OP-0131 – Tocilizumab Monotherapy is Superior to Methotrexate Monotherapy in Reducing Disease Activity in Patients with Rheumatoid Arthritis: The AMBITION Study
Jones, Gu, Lowenstein, Calvo, Gomez-Reino, Siri, Tomsic, Blackburn, Woodworth, Sebba. Australia, China, USA, Peru, Spain, Argentina, Slovenia, UK. [Sponsor, Roche]
Objectives:
To assess the efficacy and safety of tocilizumab (TCZ) monotherapy compared to methotrexate (MTX) monotherapy in patients (pts) with active RA who have not previously failed treatment with MTX or biologics.
Methods:
This was a 24 week, double-blind, double-dummay, parallel group Phase 3 study that targeted patients with RA > 3 months who were MTX naïve or had not received MTX in the past 6 months. Pts who had failed MTX or biologics in the past were excluded. Pts were randomized to receive either TCZ 8 mg/kg every 4 weeks or escalating MTX dose 7.5 to 20 mg weekly. The primary outcome was ACR20 response at week 24. The primary analysis for non-inferiority used the PP population (n=524), and the secondary analysis for superiority used the ITT population (n=570).
Results:
Mean baseline characteristics were similar between the two treatment groups (75% RF positive; 80% women, mean disease duration 6.4 yrs [40% less than 2 yrs], 2/3rds were MTX naïve, 40% were DMARD naïve). Non-inferiority was demonstrated for the primary endpoint ACR20 response at Week 24 (71% TCZ vs 52% MTX). Since non-inferiority was demonstrated, statistical analysis for superiority was pursued. Indeed, TCZ was superior to MTX treatment (see table below). Significantly higher rates of EULAR good/moderate responses and CRP normalization were seen in the TCZ group as early as 2 wks. Hemoglobin levels improved rapidly in the TCZ arm, with adjusted mean changes from baseline at Week 24 of +1.2 g/dL TCZ vs +0.1 g/dL MTX. The incidence of adverse events (AEs) was similar in both groups (80% TCZ/78% MTX). AEs leading to withdrawal were modestly increased in the MTX arm (3.8% TCZ/5.3% MTX). Serious AEs and serious infections were higher with TCZ (TCZ/MTX: 4%/3% and 1.4%/0.7%). Shifts in ALT from normal at baseline to >3x ULN occurred more frequently in the MTX arm 4% vs TCZ 2%. Shifts in total cholesterol from <200 to ≥240 mg/dL occurred in TCZ 13% vs <1% MTX. Transient decreases in neutrophil counts were more frequent with TCZ. No Grade 4 neutropenia was reported.
Results at Week 24 (ITT population) |
TCZ 8 mg/kg (n=286) |
MTX (n=284) |
p value |
ACR20 response (%) |
70 |
53 |
p<0.0001 |
ACR50 response (%) |
44 |
34 |
p=0.0023 |
ACR70 response (%) |
28 |
15 |
p=0.0002 |
Good/moderate EULAR response |
82 |
65 |
|
Pts with DAS28<2.6 (%) |
34 |
12 |
– |
Mean change in DAS28 |
-3.3 |
-2.2 |
– |
Mean change in HAQ-DI |
-0.7 |
-0.6 |
– |
Conclusion:
TCZ monotherapy is clinically superior to MTX monotherapy. TCZ is safe and well tolerated in patients with RA who have not failed previous MTX or biologic treatment.
Editorial Comment:
TCZ is a potent anti-inflamamtory agent that has a rapid onset of action. The question is whether the early clinical superiority of TCZ over MTX is sustained at 12 months. The TNF inhibitors also have rapid onset of efficacy but by 12 months, there is no difference from MTX in improvement in signs and symptoms. This longer time point is important to know as it is hard to justify a very expensive biologic as a first line agent simply for a modest advantage in the first few months.
