Advancements in Cannabinoids
Advancements in pharmaceutical development of cannabinoid compounds have largely coincided with the controversial national movement to legalize medical marijuana and decriminalize recreational marijuana use. Despite the temporal connection, the 2 topics are entirely distinct. Importantly, pharmaceutical development is largely focused on the effects of cannabidiol (CBD), which is 1 of approximately 113 cannabinoids identified from Cannabis sativa. Cannabidiol is not tetrahydrocannabinol, or THC, the compound responsible for marijuana’s psychoactive effects and addictive properties; CBD does not have any psychoactive effects and is not addictive (Figure 3).25
Figure 3. Cannabidiol (CBD) is not tetrahydrocannabinol (THC), the compound responsible for marijuana’s psychoactive effects and addictive properties.
A CBD oral solution agent recently gained FDA approval for seizures associated with Lennox-Gastaut syndrome or Dravet syndrome in patients 2 years and older; it is estimated that more than 180 trials of CBD are ongoing in the United States for various indications.26 A notable question in the development of CBD-based therapies is: What is the role of natural plant-derived CBD compared to a pure synthetic form of CBD? The latter is akin to a pharmaceutical process in which a single molecule is developed as the active drug.27 Although the potency and composition of plant-derived CBD can vary with crop conditions, plant strains, and the extraction process, a synthetic molecule would allow for consistency in safety, potency, and pharmacokinetic properties, as well as efficacy, as a consequence.26
There are intriguing data to suggest a potential use for topical CBD in the management of skin diseases, including acne vulgaris. Researchers have, for at least a decade, been investigating the role of the endocannabinoid system, which has physiologic regulatory functions in proliferation, differentiation, apoptosis and cytokine, mediator, and hormone production of various cell types in skin, hair follicles, and sebaceous glands.28 Cannabidiol has been shown to suppress proliferation of sebocytes through activation of transient receptor potential vanilloid 4 ion channels and to have anti-inflammatory effects on sebocytes.29 It has been shown to inhibit human keratinocyte proliferation through a non-CB1/CB2 mechanism30 and to possess potent antimicrobial activity against gram-positive bacteria such as P acnes.31
Given these effects on sebocytes, modulation of keratinocyte proliferation, and anti-inflammatory and antibacterial effects, CBD could prove beneficial in the management of acne vulgaris. A new synthetic CBD topical formulation, BTX 1503, is under investigation for the treatment of acne vulgaris.
Early clinical data confirm both the anti-inflammatory effects of topical BTX 1503 as well as its effects on noninflammatory lesions, with 4-week reductions in inflammatory lesion counts similar to what are reported in clinical trials for leading FDA-approved topical therapies in the same time frame.
The phase 1b trial was a 4-week, open-label study in participants with moderate to severe acne vulgaris.32 The primary end point was safety, as demonstrated by the incidence of TEAE, laboratory monitoring, and assessment of cutaneous tolerability. Exploratory end points included changes in inflammatory and noninflammatory lesion counts and IGA score. A total of 21 participants aged 18 to 65 years with moderate to severe acne vulgaris were enrolled. BTX 1503 was applied topically twice daily. At baseline, eligible participants had 20 to 50 inflammatory lesions and 20 to 100 noninflammatory acne lesions on the face, an IGA of 3 (moderate) or 4 (severe), and 3 or fewer nodular or cystic lesions (>5 mm in diameter). No serious or severe TEAEs were reported; no participants withdrew due to a TEAE. Slight erythema, slight scaling, slight dryness, and slight burning and stinging were reported; there were no reports of irritant or allergic contact dermatitis. Only 1 TEAE was thought to be possibly related to treatment: mild pain at the application site.32
In addition to presenting a potential new chemical entity for the topical treatment of acne, the novel topical vehicle formulation of BTX 1503 represents an innovative approach to drug delivery. The formulation utilizes proprietary technology to deliver high doses of drug into the skin without controversial penetration enhancers, preservatives, or other potential irritating additives. Instead, volatile excipients are used that evaporate upon application to the skin, leaving a so-called superconcentrated secondary formulation on the skin. The concentration gradient effect then drives the concentrated drug into skin. Although the formulation efficiently delivers active drug into the skin and its appendages, systemic exposure has been reported to be very low. A phase 2 randomized, double-blind, vehicle-controlled trial ongoing in the United States and Australia in 360 patients with moderate to severe acne vulgaris will provide key data to confirm the efficacy and safety of BTX 1503 (ClinicalTrials.gov Identifier NCT03573518).
Conclusion
Drug development continues to focus on the challenge of treating acne effectively and safely. Vehicle innovations are optimizing existing active drugs and creating opportunities to deliver new compounds to the skin. The approval of sarecycline as the first new chemical entity approved for acne in several years may be followed in coming years by other new actives, including clascoterone and CBD.