Repurposed and investigational disease-modifying drugs in osteoarthritis (DMOADs).
Ontology highlight
ABSTRACT:
SUBMITTER: Oo WM
PROVIDER: S-EPMC9128067 | biostudies-literature | 2022
REPOSITORIES: biostudies-literature
Publications
Repurposed and investigational disease-modifying drugs in osteoarthritis (DMOADs).
Oo Win Min WM Hunter David J DJ Hunter David J DJ
Therapeutic advances in musculoskeletal disease 20220520
In spite of a major public health burden with increasing prevalence, current osteoarthritis (OA) management is largely palliative with an unmet need for effective treatment. Both industry and academic researchers have invested a vast amount of time and financial expense to discover the first diseasing-modifying osteoarthritis drugs (DMOADs), with no regulatory success so far. In this narrative review, we discuss repurposed drugs as well as investigational agents which have progressed into phase ...[more]
Similar Datasets
Project description:Osteoarthritis (OA) is a prevalent and severely debilitating disease with an unmet medical need. In order to alleviate OA symptoms or prevent structural progression of OA, new drugs, particularly disease-modifying osteoarthritis drugs (DMOADs), are required. Several drugs have been reported to attenuate cartilage loss or reduce subchondral bone lesions in OA and thus potentially be DMOADs. Most biologics (including interleukin-1 (IL-1) and tumor necrosis factor (TNF) inhibitors), sprifermin, and bisphosphonates failed to yield satisfactory results when treating OA. OA clinical heterogeneity is one of the primary reasons for the failure of these clinical trials, which can require different therapeutic approaches based on different phenotypes. This review describes the latest insights into the development of DMOADs. We summarize in this review the efficacy and safety profiles of various DMOADs targeting cartilage, synovitis, and subchondral bone endotypes in phase 2 and 3 clinical trials. To conclude, we summarize the reasons for clinical trial failures in OA and suggest possible solutions.
| S-EPMC10184265 | biostudies-literature
Project description:Contemporary treatments for osteoarthritis (OA) pursue only to alleviate the pain caused by the illness. Discovering disease-modifying osteoarthritis drugs (DMOADs) that can induce the repair and regeneration of articular tissues would be of substantial usefulness. The purpose of this manuscript is to review the contemporary role of DMOADs in managing OA. A narrative literature review on the subject, exploring the Cochrane Library and PubMed (MEDLINE) was performed. It was encountered that many publications have analyzed the impact of several DMOAD methods, including anti-cytokine therapy (tanezumab, AMG 108, adalimumab, etanercept, anakinra), enzyme inhibitors (M6495, doxycycline, cindunistat, PG-116800), growth factors (bone morphogenetic protein-7, sprifermin), gene therapy (micro ribonucleic acids, antisense oligonucleotides), peptides (calcitonin) and others (SM04690, senolitic, transient receptor potential vanilloid 4, neural EGFL-like 1, TPCA-1, tofacitinib, lorecivivint and quercitrin). Tanezumab has been demonstrated to alleviate hip and knee pain in individuals with OA but can cause major adverse events (osteonecrosis of the knee, rapid illness progression, augmented prevalence of total joint arthroplasty of involved joints, particularly when tanezumab is combined with nonsteroidal anti-inflammatory drugs. SM04690 (a Wnt inhibitor) has been demonstrated to be safe and efficacious in alleviating pain and ameliorating function as measured by the Western Ontario and McMaster Universities Arthritis Index. The intraarticular injection of lorecivivint is deemed safe and well tolerated, with no important reported systemic complications. In conclusion, even though DMOADs seem promising, their clinical effectiveness has not yet been demonstrated for managing OA. Until forthcoming studies can proved the medications' capacity to repair and regenerate tissues affected by OA, physicians should keep using treatments that only intend to alleviate pain.
| S-EPMC9903308 | biostudies-literature
Project description:Osteoarthritis (OA) is a painful and disabling disease that affects millions of people worldwide. Symptom-alleviating treatments exist, although none with long-term efficacy. Furthermore, there are currently no disease-modifying OA drugs (DMOADs) with demonstrated efficacy in OA patients, which is, in part, attributed to a lack of full understanding of the pathogenesis of OA. The inability to translate findings from basic research to clinical applications also highlights the deficiencies in the available OA models at simulating the clinically relevant pathologies and responses to treatments in humans. In this review, the current status in the development of DMOADs will be first presented, with special attention to those in Phase II-IV clinical trials. Next, current in vitro, ex vivo, and in vivo OA models are summarized and the respective advantages and disadvantages of each are highlighted. Of note, the development and application of microphysiological or tissue-on-a-chip systems for modeling OA in humans are presented and the issues that need to be addressed in the future are discussed. Microphysiological systems should be given serious consideration for their inclusion in the DMOAD development pipeline, both for their ability to predict drug safety and efficacy in human clinical trials at present, as well as for their potential to serve as a test platform for personalized medicine. Impact statement At present, no disease-modifying osteoarthritis (OA) drugs (DMOADs) have been approved for widespread clinical use by regulatory bodies. The failure of developing effective DMOADs is likely owing to multiple factors, not the least of which are the intrinsic differences between the intact human knee joint and the preclinical models. This work summarizes the current OA models for the development of DMOADs, discusses the advantages/disadvantages of each, and then proposes future model development to aid in the discovery of effective and personalized DMOADs. The review also highlights the microphysiological systems, which are emerging as a new platform for drug development.
| S-EPMC8098772 | biostudies-literature
Project description:ObjectiveDisease-modifying osteoarthritis drugs (DMOADs) are under development. Our goal was to determine efficacy, toxicity, and cost thresholds under which DMOADs would be a cost-effective knee OA treatment.DesignWe used the Osteoarthritis Policy Model, a validated computer simulation of knee OA, to compare guideline-concordant care to strategies that insert DMOADs into the care sequence. The guideline-concordant care sequence included conservative pain management, corticosteroid injections, total knee replacement (TKR), and revision TKR. Base case DMOAD characteristics included: 50% chance of suspending progression in the first year (resumption rate of 10% thereafter) and 30% pain relief among those with suspended progression; 0.5%/year risk of major toxicity; and costs of $1,000/year. In sensitivity analyses, we varied suspended progression (20-100%), pain relief (10-100%), major toxicity (0.1-2%), and cost ($1,000-$7,000). Outcomes included costs, quality-adjusted life expectancy, incremental cost-effectiveness ratios (ICERs), and TKR utilization.ResultsBase case DMOADs added 4.00 quality-adjusted life years (QALYs) and $230,000 per 100 persons, with an ICER of $57,500/QALY. DMOADs reduced need for TKR by 15%. Cost-effectiveness was most sensitive to likelihoods of suspended progression and pain relief. DMOADs costing $3,000/year achieved ICERs below $100,000/QALY if the likelihoods of suspended progression and pain relief were 20% and 70%. At a cost of $5,000, these ICERs were attained if the likelihoods of suspended progression and pain relief were both 60%.ConclusionsCost, suspended progression, and pain relief are key drivers of value for DMOADs. Plausible combinations of these factors could reduce need for TKR and satisfy commonly cited cost-effectiveness criteria.
| S-EPMC3670115 | biostudies-literature
Project description:BackgroundOsteoarthritis (OA) is a highly prevalent degenerative joint disease involving joint cartilage and its surrounding tissues. OA is the leading cause of pain and disability worldwide. At present, there are no disease-modifying OA drugs, and the primary therapies include exercise and nonsteroidal anti-inflammatory drugs until total joint replacement at the end-stage of the disease.MethodsIn this review, we summarized the current state of knowledge in genetic and epigenetic associations and risk factors for OA and their potential diagnostic and therapeutic applications.ResultsGenome-wide association studies and analysis of epigenetic modifications (such as miRNA expression, DNA methylation and histone modifications) conducted across various populations support the notion that there is a genetic basis for certain subsets of OA pathogenesis.ConclusionWith recent advances in the development of genome editing technologies such as the CRISPR-Cas9 system, these genetic and epigenetic alternations in OA can be used as platforms from which potential biomarkers for the diagnosis, prognosis, drug response, and development of potential personalized therapeutic targets for OA can be approached. Furthermore, genome editing has allowed the development of "designer" cells, whereby the receptors, gene regulatory networks, or transgenes can be modified as a basis for new cell-based therapies.
| S-EPMC6675820 | biostudies-literature
Project description:Despite four decades of research in intra-articular drug delivery systems (DDS) and two decades of advances in disease-modifying osteoarthritis drugs (DMOADs), there is still no clinically available disease-modifying therapy for osteoarthritis (OA). Multiple barriers compromise intra-articular DMOAD delivery. Although multiple exciting approaches have been developed to overcome these barriers, there are still outstanding questions. We make several recommendations that can help in fully overcoming these barriers. Considering OA heterogeneity, we also propose a patient-centered, bottom-up workflow to guide preclinical development of DDS-based intra-articular DMOAD therapies. Overall, we expect this review to inspire paradigm-shifting innovations for developing next-generation DDS that can enable clinical translation of intra-articular DMOADs.
| S-EPMC8840969 | biostudies-literature
Project description:Alzheimer's disease (AD) is an age-dependent neurodegenerative disorder and the most common cause of dementia. The early stages of AD are characterized by short-term memory loss. Once the disease progresses, patients experience difficulties in sense of direction, oral communication, calculation, ability to learn, and cognitive thinking. The median duration of the disease is 10 years. The pathology is characterized by deposition of amyloid beta peptide (so-called senile plaques) and tau protein in the form of neurofibrillary tangles. Currently, two classes of drugs are licensed by the European Medicines Agency for the treatment of AD, ie, acetylcholinesterase inhibitors for mild to moderate AD, and memantine, an N-methyl-D-aspartate receptor antagonist, for moderate and severe AD. Treatment with acetylcholinesterase inhibitors or memantine aims at slowing progression and controlling symptoms, whereas drugs under development are intended to modify the pathologic steps leading to AD. Herein, we review the clinical features, pharmacologic properties, and cost-effectiveness of the available acetylcholinesterase inhibitors and memantine, and focus on disease-modifying drugs aiming to interfere with the amyloid beta peptide, including vaccination, passive immunization, and tau deposition.
| S-EPMC3862506 | biostudies-other
Project description:Novel agents addressing non-amyloid, non-tau targets in Alzheimer's Disease (AD) comprise 70% of the AD drug development pipeline of agents currently in clinical trials. Most of the target processes identified in the Common Alzheimer's Disease Research Ontology (CADRO) are represented by novel agents in trials. Inflammation and synaptic plasticity/neuroprotection are the CADRO categories with the largest number of novel candidate therapies. Within these categories, there are few overlapping targets among the test agents. Additional categories being evaluated include apolipoprotein E [Formula: see text] 4 (APOE4) effects, lipids and lipoprotein receptors, neurogenesis, oxidative stress, bioenergetics and metabolism, vascular factors, cell death, growth factors and hormones, circadian rhythm, and epigenetic regulators. We highlight current drugs being tested within these categories and their mechanisms. Trials will be informative regarding which targets can be modulated to produce a slowing of clinical decline. Possible therapeutic combinations of agents may be suggested by trial outcomes. Biomarkers are evolving in concert with new targets and novel agents, and biomarker outcomes offer a means of supporting disease modification by the putative treatment. Identification of novel targets and development of corresponding therapeutics offer an important means of advancing new treatments for AD.
| S-EPMC10582128 | biostudies-literature
Project description:BackgroundOsteoarthritis (OA) is common and burdensome for patients and health care systems. Our study purpose was to evaluate the long-term efficacy and safety of DMOADs in adults with knee and hip osteoarthritis.MethodsWe searched Cochrane Central Register of Controlled Trials, MEDLINE, EMBASE, and Web of Knowledge without language, publication, or date restrictions from inception through November 2018 for randomized controlled trials assessing 12 classes of DMOADs with at least 12 months of follow-up. Therapeutic effects were evaluated with pairwise and network meta-analysis. Outcomes included pain, function, minimum joint space width or cartilage volume, radiographic progression, and total joint replacement. Analyses were also performed for drug safety.ResultsTwenty-eight randomized controlled trials with 11,890 patients were included. Glucosamine and chondroitin minimally improved both structure (minimum joint width or cartilage volume: network results: glucosamine: SMD 0.16; 95% CI [0.04, 0.28], chondroitin: SMD 0.21 [0.10, 0.32]) and symptoms (glucosamine: pain: - 0.15 [- 0.25, - 0.05]; function: - 0.17 [- 0.28, - 0.07], chondroitin: pain: - 0.06 [- 0.15, 0.03], and function: - 0.15 [- 0.26, - 0.03]). Strontium demonstrated improvement in structure (minimum joint width or cartilage volume: 0.20 [0.02, 0.38]), and vitamin D on symptoms (pain: - 0.15 [- 0.27, -0.03]; function: - 0.18 [- 0.31, - 0.06]). Although doxycycline also demonstrated a favorable efficacy ranking, its safety profile was poor (withdrawal: network relative risk 1.69 [1.03, 2.75]). The therapeutic effects of other medications were not ranked as highly.DiscussionGlucosamine and chondroitin yielded statistically significant but clinically questionable long-term benefit on structure and symptoms, though both had favorable safety profiles. Strontium improved structure, and vitamin D improved symptoms. Although doxycycline had a favorable efficacy ranking, its safety profile was poor. None of the 12 classes of drugs appears to have long-term clinically significant benefit.
| S-EPMC8298729 | biostudies-literature
Project description:BackgroundThe relationship between cancer and dementia is triggering growing research interest. Several preclinical studies have provided the biological rationale for the repurposing of specific anticancer agents in Alzheimer's disease (AD), and a growing number of research protocols are testing their efficacy and safety/tolerability in patients with AD.MethodsThe aim of the present systematic review was to provide an overview on the repurposing of approved anticancer drugs in clinical trials for AD by considering both ongoing and completed research protocols in all phases. In parallel, a systematic literature review was conducted on PubMed, ISI Web, and the Cochrane Library to identify published clinical studies on repurposed anticancer agents in AD.ResultsBased on a structured search on the ClinicalTrials.gov and the EudraCT databases, we identified 13 clinical trials testing 11 different approved anticancer agents (five tyrosine kinase inhibitors, two retinoid X receptor agonists, two immunomodulatory agents, one histone deacetylase inhibitor, and one monoclonal antibody) in the AD continuum. The systematic literature search led to the identification of five published studies (one phase I, three phase II, and one phase IIb/III) reporting the effects of antitumoral treatments in patients with mild cognitive impairment or AD dementia. The clinical findings and the methodological characteristics of these studies are described and discussed.ConclusionAnticancer agents are triggering growing interest in the context of repurposed therapies in AD. Several clinical trials are underway, and data are expected to be available in the near future. To date, data emerging from published clinical studies are controversial. The promising results emerging from preclinical studies and identified research protocols should be confirmed and extended by larger, adequately designed, and high-quality clinical trials.
| S-EPMC8101105 | biostudies-literature