Rheumatology Pipeline Boasts Innovation, ID Line Is Drying Up: ACR/IDSA 2009

Several promising compounds for the treatment of rheumatoid diseases have been recently approved, are in phase 3 trials, or are about to undergo phase 3 evaluation. The following products are some of the main products that were featured at the 2009 annual meeting of the American College of Rheumatology (ACR).

Promising Therapies for Lupus, Gout, and More
Belimumab first new lupus therapy in 50 years. The investigational agent belimumab (Benlysta) is poised to become the first new drug for systemic lupus erythematosus (SLE) in 50 years. In the 1-year, phase 3, pivotal, BLISS-52 study, belimumab significantly reduced disease activity, disease flares, and steroid use, while improving fatigue and quality of life in patients with SLE compared with placebo. A second phase 3 trial called BLISS-76 showed positive results in November 2009, and the drug is expected to be submitted to the US Food and Drug Administration (FDA) for approval in early 2010. Belimumab is a human monoclonal antibody that is a specific inhibitor of the biological activity of B-lymphocyte stimulator, a protein involved in the production of autoantibodies that destroy healthy human tissue.

CP-690,550 novel oral JAK inhibitor for RA. Experts are enthusiastic about the first novel oral Janus-associated kinase (JAK) inhibitor under development as a promising treatment for rheumatoid arthritis (RA). A randomized, double-blind, 24-week phase 2B study showed that in 507 patients with active RA who are already receiving background methotrexate therapy, CP-690,550 achieved sustained responses on 5 mg, 10 mg, and 15 mg twice daily with a manageable toxicity profile. CP-690,550 also demonstrated efficacy as monotherapy in a 24-week, double-blind, placebo-controlled phase 2B study in 384 patients with active RA who had not responded to previous treatment with disease-modifying antirheumatic drugs. These patients were not taking background methotrexate. In this study, the 5-mg, 10-mg, and 15-mg twice-daily doses were the most promising. The most common treatment- emergent adverse effects, mostly mild or moderate in severity, in both studies were urinary tract infections, headache, and diarrhea. The 5-mg and 10-mg twice-daily doses are expected to be used in the phase 3 clinical trials program.

Canakinumab promising for acute gout. Canakinumab (Ilaris)—an injectable drug recently approved by the FDA for 2 rare inherited inflammatory disorders—showed promising results in the treatment of 200 patients with refractory acute gouty flares or those with acute gout who are not candidates for other gout treatments. These results, presented at a late-breaking news session, were based on an 8-week, multicenter, blinded, double-dummy, active controlled trial that compared canakinumab with triamcinolone acetonide (TA) in 200 patients. The most notable finding was that 150 mg of canakinumab provided more rapid pain relief than TA for acute flares of gout and prevented recurrence of flares. The relative risk reduction was 94% at 8 weeks postdose. This well-tolerated drug selectively targets interleukin-2 beta.

First plant-derived colchicine approved for gout. Colchicine (Colcrys) has been used to treat gout for many years without FDA approval. In 2009, the FDA approved Colcrys to treat acute flares of gout—the first FDA approval of a colchicine formulation. And just before the ACR meeting, the FDA approved a low dose of colchicine for gout prophylaxis. At the ACR meeting, a secondary analysis of the large, placebo-controlled, phase 3 pivotal AGREE (Acute Gout Flare Receiving Colchicine Evaluation) study showed that low-dose colchicine (1.2 mg, then 0.6 mg in 1 hour [ie, 1.8 mg total] was as effective as high doses (1.2 mg, then 0.6 mg hourly x 6 [ie, 4.8 mg total]) in reducing pain associated with gout; in addition, patients in the low-dose group had fewer adverse events. In the study, within 24 hours of initiating the active drug, 34.6% of the 52 patients who received high-dose colchicine achieved at least a 50% reduction in pain compared with 43% of the 74 patients taking low-dose colchicine; only 17.2% of the 58 patients in the placebo group met that end point. The lead investigator said that within 24 hours, 'excruciating pain' became 'bearable' with both doses of the drug.

Tanezumab for knee pain in osteoarthritis. Tanezumab, an investigational humanized monoclonal anti-body specific for nerve growth factor, reduced knee pain in patients with osteoarthritis in a previously reported randomized phase 3 trial. At the ACR meeting, researchers presented results from a 1-year openlabel extension study that included 281 patients from the phase 3 trial, showing that pain relief (reduced overall knee pain intensity) was maintained during open-label treatment of up to 1 year. The drug is being studied for several types of chronic pain.

Sodium oxybate for fibromyalgia. Sodium oxybate (Xyrem), a central nervous system depressant recently approved by the FDA for the treatment narcolepsy, is a controlled substance administered as an oral solution. The results of a placebo-controlled, randomized phase 3 trial were presented at ACR, showing that the drug was tolerable and efficacious as a treatment for fibromyalgia. The study included 548 subjects randomized to 2 different doses of sodium oxybate (4.5 g/night or 6 g/night) versus placebo. Clinically meaningful improvements were seen in patients who received the active drug: at least a 50% reduction in pain was reported by >40% of patients and moderate reductions in pain of at least 30% were reported by >50% of the participants. A significantly higher proportion of patients treated with either dose achieved specified reductions in the pain visual analogue scale at 14 weeks compared with placebo. Results significantly favored the active drug versus placebo on both the Fibromyalgia Impact Questionnaire and the Patient Global Impression of Change scale at week 14. Discontinua tions were similar in all 3 treatment groups. Adverse events associated with sodium oxybate— most often headache, nausea, and dizziness—were generally mild or moderate in severity.

Denosumab put on hold. During the ACR meeting, the FDA announced that it had delayed approval of denosumab (proposed trade name Prolia), for postmenopausal osteoporosis, asking for additional safety information. Denosumab is an anti-RANKL product that may halt progression of cancer to bone. It is given once monthly and its mechanism of action is different from that of other drugs FDA approved for osteoporosis. All clinical trials of this drug have been positive, and the FDA did not ask for more clinical trials. Earlier in 2009 an FDA panel voted unanimously for the approval of the drug for postmenopausal osteoporosis, with the limitation to women with a history of fractures or those at high risk for fractures.

Dearth of New Anti-Infectives, Growing Resistance
Although several studies of drugs in the pipeline (see Web Exclusive) were presented at the 2009 annual meeting of the Infectious Diseases Society of America (IDSA), experts were pessimistic about the lack of drug development for infectious diseases.

'Antibiotic drug development is dying. We are running out of new drugs at the same time that organisms are becoming more resistant to every drug we have,' said Brad Spellberg, MD, Assistant Professor of Medicine at UCLA, Torrance. He attributed this dire situation to economic pressure and regulatory pressure. 'Economic forces are dominant. A patient takes an antibiotic for 7 days and then stops. Drug companies want to develop drugs that people take over a long period of time for chronic conditions. Antibiotics are a lower return on investment.'

Ever since the Vioxx debacle, the FDA's approval process has become 'a morass,' Dr Spellberg said, 'with statisticians dominating the discussions. Clinicians have lost their voices.'

The IDSA is trying to address this problem in several ways, including promoting appropriate use of antibiotics (antibiotic stewardship), focusing on infection control, and encouraging development of new drugs. The IDSA is currently working to develop economic incentives for drug development, and is also lobbying for passage of the Strategies to Address Antimicrobial Resistance Act in Congress.

Although the rates of resistant gram-negative pathogens are rising, the drug pipeline to treat those infections is weak, said Paul G. Auwaerter, MD, Program Chair of the 2009 IDSA and Clinical Director of the Division of Infectious Diseases at Johns Hopkins School of Medicine. 'We have a limited menu of drugs to treat gram-negative infections,' Dr Auwaerter said.

A similar shortage exists for new antiviral drugs, stated Richard J. Whitley, MD, IDSA new President and Director of Pediatric Infectious Diseases at the University of Alabama, Birmingham. Supplies of oseltamivir (Tamiflu) for influenza A (H1N1) are running out; peramavir is now advised as an alternative for patients who cannot take oseltamivir (eg, patients with short bowel syndrome).