The Development of Disease-Modifying Therapies for Osteoarthritis (DMOADs): The Evidence to Date.
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ABSTRACT:
SUBMITTER: Oo WM
PROVIDER: S-EPMC8273751 | biostudies-literature |
REPOSITORIES: biostudies-literature
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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:It has now been ~ 30 years since the Alzheimer's disease (AD) research entered what may be termed the 'molecular era' that began with the identification of the amyloid ? protein (A?) as the primary component of amyloid within senile plaques and cerebrovascular amyloid and the microtubule-associated protein tau as the primary component of neurofibrillary tangles in the AD brain. These pivotal discoveries and the subsequent genetic, pathological, and modeling studies supporting pivotal roles for tau and A? aggregation and accumulation have provided firm rationale for a new generation of AD therapies designed not to just provide symptomatic benefit, but as disease modifying agents that would slow or even reverse the disease course. Indeed, over the last 20 years numerous therapeutic strategies for disease modification have emerged, been preclinically validated, and advanced through various stages of clinical testing. Unfortunately, no therapy has yet to show significant clinical disease modification. In this review, I describe 10 translational barriers to successful disease modification, highlight current efforts addressing some of these barriers, and discuss how the field could focus future efforts to overcome barriers that are not major foci of current research efforts. Seminal discoveries made over the past 25 years have provided firm rationale for a new generation of Alzheimer's disease (AD) therapies designed as disease modifying agents that would slow or even reverse the disease course. Unfortunately, no therapy has yet to show significant clinical disease modification. In this review, I describe 10 translational barriers to successful AD disease modification, highlight current efforts addressing some of these barriers, and discuss how the field could focus future efforts to overcome these barriers. This article is part of the 60th Anniversary special issue.
| S-EPMC6816258 | biostudies-literature
Project description:Sickle cell disease afflicts millions of people worldwide and approximately 100,000 Americans. Complications are myriad and arise as a result of complex pathological pathways 'downstream' to a point mutation in DNA, and include red blood cell membrane damage, inflammation, chronic hemolytic anemia with episodic vaso-occlusion, ischemia and pain, and ultimately risk of cumulative organ damage with reduced lifespan of affected individuals. The National Heart, Lung, and Blood Institute's 2014 evidence-based guideline for sickle cell disease management states that additional research is needed before investigational curative therapies will be widely available to most patients with sickle cell disease. To date, sickle cell disease has been cured by hematopoietic stem cell transplantation in approximately 1,000 people, most of whom were children, and significantly ameliorated by gene therapy in a handful of subjects who have only limited follow-up thus far. During a timespan in which over 20 agents were approved for the treatment of cystic fibrosis by the Food and Drug Administration, similar approval was granted for only two drugs for sickle cell disease (hydroxyurea and L-glutamine) despite the higher prevalence of sickle cell disease. This trajectory appears to be changing, as the lack of multimodal agent therapy in sickle cell disease has spurred engagement among many in academia and industry who, in the last decade, have developed new drugs poised to prevent complications and alleviate suffering. Identified therapeutic strategies include fetal hemoglobin induction, inhibition of intracellular HbS polymerization, inhibition of oxidant stress and inflammation, and perturbation of the activation of the endothelium and other blood components (e.g. platelets, white blood cells, coagulation proteins) involved in the pathophysiology of sickle cell disease. In this article, we present a crash-course review of disease-modifying approaches (minus hematopoietic stem cell transplant and gene therapy) for patients with sickle cell disease currently, or recently, tested in clinical trials in the era following approval of hydroxyurea.
| S-EPMC6717563 | biostudies-literature
Project description:Parkinson disease is an inexorably progressive neurodegenerative disorder. Multiple attempts have been made to establish therapies for Parkinson disease which provide neuroprotection or disease modification-two related, but not identical, concepts. However, to date, none of these attempts have succeeded. Many challenges exist in this field of research, including a complex multisystem disorder that includes dopaminergic and non-dopaminergic features; poorly understood and clearly multifaceted disease pathogenic mechanisms; a lack of reliable animal models; an absence of effective biomarkers of disease state, progression, and target engagement; and the confounding effects of potent symptomatic therapy. In this article, we will review previous, ongoing, and potential future trials designed to alter the progressive course of the disease from the perspective of the targeted underlying pathogenic mechanisms.
| S-EPMC3899477 | biostudies-literature
Project description:ObjectiveTo address concerns regarding the effect of MS disease-modifying therapies (DMTs) on the expression of coronavirus 2019 (COVID-19).MethodsReview of the current state of knowledge regarding the viral etiology of COVID-19, mechanisms of injury by SARS-CoV-2 infection, and the effect of individual DMTs on the risk of infection and COVID-19 disease expression.ResultsAlthough data are limited, MS DMTs do not obviously increase the risk of acquiring symptomatic SARS-CoV-2 infection. The severe morbidity and mortality of SARS-CoV-2 appear to be largely the consequence of an overly robust immune response rather than the consequence of unchecked viral replication. The effects of specific MS DMTs on the immune response that may increase the risk of impaired viral clearance and their potential counterbalancing beneficial effects on the development of COVID-19-associated acute respiratory distress syndrome are reviewed.ConclusionAlthough there is currently insufficient real-world experience to definitively answer the question of the effect of a specific MS DMT on COVID-19, registries presently in nascent form should provide these answers. This review provides an approach to addressing these concerns while the data are being accumulated. Early insights suggest that the risk of infection and associated morbidity of COVID-19 in this population is little different than that of the population at large.
| S-EPMC7238896 | biostudies-literature
Project description:In the past decade, the therapeutic arsenal for multiple sclerosis has expanded greatly. Newer more potent disease modifying therapies (DMTs) with varying mechanisms of actions are increasingly used early in the disease course. These newer DMTs include oral therapies (teriflunomide, dimethyl fumarate, fingolimod, siponimod, ozanimod, and cladribine) and infusion therapies (natalizumab, alemtuzumab, and ocrelizumab), and are associated with better control of disease activity and long-term outcomes in patients with MS compared to older injectable therapies (interferon beta and glatiramer acetate). However, they are associated with safety concerns and subsequent monitoring requirements. Adverse events are initially observed in phase 2 and 3 clinical trials, and further long-term data are collected in phase 3 extension studies, case series, and post-marketing reports, which highlight the need to periodically re-evaluate and adjust monitoring strategies to optimize treatment safety in an individualized approach.
| S-EPMC7823546 | biostudies-literature
Project description:ObjectiveThis study was undertaken to assess the impact of immunosuppressive and immunomodulatory therapies on the severity of coronavirus disease 2019 (COVID-19) in people with multiple sclerosis (PwMS).MethodsWe retrospectively collected data of PwMS with suspected or confirmed COVID-19. All the patients had complete follow-up to death or recovery. Severe COVID-19 was defined by a 3-level variable: mild disease not requiring hospitalization versus pneumonia or hospitalization versus intensive care unit (ICU) admission or death. We evaluated baseline characteristics and MS therapies associated with severe COVID-19 by multivariate and propensity score (PS)-weighted ordinal logistic models. Sensitivity analyses were run to confirm the results.ResultsOf 844 PwMS with suspected (n = 565) or confirmed (n = 279) COVID-19, 13 (1.54%) died; 11 of them were in a progressive MS phase, and 8 were without any therapy. Thirty-eight (4.5%) were admitted to an ICU; 99 (11.7%) had radiologically documented pneumonia; 96 (11.4%) were hospitalized. After adjusting for region, age, sex, progressive MS course, Expanded Disability Status Scale, disease duration, body mass index, comorbidities, and recent methylprednisolone use, therapy with an anti-CD20 agent (ocrelizumab or rituximab) was significantly associated (odds ratio [OR] = 2.37, 95% confidence interval [CI] = 1.18-4.74, p = 0.015) with increased risk of severe COVID-19. Recent use (<1 month) of methylprednisolone was also associated with a worse outcome (OR = 5.24, 95% CI = 2.20-12.53, p = 0.001). Results were confirmed by the PS-weighted analysis and by all the sensitivity analyses.InterpretationThis study showed an acceptable level of safety of therapies with a broad array of mechanisms of action. However, some specific elements of risk emerged. These will need to be considered while the COVID-19 pandemic persists. ANN NEUROL 2021;89:780-789.
| S-EPMC8013440 | biostudies-literature
Project description:BackgroundPromising disease modifying therapies for Huntington's disease are now entering pivotal trials, raising questions of what patients and families consider successful outcomes. Consistent with an ongoing movement to incorporate patient preferences into the development of new therapies, we conducted a pilot study to assess Huntington's disease community views on emerging DMTs to assist in planning large-scale studies of patient preferences.MethodsSemi-structured interviews were conducted with members of the Huntington's community (manifest disease, at-risk, and family/caregivers). Participants were asked which symptoms they believed should be targeted with novel treatments, as well as potential benefits and tradeoffs of delaying symptom onset versus prolonging late-stage disease.ResultsParticipants (N = 14) emphasized the need for treatments improving cognitive and/or behavioral symptoms. Many wanted treatments that delayed symptom onset up to 5-10 years, though some considered shorter delays acceptable due to potential value in advancing research to help future generations. Concern regarding potential for prolonging later-stage disease was variable, with some participants uncertain if they would want a treatment that delayed onset but prolonged later-stage disease. Others stated that any delay in onset would be desirable, regardless of potential prolongation of later stage disease.DiscussionThis study demonstrates a breadth of opinions among the Huntington's disease community surrounding both the benefits and complex tradeoffs that might occur with disease modifying treatments. These preliminary findings will inform future large-scale studies of attitudes toward disease modifying treatments, which may ultimately guide the design and outcome measure selection for clinical trials.HighlightsIn-depth interviews with the Huntington's disease community were used to explore patient and family preferences regarding potential disease modifying therapies. Many wanted symptom delay of 5-10 years, though some considered shorter delays acceptable for altruistic reasons. Opinions on trade-offs varied, suggesting larger preference studies are needed to inform trial design.
| S-EPMC7845464 | biostudies-literature
Project description:Emerging data suggest that type 1 diabetes is a more aggressive disease in children than in adults, with important differences in pathophysiology and clinical course. Therefore, the efficacy of disease-modifying therapies may be different in the two populations. Understanding the developmental and regulatory pathways for type 1 diabetes-modifying therapies in children will enable industry, academia, funders, advocacy groups, and regulators to translate new science to clinical care. This consensus report characterizes the fundamental differences in type 1 diabetes between children and adults and proposes a thoughtful approach to better understand the development and regulatory pathways for type 1 diabetes therapies.
| S-EPMC4876737 | biostudies-literature
Project description:The development of disease-modifying therapies for Alzheimer's disease (AD) is an urgent issue. Progress in the understanding of AD pathophysiology based on the amyloid hypothesis has led to the development of numerous candidate disease-modifying therapies over the past 15 years. The therapeutic target, amyloid ? (A?), starts to accumulate in AD brains long before the onset of cognitive decline. ?-secretase inhibitors, ?-secretase modulators, and ?-secretase inhibitors aim to reduce the production of toxic A? species by modifying the processing of amyloid precursor protein. Another strategy is to eliminate accumulated A? by active or passive immunotherapeutic approaches. Therapeutic strategies targeting tau protein are also currently emerging. Despite these efforts, successful disease-modifying therapies for AD have not yet been developed. Recently, very early interventional trials targeting preclinical stages of AD have begun; the paradigm shift in AD therapies from cure to prevention could be key to the success of disease modification.
| S-EPMC5790756 | biostudies-literature