Efficacy of Sarecycline
Leyden et al. compared dose ranges of sarecycline versus placebo in a 12-week phase 2 clinical trial with 285 patients. The subjects ranged from ages 12–45 years old with moderate-to-severe acne and were randomized to receive sarecycline dosed at 0.75 mg/kg, 1.5 mg/kg or 3.0 mg/kg, or placebo. Reductions of 52.7% and 51.8% in inflammatory lesions were reported in the 1.5mg/kg and 3.0mg/kg treatment groups, respectively, as compared to 38.3% for placebo. These results suggest no difference in efficacy for doses of 1.5 mg/kg and 3.0 mg/kg.
In two identical 12-week phase 3 trials (SC1401 and SC1402), a total of 2002 subjects aged 9–45 years with moderate-to-severe acne were randomized 1:1 to receive sarecycline or placebo. As early as 3 weeks, there was a mean percentage reduction in inflammatory lesions of -49.9% to -51.8% in the sarecycline group versus -35.1% to -35.4% in the placebo group.[11,12] In addition, there was significant improvement in truncal and chest acne by 12 weeks, which was observed as early as 3 weeks.[11,12] In non-inflammatory facial acne, Moore et al. revealed a larger mean change from baseline in subjects using sarecycline versus placebo at week 12. IGA also improved in truncal acne by 2 points (and clear or almost clear) at week 12 in subjects on sarecycline that had an IGA of more than 2 at baseline.[12,13]
In a pilot study of 100 patients, sarecycline demonstrated significant efficacy in papulopustular rosacea, reducing not only lesion counts, but also erythema. Additionally, one case report showed the effectiveness of sarecycline in periorificial dermatitis.
Mechanism of Action
Tetracyclines share a common four ring naphthacene core but differ by a variety of structures attached to the carbon groups. Sarecycline has a 7-[[methoxy(methyl)amino]methyl] group attached to the C7 position. It binds to the A site codon of tRNA, blocking protein synthesis and inhibiting bacterial growth (Figure 1).[16,17] Unlike other tetracyclines, sarecycline extends to mRNA due to its long C7 moiety and allows for direct interaction with the mRNA channel. This increases its stabilization, leading to better inhibitory activity by blocking tRNA accommodation and mRNA translation.[17,18]
The mechanism of action of sarecycline.
Like other tetracyclines, sarecycline binds to the 30S subunit of rRNA, preventing tRNA from binding to the A site codon. Sarecycline also has a large C7 group that interacts with the mRNA channel, further stabilizing the drug on the ribosome. Modified from: Graber, EM. Treating acne with the tetracycline class of antibiotics: A review. Dermatological Reviews. 2021.9 Severity score: 0 = absent; 1 = mild; 2 = moderate; 3 = severe; 4 = very severe.
Antimicrobial resistance complicates the prolonged use of antibiotics, in general. Due to its narrow-spectrum coverage, sarecycline is less likely to induce resistance. C. acnes displayed low propensity for the development of resistance to sarecycline with spontaneous mutation frequency of 10−10 at 4–8 times the MIC. Bacteria confer resistance to tetracyclines by forming efflux pumps and acquiring Tet proteins that bind to the A site codon of the tRNA, releasing the bacteria from the antibiotics.[16,19] The acquisition of combined Tet(K) and Tet(M) genes among S. aureus strains confers resistance against tetracyclines. Compared to the other agents in its drug class, sarecycline has shown superiority in its activity against these tetracyclineresistant S. aureus strains against Tet(K) at MIC ranging from 0.12–0.5 g/mL as compared to 16–65 g/mL with the other tetracyclines. Due to its narrow-spectrum activity, sarecycline is expected to yield lower rates of antimicrobial resistance; however, it has not been found to be statistically significant when compared to other tetracyclines. Zhanel et al. noted that sarecycline's propensity to lead to C. acnes mutations was not found to be significantly different from minocycline.
The broad-spectrum activity of minocycline and doxycycline elicits common adverse effects such as gastrointestinal symptoms, photosensitivity, dizziness, microbial resistance, and tinnitus.[1,19–21] Data has shown that, thus far, the most common adverse effect associated with sarecycline is nausea at an incidence of ≥1%. Moore et al. reported that treatment-emergent adverse events were similar in both the sarecycline and placebo groups, the most common being nausea. A phase 1 randomized, double-blinded, placebo-controlled study was conducted to assess phototoxicity in 18 healthy adult males with Fitzpatrick skin types I, II, and III on 240 mg sarecycline. There was no significant dermal response to ultraviolet light exposure. Photosensitivity reactions were uncommon and limited to mild erythema. Dizziness was experienced by <1% of patients receiving sarecycline, and no vertigo or tinnitus was reported. Sarecycline is less likely to penetrate the blood-brain barrier, which may explain the very low rates of vestibular adverse events observed in the clinical trials.
Skin Therapy Letter. 2022;27(3):5-7. © 2022 SkinCareGuide.com