Psoriasis Treatment with Oral Medication: the Small Molecule World

• Cells obey to signaling pathways with allow then to respond to local stimulation (paracrine)

• Here is a list of signaling pathways and the signals which stimulate (agonists):
  • MAPK cell cascade: activated by TNF and Il-1
  • SYK cell cascade cascade immune complexes
  • p15 cell signaling cascade activated by Il-2
  • cyclic amp / PKA cascade which is activated by Il-8. Down the line PKS activates DNA transcription. It is regulated by PDE4 (Phosphodiesterase 4)
  • pKC cell cascade stimulated by T-cell antigens
  • NFkB pathway which is activate by TNF and Il-1
  • JAK (Janus Kinase) pathways  which are activated by Il-12, Il-23, Il-6 and Ifn Gamma. Like all pathways it results in cellular DNA transcription. In this pathway, it is done by STAT proteins
    Transcription then gives the phenotype of psoriasis lesions

• A lot of small molecules are being developed:
  • JAK inhibiton: the most molecules in the pipeline
  • cAMP pathway inhibitor inhibition:  Apremilast (Otezla, Celgene) and 2728 (Anacor)
  • MAPK inhibitor

A word on the molecules which are clinically relevant:

• Apremilast (Otezla, Celgene)
  • Approved for the treatment of Psoriasis and Rheumatoid Arthritis (in the US and Europe)
  • Oral medication
  • inhibits phosphodiesterase 4
  • Efficacy shown in Psoriasis (ESTEEM study) and Psoriatic Arthriris (PALACE 1 study)
    • For psoriasis, PASI 75 improvement is achieved in 33% of patients at 16 weeks (30mg dosage)
    • For psoriatric arthritis (PsA),  40% of patients achieve ACR 20 threshhold (20 or 30mg dosage). ACR stands for American College of Rheumatology and a score of 20 is a significant improvement.
      To read more about the ESTEEM study, click HERE
• Tofactinib (Xeljanz, Pfizer)
  • Not approved for psoriasis at the time of publication (in the US or Europe)
  • Oral medication
  • JAK 1 and 3 inhibitor:
    • stops phosphorylation of JAK1 and 3
    • no effect on JAK2
    • cannot phosphorylate STAT by JAK
    • therefore transcription is stopped
  • Targeting of JAK is also used in IBD (Inflammatory Bowel Disease),  PsA, Behcet’s disease and Ankylosing Spondylarthritis
  • Topical JAK forms are being tried in AD (Atopic Dermatitis)

Small molecules in psoriasis: from outside to inside the immune cells. Bachelez H (France). Sy72 – Drugs in the Pipeline – From small molecules to antibodies