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Researchers find that apremilast and CF101 both are safe and effective for psoriasis, but apremilast outperforms CF101 through 16 weeks, until it plateaus.
Despite major steps forward in treating psoriasis over the past two decades, treatments can often take harsh tolls on the body, prompting some people to stop treatment. There’s a need, then, for new, convenient therapies that are both safe and effective, causing as little negative impact as possible.
Recently, a small molecule drug apremilast (Otezla), was approved to treat moderate-to-severe psoriasis. But, investigators are also looking into whether another mediation, CF101 (Piclidenoson), might have a longer-lasting positive effect. It’s an orally-bioavailable adenosine receptor that prompts an anti-inflammatory response, leading to the inhibition of tumor necrosis factor-âº, interleukin -6 and -12, macrophage inflammatory proteins, and receptor-activator of NF-KB ligand.
According to the result of a Phase 2/3 multi-center, randomized, double-blind, placebo-controlled study with nearly 330 participants, published in the Journal of Drugs in Dermatology, researchers found apremilast and CF101 both offer safe, effective treatments. Apremilast outperforms CF101 through 16 weeks, but its benefits plateau at that point. CF101’s ameliorative impact takes hold at this point and carries on through 32 weeks.
Consequently, investigators determined, CF101 offers promise as an effective, long-term psoriasis treatment. And, the safety results support data from other Phase 2 CF101 studies that the drug is effective across different systemic inflammatory diseases. Other studies have also demonstrated CF101 is effective in treating rheumatoid arthritis after 12 weeks of therapy.
This is important because existing research shows the median survival for biologics in psoriasis was 47 months. Between 10% and 20% of patients experience a loss of biologics efficacy each year, causing 67% of them to stop treatment altogether.
To unearth CF101’s effect, researchers assigned, in a blinded placebo-controlled period, 103 subjects to receive oral doses of CF101 1mg, CF101 2mg, or a matching placebo twice daily. After an analysis at 12 weeks, the CF101 group was deemed futile and was discontinued.
During a second study phase, investigators divided 223 additional patients between a CF101 mg oral daily group and a placebo group for 16 weeks. Subsequently, in an open label expansion period, researchers continued the CF101 participants with that therapy, but switched the placebo group to CF101 2mg for the study remainder, as well.
Safety and efficacy were examined at 4, 8, 12, 16, 20, 24, and 28 weeks. Final assessments were made at 32 weeks.
Of the initial participant group, 260 individuals (88.7%) completed the study, 125 were in the CF101 group (86.2%) and 135 received placebo treatment (91.2). Those who wither did so because of lack of efficacy, unacceptable concomitant medication or therapy, investigator decision for the patient’s best interest, non-compliance, and lost to follow-up.
Safety & Efficacy
To determine whether CF101 is safe and effective, investigators created two endpoints. First, they analyzed the number of subjects that achieved PASI 75 at 12 weeks, and, second, they looked at the number of subjects that reached PASI 75 at week 16. They also analyzed the number that achieved PGA of 0 or 1 at 12 and 16 weeks.
The first endpoints weren’t met, but between weeks 16 and 32, CF101 participants demonstrated PASI 50, 75, 90, and 100 rates of 63.5%, 35.5%, 24.7%, and 10.4%, respectively.
Figuring out the drug’s safety was also paramount. To do so, investigators examined treatment emergent-adverse events and changes in vital signs, physical examinations, clinical laboratory tests (liver, kidney, hematology, chemistry, urinalysis, and pregnancy tests), and ECG findings.
According to results data from the primary endpoint, the treatment groups showed no statistically-significant difference at week 12. Of the CF101 2mg group, only 12 of 141 participants (8.5%) achieved PASI 75 at week 12. In the placebo group, it was 10 out of 144 (6.9%).
The second endpoint also showed no statistical significance at week 12. Nine out of 141 CF101 2mg subjects (6.4%) and 5 of 144 placebo subjects (3.5%) achieved PGA of 0 or 1 during this time.
Study data also revealed more positive results. At weeks 20 to 32, the CF101 group showed linear improvement in PASI 50 (63.5% of patients at week 32), PASI 75 (35.5%), PASI 90, (24.7%), and PASI 100 (10.6%). At week 32, PASI mean percent improvement was 57%.
Researchers also compared CF101 efficacy rates against apremilast global Phase 3 trial. Based on the comparison, CF101 efficacy rates continued to rise past 16 weeks of treatment. Apremilast levels plateaued at this point.
The data supports any benefits coming from CF101 because placebo responses are rare at PASI 90 and Psi 100. The number of participants achieving PGA of 1 or 2 with CF101 2mg was also significantly higher between weeks 24 and 32.
Treatment Emergent-Adverse Events
Some participants experienced at least one treatment emergent-adverse event. In the CF101 2mg group, 37 of 145 subjects (25.5%) experienced an adverse event, as did 29 of 148 placebo participants (19.6%). Overall, these negative events occurred evenly across the studies.
In the blinded placebo-controlled period phase, for the CF101 group, infections and infestations were most common – 10 of 145 participants (6.9%) experienced one. In the placebo group, 13 of 148 (8.8%) did. Gastrointestinal disorders, including abdominal pain, diarrhea, dry mouth, and nausea were also common. Eight CF101 participants (5.5%) experienced them, and 3 placebo participants (2%) did.
Infections and infestations were also the most common negative events for the CF101 open label expansion group, affecting 23 of 275 participants (8.4%).
The remainder – and majority – of treatment emergent-adverse events that occurred were mild and determined to be unrelated to CF101. Severe adverse effects did happen, although they were also unrelated to the drug. Four participants experienced a severe problem, and one participant died.
Apremilast vs CF101
Psoriasis; Psoriatic Arthritis
Psoriasis; Psoriatic Arthritis; Rheumatoid Arthritis
Diarrhea; Nausea; Upper Respiratory Infection; Tension headache; Headache
Diarrhea; Nausea; Kidney disorders; Nervous system disorders; Musculoskeletal disorders
Small-molecule inhibitor for phosphodiesterase 4
Adenosine receptor inhibiting tumor necrosis factor-âº, interleukin-6 and -12, macrophage inflammatory proteins, and receptor activator for NF-KB ligand
Van Troostenburg AR, Clark EV, et al. Tolerability, pharmacokinetics and concentration-dependent hemodynamic effets of oral CF101, an A3 adenosine receptor agonist, in healthy young men. Int J Clin Pharmacol Ther. 2004; 42:534-42.
Warren RB, Smith CH, et al. Treatment of Psoriasis: A Prospective Observational Cohort Study from the British Association of Dermatologists Biologic Interventions Registrar (BAD-BIR). J Invest Dermatol. 2015; 172:244-52.