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A novel drug conjugate combining steroidal and tumor necrosis factor (TNF) inhibitor activity appeared highly effective in a phase IIa trial as a treatment for rheumatoid arthritis (RA).

Patients with active RA assigned to the product, called ABBV-3373, showed responses after 12 weeks that were at least as good as seen with the leading approved TNF inhibitor, adalimumab (Humira), according to Frank Buttgereit, MD, of Charité University Medicine in Berlin, and colleagues.

With changes in the 28-joint Disease Activity Score with C-reactive protein (DAS28-CRP) as the primary outcome, scores declined 2.65 points among 31 patients receiving ABBV-3373, compared with a decrease of 2.13 points in a historical cohort of 242 adalimumab-treatment patients (P=0.02), the researchers .

Another 17 patients in the trial were randomized to adalimumab, and this group showed a mean decline in DAS28-CRP of 2.51 points, which did not differ significantly from the ABBV-3373 group.

Buttgereit and colleagues estimated from these data that ABBV-3373 had a probability of superiority over adalimumab of 79.3%-99.5%.

The most notable safety finding with the novel intravenous agent was one case of anaphylactic shock. Following this incident, investigators increased the infusion duration from 3 minutes to 15-30 minutes, with no more anaphylaxis cases occurring.

Both ABBV-3373 and adalimumab are AbbVie products, and the latter serves as the new agent's anti-TNF backbone. The steroidal activity comes from "a proprietary glucocorticoid receptor modulator," Buttgereit and colleagues explained.

The idea, they added, is that the combined molecule will gravitate selectively to activated immune cells expressing TNF, "thus increasing overall efficacy, while minimizing systemic exposure to the [steroidal component]." It's hoped that this mechanism will cut incidence of the adverse effects known to come with long-term steroid treatment, while improving on adalimumab's efficacy; the .

To be eligible, patients needed DAS28-CRP scores of at least 3.2 plus at least four swollen and at least four tender joints, indicating moderate-to-severe disease activity, despite taking maximal doses of methotrexate. Past use of biologic or other targeted RA drugs was an exclusion.

ABBV-3373 was given at 100 mg IV along with subcutaneous placebo every other week; the adalimumab control group received IV placebo plus 80 mg of the active drug by subcutaneous injection every other week. Methotrexate was continued in both groups. The historical adalimumab-treated cohort was drawn from three prior trials involving the same dosage and with DAS28-CRP scores available.

Outcome measures included other DAS28-based values, ACR50 response rates (50% decline in symptoms by American College of Rheumatology criteria), physician and patient global RA assessments, and overall health status. The trial also included a 12-week extension, during which the ABBV-3373 group was switched to placebo while those assigned to adalimumab continued with it.

Mean patient age was about 52, and three-quarters were women. DAS28-CRP values at baseline averaged 5.6 in the two randomized arms and 6.5 for the historical controls. Other indicators all confirmed that the patients had moderate to severe symptoms.

Although changes in DAS28-CRP showed rough equivalence and potential superiority for ABBV-3373 versus adalimumab, ACR50 responses did not. Some 65% of patients assigned to adalimumab reached this benchmark at week 12 compared with 52% of the ABBV-3373 group (P not reported). Other secondary outcomes, though, did indicate comparable efficacy with the two agents.

Efficacy was generally maintained in both groups during the extension period as evaluated with DAS28-CRP and most other outcome measures.

Safety findings couldn't be definitive with only 48 participants in the study. Other than the anaphylactic reaction, however, no major safety issues emerged in the trial. Overall adverse events were less common with ABBV-3373 than with adalimumab (37% of patients vs 75% through week 24) and only one very mild case of liver enzyme elevation (alkaline phosphatase more than 1.5 times the upper limit of normal) was seen with the novel agent. Two serious infections were observed in the ABBV-3373 group, with none in the adalimumab arm. One patient in each group quit the study because of adverse events.

Despite the favorable results, this is probably the end of the line for ABBV-3373 because, as Buttgereit and colleagues noted, AbbVie has since developed a "slightly modified" version called ABBV-154 that is suitable for subcutaneous injection. Phase II studies with this improved product are now underway in , , and . Results could begin to appear as soon as next year.

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