Praluent versus Repatha! Who care? Nobody? RIGHT? NO! Scream Mr. Market!
Next few months/and until 2017-end, it will be …whatever…
However, let for second compare respective CVOT trials, designee and possible outcome?
Praluent: 18K pts (1 : 1), 1613 primary end-point events (8.96%), interim at 50% and 75% event occurrence. Run-in period of 2-16 weeks. Results expected by 12-2017. Projected KM placebo group incidence for primary end-point event is 3.8%/12 months, 6.4%/24 months, 9.0%/36 months and 11.4%/48 month.(Note: higher number/%-tage incidence at early months, drug benefit need time to take effects…that was a case for STATIN CVOT trials). Primary end-point : 15% hazard reduction or absolute 1.5% events reduction (from ~9% to ~7.5%/~36 months period).
Repatha (what is available to me, if someone have more data please post them): 27.5K pts (1 : 1), 12-2014… enrolment # increase from 22.5K to 27.5 K, 6-2015… enrolment completed, results expected by 10-2017 (all pts will complete 24 months treatment period). I will guess, 15% hazard reduction as primary. There is no interim analysis.
If we calculate the same %-take incidence of the CV events (9%/36 months), than Repatha trial will need 2475 events for primary results. However IF we apply Praluent metrics (~1800 events), trial my reach end-point requirement early (~24 months or ~6.5% incidence rate). (15% hazard reduction would now be absolute 0.975%). Maybe they increased # enrolment to increase statistical power? I do not know???? AMGN R&D chef stated they want event numbers FASTER!!!!???
So, it appears to me that IF they (AMGN) keep the same # events, and increase PTS pools, their primary end-point is “softer”. In statin (Lipitor) CVOT trial separation of the line started after ~18 months (http://www.accessdata.fda.gov/drugsatfda_docs/label/2009/020702s056lbl.pdf). It took time for Lipitor to demonstrate positive CV effects (at 36 months 9.0% for placebo and 5.8% for 10 mg Lipitor, 36% relative reduction or 3.2% absolute) , so in AMGN CVOT trial Repatha CV benefit at <24 months may be inflated and/or reduced. At least it is possibility. Speeding up event numbers (not rate) and ‘softer” enrolment criteria AMGN generated risk that their CVOT outcome may not be as robust as one for Praluent. At 75% interim for Praluent (my projection is 09-2016) good part of the pts will be followed for +24 to 36 months, and line separation at great significance is real possibility. Actually, I am predicting that at 75% interim they will stop trial for excessive efficacy. AMGN was aware of this (real) possibility, and to be time-competitive they increased enrolment # to generate early completion, but with possibility that outcome may not be as robust. Anyway, current FDA approval have NO requirement that CVOT be POSITIVE, only they lose marketing muscle.
All in all, as REGN SH (biased) I see advantage for Praluent (dosing, side effects, efficacy at comparable lower dose), and that this will be demonstrated (???) by CVOT. |
