Piclidenoson In The Treatment Of Plaque Psoriasis
Overview
The study focused on evaluating the effectiveness and safety of piclidenoson (CF101), an orally bioavailable agonist for the A3 adenosine receptor (A3AR), in treating moderate-to-severe plaque psoriasis. The A3AR is known to be overexpressed in the skin and peripheral blood mononuclear cells of individuals with psoriasis. Piclidenoson is specifically designed to inhibit the production of interleukin-17 (IL-17) and interleukin-23 (IL-23) in keratinocytes.
The phase 3 COMFORT-1 trial, a randomized, double-blind study, included patients who were assigned to different treatment groups: piclidenoson 2 mg twice daily (BID), piclidenoson 3 mg BID, apremilast 30 mg BID, or a placebo. At Week 16, patients in the placebo group were re-randomized to receive piclidenoson 2mg BID, piclidenoson 3 mg BID, or apremilast 30 mg BID. The primary endpoint was the proportion of patients achieving a ≥75% improvement in the Psoriasis Area and Severity Index (PASI-75) from baseline at Week 16 compared to the placebo.
Results from the safety population, consisting of 529 patients, showed that both piclidenoson doses (2 mg and 3 mg BID) exhibited similar efficacy. The primary endpoint was met with the 3 mg BID dose, demonstrating a PASI-75 rate of 9.7% versus 2.6% for piclidenoson versus placebo (p = 0.037). Additionally, the efficacy responses of piclidenoson continued to increase linearly throughout the study period. In the per-protocol population at Week 32, a higher proportion of patients in the piclidenoson 3 mg BID group achieved improvement in the Psoriasis Disability Index (PDI) compared to apremilast, although the noninferiority test trended towards significance (p = 0.072). Importantly, piclidenoson demonstrated an excellent safety and tolerability profile, surpassing that of apremilast.
In conclusion, the study findings suggest that piclidenoson exhibited increasing efficacy responses over time and displayed a favorable safety profile. These positive results support the ongoing clinical development of piclidenoson as a promising treatment for psoriasis.
Introduction
Psoriasis, an autoimmune inflammatory condition characterized by skin plaques due to excessive keratinocyte proliferation, is often resistant to apoptosis. The involvement of cytokines, specifically TNF-α, IL-17, and IL-23, in the persistent keratinocyte proliferation underscores their crucial role in the disease’s pathogenesis. While biologic therapies targeting these cytokines have been approved for psoriasis treatment, issues such as side effects, reduced efficacy, disease recurrence, and cost have prompted the exploration of alternative strategies.
A potential avenue is the A3 adenosine receptor (A3AR), a cell surface receptor associated with Gi protein that exhibits high expression in inflammatory cells. Piclidenoson (CF101), a selective A3AR agonist, demonstrates oral bioavailability and induces an anti-inflammatory effect by modulating the NF-кB signaling pathway. This modulation results in the down-regulation of pro-inflammatory cytokines (IL-1, IL-8, TNF-α, MIP-1α), inhibiting the proliferation of auto-reactive T cells and inducing apoptosis in inflammatory cells.
Skin biopsies from psoriasis patients reveal elevated A3AR levels compared to normal skin, emphasizing the receptor’s potential relevance. In a human keratinocyte cell line derived from psoriasis patients, piclidenoson demonstrated anti-proliferative effects by deregulating the NF-кB pathway, leading to the inhibition of IL-17 and IL-23 expression. Phase 2 and 2/3 trials showed piclidenoson’s safety profile comparable to placebo, with promising clinical benefits measured by the Psoriasis Area and Severity Index (PASI) and the Physician’s Global Assessment (PGA).
In a phase 3 trial (COMFORT-1), the efficacy and safety of 2 and 3 mg BID piclidenoson were evaluated against placebo and an active comparator (apremilast). The study also investigated the pharmacokinetics of piclidenoson. While initial results showed statistical significance during the extension period, supporting continued clinical development, the overall findings highlight piclidenoson’s potential as a therapeutic option for psoriasis. Further exploration, including rigorous analysis of pharmacokinetics and safety, is warranted for a comprehensive understanding of piclidenoson’s role in psoriasis management.
Methods
The COMFORT-1 study, a phase 3 multicenter clinical trial conducted across various countries, aimed to evaluate the efficacy and safety of piclidenoson in treating moderate-to-severe plaque psoriasis. The trial, registered under ClinicalTrials.gov identifier NCT03168256, employed a randomized, double-blind, controlled design, encompassing sites in Bosnia, Bulgaria, Canada, Israel, Moldova, Poland, Romania, and Serbia.
The study comprised two segments spanning Weeks 0–16 and Weeks 17–32. The initial phase involved four treatment arms, incorporating two piclidenoson doses (2 or 3 mg BID), apremilast (active comparator), and a placebo arm. Patients were randomly assigned to these arms, and blinding was maintained through a double-dummy technique. The subsequent phase (Weeks 17–32) included three treatment arms, with patients initially in the placebo arm transitioning to piclidenoson or apremilast.
Throughout the trial, blinding was rigorously upheld, and assessments were conducted every two weeks for efficacy and safety. The primary endpoint, evaluated at Week 16, focused on PASI 75 rates for the piclidenoson arms compared to placebo, emphasizing superiority and safety. Secondary endpoints included PASI 50 rates, PGA2 score, and Psoriasis Disability Index (PDI) improvement at Week 16. Additional assessments at Week 32 compared piclidenoson to apremilast.
The study, initially proceeding without major issues, encountered modifications in 2020 due to challenges arising from the COVID-19 pandemic. An interim analysis was conducted after 189 of 307 enrolled patients completed Week 16, leading to a temporary enrollment pause for evaluation by an Independent Data Monitoring Committee.
Ethical considerations were paramount, with the study approved by relevant national regulatory authorities and local Ethics Committees/Institutional Review Boards. The patient population comprised individuals aged 18–80 with moderate-to-severe chronic plaque psoriasis, candidates for systemic treatment or phototherapy, meeting specific inclusion and exclusion criteria.
Assessment metrics included PASI scores, static PGA, and Psoriasis Disability Index. Safety evaluations encompassed treatment-emergent adverse events, vital signs, physical examinations, laboratory tests, and electrocardiography findings.
In conclusion, the COMFORT-1 study employed a robust methodology to investigate the efficacy and safety of piclidenoson in treating moderate-to-severe plaque psoriasis, contributing valuable insights to the field.
Statistical Analysis
The study implemented a robust power calculation to determine sample sizes, aiming for a comprehensive evaluation of the efficacy and safety of piclidenoson compared to both placebo and apremilast in the context of psoriasis treatment. To achieve a statistical power of at least 80%, the sample size was set at 111 patients for each piclidenoson dose and 74 patients for the placebo group. The primary goal was to assess the probability of response for piclidenoson versus placebo, with the assumption that the probability of achieving a PASI 75 response at Week 32 would be 35% for the less effective piclidenoson dose and 28% for apremilast.
Four distinct analysis populations were defined to ensure a comprehensive evaluation: the safety population encompassed all patients receiving at least one dose of the study medication, the intention-to-treat (ITT) population excluded patients withdrawing before Week 16 due to COVID-19-related study suspension, the modified ITT (mITT) population was utilized for Week 16 efficacy analyses, and the per-protocol (PP) population was employed for Week 32 analyses, including only those with no major protocol violations who completed Week 16.
Treatment-emergent adverse events (TEAEs) were reported based on the Medical Dictionary for Regulatory Activities (MedDRA) definitions. For efficacy analyses, missing values post-discontinuation were treated as non-responses, and Last Observation Carried Forward (LOCF) imputation was applied for intermediate missing values. Statistical tests, including non-inferiority analyses, were conducted using appropriate methodologies, and the significance threshold was set at p < 0.05. All analyses were executed with SAS 9.4, ensuring a robust and standardized approach to data assessment.
Results
Between August 2018 and September 2021, a study involving 701 patients with moderate-to-severe plaque psoriasis was conducted, with 529 meeting eligibility criteria. The patients were randomly assigned to different treatment arms, including piclidenoson at 2mg BID and 3mg BID, apremilast, or placebo. Notably, around 30% of patients discontinued treatment in the initial 16 weeks, primarily due to the COVID-19-related study suspension.
The baseline characteristics of the patient/disease profiles were well-distributed among the treatment arms, demonstrating a balanced representation. Efficacy results at Week 16 revealed that piclidenoson 3mg BID exhibited superior effectiveness compared to placebo, with a statistically significant increase in PASI 75 rates. Piclidenoson 2mg BID also showed improvement, although not statistically significant.
Secondary endpoints, including PGA2 and other efficacy measures, demonstrated encouraging trends, with piclidenoson 3mg BID showing statistical significance in certain comparisons against placebo. However, other secondary endpoints like PASI 50 rates and PDI improvement did not exhibit significant differences between piclidenoson doses and placebo.
In comparisons with apremilast at Week 32, piclidenoson did not establish noninferiority in terms of PASI 75 rates, PASI 50 rates, and PGA2 of 0–1. Yet, a higher proportion of patients in the piclidenoson 3mg BID arm achieved improvement from baseline in PDI compared to apremilast, trending towards significance.
The safety profile of piclidenoson, both at 2mg and 3mg BID, appeared favorable, with no significant differences in the incidence of treatment-emergent adverse events (TEAEs) compared to placebo. Importantly, piclidenoson’s safety profile was more favorable than that of apremilast, showing lower frequencies of nervous system and gastrointestinal disorders.
Overall, piclidenoson was well-tolerated, and no cumulative risks were observed upon treatment beyond Week 16. Serious TEAEs were infrequent and not considered drug-related, with no deaths reported during the study period. Electrocardiography did not show any drug effect that was clinically significant.
Pharmacokinetic data indicated similar exposure levels to piclidenoson at 2mg and 3mg BID. In conclusion, while piclidenoson demonstrated efficacy against placebo, further investigation is needed to establish noninferiority compared to apremilast, and ongoing safety monitoring is essential.
Conclusion
In this phase 3 clinical trial evaluating piclidenoson as a treatment for moderate-to-severe plaque psoriasis, the primary endpoint for the 3mg BID dose was met, demonstrating superiority over placebo in PASI 75 at Week 16. The response to piclidenoson exhibited a linear improvement over time. Noninferiority versus apremilast, a secondary endpoint, was established for PASI 75 with 2mg BID at Week 32, and there was a trend towards significance for piclidenoson 3mg BID regarding the proportion of patients achieving PDI improvement from baseline.
Piclidenoson demonstrated a safe and well-tolerated profile, comparable to placebo and superior to apremilast. Both piclidenoson dosages showed similarity in safety, pharmacokinetics (PK), and efficacy, but the primary efficacy endpoint was specifically achieved by the 3mg BID dose.
These efficacy results align with earlier phase 2 and 2/3 studies, indicating clinical benefits for piclidenoson in moderate-to-severe plaque psoriasis. The excellent safety profile observed in this trial is consistent with previous studies across various diseases, including rheumatoid arthritis and dry eye disease, encompassing a total of more than 1500 subjects who received piclidenoson.
The context of psoriasis treatment in clinical practice involves systemic nonbiological therapies, targeted therapies (such as apremilast), and biological therapies. While biologics and targeted therapies represent significant advancements, they come with challenges such as high costs, parenteral administration, regular monitoring, and potential adverse events. Drug survival studies suggest discontinuation rates for biologics and apremilast, primarily due to lack/loss of efficacy.
Piclidenoson presents itself as a potential solution, offering a convenient, cost-effective, safe, and efficacious treatment for moderate-to-severe psoriasis. Its favorable safety profile, coupled with documented efficacy characterized by a linear cumulative effect, addresses an important unmet need in this patient population.
The main limitation of the trial was a COVID-19-related study suspension, resulting in an unusually high withdrawal rate. Despite this limitation, the findings support the continued clinical development of piclidenoson as a promising psoriasis treatment.
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