XL784 ¹ ²
Status
A phase 2 trial in patients with proteinuria associated with diabetic nephropathy has been completed; data were announced in October 2007.
Principal Targets
ADAM-10 and MMP2, metalloprotease enzymes that may play a role in the pathogenesis of diabetic nephropathy and renal fibrosis.
Overview
XL784 was the first small molecule compound developed using our proprietary drug discovery engine The compound is a potent inhibitor of the ADAM-10 and MMP-2 metalloprotease enzymes, targets of significant interest because of their important role in renal fibrosis and impairment. XL784 was specifically optimized to be matrix metalloprotease-1 (MMP-1) sparing, thus potentially significantly enhancing its safety profile and enabling higher dosing compared with other previously studied metalloprotease inhibitors. Results of a single dose phase 1 clinical trial of XL784 administered orally to 70 healthy volunteers demonstrated that XL784 has attractive safety and pharmacokinetic profiles.
Clinical Data
In October 2007, Exelixis announced that the completed phase 2 trial of XL784 did not meet its primary endpoint of reducing proteinuria compared with placebo in patients with proteinuria associated with diabetic nephropathy. Exelixis is continuing to analyze the data to assess whether further evaluation of the compound is warranted.
Data from the trial were presented at the American Society of Nephrology Renal Week 2007. The randomized, double-blind, placebo-controlled study enrolled 125 subjects. XL784 (200 mg once daily for 12 weeks) was compared to placebo in subjects with macro-albuminuria who were being treated concurrently with an angiotensin-converting enzyme inhibitor (ACEi) or an angiotensin receptor blocker (ARB). The primary endpoint was the reduction from baseline in the urinary albumin to creatinine ratio (ACR) at Week 12.
Investigators reported that, after 12 weeks of treatment with XL784:
- Baseline normalized ACR (end of treatment/baseline ACR) in the XL784 group was 9.9% lower than that in the placebo group (not significant).
- There was a clinically relevant mean ACR reduction from baseline of 23% (p=0.0027) in subjects randomized to XL784.
- The change in glomerular filtration rate (GFR) at Week 12 was -2.5 ml/min/1.73m2 in the XL784 group and -6.2 ml/min/1.73m2 in the placebo group (p=0.077).
In an exploratory analysis, subjects were stratified according to dose of ACEi and/or ARB received (as a percentage of the maximum FDA recommended dose). In this analysis:
- The benefit of XL784 compared to placebo increased with increasing dose of ACEi and/or ARB.
- In the subgroup of subjects treated with maximum recommended doses of ACEi and/or ARB, the difference between XL784 and placebo was 23% (p=0.13) for the primary analysis population.
XL784 was generally well tolerated, with fewer subjects reporting adverse events in the XL784 group (77%) than in the placebo group (85%). Serious adverse events (SAEs) were reported by 9.5% of subjects in the XL784 group and by 11% of subjects in the placebo group. No SAEs in the XL784 group were considered to be related to study drug.
Footnotes:
1 Pursuant to a product development and commercialization agreement between Exelixis and GlaxoSmithKline, GlaxoSmithKline has the option, after completion of proof-of-concept by Exelixis, to elect to develop up to three compounds in the Exelixis pipeline including XL880, XL820, XL184, XL844, XL281 and XL228.
2 Out-licensed to Symphony Evolution, Inc. and subject to a repurchase option.
