PDE4 inhibition in the treatment of inflammatory diseases.

The PDE-4 inhibitor apremilast was discussed as a potential option in the treatment of psoriatic arthritis at this year’s ACR Congress in San Diego. Promising results show good efficacy both for patients pretreated with DMARDs and for those taking the agent in the first-line setting. The safety profile is acceptable. Furthermore, PDE-4 inhibition has also been shown to improve oral ulceration in Behçet’s disease.

Maurizio Cutolo, MD, Genoa, spoke about PALACE 2 [1]: a controlled, randomized phase III trial that evaluated the use of the phosphodiesterase-4 (PDE-4) inhibitor apremilast (APR) in patients with psoriatic arthritis (PsA).

“PsA is a debilitating chronic disease that requires long-term management,” Dr. Cutolo said. “The 1-year data from the PALACE study show that early response rates to apremilast with continuous therapy persist over time. Based on the current efficacy and safety data from the Phase III studies, there is great potential for this agent in the long-term treatment of PsA. Apremilast appears to be an attractive new therapeutic option.”

PALACE 2

PALACE 2 compared the efficacy and safety of APR vs. placebo in patients with active PsA despite prior use of DMARDs and/or biologics. There were three study groups: Placebo, APR 20 mg, APR 30 mg.

Patients who had a reduction of less than 20% in swollen joint counts (SJCs) and tender joint counts (TJCs) compared with baseline at week 16 qualified for early exit from the first randomization phase. Those on placebo were re-randomized to APR 20 mg and APR 30 mg groups, and those on APR remained on the original APR dose. At week 24, we re-randomized all placebo patients to the two APR groups until week 52, and patients who were concomitantly using DMARDs (MTX, sulfasalazine, leflunomide, or a combination) were allowed to continue taking them at stable doses.

Results: 484 patients were randomized to receive ≥1 dose of study drug (placebo: 159; APR 20 mg: 163; APR 30 mg: 162). A significantly greater proportion of patients on APR 20 mg (38.4%; p=0.0002) and APR 30 mg (34.4%; p=0.0024) achieved an ACR20 at week 16 (primary endpoint) versus placebo (19.5%). Those participants who received APR from the beginning and consumed it for 52 weeks achieved further improvement or consistently good results in the following areas:

ACR20: 52.9% (APR 20 mg) and 52.6% (APR 30 mg).
“Health assessment questionnaire disability index” (HAQ-DI): Mean change since baseline (SD) of -0.192 (0.573) for APR 20 mg and -0.330 (0.509) for APR 30 mg.
“Physical Functioning domain score” SF-36: Mean change since baseline (SD) of 5.05 (7.96) for APR 20 mg and 6.35 (8.67) for APR 30 mg.
In patients with a “Body Surface Area” (BSA) ≥3% at baseline: A “Psoriasis Area and Severity Index-“(PASI-)75/PASI-50 achievement of 27.1/49.%/49,2% for APR 20 mg and 39%/58,9% 3/58%/58,9% for APR 30 mg.

Patients randomized to the APR group only at weeks 16 and 24 showed comparable results.
“Patients tolerated APR well. In patients taking the agent for 52 weeks, ≥5% experienced mild to moderate adverse events, including diarrhea, nausea, upper respiratory infection, headache, and nasopharyngitis.
Serious adverse events occurred in 4.7% (APR 20 mg) and 5.1% (APR 30 mg) of cases, respectively. So, in summary, APR has good long-term efficacy in the treatment of PsA with an acceptable safety profile,” Dr. Cutolo concluded his presentation.

Effect also on enthesitis and dactylitis

Pooled data from the three randomized controlled PALACE trials, also showed improvement in enthesitis and dactylitis. Prof. Dafna Gladman, MD, University of Toronto, presented the results [2]: “APR provided good control of diverse manifestations of PsA, including enthesitis and dactylitis, in the three phase III trials.”

Patients who had preexisting forms of these two concomitants showed

At week 24, a significant mean change since baseline in the “Maastricht Ankylosing Spondylitis Enthesitis Score” (MASES) on 2× APR 30 mg/d compared to placebo (-1.4 vs. -0.8, p=0.0159)
at week 24, a significant mean change since baseline in “dactylitis count” on APR 30 mg versus placebo (-1.8 vs. -1.2, p=0.0121).

For those patients taking APR for 52 weeks, the median change since baseline was -66.7% for MASES and as much as -100% for “dactylitis count.”

PALACE 4

Finally, according to Alvin Wells, MD, Franklin, the PALACE-4 trial [3] confirmed that APR also works in DMARD-untreated patients. This large randomized controlled trial studied only participants who had never taken systemic or biologic DMARDs. 527 patients were randomized.
It was shown that this specific group of patients also benefited from APR monotherapy. Further, improvements in symptoms of PsA, as well as its manifestations, were noted, for example, in HAQ-DI, PASI-75/50, and SJCs and TJCs, enthesitis, and dactylitis.

At week 16, a significantly greater number of patients on APR monotherapy achieved an ACR20 (primary endpoint) versus placebo, 29.2% on APR 20 mg (p=0.0076) and 32.3% on APR 30 mg (p=0.0011) vs. 16.9% (placebo).

For those taking the full 52 weeks of APR, the ACR20 response rate in this final week was 53.4% (APR 20 mg) and 58.7% (APR 30 mg). Side effects were consistent with findings from the other studies.

“These are encouraging results. They show a potential benefit of the compound already in first-line monotherapy,” Wells explained.

Behçet’s disease

Also presented at the ACR Congress, and already in June at EULAR in Madrid, were data from a randomized, controlled phase II study [4] investigating the PDE4 inhibitor in patients with Behçet`s disease.

This is a rare chronic inflammatory disease characterized by periodic oral and genital ulceration, skin and eye lesions (which can lead to blindness), and joint inflammation. The infection may also affect the brain and gastrointestinal tract. The study investigated the effect of APR in 111 patients with Behçet`s disease and active oral ulcer.

Results: Significantly more patients on APR achieved a complete response (no active oral ulcer) at week 12 compared to placebo (71% vs. 29%, p<0.0001). Among those with a genital ulcer at baseline (n=16), 100% experienced a complete response at week 12 on APR and 50% on placebo (p=0.036).

“Since few treatments are available for this orphan disease so far and more are urgently needed, these results give hope for a new therapy with a fast and good response. APR is thus a potentially important player in the management of Behçet’s disease with oral ulcer,” summarized Prof. Gulen Hatemi, MD, Istanbul [4].

Source: ACR/ARHP Annual Meeting, October 25-26, 2013, San Diego.

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