Efficacy and safety of topically applied therapeutic ammonia oxidising bacteria in adults with mild-to-moderate atopic dermatitis and moderate-to-severe pruritus: a randomised, double-blind, placebo-controlled, dose-ranging, phase 2b trial

Silverberg, Jonathan I.; Lio, Peter A.; Simpson, Eric L.; Li, Connie; Brownell, Daniel R.; Gryllos, Ioannis; Ng-Cashin, Judith; Krueger, Todd S; Swaidan, Victoria R.; Bliss, Robin; Kim, Hyun D.

doi:10.1016/j.eclinm.2023.102002

Cited by 15 publications

(12 citation statements)

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“…For instance, misaligned effect directionality relative to drug’s mechanism of action found in the pQTL MR for the association between TNFRSF1A and multiple sclerosis may stem from the exposure SNPs containing an epitope altering mutation. Furthermore, our pQTL MR results utilising non-PAV linked variants for two cytokine receptors: interleukin 4 receptor ( IL4R ) and interleukin-2 receptor subunit alpha ( IL2RA ) show opposite directions of effect to those established in the appropriate drug trials targeting asthma[97] and eczema[98,99], respectively.…”

Section: Discussionmentioning

confidence: 93%

Integrative Mendelian Randomization approaches for therapeutic target prioritisation in immune-mediated diseases

Sobczyk,

Gaunt

2024

Preprint

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Background: Immune-mediated diseases (IMD) encompass a wide range of autoimmune and inflammatory disorders with aetiology related to immune system dysfunction, signifying a disease area with great potential for drug repurposing. In this study, we employed the genetically informed Mendelian Randomization (MR) method with two distinct exposure types: immune blood cell abundance and protein quantitative trait loci (pQTL) to validate and repurpose 834 drug targets which have been investigated for IMD treatment. Methods: Utilizing two-sample MR, we first established causal relationships between major peripheral immune cell types and 14 IMD. Robust associations, particularly with eosinophils, were confirmed across diseases such as asthma, eczema, sinusitis, and rheumatoid arthritis, revealing 59 high-confidence relationships. Intragenic variants associated with causal immune cell types were then extracted to create instruments for 371 existing IMD drug targets ("intermediate trait" MR). In parallel, we leveraged four large blood plasma protein QTL datasets to obtain complementary instruments for 361 targets ("pQTL" MR). Results: In the intermediate trait MR analysis, we identified 811 gene-IMD associations (p-value <0.05), 169 of which were supported by strong colocalisation evidence (PPH4 > 0.8). In the pQTL MR analysis, we similarly found 841 protein-IMD associations (p-value <0.05), 83 of which were confirmed with colocalization. Comparison with a list of approved drugs indicated low sensitivities across disease outcomes for both exposure types (intermediate trait MR: 0.49 +/- 0.23 SD, pQTL MR: 0.28 +/- 0.12 SD). Conclusions: Drug targets identified in the pQTL and intermediate trait MR analyses show limited overlap (13%), presenting a comprehensive source of drug repurposing opportunities when the two approaches are combined.

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Section: Discussionmentioning

confidence: 93%

Integrative Mendelian Randomization approaches for therapeutic target prioritisation in immune-mediated diseases

Sobczyk,

Gaunt

2024

Preprint

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“…B244 is a live biotherapeutic currently under investigation for a role in the management of AD (Table 2 ). B244 consists of a purified strain of Nitrosomonas eutropha [ 40 ]. This is an bacteria that oxidizes ammonia to nitrite and nitric oxide, which is thought to promote antimicrobial and anti-inflammatory activity, respectively [ 40 ].…”

Section: Drugs In Early Phase Of Testing (B244 Detomidine Km001 Topic...mentioning

confidence: 99%

“…B244 consists of a purified strain of Nitrosomonas eutropha [ 40 ]. This is an bacteria that oxidizes ammonia to nitrite and nitric oxide, which is thought to promote antimicrobial and anti-inflammatory activity, respectively [ 40 ]. In vitro analysis found B244 to reduce Th2 cytokines associated with AD including IL-4, IL-5, and IL-13 [ 40 ].…”

Section: Drugs In Early Phase Of Testing (B244 Detomidine Km001 Topic...mentioning

confidence: 99%

“…This is an bacteria that oxidizes ammonia to nitrite and nitric oxide, which is thought to promote antimicrobial and anti-inflammatory activity, respectively [ 40 ]. In vitro analysis found B244 to reduce Th2 cytokines associated with AD including IL-4, IL-5, and IL-13 [ 40 ]. A randomized, double-blind, placebo-controlled, dose-ranging, phase 2b trial of B244 enrolled 547 patients 18–65 years old with mild to moderate AD and moderate to severe pruritus [ 40 ].…”

Section: Drugs In Early Phase Of Testing (B244 Detomidine Km001 Topic...mentioning

confidence: 99%

“…In vitro analysis found B244 to reduce Th2 cytokines associated with AD including IL-4, IL-5, and IL-13 [ 40 ]. A randomized, double-blind, placebo-controlled, dose-ranging, phase 2b trial of B244 enrolled 547 patients 18–65 years old with mild to moderate AD and moderate to severe pruritus [ 40 ]. Optical density (OD) at 600 nm was used to divide patients into a low dose group (OD 5.0), a high dose group (OD 20.0), or a vehicle group for a 4-week treatment period and 4-week follow-up period [ 40 ].…”

Section: Drugs In Early Phase Of Testing (B244 Detomidine Km001 Topic...mentioning

confidence: 99%

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Novel Topical Treatments for Itch

Mahmoud,

Biazus Soares

et al. 2024

Dermatol Ther (Heidelb)

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The experience of itch often poses a burden on patient quality of life and has the capacity to inflict significant suffering. Topical therapies are a mainstay of treatment for many cutaneous and systemic diseases and afford patients the opportunity to manage their conditions without many of the systemic side effects of non-topical therapies. We review a multitude of new topical medications targeting the skin, immune system, and neural receptors. The list includes Janus kinase inhibitors, tyrosine kinase inhibitors, phosphodiesterase inhibitors, transient receptor vanilloid inhibitors, topical cannabinoids, and topical acetaminophen. Many of the topical therapies reviewed show promising data in phase 2–3 clinical trials, but further research is needed to compare therapies head-to-head and test their efficacy on a broader range of conditions.

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