Apremilast (Otezla) approved by FDA

Apremilast (Otezla®) received FDA approval on March 21, 2014 for the treatment of adults with active psoriatic arthritis (PsA).  It is the first oral medication in the U.S. with an approved indication for the treatment of PsA. The recommended dose is 30 mg BID.

Apremilast is a phosphodiesterase 4 (PDE4) inhibitor which results in increased intracellular cAMP which helps to modulate the balance between pro-inflammatory and anti-inflammatory mediators produced by immune cells.

Pooled data from three multicenter, randomized controlled trials were analyzed to assess the efficacy and safety of apremilast.  A total of 1493 adults with active PsA (≥ 3 tender joints, ≥ 3 swollen joints) fulfilling CASPAR criteria were randomized (1:1:1) to either apremilast (20 mg BID or 30 mg BID) or placebo.  In one of the studies, patients were required to have at least 1 active psoriatic lesion measuring ≥ 2 cm.  Co-treatment with stable doses of DMARDs (methotrexate ≤ 25 mg weekly, leflunomide ≤ 20 mg daily, or sulfasalazine ≤ 2000 mg daily), corticosteroids (prednisone ≤ 10 mg daily equivalent), and NSAIDs were permitted. However, co-treatment with a TNF inhibitor was not permitted.  Previous TNF inhibitor use was allowed, but patients with inadequate response to > 1 TNF inhibitor or > 3 DMARDs were excluded.  The primary study endpoint was ACR20 response at Week 16.  A significantly higher proportion of patients in the apremilast 30 mg BID group achieved an ACR20 response compared to placebo (32-41% vs. 18-19%, respectively, p<0.05).  In one of the RCTs, active plaque psoriasis improved significantly among those who received apremilast 30 mg BID compared to placebo (PASI75: 21% vs. 5%, respectively).  Enthesitis and dactylitis were improved in subjects receiving the higher dose of apremilast.  Physical functioning at Week 16 as measured by HAQ-DI improved in apremilast 30 mg BID compared to placebo (-0.24 vs. -0.09, respectively).

Notable adverse events with apremilast include diarrhea/nausea, depression, weight loss, and drug-drug interactions. To limit the GI side effects which occur especially during medication initiation, a dose escalation schedule during the first 5 days of use is advised. Due to a higher proportion of patients who reported depression with apremilast compared to placebo (1.0% vs. 0.8%, respectively), patients should be assessed for depression and suicidal ideation before and during continued use. Weight loss may also occur with apremilast (5-10% of body weight in 10% of patients receiving apremilast 30 mg BID compared to 3.3% with placebo). Because apremilast is metabolized via the cytochrome P450 pathway, inducers of cytochrome P450 (e.g. phenytoin, carbamazepine, rifampin, etc.) are not recommended to be co-administered with apremilast.

For patients with significant renal insufficiency (CKD stage 4 or higher, eGFR < 30 mL/min), the dose of apremilast should be reduced to 30 mg daily.

Apremilast is a pregnancy class C medication, with limited safety data in pregnant women. A registry has been established to follow outcomes of apremilast in this patient population. The safety of apremilast use during lactation is similarly limited.

Editorial

PsA is chronic inflammatory arthritis in the presence of skin and/or nail psoriasis. Though it is classified as a single disease entity, PsA has at least 5 clinical phenotypes as first described by Moll and Wright. Depending on the subtype and severity of disease, various medications can be used either singly or in combination to control the symptoms and signs of PsA.

Current management of adults with active PsA includes NSAIDs, corticosteroids, DMARDs such as methotrexate, leflunomide, and sulfasalazine, as well as biological agents (e.g. TNF inhibitors and an anti-IL12/23 inhibitor). For patients with milder disease, a single DMARD may suffice, whereas those with more severe disease will likely require co-treatment with a DMARD and biologic.  Despite the availability of an increasing number of medications to treat PsA, some patients may not achieve an adequate clinical response. Consequently, there appears to be an unmet need for additional medications in the rheumatologist’s armamentarium in the treatment of PsA.

The recent FDA approval of apremilast in the treatment of adults with active PsA is welcome news for rheumatologists and other healthcare providers who care for these patients.  To some extent, it marks a monumental moment in the annals of PsA management since apremilast is the first oral medication with an approved indication for the treatment of PsA.  Despite the widespread use of methotrexate in the U.S. for PsA, methotrexate, along with leflunomide and sulfasalazine, are used off-label.  And many patients who use these medications may still have inadequate clinical response. Based on pooled data from 3 separate RCTs consisting of nearly 1500 patients with active PsA, the efficacy of apremilast at 30 mg BID was deemed by the federal regulators at FDA to outweigh the risks of medication.

Compared to the efficacy of TNF inhibitors as a class in PsA, apremilast appears to be slightly less effective.  TNF inhibitors in RCTs have been reported to have an ACR20 response of 50-60% at Week 24 compared to apremilast’s ACR20 response of 45% at Week 24.  Since the RCTs with apremilast allowed for enrollment of TNF inhibitor-inadequate responders, it is conceivable that the lower treatment response can be attributed in part to the more refractory disease in this specific subpopulation of patients with PsA.  Notably, the response to skin psoriasis is markedly less effective in apremilast compared to most TNF inhibitors (PASI 75: 21% vs. 56-60%, respectively).  The side effect profile of apremilast is reassuring with respect to major infections, including tuberculosis and invasive fungal infections, observed occasionally with TNF inhibitors.  There were no reports of these types of infections among patients receiving apremilast.  Typical infections with apremilast appear to be mild, with mostly URIs and nasopharyngitis reported in 3.9% and 2.6% of patients, respectively.  Nonetheless, GI side effects including diarrhea and nausea were significantly reported with apremilast—especially during drug initiation, prompting a dose titration during the first 5 days of use to the target dose of 30 mg BID.  Depression was reported to be higher among patients receiving apremilast compared to placebo.  However, among small molecules in the family of PDE4 inhibitors, apremilast has a higher therapeutic index and can be used more safely in patients with PsA.  Weight loss of up to 5-10% body weight occurred in 10% of patients receiving apremilast 30 mg BID.  Whether this is related to the GI side effects associated with apremilast use is unclear.

Given the relatively safer side effect profile but the lower effectiveness of apremilast compared to TNF inhibitors, where does apremilast fit into the treatment algorithm in PsA?  In patients with mild-to-moderate disease activity who have inadequate response to methotrexate, but with mild psoriasis, the addition of apremilast may make more sense than adding a TNF inhibitor.  Similarly, for PsA patients who are well-controlled on a biological agent but who experience frequent severe infections, then treatment with apremilast instead may be clinically indicated.

Before apremilast can be more broadly adopted in the management of PsA, several questions need to be clarified.  Given the heterogeneity of PsA clinical phenotypes, does apremilast work equally well in the spondyloarthritis subtype as it does the symmetric polyarthritis subtype?  There is some level of uncertainty as to the disease-modifying effectiveness of methotrexate in preventing radiographic progression in PsA.  Is apremilast like methotrexate, or does it work as well as TNF inhibitors in preserving joint integrity and physical functioning after many years of continued use?  What about patients with severe dactylitis and enthesitis?  Given the preliminary data from the RCTs, apremilast does not appear to be as effective as TNF inhibitors in treating these conditions.  Is that more related to its duration of therapy rather than its mechanism of action? Finally, the unanswered questions of depression and weight loss warrant further investigation.

Grant Louie, M.D., M.H.S.

About Grant Louie, M.D., M.H.S.

Assistant Professor of Medicine
Johns Hopkins University

Clifton Bingham, III, MD

About Clifton Bingham, III, MD

Associate Professor of Medicine
Director - Johns Hopkins Arthritis Center

Ana-Maria Orbai, MD MHS

About Ana-Maria Orbai, MD MHS

Instructor in Medicine
Johns Hopkins Arthritis Center

Victoria Ruffing, RN

About Victoria Ruffing, RN

Ms. Ruffing has been a member of the Arthritis Center since 2000, currently serving as the Nurse Manager. She is a critical member of our patient care team.