New small-molecule substances have a wide range of applications in dermatology. BRAF and MEK inhibitors have been proving their worth for several years in the treatment of melanoma. At present, a number of substances are in clinical development and testing for the treatment of psoriasis and other inflammatory diseases. The current state of knowledge was discussed in a symposium at the virtual EADV Congress on 31 October 2020.
When small molecules are mentioned, they tend to be newly developed substances that usually have intracellular targets. Most of the drugs used before the “biologics era” are also small molecules. However, there is no clear definition of what "small molecules" are. According to Menno de Rie (UMC Amsterdam, Netherlands), they usually consist of 20 to 100 atoms.
While biologicals act extracellularly and attack cytokines or cell-associated receptors, small molecules act intracellularly and attack signaling pathways. Their specificity is therefore lower. However, they can be applied orally or topically, whereas biologicals have to be given parenterally due to their molecular size and structure.
In the case of biologicals, e.g. monoclonal antibodies or fusion proteins, the effect can decrease over time due to the formation of anti-drug antibodies (ADA). Production is cost-intensive, storage with cooling and light protection is usually expensive. Many biologicals have been available for a long time, e.g. TNF-alpha blockers, so their effects and side effects are usually well known.
With new small molecules, long-term effects are usually still unclear and the safety profile has not yet been fully clarified. They are usually inexpensive to produce and store, and can be administered well orally or even topically.
According to de Rie, there is a high demand for small molecules in dermatology because they allow for further treatment individualization, taking into account the needs of the patients. In his opinion, a major advantage of the substances is that they can be applied topically.
The therapeutic revolution in the treatment of metastatic melanoma began with the introduction of vemurafenib, according to Thomas Tüting (Dermatology Department, University Hospital Magdeburg, Germany). This was followed by other substances such as dabrafenib, encorafenib, trametinib, and bimetinib, which act as BRAF and MEK inhibitors. They are currently mainly used in combination with immune checkpoint inhibitors.
They have also proven to be effective in adjuvant therapy. For example, a recently published 5-year update of the COMBI-AD study with dabrafenib and trametinib showed that the effect of a 12-month adjuvant therapy with the two small molecules can still be demonstrated after 5 years compared to placebo.
The question of whether early administration of the substances is better is currently being investigated. Various studies are investigating BRAF and MEK inhibitors without and with immune checkpoint inhibitors in the neoadjuvant setting in melanomas with locoregional metastasis.
CDK4/6 inhibitors such as abemaciclib could also become an interesting therapeutic option in melanoma. Investigations in mice and in vitro studies have shown that abemaciclib delays tumor growth while enhancing. This could enhance the effect of PD-L1 antibodies. In breast cancer, such combinations are currently being investigated in clinical trials.
CDK4/6 inhibitors can also be combined with a variety of other therapies, so it is hoped that specific combinations with optimal effects can be found for each disease. There are also numerous new small-molecule immunomodulators in preclinical and early clinical development, such as STING agonists and PD-L1 agonists.
JAK inhibitors, PDE₄ inhibitors, and Bruton Tyrosine Kinase (BTK) inhibitors are the new small molecules most commonly used in dermatology to date, according to Lidia Rudnicka (Dermatology Clinic, Medical University of Warsaw, Poland).
In psoriasis, JAK inhibitors are promising. At the moment, there is still a lack of data on long-term efficacy and safety. Among the JAH inhibitors, the most advanced is tofacitinib. However, the dose of 10 mg twice a day required to treat psoriasis led to an increased risk of thrombosis and therefore to a corresponding black box warning from the US Food and Drug Administration (FDA).
Ruxolitinib has only been studied as a topical dosage form in psoriasis. The JAK1/2 inhibitor baricitinib has shown a PASI75 response in psoriasis in a Phase 2b study in 43% of patients with 8 mg and 54% with 10 mg.
The pan-JAK inhibitor peficitinib, as well as the JAK1 inhibitors solcitinib and itacitinib are still in clinical development. The TYK2 inhibitor BMW-986165 achieved a PASI-75 response in 75% of patients at a dose of 12 mg/day after 12 weeks.
In alopecia areata, the JAK inhibitors tofacitinib, ruxolitinib, deuterated ruxolitinib, baricitinib, PF-06651600, and PF06700841 have so far shown promise. "We are currently in the process of finding the best molecule," said Rudnicka.
Tofacitinib at a dose of 2 x 5 mg/day resulted in 50% hair regrowth in 32 to 67% of patients with alopecia areata. If the therapy is stopped, recurrence occurs after eight weeks. This can be explained by the fact that alopecia areata is a chronic autoimmune disease for which optimal maintenance therapy has to be found.
The PDE₄ inhibitor apremilast is currently undergoing clinical trials in various skin diseases, including atopic dermatitis, allergic contact dermatitis, acne conglobata, and dermatomyositis. Roflumilast is being investigated in psoriasis.
Rudnicka concludes: "The small molecules are smaller than biologicals, but they are the same size as many traditional drugs. A lot of new substances for many dermatological conditions are being developed. They will change dermatology in the future."
Symposium "Small molecules in dermatology: Present and future". 29th Congress EADV Virtual, 29 to 31 October 2020, Session ID D3T01.3.