Psoriasis is a serious immune-mediated inflammatory disease, but for patients it is much more. The condition brings with it a number of other co-morbidities that impact on patients’ lives perhaps more than many other serious chronic conditions. This is because psoriasis is also associated with concomitant psychosocial effects, and those with more severe disease are at a greater risk of death from heart disease and diabetes.

Thanks to recent discoveries about the underlying immunopathology of psoriasis research, new therapies for treating psoriasis have been approved and other potential new treatments are in the late stages of clinical development based on important findings about the inner workings of the immune system.

For example, since the discovery of the role that Th17 cells play in the inflammation cascade it has opened new thinking about the immunology of psoriasis leading to the development of innovative biologics designed to ameliorate the activity of those cells. Researchers have uncovered the importance of Th17 cells that, when pathologically activated, they can attack multiple organs in the body and trigger autoimmune diseases such as multiple sclerosis, rheumatoid arthritis and psoriasis.

The elucidation of multiple inflammatory pathways involved in the disease certainly has drawn the attention of a number of biopharmaceutical companies making it one of the hot biotech research areas.

Large Market

That is hardly surprising because it is a large market. According to ISI Group analyst Mark Schoenebaum, writing in a research note, “the dermatology market is very large and fast growing. In the U.S. we estimate approximately 1.2 million people have moderate to severe psoriasis, and roughly 10 percent of this population use biologics that generate $2-3 billion and $5 billion globally.”

Currently this market is dominated by blockbuster biologics that work by blocking TNF-alpha production, thereby interrupting the inflammatory cycle of psoriatic diseases. Those include: Enbrel (etanercept, Amgen Inc.), Humira (adalimumab, Abbvie Inc.), Remicade (infliximab, Johnson & Johnson) and Simponi (golimumab, Janssen Biotech Inc.).

However, other companies are hoping to grab a piece of the action by leveraging recent research discoveries.

Novartis AG, for example, reported results at the European Association of Dermatology and Venereology (EADV) meeting in Istanbul, Turkey, from its head-to-head Phase III FIXTURE study showing secukinumab (AIN457), an interleukin-17A inhibitor, was significantly superior to Enbrel (etanercept) in moderate to severe plaque psoriasis.

The study met all primary and pre-specified key secondary endpoints. Both doses of secukinumab showed improved efficacy compared to Enbrel throughout the 52-week study with secukinumab-treated patients experiencing almost clear skin (Psoriasis Area and Severity Index [PASI] 90) and completely clear skin (PASI 100).

IL-17A, the company noted, is a central cytokine involved in the development of psoriasis, and is found in high concentrations in psoriasis skin plaques. Research has shown that IL-17A, in particular, plays a key role in driving the body’s autoimmune response in disorders such as moderate to severe plaque psoriasis and has become an important target for investigational therapies.

Amgen Inc., of Thousand Oaks, Calif., looks like it could repeat the success achieved with Enbrel following excellent Phase II data last year for brodalumab (AMG827), an antibody that targets the IL-17 receptor, and has since entered an extensive Phase III program in collaboration with London-based Astrazeneca plc.

Phase II results showed that primary and secondary endpoints were met, including many patients achieving and maintaining total skin clearance with continued brodalumab therapy. The Phase III program is evaluating treatment with brodalumab compared with Stelara (ustekinumab, Johnson & Johnson) and/or placebo.

Eli Lilly and Co., of Indianapolis, published Phase II data in the New England Journal of Medicine showing that ixekizumab (LY2439821), an anti-IL-17 monoclonal antibody, met its primary endpoint of achieving at least a 75 percent improvement in PASI scores from baseline. The study enrolled 142 subjects, and significantly more patients achieved a PASI response in the 150-mg, 75-mg and 25-mg groups (82 percent, 83 percent and 77 percent, respectively) than the placebo group (8 percent). The 10-mg dose group did not separate from placebo. Secondary endpoints included percentage of patients achieving at least 90 percent or 100 percent improvement in PASI at week 12. For PASI 90, the responses were 71, 59 and 50 for the 150-mg, 75-mg and 25-mg groups, respectively, compared to 0 percent for placebo. (See BioWorld Today, March 30, 2012.)

Important Target

Another important target, which is receiving a great deal of attention, is IL-23, which stimulates the survival and proliferation of Th17 cells. Several anti-IL-23 monoclonal antibodies already are far along in clinical development, including MK-3222 (Phase III, Merck & Co. Inc.) and CNTO 1959, (Phase II, Johnson & Johnson).

New York-based Pfizer Inc., also is conducting a large Phase III program in psoriasis with its oral Janus kinase (JAK) inhibitor, Xeljanz (tofacitinib), which already is approved in rheumatoid arthritis.

The company recently reported top-line results from two Phase III trials of tofacitinib being investigated to treat adults with moderate to severe chronic plaque psoriasis. OPT Compare is a 12-week, noninferiority study comparing the efficacy and safety of tofacitinib 5 mg and 10 mg twice daily to high-dose Enbrel 50 mg twice weekly, the approved starting dose for Enbrel for the first 12 weeks, and placebo for the treatment of adult patients with moderate to severe chronic plaque psoriasis. Top-line results from OPT Compare showed that tofacitinib met the primary endpoint of noninferiority to high-dose Enbrel at the 10-mg dose. Tofacitinib did not meet the noninferiority criteria to high-dose Enbrel at the 5-mg BID dose. OPT Retreatment is a 56-week study comparing the efficacy and safety of withdrawal and retreatment with tofacitinib 5 mg and 10 mg to placebo for the treatment of adult patients with moderate to severe chronic plaque psoriasis. The study met its primary efficacy endpoints at the 5-mg and 10-mg doses by demonstrating that a greater proportion of patients continuing tofacitinib treatment maintained their responses during the treatment withdrawal phase compared to patients who switched to placebo. (See BioWorld Today, Oct. 10, 2013.)

Incyte Corp., of Wilmington, Del., disclosed results at EADV from a 28-day Phase II proof-of-concept trial involving 50 patients with chronic plaque psoriasis for its oral JAK1 inhibitor, INCB39110. In the trial, evidence of efficacy was observed in patients treated with INCB39110 at all doses as measured by static Physician Global Assessment (sPGA) and PASI as compared to patients treated with placebo. (See BioWorld Today, Oct. 4, 2013.)

Moleculin LLC, of Houston, is taking a topical approach to treating psoriasis, developing compounds based on the direct inhibition of activated STAT3. Earlier this month, it reported positive results from a double-blind, randomized Phase IIa study with MOL4249, which was shown to be effective in the treatment of mild to moderate plaque psoriasis when compared to the vehicle. The study involved 16 patients with mild to moderate plaque psoriasis, and 10 were treated with a topical compound containing MOL4249, while six were treated with a control vehicle. Patients applied the treatment twice a day for 28 consecutive days, and 50 percent of patients treated with MOL4249 showed a 50 percent or better improvement in lesions, vs. 17 percent for the vehicle. In addition, 30 percent of MOL4249 patients demonstrated a 75 percent or better improvement in lesions, vs. 17 percent for the vehicle.