AbbVie 1Q14 – Chronic kidney disease candidate atrasentan remains in phase 3 ­– May 5, 2013

AbbVie reported 1Q14 financial results on April 25, 2014. There were no updates on the company’s chronic kidney disease candidate atrasentan, which remains in phase 3. As a reminder, atrasentan is an endothelin-receptor antagonist and began its phase 3 SONAR trial in May 2013. The trial's primary completion date is estimated to be February 2017, and we assume that the earliest it could come to market would be 2018. SONAR will serve as the single global registration trial for the compound.

According to ClinicalTrials.gov (Identifier: NCT01858532), SONAR's primary endpoint is time to first occurrence of a component of the composite renal endpoint: doubling of serum creatinine (confirmed by a 30-day serum creatinine) or the onset of end stage renal disease (needing chronic dialysis, renal transplantation, or renal death). Secondary endpoints include measures of albuminuria, estimated glomerular filtration rate (eGFR), and cardiovascular outcomes. The study will enroll an estimated 4,418 people with type 2 diabetes and nephropathy treated on maximum tolerated doses of an ACE inhibitor or ARB. People with eGFR between 25 and 75 ml/min/1.73 m² may enroll (stage 2-4 chronic kidney disease [CKD]), and the number of people with eGFR between 60 and 75 ml/min/1.73 m² (stage 2 CKD) will be limited to 10% of the population. This represents a broader patient population than bardoxolone methyl's BEACON trial (which was terminated in October 2012 due to excess mortality and serious adverse events and enrolled only very high-risk patients [stage 4 CKD] for more details). Of course, this is the population that needs the most help, but also the group of patients that is the most fragile - we hope that AbbVie's broader approach to enrolling SONAR may allow for subgroup analyses if a safety signal appears again in the very-advanced CKD population. This hard outcomes trial should provide clarity on the benefits to renal function suggested by short-term phase 2 data (which only measured changes in albuminuria [protein in the urine], a proxy for renal impairment, and not hard renal outcomes). The trial's ClinicalTrials.gov listing does not specify which dose AbbVie carried forward to phase 3.

There was no kidney-related Q&A.

• Bayer, Lilly, Pfizer, Concert Pharmaceuticals, and Vascular Pharma are also investigating treatments for diabetic nephropathy in phases 1 and 2 (See Table 1 below for details).
  • On April 25, Concert Pharmaceuticals announced positive 48-week results from its phase 2 clinical trial of its diabetic nephropathy candidate, CTP-499. The amount of urinary albumin to creatinine ratio (UACR), the trial’s primary endpoint, was not significantly altered for those taking CTP-499; however, there was a favorable trend toward a smaller ratio observed at 48 weeks. Additionally, although also not significant, participants taking CTP-499 experienced a reduction in the rate of increase of serum creatinine, one of the study’s secondary endpoints; 0.13 mg/dl vs. 0.21 mg/dl, a 38% reduction (serum creatinine is a marker of impaired kidney function). Patients on CTP-499 experienced a significant reduction in two fibrotic biomarkers evaluated in the study (fibrosis is believed to be a final common pathway for kidney failure due to diabetic kidney disease): 52% decrease in urinary fibronectin (p=0.008) and 18% decrease in plasma collagen IV (p=0.02). The most common adverse event reported was mild to moderate nausea, with no reported serious adverse events related to the drug.
  • The trial was a double-blinded, randomized, placebo-controlled study (n=151); participants taking CTP-499 took 600 mg twice daily. Part one of the study lasted 24 weeks, and participants that completed part one were eligible to continue to study for 24 weeks (86% participated in part two). All participants that completed part two were eligible to continue the study for up to 48 weeks of open-label treatment – this is currently ongoing.

Table 1: Comparison of Diabetic Nephropathy Candidates

• Certainly, the need for CKD treatments is great; currently available treatments can slow the course of disease, but cannot reverse it. The CDC estimates that 35% of adults with diabetes have CKD. Diabetic kidney disease accounts for 40% of new cases of end-stage renal disease (ESRD), and over 100,000 patients a year progress from CKD to ESRD. Effective therapies for diabetic nephropathy are especially valuable since the annual cost of treating diabetes patients with ESRD exceeds $15.6 billion (Molitch et al., Diabetes Care 2004).

--by Jessica Dong and Kelly Close