Biotech Values

[DewDiligence]

This otamixaban abstract is from The Lancet paper on the phase-2
study in ACS. The abstract gives more data—including the 95% CI’s
for the primary efficacy endpoint—than SNY’s PR in #msg-41012818.
Of the five otamixaban doses that were compared to a control arm
of UFH+Integrilin, all doses except the lowest showed a benefit in
the primary efficacy endpoint, but none of the arms had a 95% CI
whose upper bound was <1.0. All told, I consider this a ho-hum
study outcome and I’m surprised SNY is proceeding to phase-3
in ACS with a compound that seems poorly differentiated from oral
FXa inhibitors that are further along in development.

http://www.ncbi.nlm.nih.gov/pubmed/19717184

›Otamixaban for the treatment of patients with non-ST-elevation acute coronary syndromes: a randomised, double-blind, active-controlled, phase 2 trial

Lancet. 2009 Sep 5;374(9692):787-95

Sabatine MS, Antman EM, Widimsky P, Ebrahim IO, Kiss RG, Saaiman A, Polasek R, Contant CF, McCabe CH, Braunwald E.

TIMI Study Group, Division of Cardiovascular Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, MA, USA.

BACKGROUND: Otamixaban is an intravenous direct factor Xa inhibitor. We aimed to assess its efficacy and safety in non-ST-elevation acute coronary syndromes and to identify the optimum dose range for further assessment in a phase 3 study.

METHODS: In this double-blind, phase 2 trial undertaken in 196 sites in 36 countries, 3241 patients with non-ST-elevation acute coronary syndromes were randomly assigned via a central, telephone-based interactive voice response system to one of five doses of otamixaban (0.08 mg/kg bolus followed by infusions of 0.035 [n=125], 0.070 [676], 0.105 [662], 0.140 [658], or 0.175 [671] mg/kg/h) or to a control of unfractionated heparin (60 IU/kg intravenous bolus followed by an infusion of 12 IU/kg/h) plus eptifibatide [Integrilin] (180 mug/kg intravenous bolus followed by an infusion of 1.0-2.0 mug/kg/min [n=449]). Both investigators and patients were unaware of treatment allocation.

Enrolment into the lowest dose group was stopped early at the recommendation of the Data Monitoring Committee [i.e. there were originally six otamixaban arms rather than five].

The primary efficacy endpoint was a composite of death, myocardial infarction, urgent revascularisation, or bailout glycoprotein IIb/IIIa inhibitor use up to 7 days.

The primary safety endpoint was TIMI major or minor bleeding not related to coronary-artery bypass grafting.

Efficacy analyses were by intention to treat; safety analyses were in treated patients. This study is registered with ClinicalTrials.gov, number NCT00317395.

FINDINGS: Rates of the primary efficacy endpoint in the five otamixaban doses were 7.2% (nine of 125) with 0.035 mg/kg/h, 4.6% (31/676) with 0.070 mg/kg/h, 3.8% (25/662) with 0.105 mg/kg/h, 3.6% (24/658) with 0.140 mg/kg/h, and 4.3% (29/671) with 0.175 mg/kg/h (p=0.34 for trend). In the control group, the rate was 6.2% (28/449), yielding relative risks for the five otamixaban doses of 1.16 (95% CI 0.56-2.38), 0.74 (0.45-1.21), 0.61 (0.36-1.02), 0.58 (0.34-1.00), and 0.69 (0.42-1.15), respectively.

Rates of the primary safety endpoint in the five otamixaban doses were 1.6% (two of 122), 1.6% (11/669), 3.1% (20/651), 3.4% (22/651), and 5.4% (36/664), respectively (p=0.0001 for trend); the rate in the control group was 2.7% (12/448).

INTERPRETATION: In patients with non-ST-elevation acute coronary syndromes, otamixaban infusions of 0.100-0.140 mg/kg/h might reduce ischaemic events and have a safety profile similar to unfractionated heparin plus eptifibatide. Further testing in a phase 3 trial is warranted.

FUNDING: Sanofi-Aventis.‹