Early Safety Study of Atacicept Shows Promise in Rheumatoid Arthritis

Atacicept is a recombinant fusion protein that binds and neutralizes two molecules important for the maturation, proliferation, and survival of B cells: BLyS and APRIL.  While B-cell depleting therapies have demonstrated efficacy in RA, atacicept differs from the anti-CD20 targeted monoclonal antibodies, such as rituximab, as its effects extend over the entire lineage of B lymphocytes, including plasma cells.  Here, Tak et al (Arthritis Rheum 2008; 58:61) report early Phase I data on safety and pharmacology of atacicept in RA patients.

Methods

Rheumatoid factor positive RA patients were randomized in a 3:1 fashion to receive atacicept as a single subcutaneous dose of 70, 210, or 630 mg; multiple subcutaneous injections of 70, 210, or 420 mg; or placebo.  Patients were required to have active disease and no history of B cell depleting therapy.  Concomitant therapy with methotrexate (<17.5 mg per week) and prednisone (<10 mg per day) was allowed.  Safety, pharmacokinetic, pharmacodynamic, and preliminary efficacy endpoints were assessed up to three months after the last dose received.  The study was primarily conducted at sites in Russia and Eastern Europe.

Results

73 patients were randomized (18 to placebo and 6 to each of the 6 dosing cohorts).  Women made up 81% of patients with a mean age at enrollment of 56 ± 8 years.  Mean RA duration was approximately 8 years.  On average, patients had active disease, with a mean DAS28 at baseline of 6.6 ± 0.8.

One patient withdrew due to disease worsening.  Five patients discontinued study drug but completed study visits due to the following: generalized urticaria, erythema nodosum, and three for RA worsening or progression.  All five were receiving active study drug.  Overall, 44% of patients reported at least one adverse event, with only 3 events considered serious by pre-defined protocol (arthralgia, RA exacerbation, and rheumatoid nodule).  No serious infections were observed.  One patient had both a worsening of chronic pyelonephritis and an episode of bronchopneumonia occurring 6 and 8 weeks after a single dose of study drug, events of moderate severity and considered possibly related to the study drug.  Four patients developed acute skin symptoms or rash related to administration of study drug, three of whom did not have recurrence on repeated dosing.  Non-serious injection site reactions were observed in 33% of patients.  One death from lung-cancer in a long-time smoker was reported 8 months after receiving study drug.

Four patients had synovial fluid sampling, showing evidence of atacicept and atacicept/BLyS complexes in synovial fluid.  Importantly, decreases in serum immunoglobulins were noted after the first dose of drug and continued through repeated dosing for all IgG subclasses, but most notably for IgM.  Both rheumatoid factor and anti-CCP antibodies were reduced with treatment.  However, atacicept treatment was not associated with decreases in ESR or CRP.  On flow cytometry, all levels of B cells were inhibited, with memory B cells showing the greatest change.  No effect on other lymphocytes or monocytes was noted.
Clinical response data was limited.  Patients in the repeated 420 mg atacicept cohort showed a decrease in mean DAS28 from 6.4 ± 1.3 at baseline to 5.1 ± 1.4 at day 85.

Conclusions

Results of this early Phase 1b study suggest that atacicept is tolerated in the short-term.

Editorial Comment

These results are very preliminary and can only address short-term safety.  However, they are encouraging and suggest that continued study is warranted.  Another anti-BLyS agent, belimumab, has undergone late phase trials in RA.  This agent did not show sufficient efficacy to continue in the pipeline for RA, but is being investigated for use in other rheumatic diseases.  Whether the differences in mechanism between atacicept and belimumab will result in differences in efficacy profiles will require additional study.

The most obvious concern about atacicept is the profound and sustained drop in immunoglobulin levels that over time may result in an increased risk of infection.  Again, further study will help to define whether these are clinically significant.  However, they suggest that the drug may have further applications in diseases, unlike RA, in which pathogenic immunoglobulins are present.

Jon Giles, MD

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