IκB kinase inhibition as a potential treatment of osteoarthritis – results of a clinical proof-of-concept study

Grothe, Karen; Flechsenhar, K.; Paehler, Tobias; Ritzeler, Olaf; Beninga, Jochen; Saas, Joachim; Herrmann, Matthias; Rudolphi, Karl Asmund

doi:10.1016/j.joca.2016.08.010

Cited by 35 publications

(28 citation statements)

References 14 publications

(10 reference statements)

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“…Positive efficacy trends in these studies motivated the undertaking of a Phase IIa POC trial (Identifier: NCT01598415). However, SAR-113945 failed to show efficacy in this larger patient sample size [ 127 ].…”

Section: Pre-clinical Development Of Ikkβ Inhibitorsmentioning

confidence: 99%

“…More challenging is the appropriate selection of patient subgroups to achieve the desired therapeutic efficacy. For example, the proof of concept study for SAR113945 failed to show any effect in the overall group of recruited study participants for the primary endpoint; however, post-study analysis demonstrated a statistically significant difference in a patient subgroup that had presented with synovial effusion at baseline [ 127 ]. Stratification of patient subgroups to identify those with a clear NF-κB-driven, inflammatory phenotype that would benefit from IKKβ inhibition may be one solution to this problem.…”

Section: Potential Reasons For the Lack Of Clinical Success Of Ikkmentioning

confidence: 99%

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Targeting IKKβ in Cancer: Challenges and Opportunities for the Therapeutic Utilisation of IKKβ Inhibitors

Prescott

Cook

2018

Cells

106

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Deregulated NF-κB signalling is implicated in the pathogenesis of numerous human inflammatory disorders and malignancies. Consequently, the NF-κB pathway has attracted attention as an attractive therapeutic target for drug discovery. As the primary, druggable mediator of canonical NF-κB signalling the IKKβ protein kinase has been the historical focus of drug development pipelines. Thousands of compounds with activity against IKKβ have been characterised, with many demonstrating promising efficacy in pre-clinical models of cancer and inflammatory disease. However, severe on-target toxicities and other safety concerns associated with systemic IKKβ inhibition have thus far prevented the clinical approval of any IKKβ inhibitors. This review will discuss the potential reasons for the lack of clinical success of IKKβ inhibitors to date, the challenges associated with their therapeutic use, realistic opportunities for their future utilisation, and the alternative strategies to inhibit NF-κB signalling that may overcome some of the limitations associated with IKKβ inhibition.

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Section: Pre-clinical Development Of Ikkβ Inhibitorsmentioning

confidence: 99%

Section: Potential Reasons For the Lack Of Clinical Success Of Ikkmentioning

confidence: 99%

Targeting IKKβ in Cancer: Challenges and Opportunities for the Therapeutic Utilisation of IKKβ Inhibitors

Prescott

Cook

2018

Cells

106

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“…Parthenolide displays poor bioavailability and therefore has limited therapeutic application [ 142 ]. A new IKKβ inhibitor more recently developed by Sanofi-Aventis, SAR-113945, has been investigated in four different clinical trials in non-oncological patients, with initial promising results [ 143 ]. However, SAR-113945 has failed to demonstrate clinical efficacy in follow-on clinical trials, underscoring the challenge of striking an acceptable balance between efficacy and adverse side-effects [ 143 ].…”

Section: Therapeutic Targeting Of the Nf-κb Pathway In Cancermentioning

confidence: 99%

“…A new IKKβ inhibitor more recently developed by Sanofi-Aventis, SAR-113945, has been investigated in four different clinical trials in non-oncological patients, with initial promising results [ 143 ]. However, SAR-113945 has failed to demonstrate clinical efficacy in follow-on clinical trials, underscoring the challenge of striking an acceptable balance between efficacy and adverse side-effects [ 143 ]. Overall, the disappointing clinical performance of IKKβ inhibitors has considerably dampened the interest in this class of agents, and this trend is likely to continue in the future, as shown by the dramatic decline in the number of patent applications filed on these agents in recent years [ 107 ].…”

Section: Therapeutic Targeting Of the Nf-κb Pathway In Cancermentioning

confidence: 99%

Unlocking the NF-κB Conundrum: Embracing Complexity to Achieve Specificity

et al. 2017

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Transcription factors of the nuclear factor κB (NF-κB) family are central coordinating regulators of the host defence responses to stress, injury and infection. Aberrant NF-κB activation also contributes to the pathogenesis of some of the most common current threats to global human health, including chronic inflammatory diseases, autoimmune disorders, diabetes, vascular diseases and the majority of cancers. Accordingly, the NF-κB pathway is widely considered an attractive therapeutic target in a broad range of malignant and non-malignant diseases. Yet, despite the aggressive efforts by the pharmaceutical industry to develop a specific NF-κB inhibitor, none has been clinically approved, due to the dose-limiting toxicities associated with the global suppression of NF-κB. In this review, we summarise the main strategies historically adopted to therapeutically target the NF-κB pathway with an emphasis on oncology, and some of the emerging strategies and newer agents being developed to pharmacologically inhibit this pathway.

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“…A number of targets have been identified. For example, inflammatory modulators such as interleukins, [13] or the NF-κB pathway [14] have been identified as potential targets. Ion channels, such as TRPV1 [15] or voltage gated sodium channels, which are associated with pain, have also been investigated [16].…”

Section: Introductionmentioning

confidence: 99%

GSK3787-Loaded Poly(Ester Amide) Particles for Intra-Articular Drug Delivery

et al. 2020

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Osteoarthritis (OA) is a debilitating joint disorder affecting more than 240 million people. There is no disease modifying therapeutic, and drugs that are used to alleviate OA symptoms result in side effects. Recent research indicates that inhibition of peroxisome proliferator-activated receptor δ (PPARδ) in cartilage may attenuate the development or progression of OA. PPARδ antagonists such as GSK3787 exist, but would benefit from delivery to joints to avoid side effects. Described here is the loading of GSK3787 into poly(ester amide) (PEA) particles. The particles contained 8 wt.% drug and had mean diameters of about 600 nm. Differential scanning calorimetry indicated the drug was in crystalline domains in the particles. Atomic force microscopy was used to measure the Young’s moduli of individual particles as 2.8 MPa. In vitro drug release studies showed 11% GSK3787 was released over 30 days. Studies in immature murine articular cartilage (IMAC) cells indicated low toxicity from the drug, empty particles, and drug-loaded particles and that the particles were not taken up by the cells. Ex vivo studies on murine joints showed that the particles could be injected into the joint space and resided there for at least 7 days. Overall, these results indicate that GSK3787-loaded PEA particles warrant further investigation as a delivery system for potential OA therapy.

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IκB kinase inhibition as a potential treatment of osteoarthritis – results of a clinical proof-of-concept study

Cited by 35 publications

References 14 publications

Targeting IKKβ in Cancer: Challenges and Opportunities for the Therapeutic Utilisation of IKKβ Inhibitors

Targeting IKKβ in Cancer: Challenges and Opportunities for the Therapeutic Utilisation of IKKβ Inhibitors

Unlocking the NF-κB Conundrum: Embracing Complexity to Achieve Specificity

GSK3787-Loaded Poly(Ester Amide) Particles for Intra-Articular Drug Delivery

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