Background/Purpose:

Since new therapies for lupus have been extremely slow to develop and lupus patients have a great unmet medical need, an independent pharma-external effort has been undertaken to evaluate drugs for potential use in this autoimmune disease. In addition, bioinformatic analyses of gene expression profiles were used to confirm the potential utility of identified drug candidates.

Methods:

A comprehensive effort to, identify possible drug candidates for repositioning into lupus was initiated in 2013 by crowd-sourcing suggestions from the lupus community (www.linkedin.com/lrxlstat) in conjunction with a comprehensive effort at literature mining for information relevant to the more than 1000 compounds approved for human use by the FDA. In 2013, the evidence-based Composite Lupus Treatment Scoring (CoLTs) of each of 157 therapies considered potentially appropriate for lupus was carried out¹. Since the initial evaluation, the FDA has approved > 125 new drug indications, 7 of which targeted a rheumatic disease, but none of which was approved for in lupus. Additionally, >50 drugs-in-development for other indications were identified as possible lupus treatments. All drugs were ranked by the CoLT scoring system that takes into account scientific rationale, experience in lupus mice/human cells, previous clinical experience in autoimmunity, drug properties and adverse event profile. In addition, potential utility of a drug target in SLE was gauged by bioinformatic analysis of gene expression from tissues (kidneys, skin, synovium) and the periphery (whole blood, B cells, T cells, myeloid cells) from both active and inactive patients . Microarray and RNASeq data were analyzed for differentially expressed genes compared with healthy patients and for correlations with clinical parameters.

Results:

Of the >125 newly FDA–approved drug indications, fifty were judged to be potentially relevant for lupus and were evaluated in detail and nine were identified as high-priority candidates for repositioning including drugs targeting cellular metabolism, cell cycle checkpoints, kinases and various pathways in the immune system. Scoring of drugs-in-development added 25 high priority candidates including inhibitors of complement, HDAC, PARP, ubiquitin ligases and as well as antagonists of cell surface receptors and cytokines. In each circumstance, evidence from literature mining was confirmed by gene expression analysis.

Conclusion:

Independently scoring the properties of newly approved drugs and potential drug targets has not only identified unique candidates that could be useful in lupus and possibly other autoimmune/inflammatory conditions, but has also yielded a rigorous evidence-based process by which therapies can be objectively rated for possible clinical application to treat these conditions, thereby mitigating risk in drug development.

References:

1. Lupus 10:1150, 2016.

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ACR Meeting Abstracts - https://acrabstracts.org/abstract/a-systematic-literature-mining-and-gene-expression-analysis-identifies-possible-drug-candidates-for-repositioning-in-lupus/