AHA preview – PCSK9 class takes the spotlight

If last year’s American Heart Association scientific sessions gave a tantalising clue as to the potential effectiveness of PCSK9 inhibitors, this year could be a coming out party of sorts.

Late-breaking clinical data from Amgen’s AMG 145 and Pfizer’s RN316 will take centre stage this year, with Sanofi and Regeneron’s REGN727, the only candidate in the class with a sales forecast attached to it, playing an understudy. Meanwhile, Novartis will detail the positive findings from its heart failure drug serelaxin, while investigators will have a chance to pore over what went wrong with Roche’s CETP inhibitor dalcetrapib.

Antibodies for heart disease

With long use in lowering low-density lipoprotein cholesterol (LDL-C), stains have addressed a huge share of the population at risk of serious or fatal cardiovascular events. However, many patients are unable to reach LDL-C targets on statins or are intolerant to them, leading to a search for new approaches.

PCSK9, or proprotein convertase subtilisin/kexin type 9, is an enzyme that binds with LDL-C receptors primarily in the liver, and inhibits their ability to metabolise the so-called “bad cholesterol”. Blocking the enzyme’s action, such as through binding with an antibody, would thus improve cholesterol metabolism (Therapeutic Focus – PCSK9 inhibitors showing promise with early data, November 18, 2011).

Regeneron and Sanofi have the only phase III product in the PSCK9 antibody class, with a 22,000-patient clinical programme under way for the compound known as alirocumab. However, the earliest data from this will not be available for another year at the earliest; the bulk of the trials will not report until 2014 and 2015, and an 18,000-patient outcomes trial is slated to take at least six years to complete.

Two phase II trials each from Amgen’s AMG 145 and Pfizer’s RN316 will take a place in the late-breaking clinical trials programme. Pfizer will disclose how well its compound in combination with statins reducted LDL-C after 12 weeks of treatments, while Amgen will release data in both statin-intolerant patients and subjects with heterozygous familial hypercholesterolaemia over a similar time period.

A blind alley?

Work in raising high-density lipoprotein cholesterol (HDL-C), has been under way for some time, the theory being that raising the so-called “good cholesterol” can reverse atherosclerosis by helping to remove LDL-C from the walls of blood vessels. Cholesteryl ester transfer protein modulators, or CETPs, have been trialled to test this theory out – Pfizer’s torcetrapib being a notable failure.

Dalcetrapib has now also been announced as a failure (Roche’s dalcetrapib failure not end of the road for CETP, May 8, 2012). However, it will no doubt be useful for specialists to examine a full dataset from the dal-Outcomes trial to assess the promise of the two remaining compounds in this class, whether there is any readthrough to trials of Merck & Co’s anacetrapib or Eli Lilly’s evacetrapib, and perhaps subgroup analyses that will help identify patients in whom they do work.

Heart failure

Novartis already disclosed that not only had serelaxin, or RLX030, met a primary endpoint of relief of breathlessness in its 1,160-patient trial in acute heart failure, but it also managed to reduce all-cause mortality six months later (Event – Novartis heart failure data at AHA could quicken investors’ pulses, September 24, 2012). Specialists will no doubt want to assess the magnitude of benefit – however, given that mortality can be an elusive endpoint to meet there is no doubt that excitement is growing over this candidate.

The EvaluatePharma 2018 consensus revenue forecast for RLX030 has risen by two thirds in the past six months and stands at $229m, with analysts expecting near-blockbuster peak sales potential for the angiotensin II antagonist.

Given that the Ascend-HF trial showed that Natrecor does not work better than diuretics and vasodilators, and Simdax has not reduced mortality, investigators will no doubt be excited about a compound that has the promise of improved survival (AHA 2010 – Hopes for a Natrecor revival dashed by Ascend-HF data, November 14, 2010).

Drop the pressure

Six-month data from EnligHTN I, the first human trial of St Jude Medical’s renal denervation device EnligHTN, should boost the hypertension technology further. The product gained CE marking as a therapy for drug-resistant hypertension in the spring on the basis of one-month data from this trial. The novel multi-electrode radiofrequency ablation catheter caused patients’ systolic blood pressure to fall by an average of 28 points after 30 days; further data, released in August, showed that this was maintained at the three-month time point.

With several renal denervation products already available in Europe – although none in the US – and companies such as Boston Scientific aiming to get a toehold on the market, this is an ideal time for St Jude to prove what its technology can do.

To contact the writers of this story email Jonathan Gardner or Elizabeth Cairns in London at news@epvantage.com