Pfizer’s bombshell decision to halt development of the cholesterol-lowering project bococizumab will only add to doubts looming over the PCSK9 inhibitor class. The disappointing launch of Repatha and Praluent due to restrictive payer coverage could now be coupled with increased concerns about whether these drugs will have any measurable impact on cardiovascular outcomes.
An “unanticipated attenuation” of bococizumab’s effect on cholesterol levels over time was one reason given for pulling the plug, suggesting that Pfizer suspected that its own outcomes trial would fail. The sector has toiled for years to come up with a better heart-disease pill, and Repatha and Praluent have it all to prove when their own outcomes trials read out in coming months.
Pfizer was careful to say that the attenuation of boco’s effect on the lowering of LDL was seen between 12 and 52 weeks, and the same cannot be said of Amgen’s Repatha or Sanofi and Regeneron’s Praluent. This was coupled with a higher rate of injection-site reactions and immunogenicity, causing ISI Evercore analyst John Scotti to speculate that trial dropouts could have contributed to the waning efficacy trends.
Indeed, data taken from the Odyssey Long Term study of Praluent and the pooled Osler 1 and 2 trials of Repatha showed a steady effect on LDL starting at four weeks and persisting through at least a year. In those trials, treatment-related discontinuations were 7.2% and 2.4% respectively.
Pfizer gave no biological reason for the differences with boco. It could be that Praluent and Repatha, as fully human monoclonal antibodies, stimulated less of an immunogenic reaction than boco, which is humanised. This would clearly be important in what is a chronic setting.
An emphasis on “value to patients, physicians or shareholders” also hints that Pfizer saw little commercial benefit in being third to market with an inferior product.
“We’re making a decision based on the profile of our drug, not on the profiles of other drugs,” Pfizer's chief executive, Ian Read, said in today’s third-quarter earnings call. “When you look at the total profile of the drug, we don’t believe it would be commercially successful, nor would it be a benefit to patients to bring it to the market.”
Pfizer shares were down 1.8% in early trade. The move will result in a $300m R&D write-off this year.
Mr Read also said that restrictive payment policies for PCSK9 inhibitors in the US – which have resulted in a drops of around 20% in the 2020 sales forecasts of both Repatha and Praluent since launch – “meaningfully dampened our expectations for market potential”.
Whether both of the marketed products achieve their once-lofty expectations depends on outcomes trials due to return results soon – Praluent is expected to have results from a second interim analysis of the Odyssey Outcomes trial before the end of the year, while Repatha’s Fourier trial should read out in the first quarter of 2017. Amgen will also have data from a plaque regression study at the American Heart Association meeting.
There is nothing in the data yet to suggest that Praluent and Repatha would have the same weakening of LDL lowering over the length of these outcomes trials, of course – shares of Amgen, Sanofi and Regeneron were largely unmoved today.
But the field of cardiovascular disease has seen numerous cases of drugs that lower cholesterol but are unable to show that they prevent myocardial infarctions, strokes or death – notably, the CETP inhibitors have failed to show that lowering LDL and raising levels of LDL-scavenging HDL can have a benefit on patient outcomes.
The FDA asks for these massive trials for a reason. Statins have been a tough act to follow, and bococizumab’s discontinuation does nothing to build confidence that PCSK9s will do any better.
|And then there were two... The PCSK-9 class|
|Global sales ($m)||Phase III programme||Cardiovascular outcome study details|
|Product||Company||2016e||2022e||# of trials started to date||# of patients||Name||Trial ID||Data?|
|Praluent||Sanofi||206||3,201||21||28,968||Odyssey Outcomes||NCT01663402||Second interim analysis Q4'16|
|Bococizumab||Pfizer||-||1,181||10||33,071||Spire-1, Spire-2||NCT01975376, NCT01975389||Halted|
|ALN-PCSsc||Medicines Co||-||285||501-patient, phase II Orion-1 study to be presented at AHA on November 15 - NCT02597127|