Investor Update

Basel, 29 August 2011

Dalcetrapib phase II studies support the safety profile and potential for slowing of plaque progression in patients at risk of coronary heart disease

Roche (SIX: RO, ROG; OTCQX: RHHBY) announced today results from two exploratory mechanistic Phase IIb studies investigating dalcetrapib’s effects on atherosclerotic disease progression (dal-PLAQUE) and vascular function (dal-VESSEL) in patients with or at risk of coronary heart disease. The studies were presented at the European Society of Cardiology Congress (ESC) and further support the safety profile of the investigational compound dalcetrapib, a first-in-class cholesteryl ester transfer protein (CETP) modulator.

”The results of dal-PLAQUE and dal-VESSEL further support the safety profile of dalcetrapib,” said Hal Barron M.D., Chief Medical Officer and Head, Global Product Development. “In addition, secondary endpoints in dal-PLAQUE showed a promising signal in terms of effects on atherosclerotic plaque at 24 months.  Results of the ongoing Phase III study dal-OUTCOMES will determine, whether the CETP modulator dalcetrapib reduces heart attacks and strokes in patients who have experienced a recent acute coronary syndrome.”

Results of dal-VESSEL showed that dalcetrapib reduced CETP activity and increased high-density lipoprotein cholesterol (HDL-C) levels by 31 % without negatively affecting endothelial function (as measured by flow mediated dilatation) or markers of inflammation and oxidative stress. Dalcetrapib did not increase 24-hour ambulatory blood pressure (ABPM) at week 4, the primary safety endpoint.

Dal-PLAQUE is the first multicentre study to use non-invasive simultaneous multimodality imaging to assess structural and inflammatory indices of atherosclerosis as primary efficacy endpoints, and provides a rigorous safety assessment of dalcetrapib. In dal-PLAQUE, plaque burden parameters as measured by magnetic resonance imaging (MRI), improved with dalcetrapib versus placebo after 24 months (please refer to link below). The total vessel area of an index vessel – the most reproducible parameter on MRI – was significantly reduced and a trend towards reduction in average wall area was observed. Using positron emission tomography imaging (PET/CT), a technique that assesses changes in plaque inflammation over time, no evidence of a pro-inflammatory effect of dalcetrapib was observed after 6 months. The data has been accepted for fast track publication by the Lancet journal.

No safety signals were observed in both dal-VESSEL and dal-PLAQUE. Dalcetrapib was well tolerated with a safety profile similar to placebo and was not associated with an increase in blood pressure.

Patients on dalcetrapib experienced fewer adjudicated cardiovascular (CV) events compared to patients on placebo. In dal-VESSEL, 2 events occurred with dalcetrapib versus 5 events with placebo (11 versus 12 events including revascularization procedures). In dal-PLAQUE, 1 event occurred with dalcetrapib compared to 6 events with placebo (2 versus 13 events including revascularization, respectively).

An additional Phase III clinical study, dal-PLAQUE 2, is designed to further demonstrate the effect of dalcetrapib in coronary and carotid atherosclerotic disease. The study will use both intravascular ultrasound (IVUS) measurement of target coronary artery and ultrasound measurement of the carotid intima-media thickness (c-IMT). This is the first time ever that both these imaging techniques are used simultaneously in a patient population with a therapeutic intervention. Dal-PLAQUE 2 has finished recruiting patients.

Link to MR imaging parameters illustration: http://jcmr-online.com/content/11/1/10/figure/F1

About dalcetrapib

Dalcetrapib is an innovative molecule which improves the ‘good’ functional HDL-C by modulation of CETP. Its mechanism of action differs from other drugs that affect CETP activity known as CETP inhibitors, including torcetrapib. The hypothesis that dalcetrapib may prevent future CV events is currently being tested in the dal-HEART Program in more than 17,000 patients, and specifically the dal-OUTCOMES study which has enrolled 15,872 patients with stable coronary heart disease (CHD) following a recent acute coronary syndrome (ACS).

Although current therapies are effective at treating many CV risk factors, CV disease remains the leading cause of death worldwide. The major cause of CV morbidity and mortality is atherosclerosis, a disease in which cholesterol accumulates in plaques within the arterial wall. High-density lipoprotein (HDL) has the potential to remove cholesterol from atherosclerotic plaques.  Medications that improve the level of HDL-C and also maintain the functionality of HDL, may consequently slow the progression of atherosclerosis and thereby prevent CV events.

About dal-VESSEL

Dal-VESSEL is an exploratory phase IIb, randomised, double-blind, placebo-controlled study in patients with coronary heart disease (CHD), or CHD risk equivalents. 476 patients were randomised and received dalcetrapib 600 mg/day or placebo in addition to their existing treatments. The primary efficacy objective of the study was to evaluate the effect of dalcetrapib on endothelial function using brachial flow mediated dilatation (FMD) in patients receiving either dalcetrapib or placebo on top of their standard medication after 12 weeks’ treatment. FMD is a response of an intact endothelium and impairment of FMD is a validated marker of endothelial dysfunction, a process associated with the development of atherosclerosis. Baseline FMD was 4.1 ± 2.2% and 3.98 ± 2.4% in the placebo and dalcetrapib groups respectively and did not change significantly throughout the 36 week study.

The primary safety objective was to evaluate the effect of dalcetrapib on blood pressure as measured by 24-hour ABPM monitoring assessed at week 4. At baseline, ABPM averaged 125 ± 12/74 ± 8 mmHg in the placebo group and 127 ± 11/75 ± 7 mmHg in the dalcetrapib group and did not change significantly up to 36 weeks.

After 4 and 36 weeks of treatment with dalcetrapib, CETP activity decreased by 51% and 56% (p<0.001 vs placebo), respectively, while after 12 and 36 weeks of treatment HDL-C increased by 27% and 31% (p<0.001; from 39 ± 7 to 49 ± 10 and 51 ± 13 mg/dl, respectively). Triglycerides decreased by 9% and 14% (p<0.005; from 162 ± 81 to 151 ± 83 and 149 ± 71 mg/dl, respectively), while LDL-C did not change. Biomarkers of inflammation (CRP, ICAM, VCAM, IL-6), oxidative stress (MPO) and coagulation (tPA, PAI-1) did not differ at baseline nor after treatment with either placebo or dalcetrapib.

During the whole study, 23 pre-specified positively adjudicated cardiovascular events occurred.  There were 8 patients with 12 positively adjudicated CV events on placebo and 7 patients with 11 events on dalcetrapib. Dalcetrapib was well tolerated with a similar adverse event profile to placebo in the combined studies with nasopharyngitis, diarrhoea, bronchitis, back pain and upper respiratory tract infection the most common adverse events.

About dal-PLAQUE

Dal-PLAQUE is an exploratory phase IIb, randomised, double-blind, placebo controlled study in patients with CHD, or CHD risk equivalents. 130 patients were randomised and received dalcetrapib 600 mg/day or placebo in addition to their existing treatments. In dal-PLAQUE, the primary objective was to assess the effect of dalcetrapib on atherosclerotic plaque inflammation at 6 months using positron emission tomography/computed tomography (PET/CT) and on plaque burden/progression after 12 months using magnetic resonance imaging (MRI), comparing patients receiving dalcetrapib or placebo in addition to standard medication. Patients received treatment for 24 months.

There was no evidence of pro-inflammatory effects measured by (PET/CT) at 6 months, as the mean of maximum standardised uptake value and target to background ratio were unchanged with dalcetrapib vs placebo after this time (-0.05 [-0.16, 0.07]; p=0.498 and 0.09 [-0.07, 0.26]; p=0.363 respectively). Based on MRI, a significant reduction in total vessel area and a trend towards reduction in average wall area were observed with dalcetrapib vs placebo after 24 months (-4.01 mm2 [-7.23, -0.80]; p=0.041 and -2.20 mm2 [-4.54, 0.13]; p=0.120 respectively) indicating that no plaque progression on MRI had occurred during this time. Other indices of plaque burden were numerically reduced from baseline with dalcetrapib vs placebo. HDL-C increased by 31% with dalcetrapib after 24 months with no significant increases in inflammatory biomarkers. Dalcetrapib was well tolerated with a safety profile similar to placebo and was not associated with an increase in blood pressure. Fewer adjudicated CV events occurred on dalcetrapib. There were 7 patients with 13 positively adjudicated CV events on placebo and 2 patients with 2 events on dalcetrapib.

About Roche

Headquartered in Basel, Switzerland, Roche is a leader in research-focused healthcare with combined strengths in pharmaceuticals and diagnostics. Roche is the world’s largest biotech company with truly differentiated medicines in oncology, virology, inflammation, metabolism and CNS. Roche is also the world leader in in-vitro diagnostics, tissue-based cancer diagnostics and a pioneer in diabetes management. Roche’s personalised healthcare strategy aims at providing medicines in diagnostic tools that enable tangible improvements in the health, quality of life and survival of patients. In 2010, Roche had over 80’000 employees worldwide and invested over 9 billion Swiss francs in R&D. The Group posted sales of 47.5 billion Swiss francs. Genentech, United States, is a wholly owned member of the Roche Group. Roche has a majority stake in Chugai Pharmaceutical, Japan. For more information: www.roche.com   

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