Memorandum

AbbVie initiates phase 3 for atrasentan; announces phase 2b data – May 23, 2013

Executive Highlights

  • Phase 2b data for atrasentan were presented at ERA-EDTA: atrasentan reduced UACR by 36-44%, but did not significantly change eGFR.
  • The phase 3 SONAR trial has begun; it is estimated to complete in 2017.

AbbVie announced phase 2b data for atrasentan (ABT-627) at the European Renal Association- European Dialysis and Transplant Association Congress. In two parallel, double-blind, multi-national 12-week studies, atrasentan provided a 36% reduction in urinary albumin/creatinine ratio (UACR) at the 0.75 mg dose (n=78) and a 44% reduction at the 1.25 mg dose (n=83) compared to a 2% increase in UACR in the placebo group (n=50; p<0.001). The study also measured, as a secondary endpoint, changes in estimated glomerular filtration rate (eGFR); neither dose of atrasentan significantly changed eGFR from baseline: both doses conferred nonsignificant ~1 ml/min/1.73 m2 reductions in eGFR, and this change was also not significant compared to placebo. Adverse event rates were similar in the treatment and placebo groups. Peripheral edema (35% in the 0.75 mg arm, 42% in the 1.25 mg arm, and 42% placebo) and diarrhea and constipation (13% in the 0.75 mg arm, 21% in the 1.25 arm, and 14% placebo) were the most common adverse events. Study discontinuation due to adverse events (AEs) was 8% on the 0.75 mg dose, 15% on the 1.25 mg dose, and 0% on placebo. Edema was the most commonly cited reason for discontinuation due to AEs.

The lack of effect on eGFR is disappointing – for comparison, in the 52-week phase 2 BEAM trial for Reata/Abbot’s bardoxolone methyl, it provided gains of ~5-9 ml/min/1.73 m2 in eGFR compared to a ~1 ml/min/1.72 m2 reduction on placebo. However, BEAM enrolled patients with relatively low baseline eGFR (~32 ml/min/1.73 m2) and was much longer (as a reminder, bardoxolone’s phase 3 trial was terminated for safety reasons) We are curious if AbbVie will actually measure GFR in its longer phase 3 trial for atrasentan since eGFR is a surrogate measure for actual GFR – currently only eGFR is listed as an endpoint for SONAR. For reference, eGFR is a calculation incorporating serum creatinine, age, gender, and race.

Atrasentan’s phase 3 trial, SONAR, has begun (in line with management’s forecasts that the phase 3 program would initiate in 1H13). It will investigate the effect of atrasentan 0.75 mg, on top of standard of care (maximum tolerated dose of an ACE inhibitor or ARB, and a diuretic), on progression of CKD in patients with type 2 diabetes and stage 2 to 4 CKD (specifically eGFR 25-75 ml/min/1.73 m2, UACR

≥300 and <5,000 mg/g). It expects to enroll 4,148 patients and will be a multinational, double-blind, placebo-controlled study. The primary endpoint will be time to doubling of serum creatinine or onset of ESRD (defined as the need for chronic dialysis, transplant, or death due to renal failure). Patients will receive more than four years of atrasentan exposure, placing the completion date in 2017 (ClinicalTrials.gov Identifier: NCT01858532). This could mean that atrasentan may not be approved until 2018. We imagine that this long trial represents a very large investment for AbbVie, and we are glad to see the company’s continued commitment to investigating candidates for advanced CKD by including patients with stage 4 CKD. We are also glad to see AbbVie include patients with less-severe CKD as well, since some believe that Abbott and Reata should have tested bardoxolone methyl by with people with CKD stages earlier than stage 4. Since this population is frail, some speculate that spurious correlation led to the increased AEs in the bardoxolone arm leading to the trial’s termination.

  • As a reminder, atrasentan is an oral, once-daily compound that interferes with endothelin-I, a protein with vasoconstrictive and hypertensive effects. A previous phase 2 dose-ranging study, the 0.75 mg dose provided a 42% reduction in UACR after eight weeks of treatment compared to an 11% decline in the placebo group. Peripheral edema was also a common AE in this trial, affecting 18% of those on the 0.75 mg dose and 11% on placebo.

  • Lilly, Pfizer, Concert Pharmaceuticals, and Vascular Pharma are also investigating treatments for diabetic nephropathy.

    • Concert Pharmaceuticals’ candidate (CTP-499) is in phase 2; results are expected in mid-2013. According to Concert, CTP-499 is an inhibitor of inflammation, oxidation, and fibrosis meant to be used in adjunct to current standard CKD therapies such as ACE inhibitors or ARBs. Concert recently received patent protection for CTP-499– details on this update can be found at http://www.closeconcerns.com/knowledgebase/r/d7d781df. More background on CTP-499 can be found at https://closeconcerns.box.com/files/0/f/207540711/1/f_2020038350.

    • Lilly now has a total of one CKD candidate in phase 1 and three CKD candidates in phase 2. Lilly recently advanced a CKD biologic entity to phase 2 (LY3016859; mechanism undisclosed). A phase 1/2 trial recruiting according to ClinicalTrials.gov (Identifier: NCT01774981), with a primary completion date of September 2014. The remaining phase 2 candidates are a mineralocorticoid receptor antagonist (LY2623091; no active trials on ClinicalTrials.gov) and a TGF-beta monoclonal antibody (LY2382770; phase 2 trial enrolling with primary completion date of October 2014 [ClinicalTrials.gov Identifier: NCT01113801]). Lilly has not disclosed the mechanism for its small molecule CKD candidate in phase 1.

    • Pfizer has a CCR2/5 receptor antagonist (PF-04634817)and a phosphodiesterase inhibitor (PF-00489791) in phase 2. Though management previously guided for new data on the PDE inhibitor in 2013, they have not provided a recent update.

    • Vascular Pharma is advancing its preclinical diabetic nephropathy candidate, VPI-2690B, into phase 2 testing with funds secured through the company’s Series A round of financing; the company expects to file for investigational new drug (IND) approval in 2H13. Vascular Pharma also announced a deal that gives Janssen Biotech, a subsidiary of J&J, exclusive rights to acquire the company pending trial results. There are no ongoing trials for kidney disease listed on ClinicalTrials.gov.

-- by Jessica Dong and Kelly Close