CHICAGO – The novel anti–tumor necrosis factor nanobody ATN-103 looks as if it will be moving on to phase III trials, based on the good efficacy and safety results of a phase IIA trial of more than 250 patients with rheumatoid arthritis.
"The 80-mg, every-4-weeks regimen was the one [dosage] that was consistently improved over placebo by ACR 20" (the American College of Rheumatology evaluation scale that reflects a 20% improvement in specified parameters), Dr. Roy M. Fleischmann said at the American College of Rheumatology annual meeting. In addition, this dosage group comprised the only patients to achieve significantly better responses on the ACR 50 and the ACR 70 criteria than was achieved by those taking placebo.
Dr. Roy M. Fleischmann
A nanobody is the smallest functional fragment of a naturally occurring, single-chain antibody, and ATN-103 (ozoralizumab) is just one-quarter the size of conventional TNF-blockers, Dr. Fleischmann noted. As a humanized bispecific nanobody, ATN-103 contains two human TNF-binding domains that are linked to a human serum albumin–binding domain to extend half-life.
The researchers conducted a double-blind, placebo-controlled, phase IIA proof-of-concept study that included 253 patients in three treatment groups, with roughly 40 patients at each dosage level. The 4-week dosing group received the active drug (a subcutaneous injection of 10 mg, 30 mg, or 80 mg) on day 1 of weeks 4, 8, and 12. The 8-week dosing group received either 10 mg or 80 mg of the drug on day 1 of each 8-week period. Those in the placebo group received a placebo injection on day 1 of weeks 4, 8, and 12.
All of the patients had active RA (defined as at least six swollen and at least six tender joints) at the time of screening and at baseline, despite having been treated with methotrexate for at least 12 weeks. To qualify for the study, they had to meet the 1987 revised criteria for RA at least 24 weeks prior to screening, to be within ACR functional class I-III, and to have a C-reactive protein level of at least 8 mg/L. In addition, their methotrexate dose (7.5-25 mg) and route of administration had to be stable for at least 6 weeks prior to baseline. The patients were stratified by prior TNF-inhibitor use; two-thirds of them were naive to TNF-blockers.
The primary outcome of this study was ACR 20 at 16 weeks. Secondary end points were improvements over placebo in clinical scores, DAS28 (Disease Activity Score based on a 28-joint count), ACR 50, ACR 70, and EULAR responses at week 16.
The ACR criteria are used to evaluate improvement in tender or swollen joint counts, as well as improvement in three of the following five parameters: acute phase reactant, patient assessment, physician assessment, pain scale, and disability/functional questionnaire scores. The EULAR response includes not only change in disease activity but also current disease activity.
"The safety profile looked relatively clean," said Dr. Fleischmann of the Metroplex Clinical Research Center in Dallas. Of 43 patients in the 80-mg, every-4-weeks group, there were 23 adverse reactions, of which infections were the most common at 19% – a safety profile similar to that of other anti-TNFs. One patient did withdraw from this group because of adverse events (AEs), but there were no deaths, no dose-limiting toxicities, and no clinically significant increases in AEs or serious AEs with increasing dose. Overall, 13 patients reported 17 serious AEs, of which respiratory tract infections and disorders were the most common.
The trial was sponsored by Pfizer, and all of the authors noted significant financial relationships with the company.