Deucravacitinib in Plaque Psoriasis: 2-Year Results from Phase III POETYK Trials

Abstract

Deucravacitinib, an oral selective allosteric tyrosine kinase 2 (TYK2) inhibitor, has demonstrated significant promise in the management of moderate-to-severe plaque psoriasis. This article delves into the 2-year safety and efficacy results from the phase III POETYK trials, focusing on the long-term outcomes of patients treated with deucravacitinib. The study, which includes data from the ongoing POETYK long-term extension (LTE) trial, assesses both safety profiles and clinical efficacy endpoints. Results indicate that deucravacitinib maintains its efficacy and demonstrates a consistent safety profile over an extended period, with no new safety concerns emerging. The findings underscore deucravacitinib's potential as a viable long-term treatment option for patients with plaque psoriasis, contributing to the broader understanding of its therapeutic benefits and safety.

Introduction

Psoriasis is a chronic, inflammatory skin disorder characterized by erythematous, scaly plaques. It affects approximately 2-3% of the global population, presenting a significant burden on affected individuals and healthcare systems. The disease is driven by complex interactions between genetic, environmental, and immunological factors, leading to hyperproliferation of keratinocytes and chronic inflammation.

Traditionally, psoriasis treatments have included topical therapies, phototherapy, and systemic treatments, including conventional immunosuppressants and biologics. Despite the availability of various treatments, many patients continue to experience suboptimal responses, relapses, and side effects. This has created a demand for new therapies that offer improved efficacy and a better safety profile.

Deucravacitinib, a novel oral selective TYK2 inhibitor, has emerged as a promising treatment option for moderate-to-severe plaque psoriasis. TYK2 is a key enzyme involved in the signaling pathways of several cytokines implicated in psoriasis, including interleukin-23 (IL-23), interleukin-12 (IL-12), and type I interferons. By selectively inhibiting TYK2, deucravacitinib aims to modulate these pathways and reduce inflammation and keratinocyte proliferation.

The phase III POETYK trials, including POETYK PSO-1 and PSO-2, provided initial evidence of deucravacitinib's efficacy and safety over a 1-year period. These trials demonstrated that deucravacitinib was well-tolerated and effective in improving psoriasis symptoms, with a favorable safety profile compared to other systemic therapies. The current study extends these findings by evaluating the safety and efficacy of deucravacitinib over a 2-year period through the POETYK long-term extension (LTE) trial.

Literature Review

Pathogenesis of Psoriasis

Psoriasis is a complex autoimmune disorder with multifactorial pathogenesis. The disease is characterized by dysregulation of the immune system, leading to chronic inflammation and rapid turnover of skin cells. Key inflammatory cytokines involved in psoriasis include IL-23, IL-17, and IL-12. IL-23 promotes the differentiation and proliferation of Th17 cells, which in turn produce IL-17, a critical driver of inflammation and keratinocyte proliferation in psoriasis.

Genetic predisposition plays a significant role in psoriasis, with several susceptibility genes identified, including those involved in immune regulation and skin barrier function. Environmental triggers, such as infections, stress, and certain medications, can exacerbate the condition, highlighting the need for effective and targeted treatments.

TYK2 Inhibition in Psoriasis

TYK2 is a non-receptor tyrosine kinase that is crucial for the signaling of various cytokines implicated in psoriasis. It mediates the signaling of IL-23, IL-12, and type I interferons, which are involved in the inflammatory pathways of psoriasis. Inhibition of TYK2 can disrupt these signaling pathways, potentially reducing inflammation and improving psoriasis symptoms.

Deucravacitinib is a selective allosteric TYK2 inhibitor that works by binding to a specific site on the TYK2 enzyme, modulating its activity without completely inhibiting it. This selective inhibition allows for a targeted approach to managing psoriasis, potentially reducing inflammation with fewer off-target effects compared to non-selective inhibitors.

Clinical Efficacy of Deucravacitinib

The phase III POETYK PSO-1 and PSO-2 trials were pivotal in establishing the efficacy of deucravacitinib. These trials demonstrated significant improvements in key efficacy endpoints, such as PASI 75 (a 75% reduction in the Psoriasis Area and Severity Index score) and sPGA scores of 0/1 (clear or almost clear skin). Deucravacitinib showed superior efficacy compared to placebo and was comparable to other systemic treatments in terms of effectiveness.

A key advantage of deucravacitinib is its oral administration, which offers a more convenient option compared to injectable biologics. The convenience of oral therapy, combined with its efficacy, makes deucravacitinib an attractive option for patients seeking effective long-term management of psoriasis.

Safety Profile of Deucravacitinib

The safety profile of deucravacitinib has been a critical factor in its evaluation. The initial phase III trials demonstrated that deucravacitinib was well-tolerated, with a low incidence of serious adverse events. Common adverse events included upper respiratory tract infections and headache, which are consistent with the safety profiles of other systemic therapies.

Long-term safety data are crucial for assessing the sustainability of the safety profile over extended periods. The 2-year data from the POETYK LTE trial will provide valuable insights into the long-term safety of deucravacitinib, including the potential for new or emerging safety concerns. The absence of new safety signals and the maintenance of a favorable safety profile over 2 years are important considerations for clinicians and patients alike.

Comparison with Other Treatments

When assessing new treatments like deucravacitinib, it is essential to compare their efficacy and safety with existing options. The advent of newer oral therapies and biologics has expanded the treatment landscape for psoriasis, each with its own profile of benefits and risks. Comparing deucravacitinib to other TYK2 inhibitors and traditional systemic therapies provides insights into its relative advantages and limitations.

For example, comparing deucravacitinib to IL-23 inhibitors or IL-17 inhibitors can reveal differences in efficacy, onset of action, and side effect profiles. Such comparisons are crucial for clinicians to make informed treatment decisions and for patients to understand their options for managing psoriasis effectively.

Future Research Directions

Ongoing research will continue to explore the full potential of deucravacitinib in psoriasis management. Future studies may investigate its use in combination with other therapies or in different patient populations, such as those with comorbid conditions or those who have not responded well to other treatments. Additionally, research into the mechanism of action of TYK2 inhibitors and their impact on various inflammatory pathways may provide further insights into their benefits and limitations.

The long-term extension trials, like the POETYK LTE, will be essential for understanding the durability of treatment response and the potential for long-term side effects. Such data will contribute to refining treatment strategies and optimizing outcomes for patients with psoriasis.

In summary, deucravacitinib represents a significant advancement in the treatment of moderate-to-severe plaque psoriasis. Its selective TYK2 inhibition offers a targeted approach to managing inflammation, with evidence of sustained efficacy and a favorable safety profile over 2 years. Continued research will further define its role in psoriasis management and enhance our understanding of its therapeutic potential.

Methodology

Study Design

The evaluation of deucravacitinib's long-term safety and efficacy in plaque psoriasis was conducted through the phase III POETYK trials, including the POETYK PSO-1 and PSO-2 trials, followed by the POETYK long-term extension (LTE) trial. These studies utilized a randomized, double-blind, placebo-controlled design for initial efficacy assessments and an open-label extension for long-term safety and efficacy evaluation.

Participants

The study enrolled adults with moderate-to-severe plaque psoriasis who had completed either the POETYK PSO-1 or PSO-2 trials. Eligible participants had to meet specific criteria, including a diagnosis of plaque psoriasis, a baseline Psoriasis Area and Severity Index (PASI) score indicating moderate-to-severe disease, and no significant comorbidities that could confound results. Participants were required to provide informed consent and adhere to study protocols.

Treatment Administration

In the POETYK LTE trial, participants received deucravacitinib 6 mg orally once daily. This dosing regimen was consistent with the dose used in the initial phase III trials. Patients who had previously been randomized to placebo in the POETYK PSO-1 or PSO-2 trials were switched to deucravacitinib at week 16 of the initial trial. This allowed for an assessment of the drug's long-term efficacy and safety.

Safety Assessments

Safety was assessed through various measures, including monitoring for adverse events (AEs), laboratory parameter abnormalities, and vital signs. Adverse events were categorized by severity, and any serious adverse events (SAEs) were reported. Laboratory tests included assessments of haematological, chemistry, and lipid parameters to detect potential adverse effects related to deucravacitinib.

Efficacy Assessments

Efficacy endpoints were evaluated using several metrics:

• PASI 75: A 75% reduction from baseline in the Psoriasis Area and Severity Index score, reflecting significant clinical improvement.

• sPGA Scores: Static Physician's Global Assessment scores of 0 or 1, indicating clear or almost clear skin.

• Other Efficacy Endpoints: Included evaluation of secondary measures such as body weight changes and New York Heart Association (NYHA) functional classification.

Statistical Analysis

Data were analyzed using exposure-adjusted incidence rates (EAIRs) to account for varying lengths of treatment exposure among participants. Statistical significance was determined through appropriate tests, including hazard ratios for time-to-event analyses and win ratio analysis for composite outcomes.

Results

Patient Demographics

At the data cutoff on October 1, 2021, the POETYK LTE trial included 1,519 patients who had received at least one dose of deucravacitinib. Of these, 79.0% had received deucravacitinib for at least 52 weeks, and 39.9% had been treated for 104 weeks or longer. This extended treatment period allowed for a thorough assessment of long-term efficacy and safety.

Safety Outcomes

The safety profile of deucravacitinib remained consistent over the 2-year period. The EAIRs for any adverse events (229.2 per 100 person-years at 1 year versus 154.4 at 2 years) showed a decrease over time, suggesting a stable safety profile with prolonged use. Serious adverse events (5.7 per 100 person-years at 1 year versus 6.1 at 2 years) and discontinuations (4.4 per 100 person-years at 1 year versus 2.8 at 2 years) also remained low and stable.

Specific safety observations included:

• Infections: The incidence of serious infections (1.7 per 100 person-years at 1 year versus 2.6 at 2 years) and herpes zoster (0.9 per 100 person-years at 1 year versus 0.8 at 2 years) remained relatively low.

• Major Adverse Cardiovascular Events: The rates were stable at 0.3 per 100 person-years at 1 year and 0.4 at 2 years.

• Venous Thromboembolic Events: Rates were low and comparable at 0.2 per 100 person-years at 1 year and 0.1 at 2 years.

• Malignancies: The incidence was 1.0 per 100 person-years at 1 year and 0.9 at 2 years, showing no significant increase.

COVID-19 Impact

The EAIR for COVID-19 infections was notably higher at 2 years (5.1 per 100 person-years) compared to 1 year (0.5 per 100 person-years). This increase was attributed to the peak of the global COVID-19 pandemic occurring during the LTE period.

Efficacy Outcomes

Clinical responses to deucravacitinib were sustained over the 2-year period. Key efficacy findings included:

• PASI 75: At week 52, 72.4% of patients maintained a PASI 75 response, which increased to 79.7% at week 112.

• sPGA Scores: At week 52, 57.9% of patients had sPGA scores of 0 or 1, which improved to 61.1% at week 112.

Patients who received continuous deucravacitinib treatment from baseline and those who crossed over from placebo at week 16 demonstrated similar efficacy outcomes. The maintenance of clinical responses in these groups highlights the durability of deucravacitinib's efficacy.

Conclusion

The 2-year data from the POETYK LTE trial demonstrate that deucravacitinib maintains its efficacy and safety profile over an extended treatment period. The drug effectively manages plaque psoriasis, with sustained improvements in key efficacy measures such as PASI 75 and sPGA scores. Safety concerns remained minimal, and no new safety signals were identified. The findings support the continued use of deucravacitinib as a viable long-term treatment option for patients with moderate-to-severe plaque psoriasis.

Discussion

Long-Term Efficacy and Safety

The extended efficacy results from the POETYK LTE trial reinforce the effectiveness of deucravacitinib in managing psoriasis over a 2-year period. The sustained high rates of PASI 75 and improvements in sPGA scores reflect the drug's ability to provide consistent clinical benefit. This long-term data is crucial for understanding the durability of treatment responses and the potential for sustained disease management.

The safety profile of deucravacitinib remained favorable throughout the 2-year period. The low and stable incidence rates of serious adverse events and other safety outcomes indicate that the drug is well-tolerated over extended use. The increase in COVID-19 infections is a notable observation, but it is consistent with broader pandemic trends rather than a specific safety concern related to deucravacitinib.

Comparison with Other Treatments

When compared to other systemic treatments for psoriasis, deucravacitinib's oral administration offers a significant advantage in terms of convenience and adherence. The efficacy of deucravacitinib is comparable to other treatments, such as biologics, which have demonstrated high effectiveness but require injections.

The consistent safety profile of deucravacitinib adds to its appeal, especially in comparison to treatments with more frequent or severe adverse effects. This balance of efficacy and safety makes deucravacitinib a strong contender in the psoriasis treatment landscape.

Clinical Implications

The long-term efficacy and safety data support the use of deucravacitinib as a viable option for patients seeking effective and convenient psoriasis management. Clinicians can confidently recommend deucravacitinib to patients who require sustained treatment for moderate-to-severe plaque psoriasis, particularly those who prefer an oral therapy.

Future Prospects

Ongoing Research

Future research will continue to explore the full potential of deucravacitinib in various settings. Studies may focus on its use in different patient populations, including those with comorbid conditions or those who have not responded to other treatments. Additionally, research into combination therapies involving deucravacitinib could provide insights into enhancing treatment outcomes and managing complex cases.

Mechanism of Action

Further investigation into the mechanism of action of TYK2 inhibitors like deucravacitinib may reveal additional benefits and potential limitations. Understanding how deucravacitinib modulates various inflammatory pathways can help optimize its use and identify patient subsets that may benefit most from treatment.

Long-Term Safety Monitoring

Continued monitoring of long-term safety will be essential to ensure that no new safety issues emerge with extended use. Ongoing post-marketing surveillance and real-world evidence will contribute to a comprehensive understanding of deucravacitinib's safety profile.

Comparative Effectiveness Studies

Comparative studies evaluating deucravacitinib against other systemic treatments and biologics will provide valuable information on its relative efficacy and safety. Such studies can guide clinicians in making informed treatment decisions and refining treatment strategies for psoriasis management.

Personalized Treatment Approaches

Future research may also focus on personalized treatment approaches, tailoring therapy based on individual patient characteristics and disease profiles. By identifying biomarkers or genetic factors that predict response to deucravacitinib, clinicians can optimize treatment outcomes and minimize potential risks.

In summary, the 2-year results from the POETYK LTE trial confirm the efficacy and safety of deucravacitinib in managing moderate-to-severe plaque psoriasis. The drug's favorable safety profile and sustained clinical benefits make it a valuable addition to the psoriasis treatment arsenal. Ongoing research and real-world data will continue to shape its role in psoriasis management, ensuring that it remains a robust and effective option for patients with moderate-to-severe plaque psoriasis.

Integration into Clinical Practice

As deucravacitinib continues to demonstrate long-term safety and efficacy, its integration into clinical practice will likely increase. Healthcare providers can leverage the data from the POETYK LTE trial to offer informed recommendations to patients who may benefit from an oral treatment option. The drug's favorable safety profile and sustained efficacy make it a suitable choice for patients seeking a convenient, effective therapy for managing plaque psoriasis.

Patient-Centric Approaches

The patient-centric approach to managing psoriasis involves considering factors such as treatment adherence, patient preferences, and quality of life. Deucravacitinib's oral administration aligns well with these considerations, offering a more convenient alternative to injectable therapies. Future research may further explore how patient preferences impact treatment adherence and overall satisfaction with psoriasis management.

Future Directions

Expansion of Indications

Ongoing studies may explore the potential of deucravacitinib for treating other autoimmune conditions beyond psoriasis. Given its mechanism of action as a TYK2 inhibitor, there may be opportunities to investigate its efficacy and safety in conditions like lupus or ulcerative colitis. Expanding the drug’s indications could provide additional therapeutic options for patients with various autoimmune diseases.

Exploration of Combination Therapies

Combining deucravacitinib with other therapeutic agents could enhance treatment outcomes for psoriasis and potentially other conditions. Research into combination therapies may reveal synergistic effects, leading to improved efficacy or reduced side effects. Exploring these combinations will be crucial in developing comprehensive treatment strategies.

Advancements in Personalized Medicine

The future of psoriasis treatment may increasingly focus on personalized medicine approaches. Identifying biomarkers or genetic profiles that predict responses to deucravacitinib could enable more tailored treatment plans, optimizing outcomes for individual patients. Personalized treatment strategies may lead to better management of psoriasis and enhanced overall patient care.

Long-Term Impact Assessment

Long-term impact assessments will be essential to fully understand the benefits and limitations of deucravacitinib over extended periods. Continued evaluation of the drug's effects on patient quality of life, disease progression, and long-term safety will contribute to a more comprehensive understanding of its role in psoriasis management.

Regulatory and Market Considerations

As deucravacitinib becomes more established in clinical practice, regulatory agencies and market dynamics will play a significant role in shaping its availability and use. Monitoring any changes in regulatory guidelines or market access will be important for ensuring that patients have continued access to this valuable treatment option.

In conclusion, deucravacitinib’s demonstrated efficacy and safety over a 2-year period underscore its potential as a leading therapy for moderate-to-severe plaque psoriasis. With ongoing research and a focus on personalized, patient-centric approaches, deucravacitinib is well-positioned to contribute significantly to the future of psoriasis treatment and management.

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