Hotline: Apremilast for the Treatment of Psoriatic Arthritis

Apremilast (Otezla) was approved by the FDA on March 21, 2014 for the treatment of adult patients with active psoriatic arthritis. Apremilast is a member of a new class of oral small molecule inhibitors of the phosphosphodiesterase 4 (PDE4) enzyme. When PDE4 is inhibited in immune cells, it results in elevation of intracellular cyclic adenosine monophosphate (cAMP) levels, which can regulate inflammatory mediators. Further specific mechanisms of action by which apremilast exerts its therapeutic effects are not well defined, although it may reduce production of inflammatory cytokines.

Metabolism and Drug interaction

Oral administration of apremilast has an absolute biovailability of 73% with peak concentration at 2.5 hours (Tmax). The half-life of apremilast is 6-9 hours. Apremilast is metabolized by the both cytochrome (CYP) and non-CYP pathways. In vitro studies have demonstrated that apremilast metabolism is primarily mediated by the CYP3A4 pathway. Thus, concomitant use of apremilast with CYP450 enzyme inducers (such as rifampin, phenobarbital, carbamazepine, phenytoin) is not recommended. There are no significant drug-drug interactions with oral contraceptives, ketoconazole, or methotrexate.

Clinical Studies

Apremilast has been evaluated in four multicenter, randomized double blind placebo controlled trials (PALACE 1-4 trials) with data up to 52 weeks. Overall, 1,493 adults patients with active PsA, including all subtypes, were enrolled in the pivotal PALACE 1-3 trials, which enrolled patients with prior treatment with NSAIDs or DMARDs. The median duration of PsA in these trials was 5 years. Approximately 76% had received prior oral DMARD therapy and 22% had received biologic DMARDs. Apremilast improved signs and symptoms of PsA, as well as physical function, when compared to placebo. The PALACE 4 study, in DMARD naïve PsA patients, also demonstrated superiority of apremilast over placebo. Overall, these studies suggest that apremilast may be equally effective as monotherapy as in combination with existing DMARDs. Although apremilast is not approved to treat psoriasis, its use was associated with improvement in the PASI50 (51% vs 19%) and PASI75 (21% vs 5%) compared with placebo.

Table 1: Proportion of Patients with ACR Responses at Week 16 in PALACE 1, PALACE 2, and PALACE 3
PALACE 1 PALACE 2 PALACE 3
Placebo
N = 168
Apremilast
30 mg BID
N = 168
Placebo
N = 159
Apremilast
30 mg BID
N = 162
Placebo
N = 169
Apremilast
30 mg BID
N = 167
ACR 20 19% 38% b 19% 32% b 18% 41% b
ACR 50 6% 16% 5% 11% 8% 15%
ACR 70 1% 4% 1% 1% 2% 4%

Safety

The most common adverse reactions reported in clinical trials were related to gastrointestinal symptoms (nausea [8.9% vs 3.1% placebo] and diarrhea [7.7% vs 1.6% placebo]) and headache (5.9% vs 2.2% placebo). Gastrointestinal side effects occurred primarily within the first few weeks of treatment and tended to resolve over time with continued use. Overall the rates of serious AEs (5.4% APR vs. 4.2% PBO) were similar in both groups. Rates of cardiac events, serious or opportunistic infections, malignancies or laboratory abnormalities were not increased in the apremilast treated patients. In the phase 3 trials, there were four serious infections (cellulitis, bacterial wound infection, gastrointestinal clostridial infection and pneumonia). There were two myocardial infarctions (placebo and apremilast 20 mg BID) and two malignancies (placebo: prostate cancer; apremilast 30 mg BID: breast cancer). Treatment discontinuation during clinical trials was low (4.6% apremilast, 1.2% placebo). Based on the lack of laboratory abnormalities during the trials, there is no recommended blood monitoring for apremilast.

Specific Safety Concerns

Depression: During the 16 week placebo-controlled portion of the clinical trials, depression and depressed mood were reported in 1.0% of apremilast treated patients and 0.8% of placebo treated patients. Suicidal ideation and behavior were reported in 0.2% of apremilast treated patients; neither event was reported with placebo.Weight Loss: In clinical trials, 10% of apremilast subjects reported weight loss from 5-10% of body weight, compared to 3.3% in the placebo subjects. Weight should be monitored regularly while on apremilast, with discontinuation considered in the event of unexplained or significant weight loss.

Renal and Hepatic impairment: The dose of apremilast should be reduced to 30mg once a day in patients with severe renal impairment (creatinine clearance < 30ml/minute). There is no dose adjustment required for patient with hepatic impairment. Pregnancy: Apremilast has not been studied in pregnant women and is considered Pregnancy Category C. Apremilast should only be used during pregnancy or in nursing women if the potential benefit justifies the potential risk to the fetus.

Prescribing Apremilast

An initial five day titration schedule is recommended to reduce the gastrointestinal symptoms; the manufacture provides a titration pack. The maintenance dosage is 30mg twice a day taken orally. Apremilast can be taken without regard to meals; the pills should not be crushed or chewed. The wholesale acquisition cost of apremilast is $22,500/year.

The Bottom Line

Apremilast is the first oral agent approved by the FDA for the treatment of PsA. While its efficacy profile is modest compared to biologic therapy, it has a favorable safety profile and the convenience of oral dosing. It may be most appropriate for patients with less severe joint and skin manifestations who may not yet require a biologic DMARD. There are also emerging data in patients with psoriasis only suggesting apremilast is moderately efficacious for controlling skin disease. There are no radiographic data available for apremilast. Although apremilast has not been associated with an increase in overall adverse events, infections, or malignancies, symptoms of depression, including suicidal thoughts/behavior,and weight loss, have been reported.


Hotline Author: M. Elaine Husni, MD, MPH.
Hotline Editors: Eric Ruderman, MD, and Jeffrey Curtis, MD. Disclosures: Dr. Husni: consulting honoraria from Celgene. Dr. Curtis: nothing to disclose. Dr. Ruderman: consulting honoraria from Celgene.

This Hotline has been reviewed by the editors, the ACR Executive Committee, the Drug Safety Subcommittee, and the Communications and Marketing Committee.

The ACR Hotline is provided by the ACR Communications and Marketing Committee as a service to members. This Hotline reflects the views of the author and editors and does not represent a position statement of the American College of Rheumatology.

References:

  1. Apremilast (Otezla) Package Insert. Summit, NJ: Celgene Corporation. Revised. March 20, 2014
  2. Treatment of psoriatic arthritis in a phase 3 randomised, placebo-controlled trial with apremilast, an oral phosphodiesterase 4 inhibitor. Kavanaugh A et al. Ann Rheum Dis 2014;73:1020-1026