Background/Purpose: PRTX-100 is highly-purified GMP staphylococcal protein A (SpA) that binds with extremely high affinity to the Vh antibody framework region of Clade Vh3 immunoglobulins.  SpA thus binds to human monocytes and Vh3 B-cells and, at concentrations of <50 ng/mL, SpA can inhibit their activation in vitro.  In 1999 the FDA licensed an immunoabsorbent device for treatment of RA and subsequently it was demonstrated that these treatments exposed patients to low doses of SpA.  Phase I studies have characterized the safety of single intravenous doses of SpA up to 0.45 µg/kg.

Methods: This phase I multicenter sequential dose-escalation study enrolled patients with active RA on methotrexate (mean DAS28-CRP of 5.78).  Sequential cohorts were treated with 0.15, 0.45, 0.9 or 1.5 µg/kg of PRTX-100 or placebo, administered weekly for 4 weeks.  Safety and disease activity were evaluated over 16 weeks following the first dose.  The primary disease activity response endpoint was the number of patients with a DAS28-CRP <3.2 at Week 6.  Pharmacokinetics were evaluated after the first and last dose.

Results: A total of 37 patients were enrolled.  PRTX-100 was generally safe and well-tolerated; 3/29 PRTX-100-treated patients had mild to moderate infusion reactions, which were self-limiting and related to dosing rate.  Transient flare of RA occurred in 4/29 of PRTX-100 patients.  The relationship of dose to PRTX-100 C_max and AUC was linear, but clearance and AUC were extremely variable within dose cohorts.  The mean C_max at 1.5 µg/kg was 51.9 ng/mL.  PRTX-100 elicited anti-drug antibodies (ADAs) in the majority of patients but the incidence or titer of ADAs was not dose-dependent.  Higher titer ADAs were associated with an increased plasma clearance after the fourth dose.  The development of ADAs did not appear to preclude an effect of PRTX-100 on measures of disease activity.  The endpoint of DAS28-CRP <3.2 at Week 6 was met by 3/29 PRTX-100 and 0/8 placebo patients.  PRTX-100 treatment did not decrease CRP, even in patients whose swollen and tender joint count and global VAS decreased to low levels after treatment.  A post-hoc analysis was performed examining changes in CDAI scores in all patients to remove the influence of the CRP component.  At baseline the mean CDAI score for study patients was 36.8.  In the placebo, 0.15 µg/kg and 0.45 µg/kg PRTX-100 groups, 1/8 patients attained low disease activity (CDAI ≤10) on two or more consecutive visits.  Two of eight and 2/5 patients in the 0.9 and 1.5 µg/kg PRTX-100 groups, respectively, attained this same endpoint and maintained CDAI ≤10 for 12 weeks after the end of treatment.  Of the 4/5 responders in the 1.5 µg/kg group, two attained a CDAI ≤6 (remission), one attained a CDAI ≤10 (low activity), and one attained a CDAI of 10.1 over the course of the study.  The mean time to peak response in this group was 70 days.

Conclusion: Four weekly doses of intravenous PRTX-100 demonstrated an acceptable safety profile and, at the higher doses, decreased RA activity as scored by CDAI.  Results of this pilot study support further clinical trials of PRTX-100 at doses of 1.5 µg/kg and higher.

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ACR Meeting Abstracts - https://acrabstracts.org/abstract/a-phase-1-randomized-double-blind-placebo-controlled-multiple-dose-study-of-intravenous-staphylococcal-protein-a-in-patients-with-active-rheumatoid-arthritis-on-methotrexate-safety-pharmacokineti/