Next week’s annual meeting of the American Heart Association (AHA) is shaping up to be one of the more significant medical conferences of the year. Pivotal data on a wide range of novel candidates, from oral anticoagulants to gene therapy, will be presented; the meeting could even signal a comeback for CETP inhibitors.
Top billing at AHA goes to detailed results from the Rocket-AF trial of oral anticoagulant Xarelto, given the importance of the drug to Bayer and Johnson & Johnson and the speculation prompted by recent headline data (Xarelto data from Rocket trial questions lift-off potential, November 1, 2010). Meanwhile, three years on from the post-mortem into the spectacular failure of Pfizer’s CETP inhibitor, torcetrapib, Merck & Co will present preliminary data from a relatively small phase III trial of its candidate, anacetrapib. Positive efficacy and safety data will throw these agents into the spotlight once more, with Roche, Japan Tobacco and Eli Lilly seeking encouragement for their own CETP products.
The Rocket-AF data, which compares Xarelto to warfarin in preventing strokes in patients with atrial fibrillation, is expected to have a significant bearing on the commercial potential of the drug, given that this setting represents the largest commercial opportunity.
Boehringer Ingelheim's Pradaxa has set the benchmark in this setting and further data will be presented which could enhance the drug’s growing reputation.
Meanwhile any weakness in the Xarelto data will be seized upon by competitors snapping at its heels. Data from Bristol-Myers Squibb and Pfizer's apixaban, Merck and Portola Pharmaceuticals’ betrixaban and Daiichi Sankyo's edoxaban are also being presented at AHA, emphasising the current strength and depth of this particular class of drug.
The AHA conference in 2007 was the last time that CETP inhibitors grabbed any headlines, with the final analysis of why the torcetrapib and Lipitor combination caused such a safety scare; patients receiving the combination pill had a 60% higher risk of death and a 25% higher risk of heart attack, than those on Lipitor alone (CETP inhibitors – survivors proceed with caution, November 6, 2007).
With the benefit of this full analysis and after much deliberation, Merck with anacetrapib and Roche with dalcetrapib proceeded with phase III trials under the belief their candidates are much safer. Particularly, torcetrapib was linked to a significant increase in aldosterone, a so-called ‘off-target effect’, which raises blood pressure and is associated with heart attacks.
Merck and Roche have scrutinised the clinical data on their candidates and so far the indications are that aldosterone levels are not affected.
Nevertheless, there remains a lot of scepticism about CETP inhibitors in general, so the data on anacetrapib from the Define trial will be important if any confidence is to return to the class. Although the Define trial is not a large scale clinical outcomes study that will be required for approval – Roche’s dal-OUTCOMES trial with dalcetrapib is more advanced and could report in 2013 – the data at AHA could be an important milestone if CETPs are to stage a comeback.
Japan Tobacco developed dalcetrapib while Eli Lilly has its own candidate in phase II, LY2484595, companies that will also be watching the anacetrapib data with interest.
Gene therapy questions remain
The future looks bleak for Temusi (NV1FGF), Sanofi-Aventis and Vical’s DNA vaccine encoding fibroblast growth factor 1 (FGF-1), designed to try and prevent amputations resulting from critical limb ischemia (CLI).
Current expectation is that further development of the gene therapy will be ditched after topline pivotal data presented in September failed to show a significant improvement in time to amputation, or death, in CLI patients (Gene therapy suffers another blow as Temusi crashes out, September 23, 2010).
Vical shares fell 32% at the time to a 12-month low of $2.62. Full results from the Tamaris trial of Temusi will be presented at AHA. Considering Vical's stock shows no signs of recovery, in fact it touched a new 12-month low of $2.13 last week, investors are clearly not optimistic that the data will offer much hope of a reversal of fortune. Complete results should help determine whether the failure was product-related, or a result of poor trial design, as some have suggested.
Can ApoA data meet the hype?
Resverlogix will report data from a placebo-controlled phase II trial - Assert - of its oral apolipoprotein A-1 (ApoA-1) enhancer for acute coronary syndrome, RVX-208 in 299 stable coronary disease patients.
Resverlogix will hope to demonstrate a rise in ApoA-1 levels, the main component of HDL, and a sign of the anti-atherosclerotic effect of raised HDL. The drug holds promise for dyslipidemia treatment, but is early-stage. Another phase II trial – Assure - is ongoing in 120 coronary artery patients, due to complete in February next year.
There has been much hype around the drug since March when Bloomberg ran an article highlighting the drug's potential and quoting Rodman & Renshaw analysts claiming it to be “as big as Lipitor” (Resverlogix’s lucrative moment in the spotlight, March 11, 2010). Resverlogix’ share price jumped 66% to reach C$8.00 at the end of March, but slumped back to C$2.72 by July. Now trading at C$5.70 though, it seems anticipation is building ahead of AHA. Evidence of cardioprotective activity could pique big pharma interest.
Predicting cardiovascular risk
Launched in 1997, the Ascot trial is a huge, landmark study which recruited almost 20,000 patients with high blood pressure across Europe and Scandinavia. The study set out to explore the effectiveness of various treatments for hypertension at preventing cardiovascular disease.
Over the years several cuts of the data have been released, at the AHA this year an analysis looking at high sensitivity C-reactive protein (hsCRP) is included in the late breakers. This inflammatory marker has received much attention in the last few years on the back of the Jupiter study, which AstraZeneca conducted with its statin Crestor (AstraZeneca looks set for Crestor boost, November 10, 2008).
Jupiter concluded that Crestor significantly reduces the risk of cardiovascular events and death in patients with normal cholesterol levels but high levels of hsCRP. This was a significant finding for the product, essentially opening up a much broader patient population, at the same time fuelling the debate about the significance of this marker in treating cardiovascular disease.
The Ascot analysis to be presented sought to evaluate hsCRP as an independent predictor of cardiovascular events; levels were tested at the beginning of the study, and during treatment. It will be also be interesting if the data throws any light on whether the marker can be used as a target for treatment, for example how often it should be measured and whether seeing it go down is an indicator for improving outcomes.
As well as doctors, AstraZeneca will also be very interested in the presentation.
Further benefits to fish oil?
Another late breaker at AHA will look at emerging evidence for the role of Omega-3-Acid ethyl esters, fish-oil based medicines such as GlaxoSmithKline’s Lovaza, can play in preventing recurrent atrial fibrillation.
Currently Lovaza is only approved to reduce triglycerides, but omega-3s are used widely to treat patients with cardiovascular disease (EP Vantage Interview - Pronova building capacity as fish oils win more fans, September 1, 2008).
Many studies have been done examining the role of these products in patients with atrial fibrilliation, and conflicting evidence has emerged. This trial could shed further light on the issue.
|Company||Product||Trial ID||Trial name||Trial indication|
|Bayer / Johnson & Johnson||Xarelto||NCT00403767||Rocket-AF||Atrial fibrillation / Stroke|
|Boehringer Ingelheim||Pradaxa||NCT00262600||Re-ly||Atrial fibrillation / Stroke|
|Bristol-Myers Squibb / Pfizer||apixaban||NCT00496769||Averroes||Atrial fibrillation|
|Merck & Co / Portola Pharmaceuticals||betrixaban||NCT00742859||Explore-Xa||Atrial fibrillation|
|Daiichi Sankyo||edoxaban||NCT00504556||n/a||Atrial fibrillation / Thrombosis|
|Merck & Co||anacetrapib||NCT00685776||Define||Coronary artery disease|
|Roche / Japan Tobacco||dalcetrapib||NCT00658515||dal-Outcomes||Coronary artery disease|
|Sanofi-Aventis / Vical||Temusi||NCT00566657||Tamaris||Peripheral vascular disease|
|Resverlogix||RVX-208||NCT01058018||Assert||Atherosclerosis / Coronary artery disease|
|GlaxoSmithKline / Pronova BioPharma||Lovaza||NCT00402363||n/a||Atrial fibrillation|