February 1, 2014 (Vol. 34, No. 3)

Gail Dutton

Highly Innovative Therapeutics Progressing Rapidly in Rheumatoid Arthritis Space

Drug developers addressing rheumatoid arthritis (RA) therapeutics are challenging well-established TNF inhibitors with new approaches that promise better efficacy and fewer side effects. Leading contenders include multiple JAK inhibitors and interleukin inhibitors, and a potassium channel blocker that has the potential to best them all.

“At a really basic level, most of the therapies in development and on the market are based on immune suppression,” observes Chuck Magness, Ph.D., CEO, Kineta.

“TNF agents were the first biologics commonly used in RA, and are generally the first line of therapy for DMARD-IR [inadequate response to disease-modifying anti-rheumatic drugs] patients,” notes Harry Glorikian, founder and managing partner, Scientia Advisors. Although anti-TNFs are considered safe and efficacious therapeutic options for patients with moderate to severe rheumatoid arthritis, Decision Resources predicts their market share will decline from 73% in 2012 to 53% by 2022.

“Existing RA treatments often fail to dramatically improve symptoms,” explains Glorikian. “The primary efficacy criteria for anti-TNF trials is ACR20, which is only a 20% reduction in symptoms of disease, and overall, only 60–70% of patients showed a 20% reduction in symptoms.

“Additionally, many anti-TNFs are more efficacious when used in combination with methotrexate (MTX). There is a segment of RA patients that are intolerant to MTX and need to take monotherapy. While anti-TNFs are effective as a monotherapy, there could be better options,” Glorikian and his team point out.

Another problem, he continues, is that “Some patients suffer primary loss of response, so they fail to respond to treatment with any TNF inhibitor. Secondary loss of response is common with at least some TNF agents, like Remicade and Humira, as patients form antibodies to the drug that neutralize its presence in the body.” Alternatives to TNF inhibitors, therefore, are clearly needed to improve patient outcomes.


ShK-186, a synthetic peptide developed by Kineta for treating rheumatoid arthritis and other autoimmune diseases, blocks Kv1.3 potassium ion channels. Kv1.3 is directly involved in the activation of effector memory T cells, acknowledged mediators of autoimmune disease.

JAK Inhibitors

Analysts say JAK inhibitors will be the major contributors to the growth of the RA market at least through 2022. Outside the anti-TNF field, “There is significant movement to focus on the monotherapy segment, which may be as large as 30% of the RA population,” Glorikian adds.

Pfizer’s Xeljanz (tofacitinib) is approved. Data from a 12-month interim analysis demonstrates that tofacitinib inhibits progression of structural damage and improves disease activity in patients with RA who are receiving MTX, according an article in Arthritis Rheumatology.

As a novel, first-in-class therapeutic, “Tofacitinib has seen a slow uptake,” Glorikian tells GEN. “This isn’t surprising considering the safety profile—which has been described as biologic-plus by key opinion leaders—and the fact there is no long-term clinical experience for rheumatologists to lean on.” The drug has not been approved in Europe because of safety and efficacy concerns, although analysts at Decision Resources consider eventual approval likely.

Eli Lilly and Incyte have advanced baricitinib, an oral JAK1 and JAK 2 inhibitor, to Phase III trials. Results from the Phase II study announced in 2013 indicated the clinical improvements observed at week 24 were sustained through week 52 of the study.

Vertex Pharmaceuticals’ JAK3 inhibitor, VX-509, met its goals for 20% improvement in the signs and symptoms of RA during its Phase IIB trials. Depending on dosage, up to 68% of patients experienced significant improvement.

Galapagos and AbbVie also have a JAK1 inhibitor, GLPG0634, in Phase II trials, and Astellas has a JAK 1 and JAK 3 inhibitor, ASTP15K, in Phase IIB trials.


Interleukin Inhibitors

“The IL-1 inhibitors are not viewed as favorably as other agents because they are perceived as less efficacious than other biologics for the treatment of rheumatoid arthritis,” Glorikian says. Nonetheless, there is significant activity among drug developers.

A new subcutaneous formulation of Genentech’s Actemra® (tocilizumab) was approved in October, in addition to previously approved intravenous administration. This is the sixth FDA approval for this humanized IL-6 receptor antagonist in four years.

Phase III results for Regeneron and Sanofi’s Sarilumab were reported late last year. When administered with MTX in the 52-week trial, this inhibitor of the IL-6 receptor reportedly improved physical function and inhibited the progression of joint damage, thus offering an improvement against MTX alone.


BMS reported Phase IIB data from a study with Clazakizumab in October. The drug reportedly exhibited promise as a monotherapy and as an adjuvant to MTX. A humanized anti-IL-6 monoclonal antibody is directed against the IL-6 cytokine, rather than the receptor. It is expected to lower disease activity and lead to remission.

Sirukumab, an IL-6 inhibitor by Janssen and GSK, is undergoing Phase III trials, which are scheduled for completion in 2016. Ablynx currently has ALX-0061, an anti-IL6 receptor nanobody® based on single-domain antibody fragments in Phase IIA trials. Earlier trials indicated a strong disease-modifying profile.

Novartis’ IL-17 inhibitor, secukinumab (AIN457), is in Phase III trials for psoriasis, and other studies suggest efficacy in conditions such as rheumatoid arthritis and psoriatic arthritis. Results for psoriatic arthritis are scheduled for 2014 release.


An Alternative

Kineta is developing a solution that has a much more limited systemic effect than interleukin inhibitors, JAK inhibitors, or anti-TNF drugs. By blocking the kv1.3 potassium channel, which is essential for activation of the effector T cells that start the autoimmune cascade, this solution only affects about 5% of the white blood cells and leaves most of the immune system intact, Kineta’s Dr. Magness explains.

“Few cells in the body require kv1.3,” he says. “We’re blocking a cell type rather than blocking cell signaling. Broad-based approaches have potentially disastrous implications, creating off-target effects, such as opportunistic infections and increased rates of skin cancer,” Dr. Magness says.

The compound, ShK-186, began a Phase Ib multidose safety trial in the autumn with plans to start a separate study in early 2014 focusing on psoriatic arthritis patients. “Between 20 and 40 percent of psoriasis patients have severe lesions and can develop joint involvement. There have been only a few drugs developed specifically for psoriatic arthritis,” continues Dr. Magness, and the market for psoriatic arthritis medications is expected to double during the next five years. “We’re looking at this across the immune system for multiple disease states, including psoriatic arthritis, RA, lupus, multiple sclerosis, and type one diabetes,” he adds.


The Challenge

For each of these approaches, the challenge will be to overtake the existing therapeutics. “Rheumatoid arthritis is dominated by MTX, developed in the 1950s, and TNF alpha inhibitors,” Dr. Magness says. Both, despite their shortcomings, are considered to work and to have acceptable tolerability. It will take some time for alternative therapies to replace them. So, for the foreseeable future, anti-TNF cycling will still occur. As Glorikian’s team points out, “Patients are likely to use two anti-TNFs before moving on to therapeutics with another mechanism of action like Actemra or Orencia.”

The other key challenge lies with the disease itself. So far, there’s no conclusive evidence illuminating the causes of RA. “One component appears to be genetic,” Glorikian says, “while smoking remains a significant risk factor.” The immune system is thought to play a role, also.

Its role in other diseases and conditions also may complicate the issue. “Because arthritis occurs so often with other conditions like diabetes and heart disease, arthritis limitations may be interfering with the recommended management of those conditions, especially in regards to physical activity,” the CDC’s Wayne H. Giles, M.D., director of the division of population health, said in a statement.

“Thousands of genes are activated in the immune system, and it requires a delicate balance to ensure it doesn’t go out of control and attack the body. But, in rheumatoid arthritis, the immune system does go out of balance,” Dr. Magness elaborates. Part of the challenge, therefore, is that therapeutics must intercede in a finely tuned immune system, and interventions often cause negative effects elsewhere.

“Diagnostics companies, such as Crescendo Biosciences (recently purchased by Myriad) offer prognostic tests focused on determining the severity of the disease,” according to Glorikian. Those tests enable patients expected to have the most severe form of RA “to be treated aggressively with biologics, while patients likely to have less severe RA can use the more conventional step-up strategy.”

The arthritis therapeutic market is expected to grow moderately between now and 2015, with incidence in the U.S. growing by about 1 million people each year. Currently, more than 53 million American have physician-diagnosed arthritis, according to a CDC study.

When analyzing the markets in the U.S., Japan, U.K., France, Italy, Spain, and Germany, Decision Resources predicts growth from 2012 figures of $12.3 billion to $15.8 billion by 2022. Nonetheless, GBI Research, in its report, calls arthritis medications a “highly competitive” market with “highly innovative” drugs in the pipeline.