasis Foundation. That doesn’t include biosimilars, which do not follow the traditional pathway through clinic trials.
“Where we stand now, there are three primary targets for injectable biologic medications for psoriasis. Those are: tumor necrosis factor-alpha (TNF-a), which is early in the signaling cascade of immune response, and that molecule has been targeted for many years in different immune-mediated diseases, including rheumatoid arthritis,” said Michael Siegel, Ph.D., director of research programs, National Psoriasis Foundation, Portland, Ore. “The other two targets that are being primarily targeted by these injectable biologics are interleukin 23 (IL-23) and interleukin 17 (IL17). Clinical trials for the specific IL-23 and IL-17 inhibitors have been extremely promising, with high clearance rates and long-term clearance.”
Jashin (Jay) Wu, M.D., director of dermatology research for Kaiser Permanente Medical Center in Los Angeles, Calif., and a National Psoriasis Foundation medical board member, told Dermatology Times that there are several biologics in the pipeline that dermatologists should consider for the future treatment of their psoriasis patients.
“Probably the most exciting is an IL-23 inhibitor by Boehringer Ingelheim, called BI 655066,” Dr. Wu says. “That’s one of three IL-23 inhibitors in the pipeline right now and, of all the biologics, that’s actually the one that’s furthest away from approval. They’re going to start phase 3 trials soon.”
On October 8, 2015, Boehringer Ingelheim announced its investigational biologic cleared skin better, faster and for longer than ustekinumab in a phase 2 psoriasis study.
“After nine months, 69% of patients with moderate-to-severe plaque psoriasis maintained clear or almost clear skin (PASI 90) with BI 655066 in the higher-dose group compared to 30% of patients on ustekinumab. Patients also achieved this skin clearance significantly faster (approximately eight weeks versus approximately 16 weeks) and for more than two months longer (≥ 32 weeks versus 24 weeks) than those on ustekinumab. In addition, completely clear skin (PASI 100) was maintained after nine months in nearly triple the percentage of patients on BI 655066 compared with ustekinumab (43% versus 15%),” according to the press release.
There are two other IL-23 inhibitors, according to Dr. Wu: guselkumab (Janssen) and tildrakizumab (Sun Pharmaceutical Industries).
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“The other two IL-23 inhibitors in development are guselkumab and tildrakizumab. Early phase 2 results show that they are also very effective for psoriasis. They are both currently undergoing phase 3 trials, so hopefully we will know more in one to two years,” Dr. Wu says.
In a 16-week phase 2B trial of tildrakizumab, researchers studied patients on four doses at weeks 0 and 4 (5mg, 25mg, 100mg, and 200mg) versus placebo. “PASI 75 was achieved in 35, 65.5, 67.1, and 76.2 percent of patients, respectively versus 4.9% in the placebo arm and PASI 90 was achieved in 11.9, 24.4, 38.2, and 51.2 percent of patients versus 2.2% in the placebo arm. Tildrakizumab appears to be generally safe and well tolerated,” according to an article by Craig Leonardi, M.D., published April 28, 2014 in Maui Derm News.
Guselkumab, tildrakizumab and BI 655066 are p19 monoclonal antibodies, according to Jerry Bagel, M.D., M.S., dermatologist, director of the Psoriasis Treatment Center of Central New Jersey in East Windsor, N.J.
“As we have learned, p19 is one of two subunits which compose IL-23. IL-23 activates the proliferation of Th-17 cells and subsequent production of IL-17. Binding the p19 component of IL-23 thereby inhibits the proliferation of Th-17 cells and the subsequent production of IL-17. The subsequent production of IL-17 and IL-22, both of which are involved in the pathogenesis of psoriasis.” Dr. Bagel says.
Whereas the IL-17 regimens need to be administered every two to four weeks, injections of the p19 inhibitors seems to be more in line with ustekinumab (Stelara, Janssen) administration - about every eight weeks, according to Dr. Bagel.
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“With the p19 inhibitors, you might get 90% of people getting a PASI 75, or a PASI 90 in 55% of people, with a shot every eight or 12 weeks. We’re having PASI 100s in the IL17 in the 40 percentile ranges. We’re probably going to see PASI100s in the 50% ranges in the p19 inhibitors,” Dr. Bagel says.
Among the IL-17 inhibitors in phase 3 trials: Ixekizumab (Eli Lillly), which according to Dr. Wu, is impressive. And even though there are no head-to-head studies between ixekizumab and secukinumab (Cosentyx, Novartis), which is approved for the treatment of psoriasis, Dr. Wu says ixekizumab may have a slight edge on secukinumab when one looks at numbers needed to treat (NNT) to reach PASI75, PASI90, and PASI100.
The efficacy of ixekizumab is extremely high, according to Dr. Bagel.
“We’re seeing efficacy from these drugs of PASI90 above 50%, meaning that more than 50% of people are getting at least 90% better within 12 weeks. We’re getting close to 90% of people who are getting 75% better within 12 weeks. And 80% of people are maintaining this efficacy for at least one year,” Dr. Bagel says.
Ixekizumab, which will probably be approved this year, could usher IL-17 monoclonal antibody injectable options with much higher efficacy than what dermatologists and other specialists have seen with the anti-TNF inhibitors or even with the p-40 inhibitor, like ustekinumab, which blocks proteins IL12 and IL23, according to Dr. Bagel.
“The [other] one in the group is brodalumab (AstraZeneca, Valeant), which inhibits the receptor of IL17. We reported phase 3 trial results in the October 1, 2015 issue of New England Journal of Medicine. This biologic also shows very high clearance of psoriasis,” Dr. Wu says.
In fact, brodalumab was in phase 3 research with Amgen but the pharma company dropped the program, and now this drug’s future is somewhat uncertain, according to Dr. Siegel.
In November 2014, AstraZeneca and Amgen announced the compound showed superior skin clearance in a phase 3 trial when compared to ustekinumab and placebo. The following year, however, Amgen stopped co-developing brodalumab because of reports that patients were having "events of suicidal ideation and behavior." In the latest development, AstraZeneca has partnered with Valeant pharmaceuticals in a deal in which Valeant will develop and commercialize brodalumab.
Dr. Siegel says he is hesitant to talk yet about what might be exciting among the injectable drug options for psoriasis in phase 1 trials.
“We hear from a lot of people about new ideas…. People are definitely targeting different parts of the pathway and these are not just injectables,” Dr. Siegel says. “If you look at small molecule inhibitors, there’s a lot of work with the ability to deliver small molecules to target different aspects of intracellular signaling pathways involved in the evolution of different immune cells’ different signaling pathways. So, a lot is going on in that space.”
Neihulizumab, AbGenomicsCorporation.According to the AbGenomics website: “Neihulizumab/AbGn-168H is a humanized therapeutic antibody with a unique mechanism of action, which preferentially induces apoptosis of late-stage activated T cells. This novel activated-T cell apoptosis-inducing antibody effectively eliminates chronic pathogenic T cells while fully maintaining host defense. A long lasting drug-free remission and less concern of increasing infection/cancer risks are its substantial clinical benefits. These two characteristics, which have been well demonstrated in our proof of concept clinical studies, offer a sustainable competitive advantage over existing therapies.”
Tregalizumab, Biotest AG. Tregalizumab is an investigational humanized anti-CD4 monoclonal antibody, inducing selective activation of regulatory T-cells. In a press release dated June 24, 2015, Biotest announced that AbbVie and Biotest will end their collaboration on the development and commercialization of Tregalizumab (BT-061), and AbbVie will return all rights granted under the agreement at no cost to Biotest. The phase IIb study (TREAT 2b) of Tregalizumab (BT-061) in patients with moderate to severe rheumatoid arthritis (RA) did not meet its primary endpoint.
Namilumab, Takeda. Namilumab, or MT203, is a human monoclonal antibody that inhibits granulocyte-macrophage colony-stimulating factor (GM-CSF) signaling by binding the soluble cytokine, according to Takeda.com. It Is in a phase 2 study to establish proof of efficacy of namilumab in moderate-to-severe plaque psoriasis, measured as PASI 75 response rate at week 12.
Abatacept (Orencia, Bristol Myers Squibb) has been on the market for rheumatology as Orencia for a number of years and is moving into the psoriasis disease space. Abatacept is a synthetic protein produced by recombinant DNA technology. Interestingly, the drug has been shown to result in psoriasiform, in a study in which researchers concluded: “Our present study suggests that psoriasiform drug eruption caused by abatacept might develop by similar immunological mechanisms as those of psoriasis vulgaris.”
IMO-8400, Idera Pharmaceuticals. IMO-8400 is an antagonist of Toll-like receptors (TLRs) 7, 8 and 9. In March 2014, Idera announced results from a phase 2 trial of IMO-8400 in 32 patients with moderate-to-severe plaque psoriasis. “The primary objective of the trial was to evaluate the safety and tolerability of IMO-8400 over a 12-week treatment period, with a secondary objective to evaluate the clinical activity of IMO-8400. The trial met its primary objective as all treatments were well tolerated with no treatment related discontinuation, serious adverse events or dose reductions. IMO-8400 treatment met the secondary objective of demonstrating clinical activity in patients with psoriasis, as assessed by Psoriasis Area and Severity Index (PASI),” according to a company press release. “Idera’s strategy is to develop IMO-8400 for the treatment of genetically defined forms of B-cell lymphoma and orphan autoimmune diseases.”
BI 655066, Boehringer Ingelheim. BI 655066 is a selective IL23 inhibitor. On October 8, 2015, Boehringer Ingelheim reported results from a Phase II head-to-head psoriasis study, which showed superior efficacy of the biologic compound BI 655066 over ustekinumab. After nine months, 69% of patients with moderate-to-severe plaque psoriasis maintained clear or almost clear skin (PASI 90) with BI 655066 in the higher-dose group compared to 30% of patients on ustekinumab.1 Patients also achieved this skin clearance significantly faster (approximately eight weeks versus approximately 16 weeks) and for more than two months longer (≥ 32 weeks versus 24 weeks) than those on ustekinumab. In addition, completely clear skin (PASI 100) was maintained after nine months in nearly triple the percentage of patients on BI 655066 compared with ustekinumab (43% versus 15%, according to the press release.
Guselkumab, Janssen. Researchers reported at the American Academy of Dermatology’s 72nd annual meeting that higher doses of the investigational human monoclonal antibody guselkumab outperform adalimumab in the treatment of moderate to severe plaque psoriasis. The results were from the X-PLORE trial.
Certolizumab pegol (Cimzia, UBC). This is a therapeutic monoclonal antibody to TNF-alpha. The FDA approved the biologic medication September 2013 for the treatment of active psoriatic arthritis. It is also approved for treating rheumatoid arthritis, ankylosing spondylitis and Crohn’s disease, according to the National Psoriasis Foundation.
Ixekizumab, Eli Lilly and Company. Dr. Siegel told Dermatology Times that he anticipates the FDA’s approval of ixekizumab in 2016. Ixekizumab is a humanized anti–interleukin-17 monoclonal antibody for the treatment of psoriasis. Eli Lilly and Company announced Aug. 21, 2014, the results of its UNCOVER studies, suggesting that ixekizumab met all primary and key secondary objectives across three pivotal studies of 3,866 patients, the largest phase 3 moderate-to-severe plaque psoriasis program to date. And ixekizumab was superior to etanercept on all measures of skin clearance in both active comparator studies.
Tildrakizumab, Merck/ Sun Pharmaceutical Industries Ltd.Tildrakizumab is an investigational humanized, anti-IL-23p19 monoclonal antibody that binds specifically to IL-23p19 to selectively block the cytokine IL-23, according to Merck. Merck acquired the anti-IL-23 mAb tildrakizumab (MK-3222/SCH-900222). Merck announced September 2014 that Sun Pharma will acquire worldwide rights to tildrakizumab for use in all human indications from Merck, but Merck will continue clinical development and regulatory activities, which will be funded by Sun Pharma.
Brodalumab, Astra Zeneca/Valeant. Brodalumab targets the IL17 portion of the pathway. The drug was in phase 3 with Amgen but the pharma company dropped the program, and now this drug’s future is somewhat uncertain, according to Dr. Siegel. In November 2014, AstraZeneca and Amgen announced the compound showed superior skin clearance in a phase 3 trial when compared to ustekinumab and placebo. The following year, however, Amgen stopped co-developing brodalumab because of reports that patients were having "events of suicidal ideation and behavior". In the latest development, AstraZeneca has partnered with Valeant pharmaceuticals in a deal in which Valeant will develop and commercialize Brodalumab.
Disclosures: Dr. Bagel does clinical trials, speaks and/or consults for Boehringer Ingelheim, Janssen, Eli Lilly, Novartis and AbbVie and Sun Pharmaceutical Industries. Dr. Siegel is employed by the National Psoriasis Foundation. The Foundation receives unrestricted financial support from AbbVie, Amgen, Inc., Celgene Corporation, Eli Lilly and Co., Janssen Biotech Inc., LEO Pharma Inc., Novartis Pharmaceuticals, Pfizer, Inc., Stiefel, a GSK Company and Taro Pharmaceuticals. Dr. Wu received research funding from AbbVie, Amgen, AstraZeneca, Boehringer Ingelheim, Coherus Biosciences, Dermira, Eli Lilly, Janssen, Merck, Novartis, Pfizer, Regeneron, Sandoz, and Sun Pharmaceutical Industries; he is a consultant for AbbVie, Amgen, Celgene, Dermira, Eli Lilly, Pfizer, Regeneron, and Sun Pharmaceutical Industries.