Novel small-molecular therapeutics for rheumatoid arthritis

@article{Fleischmann2012NovelST,
  title={Novel small-molecular therapeutics for rheumatoid arthritis},
  author={Roy M. Fleischmann},
  journal={Current Opinion in Rheumatology},
  year={2012},
  volume={24},
  pages={335–341}
}
  • R. Fleischmann
  • Published 1 May 2012
  • Medicine
  • Current Opinion in Rheumatology
Purpose of reviewSince the introduction of biologic therapies into the treatment paradigm of rheumatoid arthritis (RA), there has been hope that oral small molecule immune modulators would be developed that would have a risk : benefit profile at least similar to biologic therapies, be more convenient for the patient and, hopefully, be less expensive. This article reviews the progress made in the development of these compounds over the past year. Recent findingsAdditional information has become… 
Oral Janus Kinase Inhibitor for the Treatment of Rheumatoid Arthritis: Tofacitinib
TLDR
Tofacitinib has a noticeable efficacy in controlling disease activity in RA with a manageable safety profile, however, longer studies are needed for its long-term safety profile.
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.
New treatments for inflammatory rheumatic disease
TLDR
The new and upcoming treatment options for rheumatoid arthritis, psoriatic arthritis, systemic lupus erythematosus, and gout are described to dissect what the authors should be aware of when discussing these new and promising molecules.
What is the future of targeted therapy in rheumatology: biologics or small molecules?
TLDR
This debate paper compares the advantages and disadvantages of the two different approaches to biologic therapeutics and small-molecule inhibitors of intracellular signal transduction pathways to shed light on the possible future of targeted therapies.
Chapter Twenty-Five - Case History: Xeljanz™ (Tofacitinib Citrate), a First-in-Class Janus Kinase Inhibitor for the Treatment of Rheumatoid Arthritis
TLDR
The tofacitinib medicinal chemistry journey, starting with lead identification through high-throughput screening, followed by lead development, taking advantage of high-speed analoging and the use of natural products as synthetic building blocks, and optimization of physical properties and pharmacokinetics within a piperidine chemical series.
Small Molecule Inhibitors in Rheumatoid Arthritis
TLDR
Among the several small molecule inhibitors in the development process, fostamatinib and tofacitinib are the closest to the clinics at the moment and showed superior efficacy over placebo with tolerable safety signals.
To fingolimod and beyond: The rich pipeline of drug candidates that target S1P signaling.
TLDR
An overview of the clinical and preclinical development of drugs targeting S1P signaling, which has been shown to regulate a diverse range of physiological processes and disease states, such as cardiovascular development, immune function, hypoxic responses, and cancer.
The problem of choice: current biologic agents and future prospects in RA
TLDR
An overview of biologic therapies currently available for patients with rheumatoid arthritis is provided, and why certain immunological regulators represent potential targets for intervention is discussed.
The future of biological agents in the treatment of rheumatoid arthritis
TLDR
The reviews explores and summarizes the latest developments and potential impact of anti-cytokine therapy, including TNF, IL-6 and IL-17, anti-lymphocyte therapies, B cell modulators and other B-cell targets,Anti-CD3, biosimilars and finally oral agents such as JAK and Syk inhibitors.
Management of rheumatoid arthritis: the 2012 perspective
TLDR
There remains much for us rheumatologists to do for the authors' patients, including patient-perspective approaches, and it is encouraged to conduct studies based on daily practice on the basis of the evidence generated from “their” patients to patients in daily practice.
...
1
2
3
4
5
...

References

SHOWING 1-10 OF 27 REFERENCES
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.
An oral Syk kinase inhibitor in the treatment of rheumatoid arthritis: a three-month randomized, placebo-controlled, phase II study in patients with active rheumatoid arthritis that did not respond to biologic agents.
TLDR
Findings indicate that there were no differences in the primary end point between the R788 and placebo groups, and differences were observed in secondary end points, particularly in those patients who entered the study with an elevated CRP level.
Treatment of rheumatoid arthritis with a Syk kinase inhibitor: a twelve-week, randomized, placebo-controlled trial.
TLDR
It is indicated that an inhibitor of Syk kinase produces significant clinical benefits at 12 weeks in a population of patients with active RA receiving methotrexate therapy, suggesting Syk Kinase may be an important new therapeutic target in RA and related autoimmune conditions.
Tofacitinib (CP-690,550), an oral janus kinase inhibitor, in combination with methotrexate reduced the progression of structural damage in patients with rheumatoid arthritis: A 24-Month Phase 3 Study
TLDR
Tofacitinib is a novel, oral JAK inhibitor that is being investigated as a targeted immunomodulator and disease modifying therapy for RA and efficacy and safety shown in Phase 2b monotherapy and background MTX dose-ranging studies.
Phase IIb dose-ranging study of the oral JAK inhibitor tofacitinib (CP-690,550) or adalimumab monotherapy versus placebo in patients with active rheumatoid arthritis with an inadequate response to disease-modifying antirheumatic drugs.
TLDR
Tofacitinib monotherapy at a dose of ≥3 mg twice a day was efficacious in the treatment of patients with active RA over 24 weeks and demonstrated a manageable safety profile.
The safety and efficacy of a JAK inhibitor in patients with active rheumatoid arthritis: Results of a double-blind, placebo-controlled phase IIa trial of three dosage levels of CP-690,550 versus placebo.
TLDR
It is indicated that CP-690,550 is efficacious in the treatment of RA, resulting in rapid, statistically significant, and clinically meaningful reductions in the signs and symptoms of RA.
An oral spleen tyrosine kinase (Syk) inhibitor for rheumatoid arthritis.
TLDR
R788, an oral inhibitor of Syk, was significantly superior to placebo at month 6 and reduced disease activity in patients with rheumatoid arthritis; adverse events included diarrhea, hypertension, and neutropenia.
Fostamatinib, a Syk inhibitor prodrug for the treatment of inflammatory diseases.
  • M. Bajpai
  • Medicine
    IDrugs : the investigational drugs journal
  • 2009
TLDR
Fostamatinib appears to be a promising therapeutic for immunological diseases, but further data are required to establish the efficacy and long-term safety of the drug in humans.
A phase IIb dose-ranging study of the oral JAK inhibitor tofacitinib (CP-690,550) versus placebo in combination with background methotrexate in patients with active rheumatoid arthritis and an inadequate response to methotrexate alone.
TLDR
In patients with active RA in whom the response to MTX has been inadequate, the addition of tofacitinib at a dosage ≥3 mg twice daily showed sustained efficacy and a manageable safety profile over 24 weeks.
Methotrexate in rheumatoid arthritis. A five-year prospective multicenter study.
TLDR
This large prospective study of long-term MTX treatment demonstrates sustained clinical response and improvement in the Westergren ESR and functional assessment scores, with an acceptable toxicity profile.
...
1
2
3
...