Biologics Take Aim at Psoriasis Despite Worry Over Reactions

Laird Harrison

March 26, 2015

SAN FRANCISCO — New findings on experimental options for plaque psoriasis were debated here at the American Academy of Dermatology 73rd Annual Meeting. The biologic agents appear to be easing symptoms but are controversial because they suppress the immune system and have been linked to malignancies, major cardiac events, herpes zoster, and tuberculosis.

Pfizer's oral drug tofacitinib is typically prescribed for rheumatoid arthritis, but two phase 3 studies explore this option for psoriasis. Newer experimental alternatives, such as Boehringer Ingelheim's BI 655066 and Eli Lilly's ixekizumab, boast of complete clearance.

"It's my belief that complete clearance is something we should be seeking because patients are telling us that is when the disease is not having an impact on their life," said ixekizumab study investigator Kenneth Gordon, MD, from the Northwestern University Feinberg School of Medicine in Chicago.

Session moderator Andrew Blauvelt, MD, president of Oregon Medical Research Center in Portland, questioned whether patients are more likely to suffer adverse effects if they achieve clearance.

"There are no data to suggest that clearance has any greater side effects," said Dr Gordon. "In fact, the analysis isn't complete, but I might argue that we have never been able to test that because we've never had drugs with complete clearance as high as some of the drugs presented today have attained."

Oral Tofacitinib

The Janus kinase inhibitor tofacitinib is an effective and safe treatment for patients with moderate to severe psoriasis, reported Kim Papp, MD, from Probity Medical Research in Waterloo, Ontario, Canada.

The design of the two phase 3 placebo-controlled studies investigating this question were identical, and were conducted at 71 and 82 centers. Patients with moderate to severe psoriasis were randomized to tofacitinib 5 mg or 10 mg twice daily or placebo for 16 weeks.

The investigators report improvements in Physician Global Assessment score and a 75% improvement in symptoms at 16 weeks, measured on the Psoriasis Area and Severity Index (PASI). The higher dose was significantly more effective than the lower dose.

Table 1. Outcomes at Week 16

Outcome Tofacitinib 5 mg, % Tofacitinib 10 mg, % Placebo, % P Value
Study 1078        
   Physician Global Assessment response 41.9 59.2 9.0 <.0001
   75% reduction in PASI 39.9 59.2 6.2 <.0001
Study 1079        
   Physician Global Assessment response 46.0 59.1 10.9 <.0001
   75% reduction in PASI 46.0 59.6 11.4 <.0001

 

Tofacitinib was well tolerated, and only 3.0% of patients discontinued the drug because of adverse effects during the 16-week study period. Lab abnormalities, including increases in cholesterol, were more common in patients treated with tofacitinib than with placebo (3.9% of vs 1.3%). None of the safety findings were new or unexpected.

The rate of herpes zoster infection appeared to be quite low, and affected less than 1% of patients during short-term use.

Table 2. Tofacitinib Safety During the 16-Week Study

Outcome Tofacitinib 5 mg (n = 745), % Tofacitinib 10 mg (n = 741), % Placebo (n = 373), %
Adverse event 53.4 58.3 48.8
Serious adverse event 2.6 2.0 1.9
Discontinuation due to adverse event 3.2 3.0 4.6
Death 0.3 0 0.3

 

"For an oral drug, the 10 mg dose seems to have efficacy rates similar to what might be expected from etanercept," said session moderator Joel Gelfand, MD, from Penn Medicine in Philadelphia. "However, this comparison should be made with caution as the placebo response rate was higher than expected and a direct comparison was not made to etanercept," he told Medscape Medical News.

"There seemes to be an imbalance of major adverse cardiac events in the treated group — with 3 events versus 0 — but there was no evidence of a dose response," Dr Gelfand noted. "This could be due to chance."

Experimental Biologic Boasts Complete Clearance

BI 655066 looks better than the other biologics for psoriasis, said session moderator Dr Blauvelt. "These are probably the most impressive phase 2 data we've seen," he told Medscape Medical News.

BI 655066 is a monoclonal antibody that specifically inhibits interleukin (IL)-23, which researchers believe plays a key role in psoriasis inflammation.

However, several other biologics are further along in the pipeline, having proven themselves in larger trials, Dr Blauvelt added. Ustekinumab (Stelara, Johnson & Johnson), a biologic already approved for moderate to severe plaque psoriasis, blocks IL-12 in addition to IL-23.

In their study, Dr Papp and his colleagues randomly assigned 166 patients to a subcutaneous injection of BI 655066 or ustekinumab.

In the BI 655066 group, patients received one of three doses. In the low-dose group, 43 patients received 18 mg at week 0 followed by placebo at weeks 4 and 16. In the medium-dose group, 41 patients received 90 mg at weeks 0, 4 and 16. In the high-dose group, 42 patients received 180 mg at weeks 0, 4, and 16.

In the ustekinumab group, 40 patients received 45 or 90 mg, depending on body weight, at weeks 0, 4, and 16.

The 48-week trial is ongoing, said Dr Papp, who presented data up to 24 weeks, but cautioned that only the 12-week analyses included all study participants.

Psoriasis Area and Severity Index (PASI) scores were better in the high-dose BI 655066 group than in the low-dose group or in the ustekinumab group.

The high- and medium-dose BI 655066 groups were combined for the primary end-point analysis, which was the percent of patients who achieved a 90% improvement in their PASI score at 12 weeks.

Significantly more patients in the combined BI 655066 group than in the ustekinumab group met the primary end point (77.1% vs 40.0%; P < .0001).

"What we see here are high levels of response across all these dose arms, and this response is maintained to 24 weeks," said Dr Papp.

In addition, more patients in the combined BI 655066 group than in the ustekinumab group achieved complete clearance, or a 100% improvement in their PASI score at 12 weeks, Dr Papp reported.

Table 3. BI 655066 Study Outcomes

Treatment Group Complete Clearance at 20 Weeks, % Drug-Related Adverse Events at 24 Weeks, %
BI 655066    
   180 mg 61.0 14.0
   90 mg 53.0 19.5
   18 mg 20.0 17.5
Ustekinumab 30.0 14.3

 

"This room has probably never been so quiet," Dr Papp said after presenting the results.

The researchers did not attribute any serious adverse events in this study to the drugs. The most common adverse events were reportedly nasopharyngitis and headache.

The results are early, but Sarah Tuttleton Arron, MD, from the University of California at San Francisco, said she is impressed. "I look forward to seeing this in development," she told Medscape Medical News.

A separate study evaluating another experimental monoclonal antibody also found complete clearance.

"Ixekizumab had a very rapid effect on psoriasis and a very high rate of response, with about 35% of patients achieving complete clearance," said Dr Gordon.

Ixekizumab blocks IL-17A, a cytokine that plays a role in the inflammation of psoriasis.

To explore the compound's safety and efficacy, Dr Gordon and his team randomly assigned 433 patients to ixekizumab 80 mg every 2 weeks, 432 patients to ixekizumab 80 mg every 4 weeks, and 431 patients to placebo.

Patients rated how itchy they felt on a 10-point scale; at baseline, the mean score was 7. "Many of these patients are suffering from significant itching," Dr Gordon explained.

The primary end points were the percent of patients with a 75% improvement in PASI score and a Physician Global Assessment score indicating clear or almost clear (0 or 1).

By the end of the first week, results were better in the ixekizumab groups than in the placebo group.

Table 4. Ixekizumab Outcomes at 12 Weeks

Outcome Ixekizumab, Every 2 Weeks, % Ixekizumab Every 4 Weeks, % Placebo, %
75% reduction in PASI 89.1 82.6 3.9
100% reduction in PASI 35.3 33.6 0
Physician Global Assessment of 0 or 1 81.8 76.4 3.2
Adverse events 1.4 2.8 1.2

 

Of the patients who achieved clear or almost clear skin at week 12, response was maintained at week 60 in more than 70%.

Patients who were completely cleared of psoriasis had much less itching than those who were almost cleared, Dr Gordon reported.

"The safety of this trial was good," he said. "The Candida rates are quite low. All these patients are mild to moderate, and no patient stopped treatment due to a Candida infection."

Malignancies were also low, he explained, but there were three major adverse cardiac events.

Session moderator Dr Gelfand asked how the response was maintained for so long.

"There are many factors that go into the maintenance of response," Dr Gordon said. "I think the primary one is the maintenance of pharmacokinetics, maintenance of drug levels."

The long maintenance of the response stands out, Dr Arron told Medscape Medical News. "The fact that they were able to maintain the response with monthly dosing for over a year gives us information about the real-world use of this medication for the future."

The tofacitinib studies were funded by Pfizer. The BI 655066 study was supported by Boehringer Ingelheim. The ixekizumab study was funded by Eli Lilly. Dr Gordon reports being a consultant for Eli Lilly. Dr Blauvelt, Dr Papp, and Dr Gelfand report participating in advisory boards or panels for multiple pharmaceutical companies, including Pfizer, Boehringer Ingelheim, and Eli Lilly. Dr Arron reports financial relationships with many companies, including Eli Lilly.

With files from Lara C. Pullen, PhD.

American Academy of Dermatology 73rd Annual Meeting: Late-breaker and Abstract F010 presented March 20, 2015; Abstract 2020 presented March 23, 2015.

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