STRUCTURAL EFFICACY OF INTRA-ARTICULAR SPRIFERMIN TREATMENT ON KNEE OSTEO-ARTHRITIS AS A FUNCTION OF SYMPTOMATIC AND RADIOGRAPHIC DISEASE SEVERITY - A POST-HOC ANALYSIS FROM THE FORWARD PHASE 2 RANDOMIZED CONTROLLED TRIAL

Abstract

INTRODUCTION

A putative disease-modifying osteoarthritis drug, “Sprifermin” was studied by a phase 2B RCT (FORWARD - NCT01919164). Given at a 100µg dose, sprifermin increased cartilage thickness, both in absolute terms and compared with placebo [1]. In the full cohort with MRI results (mITT), this effect did, however, not lead to a pain relief greater than placebo [1]. FORWARD contained patients with a variety of radiographic disease stages (KLG 2 or 3, with a medial minimum joint space width (JSW) > 2.5mm). Although all patients had to display > 40mm pain levels at screening, not all of them exceeded that threshold at the actual baseline measurement [2].

OBJECTIVE

To elucidate post-hoc whether structural treatment effects on cartilage (thickness) by sprifermin differ between severity strata of symptoms (WOMAC) and radiographic disease status. These observations may inform future clinical trials at which stage (sprifermin-) treatment is structurally and symptomatically most effective.

METHODS

Total femorotibial joint (TFTJ) cartilage thickness change at year (Y) 2 by MRI represented the primary endpoint; WOMAC pain was secondary [1]. Patients aged 40–85 with primary symptomatic TFTJ OA (KLG 2 or 3; medial mJSW ≥2.5 mm) were studied. Cartilage thickness was determined quantitatively from 1.5-3T MRI by expert readers, using proprietary software (Chondrometrics). The analysis focused on the 2Y MRI TFTJ cartilage thickness change for the two highest sprifermin dose groups (100µg given every 6 or 12 months combined) vs. placebo. The Hedges G (sample-size-independent effect size measure) was determined, with 95% CIs obtained by bootstrapping. We studied the modified intent to treat cohort with 24-month data (mITT), and the so-called “subcohort at risk” (SAR)[2] a subgroup with baseline WOMAC pain >40 and more severe radiographic involvement by mJSW criteria.

RESULTS

Of 549 FORWARD patients randomized, 474 completed 2Y follow-up. 69% of the mITT with 24M data were female; the median age was 67 and the medial BMI 29.6. The treatment effect on cartilage thickness was 45.6µm for the mITT (Hedges G=0.63). Participants with baseline WOMAC pain ≥ the median displayed a somewhat smaller effect (17±70 µm change over 2 years in treated vs. -15±55µm in placebo participants; Hedges G =0.49 [0.11, 0.86] than those with pain < median (37±69µm in treated vs. -27±84µm in placebo participants; Hedges G =0.86 [0.47, 1.25].

KLG2 subjects displayed a marginally greater treatment effect (30±75µm in treated vs. -16±46µm in placebo participants; Hedges G =0.68 [0.36, 1.00]) than KLG3 participants (13±68µm in treated vs. -33±110µm in placebo participants; Hedges G =0.55 [0.07, 1.03]). Those with JSN grade 0 (no JSN) showed a stronger treatment effect (50±59µm in those treated vs. -11±45µm in placebo participants; Hedges G =1.09 [0.63, 1.54] than those with JSN >0 (7±79µm in sprifermin treated participants vs. -26±84 µm in placebo subjects; Hedges G =0.41 [0.07, 0.75].

Structural results in the SAR were similar, with slight differences observed for JSN strata. The effect size on WOMAC pain in the SAR was relatively strong in KLG3 subjects (-34.4±20 vs. -10.6±29 in placebo; Hedges G -1.03 [-1.71, -0.35]), whereas in KLG2 participants it was weaker (-33.5±17 for sprifermin-treated vs. -36.9± 18 in placebo-treated participants; Hedges G 0.20 [-0.45, 0.85]). Similar observations were made for the JSN (data not shown).

CONCLUSION

These post-hoc results from the FORWARD RCT suggest that study participants with greater baseline pain and radiographic involvement tend to display a somewhat weaker anabolic structural response by sprifermin treatment (smaller increase in cartilage thickness) vs. placebo than those with less baseline pain or with less severe radiographic osteoarthritis. However, in a subcohort with advanced symptomatic and radiographic disease (SAR), the improvement in symptoms was stronger in knees with more advanced radiographic OA. This observation may be compared to a “full” tire gaining little in performance when inflating more air, whereas a “flat” tire improving considerably even with a small injection of it. In summary, whereas structural benefits may be numerically greater in knees with less disease, the translation to symptomatic benefit appears to be stronger in knees with more severe disease.