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Small molecules, apremilast, and TYK2

Presented by
Prof. Richard Langley, Dalhousie University, Canada
SPIN 2019
Prof. Richard Langley (Dalhousie University, Canada) contended that the value of small molecules will persist during the era of biologics [1]. Tailored use, careful patient selection, and patient preference are all important determining factors when choosing apremilast or TYK2 inhibition.

Many small molecules are being developed for psoriasis. They are small (<700 Da), chemically synthesised, generally simpler, well-defined, stable, and can be orally administered. Often, they are less expensive as well. Biologics, on the other hand, are generated in cell culture, are larger (>700 Da), and have complex tertiary structures with post-translational modifications; and the targets for biologics are usually extracellular (like anti-IL-17/-23) not intracellular (like small molecules). Currently, 3 (in some places 4) anti-TNF biologics are available: 1 anti-IL-12/23, 3 anti-IL-17s, and 4 anti-IL-23s, and many new molecules are coming out. In total, there are more than a dozen excellent options in first or second line. However, additional factors must be considered when choosing the right treatment.

For example, cost generally drives the use of methotrexate, but the reasons for choosing for apremilast are different. A recent study showed that the proportion of patients on apremilast report being extremely satisfied with their treatment vs biologics, especially with the ease of taking their treatment (P=0.018) and their comfort during treatment administration (P=0.002) [2]. There is also benefit for psoriatic arthritis patients, who are often on many medications like steroids and may not be candidates for biologics as a result, and it has a favourable safety profile.

Apremilast is an oral treatment with bioavailability of about 73%, with no food effect and a short half-life. It is a PDE4 inhibitor that is thought to have a dual effect repressing TNF-alpha, IL-23, and interferon-gamma while simultaneously increasing anti-inflammatory mediators like IL-10. The ESTEEM-1 and ESTEEM-2 studies showed the efficacy of apremilast at week 16 [3]. The CORONA psoriasis registry recapitulated similar responses for apremilast in real-world data.

In addition to being effective for psoriasis, apremilast has additional benefits. The pooled analysis of the phase 3 ESTEEM and PALACE trials and phase 3b LIBERATE trial demonstrated long-term haemoglobin (Hb) A1c changes in patients taking apremilast for psoriasis and/or psoriatic arthritis. The effect on Hb A1c could either be due to the reduction of inflammation or by induced metabolic changes; these data are entirely lacking but are of great interest if you have an overweight or borderline diabetic psoriasis patient [3]. The versatility of apremilast is further underscored by the effect apremilast has on oral ulcers after 12 weeks in patients with Behçet's syndrome [4].

Prof. Langley shared his expert opinion on the ideal candidate patient for apremilast: they would be a patient with moderate-to-severe psoriasis (with an emphasis on moderate) and stable disease who does not want to take a biologic, and, usually, other treatments have already failed to manage their disease. They may have comorbidities, as data from the CORONA database showed that patients with malignancies did well on apremilast, or can be on immunosuppressants already.

Prof. Langley ended with a few slides about TYK2 inhibition. TYK2 is interesting because it mediates signalling of fewer cytokines than its fellow Janus kinases, and is considered highly selective. BMS-986165 is a molecule that binds to a regulatory domain of TYK2 and changes the conformation such that the kinase activity is inactivated. The rationale is that it is highly selective in blocking IL-23, IL-12, and type 1 interferon signalling but does not block the binding site, and so it does not impact other Janus kinases, resulting in fewer off-target effects. The initial efficacy rates look very good and the safety profile is good, but convincing phase 3 data will be necessary to demonstrate its true narrow selective effects.

In conclusion, small molecules are usually desired by the patient. The benefit-to-risk ratio is good although the benefit aspects should improve with incremental improvements. Small molecules are attractive for paediatric patients as well as adult patients with complex comorbidities.

    1. Langley R. O039, SPIN 2019, 25-27 April, Paris, France.
    2. Lee LK, et al, AAD 2019 Poster 8254.
    3. Puig L, et al. JAAD 2018; 79(3): Suppl. 1, AB151.
    4. Hatemi G, et al. N Engl J Med. 2015 Apr 16;372(16):1510-8.


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