Milakovic 2021: PDE4i in Psoriasis Flashcards
Psoriasis def
Psoriasis is a chronic immune-mediated inflammatory disorder.
PDE4i use in psoriasis
PDE-4 degrades its substrate cyclic adenosine monophosphate (cAMP) to adenosine monophosphate (AMP), which subsequently leads to the production of pro-inflammatory mediators. Inhibitors of PDE-4 work by blocking the degradation of cAMP, which leads to a reduction in inflammation.
only approved oral PDE4i for psoriasis
apremilast
topical PDE4is
crisaborole, roflumilast
crisaborole indication
atopic dermatitis
Psoriasis immunopathogenesis involves multiple inflammatory mediators, including
- tumor necrosis factor (TNF)-α
- interleukin (IL)-12
- IL-17
- IL-22
- IL-23
- interferon (IFN)-γ.
hough topical corticosteroids (TCS) are commonly used and are often effective at treating psoriatic plaques, their long-term side effects, such as X and Y limit their usage.
atrophy and striae
cAMP is activated by G-protein coupled receptor ligands which upon activation of cAMP, mediate signal transduction mainly through protein kinase A (PKA).
Next step?
PKA then activates cAMP response element-binding protein (CREB), a response element that is possessed by numerous genes involved in the pathophysiology of psoriasis, including IL-2, IL-6, IL-10 and TNFα
Intracellular cAMP concentrations are mediated by X and phosphodiesterases (PDE).
adenylyl cyclase (AC)
PDEs are responsible for degrading cAMP, of which the X isoenzyme is the most prominent in immune cells, such as lymphocytes, granulocytes and monocytes/macrophages
PDE4i
DE-4 inhibitors can therefore suppress inflammatory cytokine generation and secretion, including IFN-γ, TNF-α, and IL-2, IL-12 and IL-23,8 as well as
reduce superoxide generation and chemotaxis
As well, PDE-4 inhibitors upregulate anti-inflammatory cytokines such as IL-10 through activation of
CREB
Both non-selective and selective PDE inhibitors are available on the market for various indications. The non-selective PDE inhibitors include
pentoxifylline and theophylline; no known benefit for psoriasis
Pentoxifylline, used in peripheral vascular disease, is a competitive
non-selective PDE inhibitor
Theophylline is a mostly non-selective PDE inhibitor that has some selective inhibition of PDE1-5 and is used to
improve airflow obstruction in asthma, chronic bronchitis and chronic obstructive pulmonary disease (COPD).
The main issue of systemic PDE inhibition
is gastrointestinal adverse effects, and newer generation, more selective agents have improved tolerability
Apremilast brand
Otezla
Otezla Phase 3 trial(s)
ESTEEM 1 and 2
The most common reported AEs with apremilast treatment were
diarrhea, upper respiratory tract infection (URTI), nausea, nasopharyngitis and headache. The AEs of diarrhea, nausea and headache were more frequent during the first 2 weeks and reduced in frequency over time. The median weight loss in the long-term apremilast-exposure group was 1.40 kg. Nineteen percent of these patients had weight loss greater than 5%. No patient discontinued treatment as a result of the weight loss.
ESTEEM 1 results
During the first 16-week period, the primary endpoint was met with a significantly greater proportion of patients receiving apremilast (33.1%) achieving a treatment reduction of over 75% in the PASI score (PASI-75) relative to placebo (5.3%, p<0.0001). Between these cohorts, a significantly greater proportion of patients re-randomized to apremilast (61.0%) achieved PASI-75 relative to 11.7% of patients re-randomized to placebo
ESTEEM 2 results
Similar results in ESTEEM 1 were reported with the primary endpoint of PASI-75 at week 16 being met with a significantly greater proportion of patients receiving apremilast (28.8%) compared to placebo (5.8%, p<0.0001)
LIBERATE trial
2017, Reich et al reported on phase 3b, multicentered, double-blinded, randomized controlled trialof 250 adults with moderate-to-severe plaque psoriasis. (apremilast). For the first 16 weeks, patients were randomized to receive either placebo, apremilast 30 mg BID or etanercept 50 mg weekly (QW)
LIBERATE results
After 16 weeks, a significantly greater proportion of patients achieved PASI-75 with apremilast (39.8%) versus placebo (11.9%, p<0.0001) at the primary endpoint. In the extension phase from week 16 to 104, all patients were switched to apremilast therapy. Here, it was reported that the PASI-75 response rate was maintained across treatment cohorts throughout week 104 (45.9–51.9%).
LIBERATE AEs
The most common AEs reported were similar to previous studies and included diarrhea, nausea, URTI and bronchitis. Most AEs were mild or moderate in nature, with the distribution of serious adverse events (SAEs) balanced across groups
recently an investigator-initiated study X comparing oral roflumilast 500 mcg to placebo has been registered with a primary endpoint of PASI-75 at week 12.
PSORRO
Topical roflumilast (ARQ-151, Arcutis Biotherapeutics) is a highly potent PDE-4 inhibitor currently under investigation for the treatment of plaque psoriasis. Based on IC50 values of inhibitor affinity for the PDE-4 molecule, roflumilast is approximately X timesmore potent than either apremilast or crisaborole depending on the comparator and PDE-4 isoform analyzed.
25-300x
Crisaborole ointment 2% (AN2728, Eucrisa®, Pfizer, New York), is a PDE-4 inhibitor that was FDA approved in 2016 for X with an extension of indication to Y in 2020
mild-to-moderate atopic dermatitis; children at least 3 months of age
Crisaborole MoA
The inhibition of PDE-4 is made possible by the unique configuration of boron within the crisaborole molecule. The boron enables the synthesis of a low molecular weight compound, allowing for effective penetration through skin. Similar to others, this PDE-4 inhibitor leads to increased cAMP-dependent activation of PKA and inhibits downstream NFAT and NF-kB signaling pathways, thereby attenuating skin inflammation.
most effective crisaborole treatment
The crisaborole 2% ointment BID regimen was most effective, well tolerated and had no safety concerns but was never developed further for use in psoriasis, and the results were never published in the literature
To further investigate the role of apremilast in the management of mild to moderate psoriasis patients, the X has been completed; however, results have not yet been published
ADVANCE trial
