STL Volume 28 Number 4 – Skin Therapy Letter https://www.skintherapyletter.com Written by Dermatologists for Dermatologists Fri, 08 Sep 2023 23:49:28 +0000 en-US hourly 1 https://wordpress.org/?v=6.8.1 DaxibotulinumtoxinA-lanm (Daxxify™): A Comprehensive Overview https://www.skintherapyletter.com/cosmetic-dermatology/daxibotulinumtoxina-lanm-daxxify/ Wed, 12 Jul 2023 23:43:14 +0000 https://www.skintherapyletter.com/?p=14587 Nicole Salame, MD1; Ariel E. Eber, MD2; Jeffrey Dover, MD, FRCPC2,3

1Department of Dermatology, Emory University School of Medicine, Atlanta, GA, USA
2SkinCare Physicians, Chestnut Hill, MA, USA
3Department of Dermatology, Yale University School of Medicine, New Haven, CT, USA

Conflict of interest: Nicole Salame and Ariel Eber have no conflicts to disclose.
Jeffrey Dover has served as an investigator in the SAKURA trials and advises for Revance Therapeutics.

Abstract:
Botulinum toxin A (BoNTA) is produced by Clostridium botulinum and widely used for aesthetic indications requiring neuromuscular blockade. For dynamic facial lines, BoNTA is effective and safe, but also temporary, requiring repeat injections approximately every 3-4 months for maintenance of effects. There is a desire by both patients and providers for a longer-lasting neurotoxin to prevent periods of suboptimal correction. Approved by the US Food and Drug Administration (FDA) in September 2022, daxibotulinumtoxinA for injection (DAXI or Daxxify™) is the first long-lasting BoNTA formulated with a 150-kDa BoNTA (RTT150) and proprietary stabilizing excipient peptide (RTP004) in place of human serum albumin. DAXI is approved for treatment of moderate to severe glabellar lines. The median duration of effect was 6 months and results lasted as long as 9 months in some patients. Its unique formulation and prolonged effectiveness positions DAXI as a safe, novel BoNTA for improved durability and patient satisfaction.

Keywords: neuromodulator, neurotoxin, botulinum toxin, daxibotulinumtoxinA, rhytids, glabellar lines, forehead lines, lateral canthal lines, aesthetics, dermatology

Introduction

Botulinum toxin type A (BoNTA) is derived from Clostridium botulinum and has a variety of medical and aesthetic indications. BoNTA has been widely used in the United States (US) and Canada for the treatment of dynamic rhytids since its initial Food and Drug Administration (FDA) approval for glabellar lines in 1989. BoNTA inhibits muscle contraction by blocking neurotransmitter release in the neuromuscular junction, preventing formation of deep facial lines. This blockade is not permanent, necessitating repeat injections every 3-4 months to maintain the aesthetic benefit. Patient surveys have identified a desire for longer-lasting neuromodulators to reduce periods of suboptimal correction.1

DaxibotulinumtoxinA-lanm for intramuscular use (DAXI or Daxxify™) is a novel peptide-formulated BoNTA engineered with a proprietary stabilizing excipient peptide (RTP004) in place of human serum albumin (HSA). On September 8, 2022, the US FDA approved DAXI as the first and only long-acting neuromodulator for the treatment of glabellar lines with a median duration of 6 months and up to 9 months for some patients.2 Its innovative formulation, prolonged durability, and overall performance has caused excitement among early practitioners for DAXI’s potential in the realm of BoNTA treatment.

The Novelty of DAXI

While DAXI shares similarities with other BoNTA formulations approved in the US, it has important characteristic differences [Table 1]. DAXI is the first BoNTA entirely produced and formulated in the US. Its biochemical structure is unique; containing a highly purified 150-kDa core BoNTA (daxibotulinumtoxinA, or RTT150), a proprietary synthetic stabilizing peptide (RTP004), and other excipients including a surfactant (polysorbate-20), buffers, and sugar.1 Importantly, DAXI’s unit definition is based on testing of biologic activity of the proprietary product with an individualized patented reference standard, rendering unit conversion to other BoNTA formulations impossible.

Table 1. Comparison of characteristics of BoNTA used for aesthetic injection in the United States.

Injectable Cosmetic Neuromodulators
Generic name DaxibotulinumtoxinA OnabotulinumtoxinA AbobotulinumtoxinA IncobotulinumtoxinA PrabotulinumtoxinA
Brand name Daxi, Daxxify Botox Dysport Xeomin Jeuveau
Manufacturer Revance Therapeutics Allergan Pharmaceuticals Ipsen Biopharm Merz Pharma Evolus
Packaging (U/vial) 100 100 500 100 100
Constituents and excipients
  • RTP004
  • Polysorbate-20
  • Sugar
  • Buffer
  • Hemaglutinin and nonhemaglutin proteins
  • HSA, 500 μg
  • Saccharose
  • NaCl
  • Hemaglutinin and nonhemaglutin proteins
  • HSA, 125 μg
  • Lactose
  • HSA, 1 mg
  • Saccharose
  • HSA
  • NaCl
Molecular weight, kDa 150 900 500-900 150 900
Preparation Lyophilized Vacuum-drying Lyophilized Lyophilized Vacuum-drying
Storage prior to reconstitution Room temperature 2°C to 8°C 2°C to 8°C Room temperature 2°C to 8°C
Shelf-life once reconstituted 72 hours 36 hours 24 hours 36 hours 24 hours
Median duration 6 months 3-4 months 4 months 3 months 1 month
U, units; HSA, human serum albumin; kDa, kilodalton; NaCL, sodium chloride; RTP004, stabilizing excipient 35 peptide

DAXI’s unique proprietary excipient, RTP004, is a 35-amino highly positively charged peptide in place of HSA. While other neurotoxin products require HSA to prevent BoNTA from aggregating and/or adsorbing to glass surfaces, RTP004 fulfills this role by stabilizing daxibotulinumtoxinA via strong electrostatic bonds. RT004’s core domain consists of 15 lysine residues flanked on each side by a protein transduction domain (PTD). Positively charged amino acids in the PTD region form non-covalent, electrostatic interactions with negatively charged surface of the core BoNTA, preventing aggregation and defeating the need for HSA. The absence of HSA also allows DAXI to remain stable at room temperature for up to 3 years before reconstitution.

In addition to replacing HSA, RTP004 also contributes to DAXI’s efficacy and durability. RTP004’s strong electrostatic interaction and stabilization of core neurotoxin permits DAXI’s effect with a similar or lesser amount of product compared to other BoNTA preparations. RTP004’s positive charge also allows DAXI to bind to negative neurons and extracellular matrix proteins, facilitating localization of product and reduced diffusion from injection sites. Lastly, RTP004’s positive charge facilitates DAXI’s high-affinity binding to negatively-charge presynaptic nerve terminals, allowing for increased neurotoxin uptake into the neuron and prolonged efficacy.

DAXI in Clinical Trials

Glabellar Lines

Studies from the DAXI Glabellar Lines Clinical Program recruited 2994 subjects who underwent a total of 4444 DAXI treatments. The program included a phase 1/2 dose-escalation study,3 the Belmont phase 2 dose-ranging study (NCT02303002) comparing DAXI (20U, 40U, 60U) to onabotulinumtoxinA (20U) or placebo,4,5 two phase 3 pivotal trials (SAKURA 1, NCT03014622 and SAKURA 2, NCT03014635)6,7 and one large, phase 3 open-label safety (OLS) study (SAKURA 3, NCT03004248) evaluating the safety and efficacy of DAXI 40U.2,8

Results supported DAXI’s safety, improved efficacy, and prolonged sustained duration of up to 24 weeks before returning to none or mild glabellar line (GL) severity and 28 weeks before returning to baseline. Results were consistent between studies and upon repeat-dosing in the OLS. A subgroup analysis comparing those who had prior BoNTA treatments (treatment-experiences) to those who had not (treatment-naïve) found similar response, duration, and tolerance to DAXI.9 Data also revealed greater efficacy with DAXI 40U as compared to onabotulinumtoxinA 20U, despite similar mass of core neurotoxin (each 0.18 ng),2 suggesting that the aforementioned effects of RTP004 peptide and absence of HAS permitted increased efficacy for a similar given amount of core neurotoxin.

Forehead Lines, Eyebrow Positioning and Lateral Canthal Lines

Promising results from the Glabellar Lines Clinical Program prompted studies evaluating DAXI for treatment of forehead lines (FHL) and eyebrow position. An open-label, dose-escalating phase 2 trial evaluated treatment of FHL after GL treatment found that 86%, 87%, 94%, and 100% of patients had none or mild FHL severity by investigator assessment with 12U, 18U, 24U, and 30U doses, respectively.10 Mean time to loss of none or mild line severity by both investigator and patient assessments was 20 weeks for 18U, 24U, and 30U dose.10

A post-hoc analysis of the phase 2 FHL dose-escalating study and the SAKURA 3 OLS study found that adults receiving DAXI 40U for GL also experienced reductions in FHL and either positive or no impact on eyebrow position.11 A separate post-hoc analysis of the phase 2 FHL dose-escalation study found that precise injection of DAXI 40U to the corrugator supercilii and procerus muscles with avoidance of the frontalis can achieve aesthetically pleasing eyebrow position with prolonged duration.12

Because the upper facial lines are often treated together in real-world practice to improve outcomes and patient satisfaction, a separate phase 2 study was conducted to evaluate the simultaneous treatment of GL, FHL, and lateral canthal lines (LCL) with DAXI.13 DAXI was found to be safe and effective for simultaneous treatment of upper facial lines with no differences in response rates for GL, FHL, or LCL.13 Mean time to loss of none or mild upper facial line severity was 25 weeks for GL, 24 weeks for FHL, and about 28 weeks for LCL.13 Optimal DAXI doses of 18U and 24U allowed for effective duration while ensuring some movement remains in the upper facial lines;13 at 30U, patients can achieve no forehead line movement. To achieve a patient’s desired aesthetic outcome, DAXI dose may be selected along a range of 18U-30U based on patient preferences for sustained movement.13

Adverse Events

Adverse events from daxibotulinumtoxinA studies were mild and included erythema, facial discomfort, and headache. In studies involving FHL,13 no cases of eyelid or eyebrow ptosis were observed. Similarly, in dose escalation studies, no patients experienced eyelid ptosis with DAXI 40U for GL,4 30U for FHL,10 or 48U for LCL.14 In the large, phase 3 OLS study of repeated DAXI 40U dosing for GL, eyelid ptosis was seen in only 0.9% of treatments.8

Immunogenicity

Although DAXI lacks HSA, the presence of RTP004 excipient has potential implications on immunogenicity. Data from SAKURA 1, 2 and 3 found presence of anti-daxibotulinumtoxinA binding antibodies in 0.8% of subjects without evidence of neutralizing antibodies.15 Anti-RTP004 antibodies were found in 1.3% of subjects with low titer (<1:200) transient neutralizing antibodies.15 No patients had antibodies to both daxibotulinumtoxinA and RTP004.15 Presence of either antibody did not impact DAXI efficacy, and no patients reported immune-related adverse effects.15

Conclusion & Future Considerations

DAXI’s unique biochemical formulation with novel excipient peptide RTP004 in place of HSA, improved efficacy, safety, and prolonged duration utilizing a similar or potentially lower amount of core neurotoxin, supports DAXI’s role as a novel, pioneering BoNTA for treatment of dynamic facial lines. Future studies may focus on expanding DAXI for other cosmetic indications, including lower facial lines, neck lines, and in combination with other BoNTA and its use for functional disorders.

Acknowledegment

The authors gratefully acknowledge Revance Therapeutics for providing data in preparing this manuscript.

References



  1. Solish N, Carruthers J, Kaufman J, et al. Overview of daxibotulinumtoxinA for injection: a novel formulation of botulinum toxin type A. Drugs. 2021 Dec;81(18):2091-101.

  2. Fabi SG, Cohen JL, Green LJ, et al. DaxibotulinumtoxinA for injection for the treatment of glabellar lines: efficacy results from SAKURA 3, a large, openlabel, phase 3 safety study. Dermatol Surg. 2021 Jan;47(1):48-54.

  3. Garcia-Murray E, Velasco Villasenor ML, et al. Safety and efficacy of RT002, an inject- able botulinum toxin type A, for treating glabellar lines: results of a phase 1/2, open-label, sequential dose-escalation study. Dermatol Surg. 2015 Jan;41(Suppl 1):S47-55.

  4. Carruthers J, Solish N, Shannon H, et al. Injectable daxibotulinumtoxinA for the treatment of glabellar lines: a phase 2, randomized, dose-ranging, double-blind, multicenter comparison with onabotulinumtoxinA and placebo. Dermatol Surg. 2017 Nov;43(11):1321-31.

  5. Bertucci V, Humphrey S, Carruthers J, et al. Comparing injectable daxibotulinumtoxinA and onabotulinumtoxinA in moderate and severe glabellar lines: additional analyses from a phase 2, randomized, dose-ranging, double-blind, multicenter study. Dermatol Surg. 2017 Dec;43:S262–73.

  6. Bertucci V, Solish N, Kaufman-Janette J, et al. DaxibotulinumtoxinA for injection has a prolonged duration of response in the treatment of glabellar lines: pooled data from two multicenter, randomized double-blind, placebocontrolled, phase 3 studies (SAKURA 1 and SAKURA 2). J Am Acad Dermatol. 2020 Apr;82(4):838-45.

  7. Carruthers JD, Fagien S, Joseph JH, et al; SAKURA 1 and SAKURA 2 Investigator Group. DaxibotulinumtoxinA for injection for the treatment of glabellar lines: results from each of two multicenter, randomized, doubleblind, placebo-controlled, phase 3 studies (SAKURA 1 and SAKURA 2). Plast Reconstr Surg. 2020 Jan;145(1):45-58.

  8. Green JB, Mariwalla K, Coleman K, et al. A large, open-label, phase 3 safety study of daxibotulinumtoxinA for injection in glabellar lines: a focus on safety from the SAKURA 3 study. Dermatol Surg. 2021 Jan;47(1):42-6.

  9. Cohen JL, Green LJ, Beer KR, et al. Prior botulinum toxin treatment does not impact efficacy or safety in clinical trials: analysis of daxibotulinumtoxinA for injection in the SAKURA program. Dermatol Surg. 2021 Apr 1; 47(4):511-5.

  10. Solish N, Green JB, Fagien S, et al. A phase 2a dose-escalation study to evaluate the efficacy and safety of daxibotulinumtoxinA for injection for the treatment of dynamic forehead lines following glabellar line injections: an interim analysis. Poster presented at the 16th annual Maui Derm for Dermatologists 2020; January 25-29, 2020; Maui, HI.

  11. Solish N, Kane MAC, Biesman BS, et al. Impact of daxibotulinumtoxinA for injection on brow position and frontalis muscle activity following treatment of glabellar lines. Aesthet Surg J. 2022 Sep 12:sjab362. doi: 10.1093/asj/sjab362. Epub ahead of print. PMID: 36095026.

  12. Bertucci V, Green JB, Fezza JP, et al. Impact of glabellar injection technique with daxibotulinumtoxinA for injection on brow position. Aesthet Surg J. 2022 Nov 2:sjac002. doi: 10.1093/asj/sjac002. Epub ahead of print. Erratum in: Aesthet Surg J. 2022 Dec 30; PMID: 36322141.

  13. Dover JS, Humphrey SD, Lorenc ZP, et al. Treatment of upper facial lines with daxibotulinumtoxinA for injection: results from an open-label phase 2 study. Dermatol Surg. 2023 Jan 1;49(1):60-5.

  14. Keany T, Bhatia A, Fezza J, et al. DaxibotulinumtoxinA for injection for lateral canthal lines: 4-week interim analysis of a phase 2a study. Presented at American Society for Dermatologic Surgery (ASDS) 2020 virtual annual meeting; October 8-11, 2020.

  15. Gallagher CJ, Bowsher RR, Clancy A, et al. Clinical immunogenicity of daxibotulinumtoxina for injection in glabellar lines: pooled data from the SAKURA phase 3 trials. Toxins (Basel) 2023 Jan 10;15(1):60.


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]]> Prevention of Shingles in Dermatology Patients on Systemic Medications https://www.skintherapyletter.com/dermatology/shingles-prevention/ Wed, 12 Jul 2023 20:45:21 +0000 https://www.skintherapyletter.com/?p=14592 Lyn Guenther, MD, FRCPC, FAAD

Division of Dermatology, Department of Medicine, Western University, London, ON, Canada
Guenther Research Inc., London, ON, Canada

Conflict of interest: Dr. Guenther has been a speaker for AbbVie, Actelion, Amgen, Altana, Aralez, Bausch, Cipher, Eli Lilly, Galderma, GSK, Janssen, Johnson and Johnson, La Roche Posay, Leo Pharma, Merck, Novartis, Pfizer, Sanofi Aventis and UCB. She has been a consultant for AbbVie, Actelion, Amgen, Aslan, Altana, Aralez, Bausch, BMS, Celgene, Eli Lilly, Galderma, Incyte, Johnson and Johnson, La Roche Posay, Leo Pharma, Merck, Pfizer, Regeneron, and UCB. She has been a principal investigator for AbbVie, Actelion, Amgen, Bausch, BMS, Boehringer Ingelheim, Celgene, Cipher, Eli Lilly, Galderma, Isotechnika, Innovaderm, Janssen, La Roche Posay, Leo Pharma, Merck, Novartis, Pfizer and UCB. She has been a member of the PSOLAR Janssen registry since its inception.

Abstract:
The lifetime risk for herpes zoster (HZ) of approximately 1 in 3 is increased with advancing age, a family history of HZ, diseases with altered immune function, immunosuppression, physical trauma and psychological stress. In dermatology, monotherapy with current biologics does not increase risk, however systemic steroids, Janus kinase inhibitors and combination biologic/conventional disease-modifying antirheumatics do. The recombinant zoster vaccine (RZV, Shingrix®), an adjuvanted non-live subunit vaccine against the glycoprotein E subunit of varicella zoster virus, is approved for prevention of HZ in adults ≥50 years of age, and adults ≥18 years of age who are or will be at increased risk of HZ due to immunodeficiency or immunosuppression due to disease or treatment. It is administered as two 0.5 ml intramuscular injections 2-6 months apart. In immunocompromised individuals, the spacing between injections may be reduced to 1-2 months. Where possible, the first dose should be administered at least 14 days before onset of immunosuppressive treatment. Studies in immunocompetent individuals have shown high efficacy including prevention of HZ, postherpetic neuralgia and other complications, with persistence of effect 10 years after vaccination. The acceptable safety profile and efficacy in five different immunocompromised populations support its use in at-risk adult dermatologic patients.

Keywords: Shingrix, recombinant zoster vaccine, vaccination, herpes zoster, immunocompromised, atopic dermatitis, psoriasis, systemic, biologic, JAK inhibitors

Introduction

New oral and biologic treatments are being developed to treat common conditions such as atopic dermatitis and psoriasis. Some of these treatments may increase HZ, the recurrent infection caused by reactivation of the varicella-zoster virus (VZV). The lifetime risk is approximately 1 in 31 and increases with advancing age,2 immunosuppression,2 a family history of HZ,3 systemic lupus erythematosus4,5 rheumatoid arthritis,4,5 inflammatory bowel disease,4,5 chronic renal disease,5 cancer,5 multiple sclerosis,4 psoriasis,4 asthma,5 chronic obstructive pulmonary disorder (COPD),5 diabetes mellitus,5 depression,5 physical trauma5 and psychological stress (Table 1).5,6

Table 1. Factors which increase the risk of developing HZ.

  • Advancing age2
  • Family history of zoster3
  • Diseases with altered immune function (e.g., systemic lupus erythematosus,4,5 rheumatoid arthritis,4,5 inflammatory bowel disease,4,5 chronic renal disease,5 cancer,5 multiple sclerosis,4 psoriasis,4 asthma,5 chronic obstructive pulmonary disorder [COPD],5 diabetes mellitus,5 depression5)
  • Physical trauma5
  • Psychological stress5
  • Systemic steroids17,18
  • JAK inhibitors24,26,27,29,31
  • Combination biologic/conventional disease-modifying antirheumatics17

Typical clinical features include a prodrome with pruritus, tingling and/or pain followed by painful erythematous macules, papules and vesicles on an erythematous base over a single dermatome.2 The eruption crusts over and usually heals within 4 weeks,2 however, complications such as postherpetic neuralgia (PHN) may persist for >1 year particularly in those over age 70 years.7 Recurrent HZ occurs in up to 6.41% of individuals.8 In immunocompromised patients, the eruption can be multi-dermatomal,9 bilateral,10 disseminated11 or necrotic,12 and there is a higher rate of HZ related complications.13

In 2006 in the US and 2011 in Canada, the first HZ vaccine, a single dose, subcutaneous, live attenuated vaccine, Zostavax™ was approved. This vaccine was discontinued in 2020 in the US and 2022 in Canada. Shingrix®, an adjuvanted non-live subunit vaccine against the glycoprotein E subunit of VZV (recombinant zoster vaccine, RZV), received approval in 2017 for immunocompetent individuals 50 years of age and older, and in 2021 for individuals 18 years of age or older who are or will be at increased risk of HZ due to immunodeficiency or immunosuppression due to disease or treatment.14 It has to be first reconstituted before administration and used within 6 hours after reconstitution. It is administered as two 0.5 ml intramuscular injections 2-6 months apart.14 In immunocompromised individuals the spacing between injections may be reduced to 1-2 months.14 Health Canada recommends that the first dose be administered at least 14 days before onset of immunosuppressive treatment.15 If this is not possible, it should be administered during periods with less immunosuppression when the immune response is expected to be stronger.13 For patients treated with rituximab, it is recommended that RZV be administered at least 5 months after the last dose and at least 4 weeks before the next dose of rituximab.16,17

Background

Some immunomodulatory medications can increase the risk of HZ and zoster-related complications. A systematic review of 35 rheumatoid arthritis studies,16 and study of psoriasis patients in the Israeli Clalit Health Services database18 showed that methotrexate was not associated with an increase in HZ. Tumor necrosis factor (TNF) antagonists do not appear to increase HZ in patients with psoriasis.18-20 A network meta-analysis showed no effect of monotherapy with anti-TNFs, ustekinumab or rituximab.21 Another systematic review in psoriasis and psoriatic arthritis (PsA) also showed no effect with biologic monotherapy, but an increased risk was associated with systemic steroids, tofacitinib and combination biologic/conventional disease-modifying antirheumatics.17 Interleukin (IL)-17 and IL-23 inhibitors do not appear to increase the risk of HZ.22,23

Janus kinase (JAK) inhibitors may increase HZ risk. In the tofacitinib psoriasis trials, HZ events per 100 patient years (PY) were 2.55 vs. 0 for placebo.24 Asian descent (HR 2.92), 10 mg vs. 5 mg twice daily dosing (HR 1.72), prior use of biologics (HR 1.72) and older age (HR 1.30) were risk factors.24 Tofacitinib has approval for PsA, rheumatoid arthritis (RA), and ulcerative colitis (UC), but not psoriasis, or alopecia areata (AA) for which there are case reports of successful hair regrowth.25 Baricitinib is a JAK inhibitor which has approval for AA as well RA, and in some countries, atopic dermatitis (AD). In AA and AD trials, the HZ events per 100 PY (1.4 and 2.3 respectively) were lower than the RA rate (3.0/100 PY).26 Psoriasis studies with 6 mg deucravacitinib, a once daily Tyk2 inhibitor, showed a rate of 0.9/100 PY during the first year and 0.7/100 PY during year 2.27 However, in a phase II PsA trial involving 203 patients randomized 1:1:1 to placebo, deucravacitinib 6 mg or 12 mg once a day, there were no cases of HZ after 16 weeks of treatment.28

During the first 16 weeks of treatment in upadacitinib AD studies, HZ rates were 0.6% for placebo, 1.6% for 15 mg and 1.5% for 30 mg.29 In adolescents, the 30 mg rate was comparable to the adult rate.29 Upadacitinib was initially approved for RA. In a pooled safety analysis of 5306 RA patients, HZ rates were also higher with the 30 mg dose than the 15 mg dose (5.3 vs. 3.0/100 PY)30 and higher than the comparators methotrexate (0.8/100 PY) and adalimumab + methotrexate (1.1/100 PY). Asian patients were at higher risk.30 In abrocitinib AD studies, the rates of HZ in patients aged 18-65 years was 3.44/100 PY and for those ≥age 65 years, 7.40/100 PY. Nine patients on 200 mg and one on 100 mg developed mild/moderate multidermatomal zoster.31

Supporting RZV Efficacy Evidence from Clinical Trials

Two randomized, placebo-controlled studies in >30,000 immunocompetent individuals (ZOE-50 for those 50 years of age and older32 and ZOE-70 for those 70 years and older33) had initial 3.1 and 3.9 year respective follow-ups.14 Assessment of efficacy was restricted to individuals who received the two vaccine doses and did not have a confirmed episode of HZ before 1 month after the second dose. In ZOE-50, vaccine efficacy in individuals ≥50 years was 97.2% (p<0.001). In individuals 70 years and older, vaccine efficacy was 91.3% and prevention of PHN 88.8%.14 There was only 1 case of other zoster complications in the ZOE-50/70 RZV group vs. 16 in the placebo group. At 5 years, participants were offered participation in a long-term follow-up study; 7277 subjects were included in efficacy assessments.34 An interim analysis of vaccine efficacy over the period from 1 month post-initial vaccination to a mean of 9.6 +/-0.3 years follow-up, showed 89% (95% CI 85.6%- 91.3%) efficacy in preventing HZ.35 Immune responses remained >5 fold higher than pre-vaccination levels.35

RZV has been studied in 1587 patients with 5 different immunocompromising (IC) situations – autologous hematopoietic stem cell transplant (auHSCT), hematologic malignancies (HM) vaccinated during or following cancer therapy course, solid tumors (ST) undergoing chemotherapy, renal transplant patients on chronic immunosuppressive therapy at the time of vaccination, and patients with human immunodeficiency virus.14 In all of these populations, RZV induced humoral and cell-mediated immune responses persisting for at least 1 year of follow-up.36 In auHSCT, vaccine efficacy was 68.2% overall with a median follow-up of 21 months.37 PHN (1 vs. 9 cases, p=0.02), other zoster-related complications (3 vs. 13 cases, p=0.02) and hospitalizations (2 vs. 13 cases, p=0.01) were also significantly reduced in vaccine vs. placebo groups, respectively.37 In the hematologic malignancies study, zoster incidence was reduced from 6.62 (placebo group) to 0.85 per 100 PY (p=0·0021) giving an 87.2% efficacy rate in a post hoc analysis.38

Safety

In immunocompetent studies, local (pain and swelling at the injection site) and general adverse events (fatigue, myalgia, headache, shivering, fever, nausea, vomiting diarrhea, and/or abdominal pain) were more common in the 50-69 year age group vs. the ≥70 year group, and generally mild to moderate with a median duration of 3 days.14 New onset or exacerbation of existing potential immune-mediated diseases (pIMDs) were noted in 1.2% who received RZV vs. 1.4% treated with placebo (median 4.4 year follow-up).14 In each group, psoriasis and autoimmune thyroiditis were each reported in 0.1%, and polymyalgia rheumatica in 0.2%. RA was reported in 0.1% treated with RZV vs. 0.2% with placebo.14 In a ≥ 65 year old post-marketing observational study, an estimated 3 excess cases per million doses administered of Guillain-Barre syndrome was noted during the 42 day follow-up period after vaccination.14 Safety in IC individuals was similar to that in immunocompetent older individuals.38

Conclusion

RZV is highly efficacious (>90%) in immunocompetent individuals with a modest decline in clinical efficacy as well as humoral and cellular immunity over 10 years. It prevents PHN and other zoster complications. The acceptable safety profile and efficacy in a broad population of IC adults including demonstration of immune responses in 5/5 different IC populations and efficacy in two different IC populations, including auHSCT at a time of greatest risk, support its use in our IC adult dermatologic patients. Dermatologists should be proactive in recommending RZV to all patients over age 50 years, particularly those with a family history of zoster and diseases with altered immune function. Adult patients who are immunocompromised because of their diseases or treatment (e.g., systemic steroids, JAK inhibitors, combination biologic/conventional disease-modifying antirheumatics), should also be encouraged.

References



  1. Harbecke R, Cohen JI, Oxman MN. Herpes zoster vaccines. J Infect Dis. 2021 Sep 30;224(12 Suppl 2):S429-42.

  2. Guenther LC, Lynde CW. A refresher on herpes zoster, current status on vaccination, and the role of the dermatologist. J Cutan Med Surg. 2011 Jul-Aug; 15(4):185-91.

  3. Tanuseputro P, Zagorski B, Chan KJ, et al. Population-based incidence of herpes zoster after introduction of a publicly funded varicella vaccination program. Vaccine. 2011 Nov 3;29(47):8580-4.

  4. Chen SY, Suaya JA, Li Q, et al. Incidence of herpes zoster in patients with altered immune function. Infection. 2014 Apr;42(2):325-34.

  5. Marra F, Parhar K, Huang B, et al. Risk factors for herpes zoster infection: a meta-analysis. Open Forum Infect Dis. 2020 Jan 9;7(1):ofaa005.

  6. Lasserre A, Blaizeau F, Gorwood P, et al. Herpes zoster: family history and psychological stress-case-control study. J Clin Virol. 2012 Oct;55(2):153-7.

  7. De Moragas JM, Kierland RR. The outcome of patients with herpes zoster. AMA Arch Derm. 1957 Feb;75(2):193-6.

  8. Shiraki K, Toyama N, Daikoku T, et al; Miyazaki Dermatologist Society. Herpes zoster and recurrent herpes zoster. Open Forum Infect Dis. 2017 Jan 28;4(1):ofx007.

  9. Beuerlein KG, Strowd LC. Multidermatomal herpes zoster: a pain in the neck? Dermatol Online J. 2019 Nov 15;25(11):13030/qt9kz407dx.

  10. Kantaria SM. Bilateral asymmetrical herpes zoster. Indian Dermatol Online J. 2015 May-Jun;6(3):236.

  11. Yoon KJ, Kim SH, Lee EH, et al. Disseminated herpes zoster in an immunocompetent elderly patient. Korean J Pain. 2013 Apr;26(2):195-8.

  12. Wollina U. Variations in herpes zoster manifestation. Indian J Med Res. 2017 Mar;145(3):294-8.

  13. Anderson TC, Masters NB, Guo A, et al. Use of recombinant zoster vaccine in immunocompromised adults aged ≥19 years: recommendations of the Advisory Committee on Immunization Practices – United States, 2022. MMWR Morb Mortal Wkly Rep. 2022 Jan 21;71(3):80-4.

  14. SHINGRIX (Herpes Zoster vaccine non-live recombinant, AS01B adjuvanted) [ product monograph ]. Date of revision: November 15, 2022. GlaxoSmithKline Inc., Mississauga, ON. Available from: https://ca.gsk.com/media/6259/ shingrix-pm-en.pdf

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]]> Update on Drugs & Devices: July – August 2023 https://www.skintherapyletter.com/drug-updates/july-august-2023/ Wed, 12 Jul 2023 14:13:28 +0000 https://www.skintherapyletter.com/?p=14585 Roflumilast cream 0.3%

Trade Name: Zoryve™
Company: Arcutis Biotherapeutics

Approval Dates/Comments: Health Canada approved the first topical phosphodiesterase-4 inhibitor in April 2023 as a once-daily, non-steroidal therapy for mild, moderate and severe plaque psoriasis, including treatment of psoriasis in the intertriginous areas, in patients ≥12 years of age. In two clinical trials, DERMIS-1 and DERMIS-2, roflumilast cream achieved investigator-assessed treatment success in over 40% of patients at week 8 compared with vehicle. This drug gained US FDA approval in July 2022.

Adalimumab-aaty SC use

Trade Name: Yuflyma®
Company: Celltrion

Approval Dates/Comments: In May 2023, the FDA approved adalimumab-aaty, a high-concentration (100 mg/mL) and citrate-free biosimilar to adalimumab (Humira®) to treat 8 conditions, including psoriatic arthritis, plaque psoriasis and hidradenitis suppurativa.

Beremagene geperpavec-svdt topical gene therapy

Trade Name: Vyjuvek™
Company: Krystal Biotech

Approval Dates/Comments: In May 2023, the first and only topical gene therapy was approved by the FDA to treat dystrophic epidermolysis bullosa in patients ≥6 months of age. Vyjuvek™ is a herpes-simplex virus type 1 vector-based gene therapy that addresses the underlying genetic cause of the disease by delivering functional copies of the human COL7A1 gene to provide wound healing and sustained functional COL7 protein expression with redosing.

Molecular imaging device

Trade Name: Orlucent® Skin Fluorescence Imaging System
Company: Orlucent, Inc.

Approval Dates/Comments: The FDA granted Breakthrough Device designation to the Orlucent® system in May 2023. This handheld point-of-care molecular-based imaging system is designed to non-invasively identify and clinically assess the presence of biological tissue remodeling activity associated with the development of atypical moles in adults. In conjunction with visual skin examination, this device aids physicians to determine clinical decisions and identify the earliest stages of melanoma.

Tirbanibulin ointment 1% w/w

Trade Name: Onakta™
Company: Avir Pharma

Approval Dates/Comments: In May 2023, Health Canada approved a new topical microtubule inhibitor indicated for the field treatment of nonhyperkeratotic, non-hypertrophic actinic keratosis (Olsen grade 1) on the face or scalp in adults. Tirbanibulin ointment should be applied to the affected area on the face or scalp (up to 25 cm2) once-daily for 1 treatment cycle of 5 consecutive days using 1 single-dose sachet per application. FDA approval was gained in December 2020 (trade name: Klisyri®).

Pegunigalsidase alfa-iwxj for IV use

Trade Name: Elfabrio®
Company: Chiesi Global Rare Diseases

Approval Dates/Comments: The FDA approved pegunigalsidase alfa-iwxj, a PEGylated enzyme replacement therapy, in May 2023 for the treatment of adult patients with Fabry disease. As Fabry disease is caused by deficiency of the lysosomal enzyme α–Galactosidase–A, this treatment provides an exogenous source.

Autologous cell harvesting device

Trade Name: Recell® System
Company: Avita Medical

Approval Dates/Comments: In June 2023, the FDA granted premarket approval to the Recell® System for the treatment of vitiligo. This is a one-time treatment at the point-of-care, whereby a clinician prepares and delivers autologous skin cells from pigmented skin to stable depigmented areas.

Odevixibat capsules/pellets

Trade Name: Bylvay® 
Company: Ipsen

Approval Dates/Comments: The FDA expanded the approved uses of oral odevixibat in June 2023 to include treatment of cholestatic pruritus in patients ≥12 months of age with Alagille syndrome. Odevixibat is a once-daily, non-systemic ileal bile acid transport inhibitor that acts locally in the small intestine and has minimal systemic exposure.

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