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Amgen has already reported the positive topline result of its FOURIER cardiovascular outcomes trial for its PCSK9 inhibitor Repatha, but analysts from Datamonitor Healthcare and Biomedtracker lay out the reasons to check out the full results and other highlights at the upcoming American College of Cardiology meeting



Cholesterol Plaque



The headline presentation at the American College of Cardiology annual scientific sessions, being held March 17-19 in Washington, DC, is Amgen Inc.'s FOURIER cardiovascular outcomes trial of its PCSK9 inhibitor Repatha (evolocumab) – and while the overall positive findings were already released, analysts at Datamonitor Healthcare and Biomedtracker explain there are several important implications to be gleaned from the full results.


In their conference planner, Datamonitor and Biomedtracker analysts note that Amgen "already revealed that the trial met its primary composite endpoint and the key secondary endpoint of three-point [major adverse cardiovascular events (MACE)] (CV death, non-fatal MI, non-fatal stroke) without new safety findings, but much will depend on the magnitude of the benefit and other details."


Payers, practitioners and sponsors have long been anticipating the results of cardiovascular outcomes trials to fully understand the potential of the PCSK9 class. With the topline results of FOURIER released last month, Amgen beat rivals Sanofi/Regeneron Pharmaceuticals Inc., which have the ODYSSEY OUTCOMES trial ongoing for their PCSK9 inhibitor Praluent (alirocumab).


The 27,000-patient FOURIER trial showed a benefit versus placebo in statin-treated atherosclerotic patients in terms of the number of cardiovascular deaths, non-fatal myocardial infarctions and strokes, hospitalizations for unstable angina or coronary revascularizations – but the level of benefit will be revealed at the ACC meeting.


A large effect on cardiovascular morbidity and mortality could help Repatha gain better reimbursement coverage and uptake in a wider patient population, potentially allowing it to reach the blockbuster sales originally expected for the class. Amgen reported $141m in sales in 2016. Payers have put up significant hurdles to use of the PCSK9 drugs; Amgen is also presenting at ACC an analysis on payer restrictions on PCSK9 use.


The outlook for the PCSK9 class also depends on the outcome of patient litigation; a decision could be reached by June. (Also see "PSCK9 Battle: Sanofi Not Negotiating Praluent Fate With Amgen; Ruling Possible By June" - Pink Sheet, 12 Feb, 2017.)


Details To Watch

While the trial was powered for at least a 15% hazard reduction in major cardiovascular events across the three categories of CV death, non-fatal myocardial infarction and non-fatal stroke, the analysts point out that given the size of FOURIER, "it could still be statistically significant with a smaller reduction, which would be disappointing. However, even 15% is somewhat modest, and [key opinion leaders (KOLs)] at the last [American Heart Association (AHA)] meeting expected benefits closer to 25% or 25%-35%."


The detailed results of FOURIER should also allow for better prognostication on the ODYSSEY OUTCOMES trial of Praluent. Sanofi/Regeneron's drug did not meet an interim analysis that required a 20% risk reduction at 75% of the total events planned in the trial. "Hence if Repatha shows a more promising benefit, it will be interesting to get opinions on what is occurring in the Praluent trial," the report notes.


A robust benefit in FOURIER, at least comparable to the LDL-cholesterol lowering seen in statin trials, would help reinforce use of LDL-C as a biomarker. (Also see "Advicor, Simcor Withdrawals Show There's A Lot Riding On CV Outcomes Studies" - Pink Sheet, 25 Apr, 2016.)


"This would add weight to the argument that the FDA, which has had more concern about this than the EMA, should approve other drugs with straightforward LDL-C lowering mechanisms prior to CVOT results (such as [Esperion Therapeutics Inc.]'s bempedoic acid)," the analysts point out. (Also see "Phase III Boost For Esperion But Does It Own Its Destiny?" - Scrip, 17 Oct, 2016.)


Will It Be Enough To Win Over Payers?

Much like regulators have been waiting for the massive outcomes trials to settle questions about cholesterol surrogate endpoints, payers and practitioners have been waiting to assess the outcomes data to assess appropriate use and coverage of the expensive drugs.


Datamonitor and Biomedtracker stress that "the benefit will need to be meaningful to impact payers, though there is variability in opinion on what precisely they will need to see, and in the US, it is unlikely they would completely remove pre-authorization without substantial concessions on pricing. Aggressive pre-authorization has thus far hampered uptake of the class in the market."


Payers interviewed by Datamonitor suggested at a 3% reduction in absolute risk was needed to be persuasive. "Still, payers indicated they would retain prior authorization without substantial price declines (e.g. to $4,000-$5,000/year), saying that manufacturers have misjudged their willingness to pay for such a large patient population.


Real Endpoints CEO Roger Longman argued that a 2% absolute risk reduction, or about a 30% relative risk reduction, "would make it difficult for US payers to say 'no,' in part as physicians would become fairly agitated." He suggested that even with a more minimal benefit, there will be some degree of greater access in the US.


[Editor’s note: For more information, see Datamonitor Healthcare’s in-depth report on PCSK9 inhibitor pricing and reimbursement.]


Other Highlights

Also from the PCSK9 class, findings from Pfizer Inc.'s cardiovascular outcomes trials for bococizumab will be of interest – although both the trials and development of the drug were suspended because of waning efficacy on LDL-C over time and immunogenicity issues. (Also see "Pfizer Dashes Hopes For A PCSK9 Pill" - Scrip, 2 Aug, 2016.) "Nevertheless, it will be interesting to see whether there is sufficient data to determine if it had an impact on CV outcomes that correlated with its LDL-C effects," the preview states. A lack of correlation could have consequences for other types of LDL-lowering drugs, the analysts caution.
Full data from the ORION 1 trial of The Medicines Co./Alnylam Pharmaceuticals Inc.'s long-acting PCSK9 inhibitor inclisiran should give greater clarity on the market potential for the novel siRNA therapeutic in the cholesterol field. Preliminary data from the Phase II trial have made it clear that it could be dosed only two or three times a year – which would be a major differentiation from the every-other-week or monthly dosing of competitors, the analysts add.
Johnson & Johnson/Bayer AG will have data from label-expansion trials for their anticoagulant Xarelto (rivaroxaban), which will include a lower dose intended to reduce bleeding risk.


Cerenis Therapeutics SA will have details from CARAT, an atherosclerosis imaging trial of its HDL mimetic CER-001 that was just reported to have failed, further dimming hopes for the approach after the failure of MDCO-216 last year. Other CER-001 trials are continuing.

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