Repurposing approved therapeutics for new indication: Addressing unmet needs in psoriasis treatment

Jain, Harsha; Bhat, Aditi; Dalvi, Harshita; Godugu, Chandraiah; Singh, Shashi Bala; Srivastava, Saurabh

doi:10.1016/j.crphar.2021.100041

Cited by 16 publications

(12 citation statements)

References 122 publications

(136 reference statements)

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“…Notably, the α i k parameters are unidentifiable because we are modeling our data using a contrast-based approach. However, the advantage of the decomposition in ( 4) is that it, together with the joint prior distribution in (5), induces a 2…”

Section: The Multivariate Normal Approachmentioning

confidence: 99%

“…These indications are psoriatic diseases arising from malfunctioning immune responses that lead to inflammation and may be successfully treated with several of the same treatments (e.g., Stelera and Cosyntyx). 4,5 The decision to pursue supplemental indications is costly, challenging, and complex. Given the rising costs of clinical trials, sponsors often rely on quantitative methods to support critical business decisions such as whether to continue drug development or redistribute resources to more promising alternatives.…”

Section: Introductionmentioning

confidence: 99%

“…Two indications for which drug repurposing has been successful are psoriasis and psoriatic arthritis. These indications are psoriatic diseases arising from malfunctioning immune responses that lead to inflammation and may be successfully treated with several of the same treatments (e.g., Stelera and Cosyntyx) 4,5 …”

Section: Introductionmentioning

confidence: 99%

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Network meta analysis to predict the efficacy of an approved treatment in a new indication

Proper,

Chu,

Prajapati

et al. 2023

Research Synthesis Methods

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Drug repurposing refers to the process of discovering new therapeutic uses for existing medicines. Compared to traditional drug discovery, drug repurposing is attractive for its speed, cost, and reduced risk of failure. However, existing approaches for drug repurposing involve complex, computationally‐intensive analytical methods that are not widely used in practice. Instead, repurposing decisions are often based on subjective judgments from limited empirical evidence. In this article, we develop a novel Bayesian network meta‐analysis (NMA) framework that can predict the efficacy of an approved treatment in a new indication and thereby identify candidate treatments for repurposing. We obtain predictions using two main steps: first, we use standard NMA modeling to estimate average relative effects from a network comprised of treatments studied in both indications in addition to one treatment studied in only one indication. Then, we model the correlation between relative effects using various strategies that differ in how they model treatments across indications and within the same drug class. We evaluate the predictive performance of each model using a simulation study and find that the model minimizing root mean squared error of the posterior median for the candidate treatment depends on the amount of available data, the level of correlation between indications, and whether treatment effects differ, on average, by drug class. We conclude by discussing an illustrative example in psoriasis and psoriatic arthritis and find that the candidate treatment has a high probability of success in a future trial.

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Section: The Multivariate Normal Approachmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Network meta analysis to predict the efficacy of an approved treatment in a new indication

Proper,

Chu,

Prajapati

et al. 2023

Research Synthesis Methods

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“…To decrease toxicity and enhance efficacy, a few anti-metabolites are currently being repurposed and investigated as potential therapeutic agents for the management of psoriasis [67]. Metformin, an antidiabetic drug, has the potential to exert an antipsoriatic effect via.…”

Section: Therapeutics In Psoriasismentioning

confidence: 99%

Th17/IL-17, Immunometabolism and Psoriatic Disease: A Pathological Trifecta

Chhabra¹,

Sahu²,

Sharma³

et al. 2022

Psoriasis - New Research

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The burgeoning arena of immunometabolism provides evidence of how cellular, as well as local (tissue)/systemic metabolic pathways, are playing an important role in controlling immunity and inflammation. An intricate and elaborate network of various metabolic circuits specifically glycolysis, fatty acid oxidation and synthesis and amino acid metabolism precisely generate metabolites that rewire the immune response. Psoriasis is a chronic progressive self-perpetuated “IL-17-centric” inflammatory disease characterized by the co-existence of autoimmune and autoinflammatory pathways. Metabolic responses, governed by oxygen levels, nutrient availability, growth factors, cytokines, AMP/ATP ratios and amino acids, play a pivotal role in programming Th17 cell fate determination. Understanding the intricate interactions and complex interplay of molecular mechanisms responsible for Th17 cell metabolic rewiring, an important determinant of Th17 cell plasticity and heterogeneity, holds the potential to reshape psoriatic therapeutics in ways currently unimagined. This chapter entails with most recent updates on major cellular and systemic metabolic pathways regulating differentiation of Th17 cells as well their cross-talk with intracellular signaling mediators and also sheds light on how dysregulation of these pathways can be responsible for immune impairment and development of psoriatic disease. A better understanding of these metabolic processes could unveil an intriguing leverage point for therapeutic interventions to modulate metabolic programming and Th17 cell responses in this multi-systemic inflammatory disease.

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“…3,12 Topical treatments can rapidly act and exert localized effects with minimal shortterm adverse events. 12 Nonbiologic oral agents (e.g., methotrexate, apremilast, acitretin, or cyclosporine) offer more options for treating widespread inflammation; however, they are associated with significant toxicities (e.g., hepatotoxicity, nephrotoxicity, hypertension, dyslipidemia, malignancy, and teratogenicity). 3,12 Biologics (e.g., TNF and IL inhibitors) target specific immune response components.…”

Section: Introductionmentioning

confidence: 99%

Brilaroxazine lipogel displays antipsoriatic activity in imiquimod‐induced mouse model

Bhat,

Ramakrishnan

et al. 2024

Skin Research and Technology

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BackgroundDopamine (D) and serotonin (5‐HT) pathways contribute to psoriasis pathobiology. Disruptions incite increased inflammatory mediators, keratinocyte activation and deterioration, and worsening symptoms. Brilaroxazine (RP5063), which displays potent high binding affinity to D2/3/4 and 5‐HT1A/2A/2B/7 receptors and a moderate affinity to serotonin transporter (SERT), may affect the underlying psoriasis pathology.MethodsAn imiquimod‐induced psoriatic mouse model (BALB/c) evaluated brilaroxazine's activity in a topical liposomal‐aqueous gel (Lipogel) formulation. Two of the three groups (n = 6 per) underwent induction with 5% imiquimod, and one group received topical brilaroxazine Lipogel (Days 1–11). Assessments included (1) Psoriasis Area and Severity Index (PASI) scores (Days 1–12), skin histology for Baker score based on H&E stained tissue (Day 12), and serum blood collection for serum cytokine analysis (Day 12). One‐way ANOVA followed by post hoc Dunnett's t‐test evaluated significance (p < 0.05).ResultsImiquimod‐induced animal Baker scores were higher versus Sham non‐induced control's results (p < 0.001). Brilaroxazine Lipogel had significantly (p = 0.003) lower Baker scores versus the induced Psoriasis group. Brilaroxazine PASI scores were lower (p = 0.03) versus the induced Psoriasis group (Days 3‐12), with the greatest effect in the last 3 days. The induced Psoriasis group showed higher Ki‐67 and TGF‐β levels versus non‐induced Sham controls (p = 0.001). The brilaroxazine Lipogel group displayed lower levels of these cytokines versus the induced Psoriasis group, Ki‐67 (p = 0.001) and TGF‐β (p = 0.008), and no difference in TNF‐α levels versus Sham non‐induced controls.ConclusionBrilaroxazine Lipogel displayed significant activity in imiquimod‐induced psoriatic animals, offering a novel therapeutic strategy.

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Repurposing approved therapeutics for new indication: Addressing unmet needs in psoriasis treatment

Cited by 16 publications

References 122 publications

Network meta analysis to predict the efficacy of an approved treatment in a new indication

Network meta analysis to predict the efficacy of an approved treatment in a new indication

Th17/IL-17, Immunometabolism and Psoriatic Disease: A Pathological Trifecta

Brilaroxazine lipogel displays antipsoriatic activity in imiquimod‐induced mouse model

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