According to statistics from the U.S. Centers for Disease Control and Prevention, arthritis in all its various disease states affects approximately one in five adults in America and the debilitating symptoms of the severe long-term pain associated with these conditions exerts a tremendous toll on the economy. As the population ages the incidence of these various musculoskeletal diseases is predicted to increase, so there's a constant demand for new medicines. For example, although multiple treatment options are already available for people suffering from rheumatoid arthritis (RA), there will always remain room for effective new therapies due to the high variability of response rates to the leading biologics now used.

In a recent report the Pharmaceutical Research and Manufacturers of America (PhRMA) identified more than 50 medicines targeting RA being developed by pharma and biotech companies. Among the close to 100 compounds in development for arthritis the report identified seven that target psoriatic arthritis (PsA), an inflammatory condition that occurs in a subset of people who have psoriasis.

One of these compounds – AIN457 (secukinumab) – is being developed by Novartis AG, of Basel, Switzerland. This anti-IL17 antibody has shown promising results in dialing down the action of interleukin-17A (IL-17A), which is a central player in the development of inflammatory diseases.

At the recent American College of Rheumatology Congress (ACR) held in Boston, the company reported the first ever results from its pivotal phase III FUTURE 1 and FUTURE 2 studies showing that secukinumab demonstrated rapid and significant clinical improvements versus placebo in improving the signs and symptoms of PsA.

The data showed significant improvements in signs and symptoms of PsA were achieved versus placebo, as measured by a 20 percent reduction in the American College of Rheumatology response criteria (ACR 20), a standard tool used to assess improvement at week 24.

Christopher Ritchlin, Department of Medicine, University of Rochester, said that between 50 percent and 54 percent of secukinumab patients achieved at least ACR 20 in both FUTURE 1 (150 mg) and FUTURE 2 (150 and 300 mg). This is in comparison to 17.3 percent and 15.3 percent of placebo patients who achieved ACR 20 in FUTURE 1 and FUTURE 2, respectively.

RAPID ONSET

Secukinumab patients in all dose groups experienced rapid onset of effect as early as week one in FUTURE 1 and week three in FUTURE 2 (150 mg and 300 mg). Long-term data from FUTURE 1 also confirmed these improvements were sustained through 52 weeks of treatment. Also Ritchlin noted, clinical benefits with secukinumab were observed in patients who had not been previously treated with anti-TNF therapies (anti-TNF naïve), the current standard of care for PsA, and also in patients who had an inadequate or no response to anti-TNFs.

In FUTURE 1, more than 80 percent of patients experienced no progression of joint structural damage, which is suffered by approximately two-thirds of patients with PsA, and is associated with loss of function and disability. Improvements in joint damage were shown in both anti-TNF naïve patients and in the patients with inadequate or no response to anti-TNFs. Additionally, secukinumab demonstrated rapid, significant and sustained improvements in skin psoriasis in both FUTURE 1 and FUTURE 2 which was consistent to results of phase III psoriasis studies with Secukinumab involving nearly 4,000 patients. (See BioWorld Insight, Oct. 28, 2013.)

In addition to PsA, secukinumab is also in clinical trials for the treatment of ankylosing spondylitis (AS) and rheumatoid arthritis. Global regulatory applications for secukinumab in AS and PsA are planned for 2015. This follows the secukinumab global regulatory applications for moderate-to-severe plaque psoriasis, which were filed in October 2013 with approvals anticipated in late 2014 or early 2015.

Amgen Inc., of Thousand Oaks, Calif., and Astrazeneca plc, of London, are also working with a candidate drug that targets the interleukin-17 receptor, brodalumab. They reported phase II results in The New England Journal of Medicine, showing that data from a 168-patient study revealed significantly improved signs and clinical symptoms associated with psoriatic arthritis at 12 weeks, as measured by the ACR20 response criteria. The study also showed many patients continued to improve, and that the improvements were sustained through the first 52 weeks.

At the ACR meeting, Alder Biopharmaceuticals Inc., of Bothell, Wash., presented data from a randomized, double-blind, placebo-controlled, dose-ranging multicenter, phase IIb trial evaluating the safety and efficacy of clazakizumab in adults with active psoriatic arthritis. Clazakizumab met the primary endpoint of the study, which was ACR20 response rate at week 16 versus placebo. Though there was no clear dose response, ACR 20/50/70 response rates were higher than placebo for all clazakizumab treatment arms at week 24. Clazakizumab is a humanized, monoclonal antibody, designed to block the pro-inflammatory molecule interleukin-6 (IL-6), which plays a key role in the inflammatory cascade leading to the inflammation, swelling, pain and destruction of large and small joints associated with arthritis. (See BioWorld Today, Nov. 16, 2014.)

In September Alder regained worldwide rights to clazakizumab from Bristol-Myers Squibb Co., of New York. Alder said the decision was based on a portfolio prioritization at BMS and was "not based on any new or unexpected efficacy or safety data or technical issues." (See BioWorld Today, Sept. 3, 2014.)

Pfizer Inc. also is conducting a clinical program in PsA with its oral Janus kinase (JAK) inhibitor, Xeljanz (tofacitinib), which already is approved in rheumatoid arthritis. The company has an ongoing 12 month study, which is investigating the effectiveness and safety of tofacitinib in treating the signs and symptoms, improving physical function and preserving bone structure in patients with active psoriatic arthritis and who have had an inadequate response to a traditional, non-biologic disease modifying anti-rheumatic drug.

In March of this year Celgene Corp. moved its oral phosphodieasterase-4 (PDE4) inhibitor Otezla (apremilast) over the goal line with its FDA approval for adults with active psoriatic arthritis.

PERSONALIZED APPROACH

One of the problems physicians face is to determine the most appropriate therapy for arthritic conditions due to the variable responses exhibited in patients. Research findings presented at ACR may help help.

For example, it is known that the response to TNF-alpha inhibitor drugs varies considerably among RA patients. For this reason researchers at the Mayo Clinic, the Feinstein Institute, the University of Alabama and other institutions looked at whether circulating type-I interferon (IFN) levels could be used to predict treatment response to TNF-alpha inhibitors and other biologic drugs in RA.

The goal of the study was to find a pre-treatment blood test that might predict the response to TNF-alpha inhibitor therapy. The test "could be used to assist the decision-making process about which drug to use in a particular RA patient," noted Timothy Niewold, of the Mayo Clinic in Rochester, Minn., and a lead author on the study.

Their findings could eventually lead to a viable treatment guide test. They found that an increased ratio of IFN-beta/IFN-alpha greater 1.3 in the patients' pre-treatment serum sample was associated with lack of response. Similarly, a higher ratio score was positively correlated with higher Disease Activity Scores at the same point in treatment with the TNF-alpha inhibitor.

The study's authors concluded that pre-treatment serum interferon levels predict response to TNF-alpha inhibitor therapy in RA and that a pre-treatment blood test result could predict a particular patient's response to TNF-alpha inhibitors.