Sarecycline: A Narrow-Spectrum Antibiotic

Susuana Adjei, MD; Austinn C. Miller, MD; Laurie A. Temiz, BA; Stephen K. Tyring, MD, PhD, MBA

Disclosures

Skin Therapy Letter. 2022;27(3):5-7. 

In This Article

Discussion

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.[10] 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.[10]

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.[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.[14] Additionally, one case report showed the effectiveness of sarecycline in periorificial dermatitis.[15]

Mechanism of Action

Tetracyclines share a common four ring naphthacene core but differ by a variety of structures attached to the carbon groups.[16] 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.[16] This increases its stabilization, leading to better inhibitory activity by blocking tRNA accommodation and mRNA translation.[17,18]

Figure 1.

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.

Antibacterial Resistance

Antimicrobial resistance complicates the prolonged use of antibiotics, in general. Due to its narrow-spectrum coverage, sarecycline is less likely to induce resistance.[6] 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.[6] 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.[6] 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.[6] 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.[6] Zhanel et al. noted that sarecycline's propensity to lead to C. acnes mutations was not found to be significantly different from minocycline.[6]

Safety Profile

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%.[10] Moore et al. reported that treatment-emergent adverse events were similar in both the sarecycline and placebo groups, the most common being nausea.[12] 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.[22] There was no significant dermal response to ultraviolet light exposure. Photosensitivity reactions were uncommon and limited to mild erythema.[22] Dizziness was experienced by <1% of patients receiving sarecycline, and no vertigo or tinnitus was reported.[23] 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.[23]

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