Latest Clinical Considerations for Timing of a Systemic Treatment in Plaque Psoriasis Patients with Limited Skin Disease

The landscape of plaque psoriasis treatment is evolving, particularly in how physicians think about disease severity, treatment goals and the timing of systemic therapy use or initiation.¹ Recent guidance has redefined how we classify psoriasis severity, recognizing that even patients with limited skin involvement may experience substantial disease burden and could benefit from systemic therapy.^1-3 Emerging research continues to enhance our understanding of treatment approaches for these patients and may help inform optimal management strategies.²

A recent large-scale, real-world evidence study has provided important insights into the impact of timing of initiating a systemic therapy in plaque psoriasis treatment.² To explore these findings, we spoke with two leading experts in the field: Dr. Linda Stein Gold, Division Head of Dermatology at Henry Ford Health System and former vice president of the American Academy of Dermatology, and Dr. April Armstrong, Chief of Dermatology at University of California, Los Angeles. Both doctors were investigators on the real-world study discussed below.

Indication
Otezla® (apremilast) is indicated for the treatment of adult patients with plaque psoriasis who are candidates for phototherapy or systemic therapy.

Important Safety Information

Contraindications

Otezla® (apremilast) is contraindicated in patients with a known hypersensitivity to apremilast or to any of the excipients in the formulation.

Please see additional Important Safety Information further below.

Otezla Clinical Evidence: The ADVANCE Trial

Before examining the real-world evidence, it's important to understand the foundational clinical data that preceded it. The pivotal Phase 3 ADVANCE trial was a multicenter, randomized, placebo-controlled, double-blind study evaluated Otezla® (apremilast) in 595 adult patients with mild to moderate plaque psoriasis.⁴

The study population had a mean baseline body surface area (BSA) of 6.4%, with inclusion criteria requiring BSA involvement of 2%-15%, a Psoriasis Area and Severity Index (PASI) score of 2-15, and a static Physician's Global Assessment (sPGA) score of 2-3. These were patients who had been inadequately controlled with or intolerant to topical therapy and were allowed unmedicated emollients for body lesions and nonmedicated shampoos for scalp.⁴ Patients were randomized 1:1 to receive either Otezla 30 mg twice daily (n=297) or placebo (n=298) for the first 16 weeks, followed by an open-label extension phase through week 32.⁵

The trial met its primary endpoint, with 21.6% (n=297) of patients receiving Otezla achieving an sPGA^* response at week 16 compared to 4.1% (n=298) with placebo (p<0.0001). The study also demonstrated statistically significant improvements in key secondary endpoints at week 16, including Whole Body Itch Numeric Rating Scale response^† (43.2% versus 18.6%) and Scalp Physician's Global Assessment response^‡ (44% versus 16.6%) compared to placebo. The safety profile remained consistent with the safety profile in patients with moderate to severe plaque psoriasis, with the most commonly reported treatment-emergent adverse events (≥5%) being diarrhea, headache, nausea, nasopharyngitis, and upper respiratory tract infection.^4-5

"The ADVANCE trial addressed a critical gap in our understanding," explains Dr. Stein Gold, who was also an investigator on this trial. "The five-fold improvement in response rates demonstrated the potential for systemic therapy in this patient population, with 21.6% of patients taking Otezla achieving an sPGA response at week 16, compared to just 4.1% with placebo."

While ADVANCE demonstrated how Otezla can help patients with mild to moderate plaque psoriasis, an important question remained: what impact could the timing of initiating Otezla have on patients? A subsequent real-world study helped shed light on this critical question.²

Real-World Evidence: Examining Timing of Initiating Otezla

A recent real-world study has provided insight into the impact of the timing of initiating Otezla in patients with mild to moderate plaque psoriasis. "Real-world data really complement the clinical trial data," explains Dr. Armstrong. "In clinical trials, you often have a very curated population of patients. Whereas in the real world, in our clinical practice, dermatologists have a heterogeneous population of patients that we manage and treat every day. Therefore, real world data that reflect the realities of our daily practice can help inform certain treatment decisions.

The retrospective, observational analysis examined electronic medical record and claims data from the OM1 database, including over 13,000 U.S. adults with mild to moderate plaque psoriasis. The study focused on patients whose first available BSA value after diagnosis was between ≥1% to ≤10% -- designated as the index date. These patients were new to systemic treatment, had no prior psoriatic arthritis diagnosis, had at least a year of baseline data, and either initiated Otezla or started a second topical prescription between 2014 and 2023.³ Note: Patients on topicals could either have switched or added a new topical. Notably, patients had a mean BSA of 5.5% at baseline, and in the Otezla arm, about 50.5% used concomitant topical therapy during the study.^2,6

A total of 3,589 patients had started Otezla, with 2,073 starting Otezla within 6 months of their index date and 1,516 starting at least 6 months after their index date. Early initiators had a median time to Otezla start of just 2 weeks after their index date, while late initiators didn't initiate treatment until a median of 16 months after their index date.²

The studies showed that the early initiator group (n=2,073) experienced a 2% BSA increase from index date to Otezla start (≤6 months; median 2 weeks). In the late initiator group (n=1,516) there was a 49% BSA increase from index date to Otezla start (>6 months; median 16 months).

The study also demonstrated that in the group that initiated Otezla early, 6.0% mean BSA at index date slightly increased to 6.1% mean BSA at Otezla initiation. In the late initiation group, however, 4.9% mean BSA at index date increased to 7.3% mean BSA at Otezla initiation.

The study also revealed important insights about treatment history. "What's particularly noteworthy," Dr. Stein Gold points out, "is that before starting Otezla, 54% of early initiators and 75% of late initiators had tried three or more topicals. This highlights the varying treatment journeys patients may experience before initiating systemic therapy.”

"These findings underscore the timing of systemic therapy," notes Dr. Stein Gold. "Patients who were late Otezla initiators (n=1,516) saw an average of 49% increase in BSA from index date."

Of note, this real-world study had several important limitations to consider. While prescription data was available, actual medication adherence couldn't be confirmed. Additionally, while the study was anchored on the first observed BSA value, this may not have been the patient's first BSA measurement, and disease duration before the index date was unknown. For the topical group, it wasn't possible to distinguish between treatment switching and adding a new topical to an existing regimen.⁶

It's also worth noting that patients with disease severity measures (BSA values) may be different from patients that don't have these measures, though a database comparison suggested no major differences in patient characteristics between these groups. Finally, since this is real-world evidence and not a clinical trial, conclusions about statistical or clinical significance cannot be drawn.⁶

Looking Forward: Evolving Approaches to Treating Plaque Psoriasis

The treatment landscape for limited plaque psoriasis continues to evolve, informed by both clinical trials and real-world evidence. The ADVANCE trial demonstrated the efficacy and safety of Otezla in mild-to-moderate disease, while real-world evidence has now highlighted the impact of the timing of initiating Otezla.^2,4,7 Moving forward, a key opportunity lies in better identifying which patients with limited disease might benefit from systemic therapy before cycling through multiple topicals.

IMPORTANT SAFETY INFORMATION CON'T

Warnings and Precautions

• Hypersensitivity: Hypersensitivity reactions, including angioedema and anaphylaxis, have been reported during postmarketing surveillance. If signs or symptoms of serious hypersensitivity reactions occur, discontinue Otezla and institute appropriate therapy
• Diarrhea, Nausea, and Vomiting: Cases of severe diarrhea, nausea, and vomiting were associated with the use of Otezla. Most events occurred within the first few weeks of treatment. In some cases, patients were hospitalized. Patients 65 years of age or older and patients taking medications that can lead to volume depletion or hypotension may be at a higher risk of complications from severe diarrhea, nausea, or vomiting. Monitor patients who are more susceptible to complications of diarrhea or vomiting; advise patients to contact their healthcare provider. Consider Otezla dose reduction or suspension if patients develop severe diarrhea, nausea, or vomiting
• Depression: Carefully weigh the risks and benefits of treatment with Otezla for patients with a history of depression and/or suicidal thoughts/behavior, or in patients who develop such symptoms while on Otezla. Patients, caregivers, and families should be advised of the need to be alert for the emergence or worsening of depression, suicidal thoughts or other mood changes, and they should contact their healthcare provider if such changes occur
  • Plaque Psoriasis: Treatment with Otezla is associated with an increase in depression. During clinical trials in adult patients with moderate to severe plaque psoriasis, 1.3% (12/920) of patients reported depression compared to 0.4% (2/506) on placebo. Depression was reported as serious in 0.1% (1/1308) of patients exposed to Otezla, compared to none in placebo-treated patients (0/506). Suicidal behavior was observed in 0.1% (1/1308) of patients on Otezla, compared to 0.2% (1/506) on placebo. One patient treated with Otezla attempted suicide; one patient on placebo committed suicide
  • Psoriatic Arthritis: Treatment with Otezla is associated with an increase in depression. During clinical trials, 1.0% (10/998) reported depression or depressed mood compared to 0.8% (4/495) treated with placebo. Suicidal ideation and behavior was observed in 0.2% (3/1441) of patients on Otezla, compared to none in placebo-treated patients. Depression was reported as serious in 0.2% (3/1441) of patients exposed to Otezla, compared to none in placebo-treated patients (0/495). Two patients who received placebo committed suicide compared to none on Otezla
  • Behçet’s Disease: Treatment with Otezla is associated with an increase in depression. During the clinical trial, 1% (1/104) reported depression or depressed mood compared to 1% (1/103) treated with placebo. No instances of suicidal ideation or behavior were reported in patients treated with Otezla or treated with placebo
• Weight Decrease: Monitor body weight regularly; evaluate unexplained or clinically significant weight loss, and consider discontinuation of Otezla
  • Plaque Psoriasis: Body weight loss of 5-10% occurred in 12% (96/784) of adult patients with moderate to severe plaque psoriasis treated with Otezla and in 5% (19/382) of patients treated with placebo. Body weight loss of ≥10% occurred in 2% (16/784) of adult patients treated with Otezla compared to 1% (3/382) of patients treated with placebo. Body weight loss of 5%-10% occurred in 12% (19/163) of pediatric patients with moderate to severe plaque psoriasis treated with Otezla compared to 2.5% (2/80) with placebo. Body weight loss of ≥ 10% occurred in 1% (1/163) of pediatric patients treated with Otezla twice daily compared to 0% (0/80) of patients with placebo. Closely monitor growth (height and weight) in Otezla-treated pediatric patients. Pediatric patients who are not growing or gaining weight as expected may need to have their treatment interrupted
  • Psoriatic Arthritis: Body weight loss of 5-10% was reported in 10% (49/497) of patients taking Otezla and in 3.3% (16/495) of patients taking placebo
  • Behçet’s Disease: Body weight loss of >5% was reported in 4.9% (5/103) of patients taking Otezla and in 3.9% (4/102) of patients taking placebo
• Drug Interactions: Apremilast exposure was decreased when Otezla was co-administered with rifampin, a strong CYP450 enzyme inducer; loss of Otezla efficacy may occur. Concomitant use of Otezla with CYP450 enzyme inducers (e.g., rifampin, phenobarbital, carbamazepine, phenytoin) is not recommended

Adverse Reactions

• Plaque Psoriasis: The most common adverse reactions (≥ 5%) are diarrhea, nausea, upper respiratory tract infection, and headache, including tension headache. Overall, the safety profile of Otezla in adult patients with mild to moderate plaque psoriasis and pediatric patients with moderate to severe plaque psoriasis was consistent with the safety profile established in adult patients with moderate to severe plaque psoriasis
• Psoriatic Arthritis: The most common adverse reactions (≥ 5%) are diarrhea, nausea, and headache
• Behçet’s Disease: The most common adverse reactions (≥ 10%) are diarrhea, nausea, headache, and upper respiratory tract infection

Use in Specific Populations

• Otezla has not been studied in pregnant women. Advise pregnant women of the potential risk of fetal loss

Please click here for the full Prescribing Information.

INDICATIONS

Otezla^® is indicated for the treatment of:

• Adult patients with plaque psoriasis who are candidates for phototherapy or systemic therapy
• Pediatric patients 6 years of age and older and weighing at least 20 kg with moderate to severe plaque psoriasis who are candidates for phototherapy or systemic therapy
• Adult patients with active psoriatic arthritis
• Adult patients with oral ulcers associated with Behçet’s Disease

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*sPGA response was defined as the percentage of patients who achieved sPGA score of 0 (clear) or 1 (almost clear) and ≥2-point reduction from baseline.

†Patients achieving a ≥4-point reduction in WBI-NRS from baseline

‡In patients with ScPGA ≥2 at baseline. ScPGA score of clear [0] or almost clear [1] with at least a 2-point reduction from baseline.

References:

1. Strober B, Caitriona R, van de Kerkhof P, van der Walt J, Kimball A, et al. Recategorization of psoriasis severity: Delphi consensus from the International Psoriasis Council, J Am Acad Dermatol. 2020 Jan; 82(1):117-122.
2. Strober B, Stein Gold L, Gisondi P, et al. Presented at: 7th World Psoriasis and Psoriatic Arthritis Convention; June 27-29, 2024; Stockhom, Sweden
3. Lebwohl M, Langley RG, Paul C, Puíg L, Reich K, van de Kerkhof P, Wu HL, Richter S, Jardon S, Gisondi P. Evolution of Patient Perceptions of Psoriatic Disease: Results from the Understanding Psoriatic Disease Leveraging Insights for Treatment (UPLIFT) Survey. Dermatol Ther (Heidelb). 2022 Jan;12(1):61-78.
4. Data on file, Amgen Inc.
5. Stein Gold L, Papp K, Pariser D, Green L, Bhatia N, Sofen H, Albrecht L, Gooderham M, Chen M, Paris M, Wang Y, Callis Duffin K. Efficacy and safety of apremilast in patients with mild-to-moderate plaque psoriasis: Results of a phase 3, multicenter, randomized, double-blind, placebo-controlled trial. J Am Acad Dermatol. 2022 Jan;86(1):77-85.
6. Strober B, Stein Gold L, Gisondi P, et al. Presented at: Maui Derm Hawaii; January 22-26, 2024; Maui, HI
7. Menter A, Gelfand JM, Connor C, Armstrong AW, Cordoro KM, Davis DMR, et al. Joint American Academy of Dermatology-National Psoriasis Foundation guidelines of care for the management of psoriasis with systemic nonbiologic therapies. J Am Acad Dermatol. 2020 Jun;82(6):1445-1486.