FDA Clears Apremilast (Otezla) for Psoriatic Arthritis

Megan Brooks

March 21, 2014

DENVER — At higher doses, the investigational human monoclonal antibody guselkumab outperforms adalimumab in the treatment of moderate to severe plaque psoriasis, according to a new study.

"The results are very encouraging. The drug demonstrates really good safety and excellent efficacy," said investigator Kristina Callis Duffin, MD, assistant professor of dermatology at the University of Utah School of Medicine in Salt Lake City.

"I see this particular drug as a very promising part of the new wave of products that have better efficacy than their predecessors and still have excellent safety," she told Medscape Medical News.

Dr. Duffin presented results from the X-PLORE trial here at the American Academy of Dermatology 72nd Annual Meeting.

Guselkumab is an investigational human monoclonal antibody with a novel mechanism of action that targets the protein interleukin (IL)-23, which plays a central role in the pathogenesis of psoriasis. It is being developed as a subcutaneously administered therapy for the treatment of moderate to severe plaque psoriasis.

The drug follows on the heels of ustekinumab, developed by Centocor and approved for psoriatic arthritis, which targets both IL-23 and IL-12.

"What is the relative contribution of IL-12 and IL-23 to the biology of psoriasis? That is one of the questions coming out of guselkumab's development," said Yasmine Wasfi, MD, PhD, director of clinical research at Janssen Pharmaceuticals, and one of the study investigators.

"One of our goals in pursuing this program was to better understand that question," she told Medscape Medical News.

The investigators conducted a phase 2b randomized placebo-controlled trial of patients with moderate to severe plaque psoriasis. All patients were candidates for systemic or phototherapy, and all had a Psoriasis Area Severity Index (PASI) score of at least 12, a Physician Global Assessment score of at least 3, and body surface area involvement of at least 10%.

In the 7-group study, subjects were randomized to receive 1 of 5 doses of guselkumab (5 mg at weeks 0 and 4 and every 12 weeks thereafter; 15 mg every 8 weeks; 50 mg at weeks 0 and 4 and every 12 weeks thereafter; 100 mg every 8 weeks; and 200 mg at weeks 0 and 4 and every 12 weeks thereafter); adalimumab (an initial 80 mg dose followed by 40 mg every other week starting 1 week after initial dose); or placebo.

The primary end point was cleared or minimal plaque psoriasis at week 16, as indicated by the PGA score. Secondary end points included improvement in psoriasis severity of at least 75% at week 16, as indicated by the PASI score.

At week 16, significantly more patients in the guselkumab groups than in the placebo group had cleared or minimal plaque psoriasis, and more had an improvement in severity of at least 75%.

Patients in the adalimumab group also fared better than those in the placebo group.

Table 1: Psoriasis Outcomes at Week 16

Treatment Group Cleared or Minimal, % >75% Improvement in Severity, % >90% Improvement in Severity, %
Guselkumab      
   5 mg 34 44* 34*
   15 mg 61* 76 34*
   50 mg 79* 81 45*
   100 mg 86* 79 62*
   200 mg 83* 81 57*
Adalimumab 58 70 44
Placebo 7 55 2

*P < .001 vs placebo

Beyond week 16, the proportion of guselkumab-treated patients achieving the primary end point of cleared or minimal psoriasis and the secondary end points of improvement in psoriasis severity of at least 75% and or at least 90% remained constant or continued to improve out to week 40.

Serious infections occurred in 2 patients treated with guselkumab (appendicitis, lung abscess). At week 16, no malignancies or major adverse cardiovascular events were observed in any group.

At week 52, no additional serious infections occurred in guselkumab-treated patients, but 1 patient treated with adalimumab developed pneumonia. There were no cases of tuberculosis or opportunistic infections.

One guselkumab-treated patient developed cervical intraepithelial neoplasia 3, and 3 experienced a major adverse cardiovascular event (1 fatal and 1 not fatal myocardial infarction, 1 cerebrovascular accident), but all 3 had multiple pre-existing cardiovascular risk factors.

Table 2. Adverse Events Reported

Outcomes Guselkumab Groups, % Adalimumab Group, % Placebo Group, %
Week 16      
   Adverse events 50 56 52
   Serious adverse events 1 2 2
Week 52      
   Adverse events 66 72
   Serious adverse events 3 5

 

"This study shows a fairly dramatic and what appears to be statistically significant benefit at the higher doses of guselkumab," said Vail Reese, MD, a dermatologist from Union Square Dermatology in San Francisco.

"Should this proceed to FDA approval and become available, it may be an option for patients who have not been cleared fully with adalimumab," he told Medscape Medical News. "And it would certainly add another option for severe psoriasis."

The study did spark some concerns, however, particularly related to the 3 major adverse cardiovascular events in the guselkumab-treated patients.

Although the numbers were small, "it's a little worrisome to hear about 3 events in such a small study group. We want our patients with psoriasis to be clear of lesions, but we don't want to put them at risk for cardiovascular events," Dr. Reese noted. "This may be an option for patients who aren't smoking and who don't have the dietary risk factors or family history of cardiovascular disease."

The study was funded by Janssen. Dr. Duffin is a consultant, advisor, and investigator for Janssen, Amgen, Pfizer, Eli Lilly, and Bristol Myers Squibb. Dr. Wasfi is an employee of Janssen. Dr. Reese has disclosed no relevant financial relationships.

American Academy of Dermatology (AAD) 72nd Annual Meeting. Presented March 22, 2014.

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