The novel lipid-lowering agent alirocumab led to big reductions in LDL cholesterol in high-risk patients struggling to control their cholesterol with other lipid-lowering therapies, results from a group of large trials have shown.
The new drug – which is given in twice-weekly subcutaneous injections – is one of the new class of monoclonal antibodies targeting PCSK9 (proprotein convertase subtilisin / kexin type 9), which controls LDL receptor levels.
Researchers said the findings represent a major breakthrough for patients in whom there are currently few options, although GP experts said data on clinical outcomes expected in years to come will be critical even if the drug gets approved by drugs regulators on the basis of its lipid-lowering efficacy.
The studies – part of the ODYSSEY programme of research – were presented over the weekend at the European Society of Cardiology annual congress.
One, the ODYSSEY COMBO II trial, compared the alirocumab injections with ezetimibe in over 700 patients, aged around 62, with high cholesterol or other risks of cardiovascular disease who were already taking as high a dose of statin as they could tolerate. Patients who received alirocumab had two injections a week of a 75 mg to 100 mg dose; those randomised to ezetimibe took 10 mg daily.
Results showed the alirocumab injections reduced patients’ LDL cholesterol by 50% more than ezetimibe at both 24 and 52 weeks – and over three-quarters of the alirocumab group achieved LDL cholesterol of 1.8 mmol/L (70 mg/dl) or lower, compared with less than half of the ezitimibe group.
Two additional trials, ODYSSEY FH II and III, looked at over 700 patients with heterozygous familial hypercholesterolaemia, who again did not have control of their cholesterol levels despite maximal statin dosing, who were given either the alirocumab 75-100mg twice weekly injections or placebo.
Alirocumab resulted in an almost a 49% reduction in LDL cholesterol from baseline in the familial hypercholesterolaemia groups, compared with slight increases in cholesterol in the two placebo groups, over 24 weeks.
Researchers said adverse events were similar between the two groups, with no sign of increased injection site reactions.
A further study in over 2,000 patients, which confirmed the safety outcomes longer term, also suggested alirocumab also resulted in a significant reduction in cardiovascular events after a mean of 65 weeks follow-up, although the authors stressed the study was not a prospective analysis and therefore not ‘powered’ to be statistically robust.
Professor Kausik Ray, professor of cardiovascular prevention and honorary consultant cardiologist at St George’s Hospital NHS Trust in London, who is leading an ongoing outcomes trial of alirocumab, told Pulse the results promised a breakthrough for patients whose options have run out.
Professor Ray said: ‘I think it’s really exciting, to have a treatment that can lower LDL cholesterol in these high-risk groups. For these people that can’t [lower their cholesterol] but are at very high risk – we’ve had really weak treatments and thought, what do we do? They’ve had a heart attack, a bypass, or they can’t tolerate this or that – and their [cholesterol] is still bad despite everything. So in these selected individuals we are going to get a therapeutic choice.’
Professor Ray said the injections would likely be overseen by GPs in the future.
He said: ‘With any new treatments like this, it will start off being initiated by specialists rather than in general practice but after a period of time there is no reason why it can’t be done by GPs. And the patients in the trial were self-injecting – they had been trained to do it, so you didn’t need nurses to do it – in the same way as insulin for diabetics.’
Professor Mike Kirby, editor in chief of the Primary Care Cardiovascular Journal and a GP in Hertfordshire, said the findings look ‘really good’ taken at face value, although he questioned whether patients would take to having the injections and also said the reductions in risk with ezetimibe in the ODYSSEY COMBO II trial were smaller than would be expected.
Professor Kirby said: ‘Alirocumab ( PCSK9 class) looks really good and would be great for familial hypercholesterolaemia patients. Injections are not popular with patients, however, and I would have expected ezetimibe to do a bit better which raises a concern over the data.’
Dr Alan Begg, a GPSI in cardiology in Tayside, who has penned a review of novel lipid-lowering approaches in the British Journal of Cardiology, said the outcomes data would be key.
Dr Begg said: ‘PCSK9[s] are very effective at lowering cholesterol. Outcome data will be the challenge – we need to look at anything published at present with a healthy sceptism (trials are recruiting at present) but certainly they are up and coming drugs.’