Selective JAK inhibitors in development for rheumatoid arthritis

@article{Norman2014SelectiveJI,
  title={Selective JAK inhibitors in development for rheumatoid arthritis},
  author={Peter Dr. Norman},
  journal={Expert Opinion on Investigational Drugs},
  year={2014},
  volume={23},
  pages={1067 - 1077}
}
  • P. Norman
  • Published 11 July 2014
  • Biology, Medicine
  • Expert Opinion on Investigational Drugs
Introduction: The JAK kinases are a family of four tyrosine receptor kinases that play a pivotal role in cytokine receptor signalling pathways via their interaction with signal transducers and activators of transcription proteins. Selective inhibitors of JAK kinases are viewed as of considerable potential as disease-modifying anti-inflammatory drugs for the treatment of rheumatoid arthritis. Areas covered: This article provides a review of the clinical development and available clinical results… 
The effect of JAK1/JAK2 inhibition in rheumatoid arthritis: efficacy and safety of baricitinib.
TLDR
A narrative review focuses on the clinical efficacy and safety of baricitinib, but also provides an overview of its mechanism of action in relation to JAK1/JAK2 signalling and discusses the possible clinical implications in patients with RA.
Janus kinase inhibitors for the treatment of inflammatory bowel diseases: developments from phase I and phase II clinical trials
TLDR
An overview of the JAK inhibitors currently under investigation in phase I and II clinical trials for patients with Crohn’s disease and ulcerative colitis and the possible future perspectives for the treatment of IBD patients with this class of drugs are provided.
A novel treatment for psoriatic arthritis: Janus kinase inhibitors
TLDR
Although there are still issues in terms of their efficacy and safety currently, JAK inhibitors are expected to benefit more PsA patients in future.
JAK3-selective inhibitor peficitinib for the treatment of rheumatoid arthritis
TLDR
It is thought that more cautious consideration and measurement for adverse events are needed, after considering the safety results of ongoing clinical studies of peficitinib, which is currently being evaluated by the FDA to treat adult patients with moderately to severely active RA who show inadequate response to or are intolerant of methotrexate.
JAK Inhibitors for Rheumatoid Arthritis
TLDR
Tofacitinib has been carefully evaluated in multiple phase 3 clinical trials, and although safety concerns cannot fully be answered until the drug is studied over longer periods of time, the data to date suggest that this drug—and perhaps other JAK inhibitors—may represent an important addition to the therapeutic armamentarium.
Progress toward JAK1-selective inhibitors.
TLDR
The state-of-the-art research that evokes JAK1 selective inhibition is discussed, which shows a critical and potentially dominant role in the transduction of γc cytokine and in IL-6 signaling.
JAK inhibitors impair GM-CSF-mediated signaling in innate immune cells
TLDR
It is concluded that incubation with JAKi prevents GM-CSF-mediated JAK2/STAT5 activation in human innate immune cells, and although baricitinib and upadacitinib almost completely blocked GM- CSF- mediated Jak2/ STAT5 signaling, the inhibitory effects of tofacitinIB were weaker at lower concentrations suggesting that variation exists among these JAKs in the inhibition of JAK 2 signaling pathways.
Comparative Efficacy of JAK Inhibitors for Moderate-To-Severe Rheumatoid Arthritis: A Network Meta-Analysis
TLDR
The NMA found that upadacitinib 15 mg once daily had numerically higher efficacy in terms of ACR response and clinical remission among approved JAK combination therapies and monotherapies for csDMARD-IR patients with RA.
Erratum to: JAK–STAT Signaling as a Target for Inflammatory and Autoimmune Diseases: Current and Future Prospects
TLDR
The JAK–STAT pathway is described, its role in autoimmunity is outlined, and the rationale/pre-clinical evidence for targeting JAK-STAT signaling is explained, starting with the FDA-approved Jakinib tofacitinib, and continuing on to next-generation JakinIBs.
...
1
2
3
4
5
...

References

SHOWING 1-10 OF 92 REFERENCES
Clinical utility of the oral JAK inhibitor tofacitinib in the treatment of rheumatoid arthritis
TLDR
Tofacitinib is an oral JAK inhibitor that is now available and effective in RA treatment, as shown in multiple Phase II and Phase III clinical trials, however, long-term safety data and comparisons with other disease-modifying antirheumatic drugs and small molecule inhibitors are necessary to better determine the role of tofacitinIB in RA.
Kinase inhibitors: a new class of antirheumatic drugs
  • V. Kyttaris
  • Medicine, Biology
    Drug design, development and therapy
  • 2012
TLDR
Fostamatinib and tofacitinib were associated with increased rates of infection, elevation of liver enzymes, and neutropenia, while fostamatinIB caused elevations of blood pressure and diarrhea, while tofacITinib was associated with an increase in creatinine and elevation of lipid levels.
Kinase inhibitors: a new approach to rheumatoid arthritis treatment
TLDR
Inhibitors of more upstream protein-tyrosine kinases involved in cellular signaling appear to be viable molecular candidates for rheumatoid arthritis and if the results seen in phase 2 studies are confirmed in larger phase 3 studies, the authors may soon have new, oral DMARD therapies available.
Selective Inhibition of JAK1 and JAK2 Is Efficacious in Rodent Models of Arthritis: Preclinical Characterization of INCB028050
TLDR
Data suggest that fractional inhibition of JAK1 and JAK2 is sufficient for significant activity in autoimmune disease models, as assessed by improvements in clinical, histologic and radiographic signs of disease.
Role of Spleen Tyrosine Kinase Inhibitors in the Management of Rheumatoid Arthritis
TLDR
The results of the phase II trials were sufficiently encouraging for a phase III programme to be initiated and a meta-analysis of ACR responses in these trials, using responses to the highest dose in each trial for comparisons with placebo therapy in a random effects model, showed a borderline benefit with ACR20 responses.
Selective p38alpha inhibitors clinically evaluated for the treatment of chronic inflammatory disorders.
TLDR
It is concluded that p38R inhibition alone is unlikely to be a successful strategy toward treating chronic inflammatory disorders and the era of optimism surrounding the use of p38 MAPK inhibition for the treatment of RA is over.
THU0127 Pharmacodynamics of A Novel JAK1 Selective Inhibitor in Rat Arthritis and Anemia Models and in Healthy Human Subjects
TLDR
ABT-494 is a Jak1-selective inhibitor that demonstrates efficacy in rat arthritis models and spares relevant essential physiological processes such as erythropoietin signaling and peripheral NK cell counts at similarly efficacious doses in rats.
New drugs beyond biologics in rheumatoid arthritis: the kinase inhibitors.
TLDR
Inhibitors of the non-receptor tyrosine kinases, spleen tyosine kinase and janus kinase 3, have demonstrated a significant clinical efficacy together with an acceptable safety profile in RA.
SB1578, a Novel Inhibitor of JAK2, FLT3, and c-Fms for the Treatment of Rheumatoid Arthritis
TLDR
SB1578 not only prevents the onset of arthritis but is also potent in treating established disease in collagen-induced arthritis mice with beneficial effects on histopathological parameters of bone resorption and cartilage damage.
Inhibition of spleen tyrosine kinase in the treatment of rheumatoid arthritis.
TLDR
The most common adverse events included gastrointestinal effects, hypertension, neutropenia and transaminitis, but many adverse effects were dose responsive and hypertension was amenable to treatment.
...
1
2
3
4
5
...