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(CCR2015) Nearly 100 new molecules are in development as RA treatments. This summary of a recent presentation by the ever-eloquent Ed Keystone MD gives a brief rundown of their mechanisms, progress, and potential.
The dozens of new rheumatoid arthritis (RA) treatments under development will lead to clinical advances in the near future, said University of Toronto rheumatologist Edward Keystone MD at the Congress of Clinical Rheumatology 2015 meeting in Destin, FL.
“The landscape for emerging novel therapies in RA shows 47 molecules in phase II trials," said Keystone. "Almost 100 new molecules are being developed and moving along.”
These represent the fruits of translational research, he pointed out in conclusion. “To translate research findings from the bench to the bedside, you need to understand the pathogenesis of disease,” he said.
Novel therapeutic strategies include the cytokine target interleukeins (IL) IL-6, IL-17, and granulocyte macrophage-colony stimulating factor (GM-CSF); a hybrid anti-TNF/IL-17 monoclonal antibody; and the Janus kinase (JAK) signal transduction inhibitors JAK 1/3, JAK 1/2, JAK 3, and JAK 1.
Candidate treatments include:
Sarilumab, sirukumab, and clazakizumab: Subcutaneous IL-6 inhibitors. “New anti-IL-6 monoclonal antibodies have variable efficacy in phase II trials," said Keystone, who is professor of medicine at the University of Toronto. "Some may have a more rapid onset. Some may have similar efficacy post-methotrexate and post-tumor necrosis factor (TNF) therapy. Dosing may vary between every 2 to 4 weeks. There are no new safety signals.”
Secukinumab, ixekizumab, and brodalumab: Subcutaneous IL-17 inhibitors. “Preliminary 12-week results show, in general, ACR 20, 50, and 70 responses are a little low," he said. "So far, IL-17 inhibitors may be only modestly effective in phase II studies. Their safety profile is comparable to other biologic therapies. IL-17 inhibitors may not compete in the marketplace in RA.”
Mavilimumab: Targets the GM-CSF receptor that drives macrophages, which Keystone called the "central" cell in RA pathogenesis. This pro-inflammatory cytokine “plays a central role in RA though the activation, differentiation, and survival of macrophages and neutrophils," he added.
High doses of mavrilimumab every 2 weeks subcutaneously seem to lead to an early response. “Efficacy is similar to other biologics at week 12, there is rapid onset of action, and safety issues are comparable to other biologics,” he said, noting that high doses have led to aveolar proteinosis in monkeys.
A divalent anti-TNF/IL-17 molecule has been tested in a mouse model successfully. Phase I and II human studies are underway, but “we have no ideas if it will work in RA yet,” he said.
Tofacitinib: A small molecule that modulates JAK 1 and 3, thereby blocking multiple cytokines. "Tofacitinib 5-mg dose is the first approved oral small molecule JAK inhibitor with twice-daily dosing," Keystone observed. "Responses in clinical trials are similar to biologics, with a more rapid onset of action, and it is effective as monotherapy." He added that tofacitinib at 10 mg may be even more effective.
Safety issues of tofacitinib include reduced hemoglobin and increased lipids, creatinine, and neutropenia, as well as lymphopenia and herpes zoster infections.
Baricitinib: Inhibits JAK 1/2 which mediates signal transduction for a variety of cytokines involved in inflammatory conditions. Baricitinib shows good, early ACR 50 and 70 responses in phase II trials.
“Baricitinib will be on the market at some point," Keystone predicted. "Five phase III trials will be published soon. This oral, once-daily drug leads to therapeutic responses similar to biologics, with rapid onset of action and side effects consistent with other small molecules.”
VX-509: A candidate JAK 3 inhibitor. As oral monotherapy it has rapid onset of action, with efficacy similar to other small molecules. The safety profile includes increased liver function test abnormalities, reduced neutrophils, and increased lipids.
Filgotinib: A JAK 1 inhibitor. Data released just 2 weeks ago from a 12-week phase II study show that this oral drug taken once or twice a day allowed patients to achieve ACR 20 responses that appear to be higher than for other biologics.
“We may finally be breaking the ACR 60/40/20 response barrier. The drug appears to have a consistent rapid onset of action,” he said.