Background/Purpose: Knee
osteoarthritis (OA) is characterized by the destruction of articular cartilage,
subchrondral bone alterations and varying degrees of synovitis. Current OA
treatments are limited to relieving pain as there are no drug therapies
approved which treat the underlying cause of the disease. The Wnt signaling
pathway is known to play a central role in the formation of joint tissues and
altered Wnt signaling has been associated with cartilage loss in preclinical
and clinical studies.¹ SM04690 is a small molecule inhibitor of the
Wnt pathway which is administered via intra-articular (IA) injection. This
report provides interim magnetic resonance imaging (MRI) data from an ongoing
phase I randomized, double-blind, placebo-controlled, dose-escalation clinical
trial of SM04690 in knee OA subjects.

Methods: Subjects with symptomatic,
radiographic knee OA were randomized to receive a single IA injection in the
target knee with either 0.03, 0.07, 0.23 mg SM04690 or placebo (volume 2mLs) in
a 4:1 SM04690 (N=16):placebo (N=4) ratio. Knee MRIs
were obtained with a 16 channel knee coil on a 3.0T MRI machine using a standard
diagnostic protocol, and were collected at baseline visit (which could occur ≤28
days prior to study injection), Week 12 and 24. Average cartilage thickness
over covered subchondral bone was reported for medial
and lateral femoral condyles as well as medial and lateral tibial
plateaus. Also, the average of the lowest 1% of cartilage thickness was
reported for all 4 compartments. The total for both average thickness and
lowest thickness were derived by summing each of the 4 compartments’
observations. An exploratory analysis of change in imaging outcomes was
conducted using repeated measures analysis of covariance (ANCOVA) adjusting for
baseline.

Results: 61 subjects (average age 62.6
[±5.7] years, female N=41 [67%], average BMI 30.4 [±4.7] kg/m²) were
enrolled. At time of abstract submission, 41 subjects had completed the 24-week trial: Cohort 1: 0.03 mg (N=17), Cohort 2: 0.07 mg
(N=16) and placebo (N=8). Cohort 2 24-week imaging data are under review and
Cohort 3 (subjects treated with 0.23 mg [N=16] and placebo [N=4]) is ongoing;
these data are not reported at this time. At Week 12, total average cartilage
thickness decreased 0.07 mm and 0.02 mm for 0.03 mg and 0.07 mg, respectively,
adjusting for the baseline value (Table). However, total average thickness of
the lowest 1% increased 0.10 mm and 0.08 mm for 0.03 mg and 0.07 mg,
respectively, adjusting for baseline value. Moreover, total average cartilage
thickness increased 0.02 mm and total average thickness of the lowest 1%
increased 0.12 mm in the 0.03 mg group at Week 24.

Conclusion: Preliminary data
from this interim, exploratory analysis of MRI outcomes from an ongoing Phase 1
trial suggest that SM04690 may maintain or increase cartilage thickness, both
at the site of maximal cartilage degradation as well as overall.

Reference: 1. Gelse
K. Osteoarthr Cartil
2012; 20(2):162-71