BOSTON, Massachusetts—The experimental B-cell depleting small modular immunopharmaceutical (SMIP), TRU-015 (Trubion Pharmaceuticals Inc, Seattle), may hold some advantages over other such drugs in terms of convenience and safety for treating rheumatoid arthritis (RA), according to late-breaking phase II data presented at the annual meeting of the American College of Rheumatology.¹

Given via intravenous infusion, TRU-015 is a novel single-chain polypeptide targeting CD20 on the surface of B-cells.

"The drug clearly has activity and does what you want a B-cell depleting agent to do," lead study author Daniel Burge, MD, of Trubion Pharmaceuticals told MSKReport.com. "I am very optimistic and think we have come up with an approach that is unique and has advantages over other molecules out there in terms of safety and convenience."

According to Dr. Burge, TRU-015 has the ability to engage the complement system and has activity with a single infusion; other B-cell depleting drugs require multiple infusions. However, one outside expert said that it is still too early to tell how many infusions of this drug will be needed to maintain efficacy.

65% of RA patients on 800 mg single dose still in ACR20 at 24 weeks

In the dose-escalating study, 276 patients with active RA received a single infusion of TRU-015 at 200, 400, 800, or 1600 mg with placebo. Patients who received the 800 mg dose showed improvements in the disease activity score 28 (DAS28), compared with placebo at 12 weeks and at all subsequent assessments.

Patients in the 1600 mg arm showed improvements in the DAS28 at 16 weeks and beyond. At 24 weeks, 61% of patients who received the 1600 mg dose of TRU-015 achieved ACR20, 13% achieved ACR50 by 24 weeks, and 4% achieved ACR70. Also at 24 weeks, 65% of patients in the 800 mg group achieved an ACR20 response, 26% achieved an ACR50 response; none achieved ACR70. In the placebo group, 33% achieved an ACR20 response, 9% achieved ACR 50 and 2% achieved ACR70 at 24 weeks.

Patients in the 1600 mg and 800 mg groups showed improvements on the Health Assessment Questionnaire Disability Index, C-reactive protein levels improved ~57% in the 1600 mg group, ~48% in the 800 mg group, and 28% in the placebo group, the study showed.

The infusions were generally well tolerated. One participant from the 400 mg group experienced a grade 3 adverse event on the day of infusion. Eight patients experienced serious adverse effects including two patients in the 1600 mg group, one patient in the 800 mg group, three in the 400 mg group, one in the 200 mg group, and one in the placebo arm.

Safety edge: B-cell recovery does not affect clinical response

In terms of safety advantages, response is maintained at 2 and 6 months with B-cell recovery. "The mantra is, ablate B-cells and get rid of them forever and ever. But we are seeing a maintenance and accrual of clinical response with B-cell recovery," Dr. Burge said.

Exactly which patients should benefit from this new agent is yet to be elucidated, but TNF-failures may be prime candidates. "Certainly that is where all biologics are started, but as people get more comfortable with their action and safety profile, there will undoubtedly be an opportunity for [new] drugs to be chosen as first-line biologics."

David G. Borenstein, MD, a rheumatologist at Arthritis & Rheumatism Associates in Washington, DC, is tempering his enthusiasm for the new agent until he sees more long-term data. "There is clearly evidence with other B-cell agents to suggest that patients improve when B-cells are depleted or diminished, and if B-cell recovery does not reverse this, there may be safety benefits." There is, however, no linear correlation between number of B-cells and patient benefit with other B-cell depleting agents such as rituximab. "Some people get worse even though their B-cells are down and other people retain improvements even though their B-cells come up," Dr. Borenstein noted.

Longer studies would be needed to determine how many infusions are necessary to achieve and maintain a clinical response. "Six months is great, but it doesn't tell the whole story. I wouldn't fault the drug if it needed to be repeated."

The good news is that the pipeline is full of new drugs for RA. "I am very excited," Dr. Borenstein continued. "Drugs that we used before now have been shown to cause remission, and we now have two or three new agents affecting new parts of the immune system for individuals who might not have done well [on existing drugs]. This is a very good time to be a rheumatologist."

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