A randomized, double-blind, placebo-controlled, phase 2a study of the efficacy, safety, and pharmacokinetics of MLN3897 in patients with rheumatoid arthritis taking methotrexate.

Reumatoid arthritis (RA) is a chronic inflammatory disease primarily involving
the joints. Pain and stiffness cause disability in RA patients. Moreover, the
inflammation can cause joint destruction, leading to permanent disability.
There is no cure for RA. Certain available therapies can decrease inflammation
and slow progression of joint destruction. However, these therapies do not work
for all RA patients. New therapies against RA are therefor required.
The inflamed synovial tissue of RA patients is characterized by large numbers
of immune cells. Chemokines facilitate the influx of these cells into the
joints. The aim of the agent under investigation in this study (MLN 3897), is
to block chemokine function.

This is the first study of MLN3897 in any disease population. It seeks to
establish:
1) The ability of MLN3897 to modify the signs and symptoms of RA.
2)The safety and tolerability of MLN3897 in combination with MTX.
3)The PK/PD profile of MLN3897 in the RA population, and comparison to that in
the healthy volunteer population with respect to CCR1 receptor blockade.
4) MTX PK and MLN3897 PK and PD when these drugs are used in combination.

This phase 2a, double-blind, placebo-controlled, randomized study will be
conducted in approximately 186 patients with RA who are taking stable doses of
MTX yet continue to manifest evidence of active disease. All patients will be
required to have been receiving MTX for at least 6 months prior to study entry
and at stable doses of 7.5 mg to 25 mg for at least 6 weeks prior to
enrollment. The main study will include a screening period, a 12-week active
treatment period with 5 study visits (Days 1, 14, 28, 56, and 84), and an end
of study (EOS) visit (30 days post-treatment follow-up visit [Day 114/EOS]).
All patients will be randomized 1:1 to receive either 10 mg MLN3897 or matching
placebo on a daily basis from Day 1 through Day 83. Patients will continue
throughout the entire study to follow their once-weekly MTX dosing regimen.
Of the 186 RA patients, a subset of approximately 16 evaluable patients (12
patients in the MLN3897 + MTX combination arm, and 4 in the placebo + MTX arm)
will participate in intensive PK sampling for determination of MLN3897 and MTX
PK. This subset of patients will be screened for eligibility during the
screening period, have 8 study visits (Days -1, 1, 14, 27, 28, 29, 56, and 84),
and an end of study visit (30 days post-treatment follow-up visit [Day
114/EOS]).
See protocol page 42.

Patients will receive orally 10 mg MLN3897 or matching placebo once daily for
83 days starting on Day 1.
All patients will take MTX orally every seventh day at their previously
established stable dose. Patients participating in the PK substudy will be
instructed to synchronize their weekly dosing of MTX with the clinic visit
schedule.

* QT interval prolongation.
* A greater chance of getting an infection or difficulty fighting off an
infection
* Decreased visual function
* Nausea, vomiting, constipation
* Mood changes, dizziness
* Blood in urine
* Abnormal lab results (for example increased blood levels of muscle or liver
enzymes)