Editor

The phrase "rheumatoid arthritis" almost right away calls to mind Genentech Inc.'s Rituxan (rituximab, which targets the CD20 antigen, for RA and non-Hodgkin's lymphoma).

Partnered for marketing with Biogen Idec Inc. and cleared by the FDA for patients who have failed to respond to treatment with anti-TNF drugs such as Enbrel (etanercept, Amgen Inc.), Remicade (infliximab, Centocor Inc.), or Humira (adalimumab, Abbott), Rituxan sold $572 million in the third quarter, compared with the consensus estimate of $588 million, and $509 million a year ago.

Physicians and pharmacy shelves offer a full arsenal aside from the mainstay antimetabolite, methotrexate. These include non-steroidal anti-inflammatory drugs, corticosteroids and disease-modifying anti-rheumatic drugs (DMARDs), as well as COX-2 inhibitors, immunosuppressants and the anti-TNF biologics mentioned above.

Each approach to RA carries its own benefits as well as risks - in some cases, significant risks - and patients often cycle through several drugs as they try to find relief from the pain, stiffness, swelling and fatigue brought on by the disease.

Many patients, though, shy away from talking with the doctors about trying something new, according to a new Harris survey sponsored by Genentech. And a pool of rheumatologists surveyed separately had a much different view of their patients' situations. The phone survey consulted 512 patients with moderate-to-severe RA, and 153 rheumatologists, though not specifically the doctors who are treating the patients polled.

Though patients have been on prescription drugs for more than 12 years on average, and have switched an average of six times during the period, 75 percent said they still must deal with symptoms, and more than 70 percent of those describe their afflictions as still in the moderate-to-severe range.

More than 85 percent of patients said they'd like to try a new RA therapy (such as Rituxan) that could improve and prolong symptom relief, nine out of 10 rheumatologists said they would try instead another TNF antagonist if a patient wanted to switch. And while 45 percent of patients said they had asked about a new drug, rheumatologists said only about 20 percent of their patients have asked.

"Physicians are saying, 'Heck, my patients are doing fine. They're not bringing this up with me,'" said Philip Mease, during a conference call regarding the Harris results. "There is an overall, underlying knowledge that there are a great deal of patients out there not getting adequate symptom relief with a regimen that typically includes an anti-TNF therapy," he added, though patients are "variably able to communicate this issue with their physicians."

When a participant suggested the poll might be intended to suggest that doctors prescribe more Rituxan, Mease conceded that "one would naturally anticipate" an interest by Genentech and Biogen in the poll's findings. Another anti-TNF alternative is Bristol-Myers Squibb Co.'s Orencia (abatacept), he noted, adding that he was making a more general point. Orencia is a selective co-stimulation modulator that inhibits T cell activation by binding to CD80 and CD86, thereby blocking interaction with CD28.

"You don't even have to go to those specific recommendations, and that's not what I'm saying," Mease told listeners on the call. He pointed to the trial known as TICORA, a rough acronym for "tight control of rheumatoid arthritis." The two-arms study, from which the first results emerged in 2004, found that careful monitoring of RA patients through more scientific, less subjective means led to better outcomes.

"This didn't even involve switching amongst different biologic agents," said Mease, who recommended patients be more proactive and direct with doctors. Aside from the anti-TNFs, Rituxan, and Orencia, research is under way on various fronts to find new therapies, a handful of them making news lately.

The Israel-based firm Can-Fite BioPharma Ltd., for example, said last week that it plans a confirmatory Phase IIb with CF101, an oral drug that targets the adenosine A3 receptor. Over the summer Can-Fite published the results of a Phase IIb study with CF101 in combination with methotrexate showing that the ACR20 response, the primary efficacy end point of the study, showed no difference between the CF101-treated and placebo groups. However, a substantial difference in favor of CF101 was seen in the ACR50, the ACR70 and the EULAR responses, and Can-Fite estimates that the second trial will start in next year's first quarter, finishing about a year later.

Adolor Corp., of Exton, Pa., started a second Phase II study of ADL5859, a delta opioid agonist in development for pain. The study, called 33CL232, is expected to enroll about 60 subjects. ADL5859 also is being tested in an acute pain study, which began in the second quarter, and Adolor said a third trial in neuropathic pain likely will start later this year.

In Germany, 4SC AG this month said the last patient was released from the Phase IIa trial with SC12267 for RA, as scheduled. The small molecule DMARD was tested in a three-tiered, placebo-controlled study, with 120 patients given two doses of SC12267 per day over a three-month period. Results are expected later this quarter.

FivePrime Therapeutics Inc.'s spring 2006 research collaboration for RA therapies with another German firm, Boehringer Ingelheim GmbH, at the start of the month yielded proteins identified by FivePrime that could prove useful, and the finding represents a target discovery milestone in their deal. Boehringer has exclusive, worldwide rights to develop and commercialize products and targets.

Catching the eye of CIBC World Markets was Rigel Pharmaceuticals Inc., with its Syk kinase inhibitor R788, which began a Phase II ascending-dose trial with the DMARD in RA last fall. Top-line data are expected in the second half of this year. CIBC initiated coverage of Rigel with a "sector outperformer" rating last week, setting a price target of $16. The stock was trading around $9.75 last week.

Syk, an intermediary in several immunologic and hematologic signaling cascades, could also prove useful in B-cell lymphomas by interfering with a B-cell survival mechanism. The drug improved symptoms and pathology in an animal model of RA, restored platelet counts in an ITP model, and improved survival in lupus-prone mice, affecting markers of Syk inhibition dose-dependently, with a neutropenia toxicity at higher doses.

"Based on the compelling mechanism of action, therapeutic benefits observed in animal models, and indications of on-target effects in humans, we believe R788 is likely to have activity in a variety of immune-related disorders," CIBC analysts wrote in a research report, anticipating December results from the Phase II study.

"We believe there is a good probability the trial will show clear signals of efficacy and an acceptable safety profile for R788, catalyzing near-term upside for Rigel shares," CIBC went on. "We also expect updated results in November from an ongoing open-label study of R788 in immune thrombocytopenia purpura," and noted that the compound already has shown activity in that indication.

Rigel also has R348, the Phase I-stage lead compound in its JAK3 kinase inhibitor program, but R788 has "blockbuster potential," in CIBC's view and "could potentially be positioned ahead of the currently-used injectable biologic therapies." The compound might also work in lymphoma and multiple sclerosis, and CIBC said peak annual sales could surpass $1 billion.

In early May, Rigel - whose partners include such names as Janssen Pharmaceutica NV, Novartis Pharma AG, Daiichi Pharmaceuticals Co. Ltd., and Merck & Co. Inc. - raised $48.8 million to pursue its programs. The firm also has out-licensed its aurora kinase inhibitor program, in Phase I for cancer, to Merck Serono SA and its preclinical inhaled SYK kinase inhibitor program to Pfizer Inc.

Also in RA, last week Galapagos NV signed with Janssen a deal that could mean as much as €1 billion (US$1.4 billion) in up-front payments, license fees and milestones, and could involve as many as 15 to 19 targets, in an arrangement that Galapagos hailed as the largest RA research alliance ever. The Belgian firm has been working on oral RA drugs, aims to put its lead program, based on the kinase target GT418, into the clinic next year. Galapagos has identified two more programs in the discovery stage, going after GT146 and GT442, and Janssen alliance lets the firm investigate 16 more potential RA targets.