STL Volume 27 Number 3 – Skin Therapy Letter https://www.skintherapyletter.com Written by Dermatologists for Dermatologists Thu, 19 May 2022 18:58:46 +0000 en-US hourly 1 https://wordpress.org/?v=6.8.1 Halobetasol Propionate 0.01% Lotion for Plaque Psoriasis and Corticosteroid-Responsive Dermatoses https://www.skintherapyletter.com/psoriasis/halobetasol-propionate-lotion/ Sun, 01 May 2022 21:23:44 +0000 https://www.skintherapyletter.com/?p=13389 Abrahim Abduelmula, BScN1; Brian D. Rankin, PhD2; Ronald Vender, MD3,4;
Jensen Yeung, MD5-8; Alim R. Devani, MD9-11; Vimal H. Prajapati, MD9-14

1Faculty of Medicine, University of Western Ontario, London, ON, Canada
2Cumming School of Medicine, University of Calgary, Calgary, AB, Canada
3Department of Dermatology, McMaster University, Hamilton, ON, Canada
4Dermatrials Research Inc. & Venderm Innovations in Psoriasis, Hamilton, ON, Canada
5Division of Dermatology, Department of Medicine, University of Toronto, ON, Canada
6Women’s College Research Institute, Women’s College Hospital, Toronto, ON, Canada
7Sunnybrook Health Sciences Centre, Toronto, ON, Canada
8Probity Medical Research, Waterloo, ON, Canada
9Dermatology Research Institute, Calgary, AB, Canada
10Skin Health & Wellness Centre, Calgary, AB, Canada
11Probity Medical Research, Calgary, AB, Canada
12Division of Dermatology, Department of Medicine, University of Calgary, Calgary, AB, Canada
13Section of Community Pediatrics, Department of Pediatrics, University of Calgary, Calgary, AB, Canada
14Section of Pediatric Rheumatology, Department of Pediatrics, University of Calgary, Calgary, AB, Canada

Conflict of interest:
Abrahim Abduelmula and Brian D. Rankin have no relevant disclosures. Ronald Vender has been an advisor, consultant, speaker, and/or investigator for AbbVie, Actelion, Amgen, Astellas, Celgene, Dermira, Eli Lilly, Galderma, Janssen, LEO Pharma, Merck, Novartis, Pfizer, Regeneron, and Takeda. Jensen Yeung has been an advisor, consultant, speaker, and/or investigator for AbbVie, Allergan, Amgen, Astellas, Boehringer Ingelheim, Celgene, Centocor, Coherus, Dermira, Eli Lilly, Forward, Galderma, GSK, Janssen, LEO Pharma, Medimmune, Merck, Novartis, Pfizer, Regeneron, Roche, Sanofi Genzyme, Sun Pharma, Takeda, UCB, Valeant, and Xenon. Alim R. Devani has been an advisor, consultant, speaker, and/or investigator for AbbVie, Amgen, AnaptysBio, Arcutis, Arena, Bausch Health, Boehringer Ingelheim, Bristol Myers Squibb, Celgene, Concert, Dermavant, Dermira, Eli Lilly, Galderma, GSK, Incyte, Janssen, LEO Pharma, Medexus, Nimbus Lakshmi, Novartis, Pediapharm, Pfizer, Regeneron, Reistone, Sanofi Genzyme, Sun Pharma, Tribute, UCB, and Valeant. Vimal H. Prajapati has been an advisor, consultant, speaker, and/or investigator for AbbVie, Actelion, Amgen, AnaptysBio, Aralez, Arcutis, Arena, Aspen, Bausch Health, Boehringer Ingelheim, Bristol Myers Squibb, Celgene, Cipher, Concert, Dermavant, Dermira, Eli Lilly, Galderma, GSK, Homeocan, Incyte, Janssen, LEO Pharma, Medexus, Nimbus Lakshmi, Novartis, Pediapharm, Pfizer, Regeneron, Reistone, Sanofi Genzyme, Sun Pharma, Tribute, UCB, and Valeant. Funding sources: None.

Abstract:
A novel topical corticosteroid, halobetasol propionate (HP) 0.01% lotion (Bryhali™), has recently been introduced for the treatment of plaque psoriasis and corticosteroid-responsive dermatoses in adults. Once daily application of HP 0.01% lotion is indicated for use up to 8 weeks. Treatment success for plaque psoriasis in the pivotal phase 3 clinical trials (defined as an Investigator Global Assessment [IGA] of clear/almost clear [IGA 0/1] with ≥2-grade improvement from baseline) occurred in over one-third of patients by week 8. Treatment-emergent adverse events were typically mild-to-moderate in intensity and usually limited to the application site(s). No treatment-related cases of skin atrophy have been reported from the studies. Counselling should be considered to optimize treatment outcomes.

Key Words:
Bryhali™; halobetasol; topical; therapeutics; corticosteroid; psoriasis; clinical trial

Introduction

Topical corticosteroids are a mainstay in the management of plaque psoriasis and other corticosteroid-responsive dermatoses. Bryhali™ is a super-potent topical corticosteroid lotion with halobetasol propionate (HP) 0.01% as the active ingredient. It was approved by the US FDA in 2018 for plaque psoriasis and by Health Canada in 2021 for both plaque psoriasis and corticosteroid-responsive dermatoses. Available in 45 g, 60 g, and 100 g tubes containing 0.1 mg of HP 0.01% per gram, HP 0.01% lotion is applied once daily to affected areas (maximum dose of 50 g per week).1,2 It has a safety profile allowing for extended use up to 8 weeks without physician re-evaluation (provided there are observed improvements in the condition being treated).3 Non-medicinal ingredients of this product include carbomer copolymer type b, carbomer homopolymer type a, diethyl sebacate, edetate disodium dihydrate, light mineral oil, methylparaben, propylparaben, purified water, sodium hydroxide, sorbitan monooleate, and sorbitol solution 70%. No data is currently available for its use in pediatric or pregnant patients; therefore, HP 0.01% lotion has not been approved for utilization in children/adolescents (<18 years of age), nor is it recommended in pregnant women.1

Background

Plaque psoriasis and certain corticosteroid-responsive dermatoses, such as atopic dermatitis, are chronic, immunemediated, inflammatory skin diseases that vary in severity. Topical corticosteroids are used across all severities, although moderate-to-severe disease often requires the addition of phototherapy or systemic therapies.4 Despite their efficacy, these conditions can quickly recur if treatment is discontinued; however, extended use of topical corticosteroids can also result in adverse events (AEs) that are either local (e.g., skin atrophy, folliculitis, striae, and telangiectasia) or systemic (e.g., hypothalamic-pituitary-adrenal [HPA] axis suppression).5

HP 0.05% cream or ointment (Ultravate®) is a commonly prescribed topical corticosteroid applied once or twice daily per physician direction (maximum dose of 50 g per week).6 According to the product monograph, patients should limit use to a maximum of 2 weeks unless re-evaluated by a physician. However, considering the chronic nature of plaque psoriasis and many other corticosteroid-responsive dermatoses, such as atopic dermatitis, this limited treatment duration can become an issue for long-term utilization and compliance.6 Studies on HP 0.01% lotion have shown that despite demonstrating comparable efficacy to HP 0.05% cream, the safety profile allows it to be used for intervals longer than 2 weeks without the need for physician re-evaluation at 2 weeks.7

HP is a water-insoluble synthetic corticosteroid thought to act via the induction of lipocortins, a group of phospholipase A2 inhibitory proteins. It is theorized that these proteins act on pro-inflammatory mediators, such as prostaglandins and leukotrienes, via inhibition of the precursor arachidonic acid.8 HP has anti-inflammatory, anti-proliferative, antipruritic, and vasoconstrictive effects.1,7

The once daily HP 0.01% lotion is formulated with proprietary PRISMATREX™ technology, a novel polymeric emulsification system that features oil droplets containing the active ingredient and other hydrating/moisturizing excipients dispersed evenly in an oil-in-water emulsion and separated by a 3-dimensional mesh matrix.1,9 This allows for uniform distribution and enhanced penetration when applied onto the skin surface. The latter may provide rationale for the comparable efficacy of HP 0.01% lotion and HP 0.05% cream despite a 5-fold difference in the concentration of HP.7

Supporting Evidence from Clinical Trials (Table 1)

Table 1

PHASE 27
 WEEK 2
HP 0.01% HP 0.05% P-value
Treatment successa
 30.0% 31.6% p=0.854
Treatment success for specific psoriasis signs
(erythemab/elevationc/scalingd) at target lesion site
 38.3%/40.0%/43.3% 31.6%/36.8%/47.4% p=0.446/p=0.727/p=0.663
Percent change in mean BSA from baseline 22.3% reduction 20.9% reduction p=0.787
PHASE 3 WEEK 8
Study110
 HP 0.01% Vehicle P-value
Treatment successa
 36.5% 8.1% p<0.001
Treatment success for specific psoriasis signs
(erythemab/elevationc/scalingd) at target lesion site
 46.7%/52.5%/54.9% 17.9%/24.1%/20.2% p<0.001 (for all comparisons)
Percent change in mean BSA from baseline 34.2% reduction 2.0% reduction p<0.001
Percent change in mean DLQI score from baseline 57.7% reduction NR p=0.001
Study 210
 HP 0.01% Vehicle P-value
Treatment successa
 38.4% 12.0% p<0.001
Treatment success for specific psoriasis signs
(erythemab/elevationc/scalingd) at target lesion site
 56.3%/62.7%/63.1% 19.5%/24.2%/25.8% p<0.001 (for all comparisons)
Percent change in mean BSA from baseline 36.2% reduction 9.0% reduction p<0.001
Percent change in mean DLQI score from baseline 58.7% reduction NR p=0.004
Pooled Analysis3,10
 HP 0.01% Vehicle P-value
Percent change in mean IGAxBSA composite score from baseline 49.4% reduction 13.4% reduction p<0.001
Proportion of patients achieving IGA×BSA-50 56.8% 17.2% p<0.001
Proportion of patients achieving IGA×BSA-75 39.3% 9.7% p<0.001
Proportion of patients achieving IGA×BSA-90 19.3% 2.8% p<0.001
Table 1. Summary of the efficacy and patient-reported outcomes data for HP 0.01% lotion (Bryhali™) from phase 2 and phase 3 clinical trials.
 
aTreatment success was defined as an IGA score of clear or almost clear (IGA 0/1) with ≥2-grade improvement from baseline.
bTreatment success for erythema was defined as ≥2-grade improvement from baseline in score.
cTreatment success for elevation was defined as ≥2-grade improvement from baseline in score.
dTreatment success for scaling was defined ≥2-grade improvement from baseline in score.
 
BSA, body surface area; DLQI, Dermatology Life Quality Index; HP 0.01%, halobetasol propionate 0.01%; HP 0.05%, halobetasol propionate 0.05%; IGA, Investigator Global Assessment; IGAxBSA-50, 50% improvement in IGAxBSA composite score from baseline; IGAxBSA-75, 75% improvement in IGAxBSA composite score from baseline; IGAxBSA-90, 90% improvement in IGAxBSA composite score from baseline; NR, not reported.

Plaque Psoriasis

In a phase 2 multicenter, randomized, double-blind, vehicle-controlled clinical trial (n=150), the efficacy and safety of HP 0.01% lotion (n=60) versus HP 0.05% cream (n=57) was evaluated in adult patients with moderate-to-severe plaque psoriasis (Investigator Global Assessment [IGA] score: moderate [3] or severe [4]; affected body surface area [BSA]: 3% to 12%).7 At week 2: the primary endpoint of an IGA score of clear or almost clear (IGA 0/1) with ≥2-grade improvement from baseline (treatment success) was achieved by 30.0% and 31.6% of patients treated with HP 0.01% lotion and HP 0.05% cream, respectively (p=0.854); a 2-grade improvement from baseline in the 3 key signs of plaque psoriasis—erythema, elevation, and scaling—at the target lesion site (treatment success for specific psoriasis signs) was achieved by 38.3%, 40.0%, and 43.3% of patients treated with HP 0.01% lotion versus 31.6%, 36.8%, and 47.4% of patients treated with HP 0.05% cream, respectively (p=0.446, p=0.727, and p=0.663, respectively); and BSA improved by 22.3% with HP 0.01% lotion versus 20.9% with HP 0.05% cream (p=0.787). Both HP 0.01% lotion and HP 0.05% cream were more effective than vehicle at all time points, with HP 0.01% lotion demonstrating greater efficacy than HP 0.05% cream for patients with more severe disease (IGA=4) at baseline. Safety evaluation revealed AEs of treatment-related dermatitis (n=1) and severe itching (n=1) with HP 0.01% lotion as well as treatment-related severe itching (n=2) and severe burning/ stinging (n=1) with HP 0.05% cream. No treatment-related cases of skin atrophy, folliculitis, striae, or telangiectasia were observed in either treatment group.7 In summary, HP 0.01% lotion was comparable to HP 0.05% cream in terms of overall treatment success, treatment success for specific psoriasis signs at the target lesion site, and reduction in BSA, with both treatments demonstrating a favorable safety profile.

In a pooled analysis of 2 phase 3 multicenter, double-blind, randomized, parallel-group clinical trials (n=430), the efficacy and safety of HP 0.01% lotion (n=285) versus vehicle (n=145) was evaluated in adult patients with moderate-to-severe plaque psoriasis (IGA score: 3 or 4; affected BSA: 3% to 12%).9 At week 8: the primary endpoint of treatment success was achieved by 36.5% (Study 1) and 38.4% (Study 2) of patients treated with HP 0.01% lotion versus 8.1% (Study 1) and 12.0% (Study 2) of patients treated with vehicle (p<0.001 for both comparisons versus vehicle), with HP 0.01% lotion demonstrating statistically significant superiority over vehicle as early as week 2 (Study 1) and week 4 (Study 2); HP 0.01% lotion achieved treatment success for specific psoriasis signs at the target lesion site in 46.7% (Study 1) and 56.3% (Study 2) of patients for erythema, 52.5% (Study 1) and 62.7% (Study 2) of patients for elevation, as well as 54.9% (Study 1) and 63.1% (Study 2) of patients for scaling (p<0.001 for all comparisons versus vehicle); BSA improved by 34.2% (Study 1) and 36.2% (Study 2) with HP 0.01% lotion (p<0.001 for both comparisons versus vehicle), with HP 0.01% lotion demonstrating statistically significant superiority over vehicle as early as week 2 (both Study 1 and Study 2); mean Dermatology Life Quality Index (DLQI) score was reduced by 57.7% (Study 1) and 58.7% (Study 2) with HP 0.01% lotion (p=0.001 and p=0.004, respectively, versus vehicle); mean IGAxBSA composite score (calculated by multiplying the IGA by the BSA; range: 9-48) was reduced by 49.5% with HP 0.01% lotion versus 13.4% with vehicle (p<0.001), with HP 0.01% lotion demonstrating statistically significant superiority over vehicle as early as week 2; and the proportion of patients achieving ≥50%, ≥75%, and ≥90% reduction in IGAxBSA composite score from baseline (IGAxBSA-50, IGAxBSA-75, and IGAxBSA-90, respectively) was 56.8%, 39.3%, and 19.3% with HP 0.01% lotion versus 17.2%, 9.7%, and 2.8% with vehicle (p<0.001 for all comparisons versus vehicle).3,9 Safety evaluation revealed similar rates of AEs between the treatment groups: 21.5% with HP 0.01% lotion and 23.9% with vehicle. Most AEs (90.2%) were mild-to-moderate in intensity. No cases of treatment-related skin atrophy, folliculitis, or striae were reported.10 There was one AE of telangiectasia with HP 0.01% lotion, not deemed to be treatment-related. In summary, HP 0.01% lotion was superior to vehicle in terms of overall treatment success, treatment success for specific psoriasis signs at the target lesion site, reduction in BSA, as well as improvements in mean DLQI and mean IGAxBSA composite scores, with HP 0.01% lotion demonstrating a favorable safety profile.

Corticosteroid-Response Dermatoses

There are no clinical trials investigating the efficacy and safety of HP 0.01% lotion for corticosteroid-responsive dermatoses.

Dosage and Administration

The on-label recommendation is to apply a thin layer of Bryhali™ once daily to areas affected by plaque psoriasis or other corticosteroid-responsive dermatoses until disease control is achieved.1 The total amount used should not exceed 50 g per week due to the concern for HPA axis suppression. Uninterrupted treatment beyond 8 weeks is not recommended.1

Counselling: Practical Tips to Optimize Use

A thin layer of HP 0.01% lotion should be applied, just enough to cover the areas affected by plaque psoriasis or other corticosteroid-responsive dermatoses. It is essential to rub in gently and inform patients that applying excessive amounts will not improve treatment efficacy. If HP 0.01% lotion is applied after bathing, the treatment site(s) should be dry before application.

It is also important to allow sufficient time for the medication to dry before putting clothes on to prevent inadvertent spread onto unaffected skin. HP 0.01% lotion should not be used with occlusive dressings unless recommended by a physician. It is for external use only and must be kept away from the eyes, nose, mouth, and other mucosal sites. HP 0.01% lotion should not be applied to the scalp or sensitive sites, such as the face, groin, and axillae, nor on ulcers or wounds.1 It is also advised to avoid application on areas affected by untreated bacterial, tubercular, fungal and viral infections involving the skin.1

Conclusion

Once daily application of HP 0.01% lotion (Bryhali™) is a convenient topical therapy with comparable efficacy to HP 0.05% cream (Ultravate®), despite a 5-fold difference in concentration of HP. One of the main advantages is its ability to be used safely for up to 8 weeks without concern for AEs (especially skin atrophy) and the requirement for physician re-evaluation (provided there are observed improvements in the condition being treated). Counselling with application tips should be considered for all patients.

References



  1. BRYHALI™ (halobetasol propionate lotion 0.01% w/w) [product monograph]. Revised April 13, 2021. Bausch Health Canada Inc., Laval, QC. Available at: https://pdf.hres.ca/dpd_pm/00060714.PDF. Accessed March 28, 2022.

  2. BRYHALI® (halobetasol propionate lotion) [prescribing information]. Revised June 2020. Bausch Health US, LLC, Bridgewater, NJ. Available at: https://www. bauschhealth.com/Portals/25/Pdf/PI/Bryhali-PI.pdf Accessed March 28, 2022.

  3. Sugarman JL, Weiss JS, Tanghetti EA, et al. Safety and efficacy of halobetasol propionate lotion 0.01% in the treatment of moderate to severe plaque psoriasis: a pooled analysis of 2 phase 3 studies. Cutis. 2019 Feb;103(2):111-6.

  4. Griffiths CE, Barker JN. Pathogenesis and clinical features of psoriasis. Lancet. 2007 Jul 21;370(9583):263-71.

  5. Armstrong AW, Read C. Pathophysiology, clinical presentation, and treatment of psoriasis: a review. JAMA. 2020 May 19;323(19):1945-60.

  6. ULTRAVATE® (topical halobetasol propionate) [product monograph]. Revised October 7, 2020. Bausch Health Canada Inc., Laval, QC. Available at: https:// bauschhealth.ca/wp-content/uploads/pdf/Ultravate%20PM-E-2020-10-07.pdf. Accessed March 28, 2022.

  7. Kerdel FA, Draelos ZD, Tyring SK, et al. A phase 2, multicenter, double-blind, randomized, vehicle-controlled clinical study to compare the safety and efficacy of a halobetasol propionate 0.01% lotion and halobetasol propionate 0.05% cream in the treatment of plaque psoriasis. J Dermatolog Treat. 2019 Jun;30(4):333-9.

  8. National Center for Biotechnology Information. National Library of Medicine. PubChem compound summary for CID 5311167, halobetasol. https:// pubchem.ncbi.nlm.nih.gov/compound/Halobetasol. Accessed March 28, 2022.

  9. Tanghetti EA, Stein Gold L, Del Rosso JQ, et al. Optimized formulation for topical application of a fixed combination halobetasol/tazarotene lotion using polymeric emulsion technology. J Dermatolog Treat. 2021 Jun;32(4):391-8.

  10. Green LJ, Kerdel FA, Cook-Bolden FE, et al. Safety and efficacy of a once-daily halobetasol propionate 0.01% lotion in the treatment of moderate-to-severe plaque psoriasis: results of two phase 3 randomized controlled trials. J Drugs Dermatol. 2018 Oct 1;17(10):1062-9.


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]]> Sarecycline: A Narrow-Spectrum Antibiotic https://www.skintherapyletter.com/acne/sarecycline-narrow-spectrum-antibiotic/ Sun, 01 May 2022 18:02:48 +0000 https://www.skintherapyletter.com/?p=13399 Susuana Adjei, MD1; Austinn C. Miller, MD1; Laurie A. Temiz, BA1,2; Stephen K. Tyring, MD, PhD, MBA1,3

1Center for Clinical Studies, Webster, TX, USA
2Meharry Medical College, Nashville, TX, USA
3Department of Dermatology, University of Texas Health Science Center, Houston, TX, USA

Conflict of interest:
Susuana Adjei, Austinn Miller and Laurie Temiz have no conflicts of interest to disclose. Stephen Tyring was a principal investigator for the Almirall PROSES clinical trial.

Abstract:
Tetracycline-class drugs have been used for first-line treatment of moderate-to-severe acne and rosacea for decades. Recently, a new third generation tetracycline, sarecycline, was US FDA-approved for the treatment of moderate-to-severe acne. This narrow-spectrum tetracycline-derived antibiotic has been shown to be effective with an improved safety profile.

Key Words:
sarecycline, tetracyclines, moderate-to-severe acne, antimicrobial resistance, adverse effects

Introduction

To date, one of the first-line classes of oral antibiotic treatments for moderate-to-severe acne has been tetracycline-class antibiotics due to their anti-inflammatory effects, antimicrobial activity, bioavailability, and lipophilicity.1 The pathogenesis of acne vulgaris is multifaceted with key factors being abnormal follicular keratinization, Cutibacterium acnes (C. acnes) proliferation/ colonization, and increased sebum production.2 Inflammation also ensues with the expression and upregulation of inflammatory factors/cells such as CD3+, CD4+ T cells, interleukin-1, integrins, toll-like receptors, and macrophages.2

Various methods for grading acne severity have been debated. Consensus remains elusive, as acne assessment must account for a spectrum of factors such as the number, location, type of lesions, associated scarring, and psychosocial influences.1,3 In fact, the established scoring tools Global Acne Grading System (GAGS) and Investigator Global Assessment (IGA), which are widely used in clinical trials, FDA efficacy endpoints, and patient care, do not account for all the associated factors in acne assessment.3

Moderate-to-severe acne classically presents with inflamed papules, pustules, and occasional nodules with lesions commonly affecting the face, chest, and back.4,5 Oral antibiotics are a mainstay of treatment (Table 1).1 Tetracyclines, specifically doxycycline and minocycline, are broad-spectrum antibiotics widely used for acne treatment as they limit inflammation by inhibition of protein synthesis and proliferation of C. acnes.6 However, because of their broad-spectrum activity, tetracyclines not only contribute to the emergence of bacterial resistance, but also disrupt the gut and skin normal microflora, resulting in dysbiosis.7,8 Dysbiosis of the gut has been linked to inflammatory bowel disease. Doxycycline has shown to be associated with 2.25-fold increase in the risk of developing Crohn’s disease.9

Table 1

Name Mechanism of Action Coverage Safety Profile Strength of Recommendation Additional Comments
Sarecycline Bacteriostatic; inhibits 30S ribosomal subunit of bacteria; extends to mRNA and increases inhibitory effect Narrow-spectrum; clinically relevant gram-positive bacteria
  • GI disturbance (<5%)
  • Vestibular effects (<1%)
  • Photosensitivity (<1%)\
  • Vulvovaginal candidiasis (0.3-1.1%)
 A
  • Least likely to cause GI upset
  • Less likely to induce bacteria resistance
Minocycline Bacteriostatic; inhibits 30S ribosomal subunit of bacteria Broad-spectrum; gram-positive, gram-negative, and atypical bacteria
  • GI disturbance (1.5-25%)
  • Vestibular toxicity (~10%)
  • CNS problems (~17%)
  • Vulvovaginal candidiasis
  • Blue/grey skin pigmentation
  • Rare but serious autoimmune disease
 A
  • Most lipophilic among tetracyclines
  • Can cause minocycline-related autoimmune disorders
Doxycycline Bacteriostatic; inhibits 30S ribosomal subunit of bacteria Broad-spectrum; gram-positive, gram-negative, and atypical bacteria
  • GI disturbance (10-25%)
  • Photosensitivity (15-30.5%)
  • Vulvovaginal candidiasis
 A
  • Most likely to cause photosensitivity and GI problems when compared to the rest of the tetracyclines
Tetracycline Bacteriostatic; inhibits 30S ribosomal subunit of bacteria Broad-spectrum; gram-positive, gram-negative, and atypical bacteria
  • GI disturbance
  • Vulvovaginal candidiasis
  • Fixed drug eruptions
  • Dizziness
  • Tooth discoloration
 A
  • Must be taken on an empty stomach
TMP-SMX Bactericidal due to synergy; TMP: folic acid analog that inhibits the enzyme dihydrofolate reductase SMX: blocks bacterial synthesis of folic acid Gram-positive, and gram-negative bacteria, fungi, protozoa
  • Hyperkalemia
  • Renal insufficiency
  • Stevens-Johnson syndrome/ toxic epidermal necrolysis
 B
  • Adverse effects are mostly due to sulfonamides
TMP Bacteriostatic; folic acid analog that inhibits the enzyme dihydrofolate reductase Gram-positive, and gram-negative bacteria, fungi, protozoa
  • Drug eruption
 B
Erythromycin Bacteriostatic; inhibits 50S ribosomal subunit of bacteria Anaerobic and aerobic grampositive cocci
  • GI disturbance
  • QT prolongation
 A
  • High resistance rate
Azithromycin Bacteriostatic; inhibits 50S ribosomal subunit of bacteria Anaerobic and aerobic grampositive cocci
  • GI disturbance
 A
  • Dosed intermittently due to long half-life
Table 1. Oral antibiotics available for moderate-to-severe acne treatment.1,24,25
 
CNS = central nervous system; GI = gastrointestinal; TMP-SMX = trimethoprim-sulfamethoxazole
Strength of recommendation: A = based on consistent and good quality patient-oriented evidence; B = based on inconsistent, limited quality patient-oriented evidence.

In 2018, a new tetracycline derivative, sarecycline, was US FDA-approved for the treatment of inflammatory lesions of non-nodular, moderate-to-severe acne vulgaris in patients aged 9 years and older.10 This once-daily 1.5 mg/kg antibiotic exhibits a better tolerability and efficacy profile as a result of its narrow-spectrum coverage against C. acnes and clinically-relevant gram-positive bacteria with little activity against gram-negative bacteria commonly found in the human gut.10 In vitro studies by Zhanel et al. showed that all tetracyclines had similar activity against C. acnes, even isolates highly resistant against erythromycin ranging at minimum inhibitory concentration (MIC) of 0.5 μg/mL to 32 μg/mL.6 Activity against methicillin-susceptible and resistant isolates of Staphylococcus aureus (including MRSA) revealed a MIC90 of all tetracyclines, including sarecycline, to be 0.5 μg/mL.6 Compared to doxycycline and minocycline, sarecycline had little or no activity against gram-negative enteric bacilli with MIC50 at 32 μg/mL (16-fold less than doxycycline and minocycline).6

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 of the mechanism of action of sarecycline.
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

Conclusion

Sarecycline is a novel antibiotic that has shown significant promise in acne treatment due to its narrow-spectrum activity and weight-based dosing. The advantages of this new systemic therapy include improved tolerability, reduced drug resistance and potentially longer-lasting efficacy. There remain more avenues to explore including sarecycline’s utility in treating other cutaneous infections and inflammatory dermatoses.

References



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]]> Update on Drugs & Devices: May-June 2022 https://www.skintherapyletter.com/drug-updates/may-june-2022/ Sun, 01 May 2022 12:08:07 +0000 https://www.skintherapyletter.com/?p=13403 Nivolumab + Relatlimab-rmbw for IV use

Trade Name: Opdualag™
Company: Bristol-Myers Squibb

Approval Dates/Comments: In March 2022, the US FDA approved this first-in-class, fixed-dose dual immunotherapy combination treatment consisting of the PD-1 inhibitor nivolumab (Opdivo®) and the novel lymphocyte activation gene-3 (LAG-3)-blocking antibody relatlimab for treating patients ≥12 years of age with unresectable or metastatic melanoma. It is administered as a single intravenous infusion. The approval is based on the Phase 2/3 RELATIVITY-047 trial comparing Opdualag™ (n=355) to nivolumab monotherapy (n=359). The trial met its primary endpoint, progression-free survival (PFS). Opdualag™ more than doubled the median PFS compared to nivolumab monotherapy, 10.1 months vs. 4.6 months; 1-year PFS rates were 47.7% and 36.0%, respectively. In RELATIVITY-047, there were no new safety events with Opdualag™ compared with nivolumab alone, however Grade 3 to 4 treatment-related adverse events were more common in the combination group vs. monotherapy group, 18.9% and 9.7%, respectively.

Sirolimus topical gel 0.2%

Trade Name: Hyftor™
Company: Nobelpharma America

Approval Dates/Comments: The FDA approved sirolimus topical gel in March 2022 for the treatment of facial angiofibroma associated with tuberous sclerosis complex (TSC) in adults and pediatric patients ≥6 years of age. In clinical studies, this mTOR inhibitor immunosuppressant was shown to improve the size and redness of facial angiofibromas at 12 weeks. Regulatory approval was based on findings from a Phase 3 randomized, double-blind, vehicle-controlled, multicenter trial (ClinicalTrials.gov Identifier: NCT02635789) that assessed the efficacy and safety of sirolimus gel in 62 patients with facial angiofibroma associated with TSC. Patients were randomly assigned to receive either sirolimus 0.2% topical gel (n=30) or vehicle (n=32) twice daily to the skin of their face affected with angiofibroma for 12 weeks. At weeks 4, 8, and 12 of treatment no response was observed in the placebo group, whereas the response rates of angiofibromas to sirolimus therapy was 20%, 43%, and 60%, respectively. The most common adverse reactions reported with Hyftor™ were dry skin, application site irritation, pruritus, acne, acneiform dermatitis, ocular hyperemia, skin hemorrhage, and skin irritation.

Oral epinephrine

Trade Name: AQST-109
Company: Aquestive Therapeutics

Approval Dates/Comments: In March 2022, the FDA granted Fast Track designation to AQST-109, the first and only orally delivered epinephrine-based product candidate for the emergency treatment of allergic reactions, including anaphylaxis. AQST-109 is a polymer matrix-based epinephrine prodrug administered as a sublingual film applied under the tongue for the rapid delivery. The product is similar in size to a postage stamp, weighs less than an ounce, and begins to dissolve on contact.

Bimekizumab for SC use

Trade Name: Bimzelx®
Company: UCB Canada Inc.

Approval Dates/Comments: Health Canada approved this dual interleukin 17A (IL- 17A) and interleukin 17F (IL-17F) inhibiting humanized monoclonal antibody in February 2022 for the treatment of adults with moderate to severe plaque psoriasis who are candidates for systemic therapy or phototherapy. Bimekizumab is designed to selectively and directly inhibit both IL-17A and IL-17F, two key cytokines driving inflammatory processes. Phase 3 clinical trials demonstrated significant improvement in the measures of disease activity compared to placebo, ustekinumab and adalimumab at Week 16. Significant improvements were also observed in psoriasis involving the scalp, nails, hands and feet in patients treated with bimekizumab at Week 16.

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