Event – PCSK9 Odyssey nears its Ithaca
The fate of the cholesterol-lowering PCSK9 class should be sealed by the end of the first quarter when the Odyssey Outcomes trial of Sanofi and Regeneron’s Praluent reports data.
A best-case scenario would see Praluent surpass the outcomes reported by Amgen’s Repatha in its Fourier trial, which misfired when it showed it was no better at preventing death or cardiovascular events than a combination of cheaper pills. Odyssey Outcomes will need to show that Praluent is better – and given that it is no better than Repatha at lowering cholesterol, there is no reason to believe that will happen.
Speaking to investors at the JP Morgan healthcare conference last week, Sanofi chief executive Olivier Brandicourt acknowledged that Praluent is one of three launches that has fallen flat in the past three years and impaired Sanofi's ability to meet 2020 strategic goals. But he added, “We are waiting for the results of the Odyssey Outcomes study, and we do think those results will change the trajectory of Praluent.”
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There is every reason to believe, of course, that Odyssey Outcomes will be judged a success by the standards set by its investigators. It compares Praluent to placebo in preventing cardiovascular events, which is a composite of: death by coronary heart disease; non-fatal heart attack; fatal and non-fatal ischaemic stroke; and unstable angina requiring hospitalisation. An event-driven trial, it will continue until there are 1,613 such events out of a population of 18,000 patients.
Repatha’s very similar Fourier trial scored a clinical success, showing a 15% reduction of death and cardiovascular complications. It was viewed as a commercial debacle, however, since that level of prevention is no better than a combination of statins with Zetia (ACC – No Repatha of glory, March 17, 2017).
To represent a significant gain on that combination, specialists believed a 20% reduction in CV events was necessary, and some argued that based on its cholesterol-lowering potency Repatha should have been able to achieve a 30% reduction (ACC – Repatha’s next challenge is expectations, March 6, 2017).
The 15% was the bare minimum of what Fourier’s trial was designed to detect, and Odyssey Outcomes is similarly designed to detect a 15% risk reduction.
Achieving 20%, a threshold that could yield commercial success, would be a massive win. Based on the existing data it would be an equally massive surprise.
Looks about the same
In the key population of patients with CV disease on maximum doses of statins, Praluent plus statins was able to reduce low density lipoprotein (LDL) levels by 52%. A similar study of Repatha yielded the exact same numerical LDL-lowering benefit.
The PCSK9 class of Repatha and Praluent has spectacularly underperformed early expectations mostly because they have been going up against off-patent statins and payers have taken an aggressive line toward the $13,000-$14,000 a year injections.
A study of prescription data released at the ACC meeting last year showed a high proportion of rejected prescriptions, and that less than a third of US patients receiving an initial prescription of either agent ended up filling it (ACC – Aggressive payers block access to PCSK9s, March 20, 2017).
Not long after launch, both drugs were reckoned to be multi-blockbusters by 2022 – in April 2016, Repatha’s forecast was $5bn in sales and Praluent’s was $4bn, according to EvaluatePharma data. Now those same forecasts stand at $2.6bn and $1.4bn, respectively.
Mr Brandicourt is showing the bravado demanded of a biopharma chief executive, but the probable conclusion is that Praluent will not show a persuasive benefit on cardiovascular outcomes. Odyssey Outcomes is far more likely to be the epilogue to one of the most disappointing stories in drug development.