Biological drugs are large and complex, often consisting of heterogeneous mixtures.
Compared to biologic drugs, small molecules differ in terms of size, production, structure, etc.
For skin diseases there are many biologics available (anti-IL-17, 23 etc.).
Small-molecule drugs are usually chemically synthesized with a fixed, known structure having a molecular weight of less than 1000 daltons, and typically between 300 and 700 daltons (for reference, aspirin is 180 daltons and paclitaxel is 854 daltons).
Compared to biologic drugs, small molecules differ in terms of size, production, structure, stability and administration (see Table 1).
IL-23/T17 mediated effects on immune cell populations and keratinocyte biology in psoriasis (PsO) skin and biologics target extra-cellular molecules whilst small molecules targets are intra-cellular .
Pro-inflammatory mediators signal through different intracellular pathways .
There are many biologics available (especially anti-IL-23 and anti-IL-17), which have better efficacy compared to apremilast, but treatment satisfaction is higher with apremilast . The benefits for the patients include the simplicity of oral assumption and the risk benefit.
The modulation of pro-inflammatory mediators (ie. TNF-α, Il-23, IFN-γ) and anti-inflammatory mediators (IL-10) occurs via the cAMP and NF-KB Pathways . The molecule itself reaches peak plasma concentration quickly (2.5 hours) and plasma clearance relatively quickly (10 L/hour) with elimination within 6-9 hours .
The ESTEEM 1 and 2 studies proved the efficacy at week 16 of 33% of PASI 75  and over five years the efficacy and safety continues to improve over time (unpublished data). “It seems to be that if it works, patients are happy with this drug.”
The main reason for prescribing apremilast is the safety profile, with the main adverse events being gastro intestinal transient/mild events .
In the UNVEIL phase 4 randomized controlled trial for the treatment of moderate PsO (apremilast vs. placebo), showed a BSA of 7% and a Dermatology Life Quality Index (DLQI) score of 11; illustrating that the patients were clearly affected in their daily lives . Apremilast reported an efficacy rate of around 30%.
Similar results were obtained from the Corrona PsO Registry .
When we are considering the treatments, we need to look beyond the skin.
For the first time, the cardiology association has included PsO as a risk enhancer , and pooled data, including the LIBERATE trial, showed that long-term hemoglobin A1c change is associated with apremilast .
TYK2 mediates signaling of fewer cytokines compared with JAKs 1-3 .
BMS-986165 (an oral treatment being tested for PsO and psoriatic arthritis) has a unique mechanism of action distinct from other kinase inhibitors, reducing off-target and non-specific JAK inhibition .
BMS-986165 reduces the Th17 pathway .
BMS-986165 is generally well tolerated with generally light possible side effects .
Treatment with BMS-986165 reduces the expression of genes of the IL-23/th17 and type I IFN pathways.
Biomarkers for inhibition of JAK1, JAK2 or JAK3 were not affected by BMS-986165 demonstrating selectivity for TYK2.
Robust clinical efficacy with an acceptable safety profile, supporting the ongoing POETYK PsO phase 3 program.
6. Reich K, et al. AAD 2014, P8296; Paul C, et al. EADV 2014, FC05.09.
7. Papp K, Reich K, Sobell JM, et al. Two-Year safety of apremilast, an oral phosphodiesterase 4 inhibitor, in patients with moderate to severe plaque psoriasis: Results from a phase 3, randomized, controlled trial (ESTEEM 1). AAD 2015, P1055.
8. Strober B, Bagel J, Lebwohl M, et al. Efficacy and safety of apremilast in patients with moderate plaque psoriasis with lower BSA: Week 16 results from the UNVEIL study.J Drugs Dermatol. 2017;16:801-8.
9. Merola JF, Gottlieb A, McLean R, et al. Real-World Efficacy of apremilast in patients with moderate plaque psoriasis: Results from the Corrona psoriasis registry. AAD 2019, P9718.
11. Puig L, Korman N, Greggio C, et al. Long-term hemoglobin A1c changes with apremilast in patients with psoriasis and psoriatic arthritis: Pooled analysis of phase 3 ESTEEM and PALACE trials and phase 3b LIBERATE trial. AAD 2019, P9706.
12. Baker KF, Isaacs JD. Novel therapies for immune-mediated inflammatory diseases: What can we learn from their use in rheumatoid arthritis, spondyloarthritis, systemic lupus erythematosus, psoriasis, Crohn’s disease and ulcerative colitis? Ann Rheum Dis. 2018;77:175-87.
13. Gillooly KM, Pulicicchio C, Pattoli MA, et al. Bruton’s tyrosine kinase inhibitor BMS-986142 in experimental models of rheumatoid arthritis enhances efficacy of agents representing clinical standard-of-care. PLoS One. 2017;(7):e0181782.
14. Krueger JK, et al. EADV 2018, Late-breaking news D3T01.
Presenter disclosure(s): Richard Langley has been involved in clinical trials for AbbVie, Amgen, Celgene, Centocor, Jannsen, Eli-Lilly, Leo, Merck (SUN), Novartis, Pfizer, UCB and performs peer review for Canadian Dermatology Foundation, dMRF and NSHRF.
With this collection of summaries from selected presentations at SPIN 2019, and interviews with international experts, we hope to share with you some of the highlights of this year’s congress. The international network met … [ Read all ]