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204886Orig1s000 CENTER FOR DRUG EVALUATION AND RESEARCH APPLICATION NUMBER: 204886Orig1s000 MEDICAL REVIEW(S) DIVISION OF CARDIOVASCULAR & RENAL PRODUCTS Divisional Memo NDA: 204886 Zontivity; vorapaxar for reduction of atherothrombotic events in patients with a history of myocardial infarction. Sponsor: Merck Review date: 25 April 2014 Reviewer: N. Stockbridge, M.D., Ph.D., HFD-110 Distribution: NDA 204886 This memo conveys the Division’s recommendation to approve this application. This application has been the subject of reviews of CMC (Wong; 9 January 2014), biopharmaceutics (Eradiri; 9 January 2014), pharmacology/toxicology (Harlow; 17 December 2013, 19 February 2014), clinical pharmacology (Hariharan, Bilal, and Li; 16 December 2013), clinical (Rose and Levine; 16 December 2013, 18 April 2014) and statistics (Chen; 13 December 2013). There is a comprehensive CDTL memo (Marciniak; 18 April 2014) with which I am in general agreement. I highlight a few matters here. Vorapaxar is a low molecular weight blocker of PAR-1. On platelets, PAR-1 mediates platelet activation by thrombin, the hexapeptide TRAP, and possibly other short peptides. PAR-1 receptors exist in many other places, although vorapaxar’s effects seem only to be important at the platelet. Although inhibition of PAR-1 is reversible, the half-life of the drug in circulation is longer even than the life of platelets. There are no pending CMC issues. Vorapaxar has 7 chiral centers (b) (4) a single isomer that apparently does not undergo racemization. Crystalline vorapaxar tends to assume an amorphous form upon storage, but these forms are both highly soluble. Manufacturing site inspections are complete. Release specifications have been negotiated. Phospholipidosis is seen in animals, a finding that frequently portents QT prolongation, but vorapaxar did not appear to be a hERG blocker or human QT prolonger. Rats in some studies demonstrated vacuolization in their retinas, but this finding is believed to be a drug-mediated effect on a known fixation artifact. Vacuolization was not seen in the 2-year carcinogenicity studies. There appears to be some excess postnatal mortality; it is not clear whether this is a reproducible finding, much less what the implications might be for human use. Vorapaxar is highly bioavailable; peak plasma levels are seen1-2 hours after oral administration, independent of food. The accumulation half-life is several days; steady- state accumulation is about 5-fold. Metabolism is by CYP3A and CYP2J2. Strong CYP3A inhibition and induction lead to factor-of-2 effects; the clinical pharmacology review team recommends avoiding them and ignoring lesser CYP3A drugs. 2J2 is thought to be important in steroid ring metabolism; drug interaction studies with vorapaxar are not described. There is at least one active metabolite (M20) whose kinetics track those of the parent; it probably does not contribute greatly to PAR-1 inhibition. Vorapaxar is >99% protein-bound (so it will not likely be dialyzable); its volume of distribution is >600 L. For reasons no one seems to understand, there are wildly discrepant estimates of EC50 among studies, but with once-daily dosing at 2.5 mg, it takes several days to get to 80-90% PAR-1 inhibition (assessed with TRAP) and about 6 weeks to get back below 50%. It is not clear to C:\Users\STOCKBRIDGEN\Documents\NDA\N204886 Vorapaxar\ZontivityDivMemo.doc Last saved 1 10:57 Friday, April 25, 2014 Reference ID: 3495840 Divisional memo NDA 204886 Zontivity (secondary prevention in cardiovascular disease) me whether these data are all internally consistent or sufficient to parameterize a model of vorapaxar’s pharmacokinetics and pharmacodynamics. There are no exposure-response data in the phase 3 program, but I will return to analyses of factors affecting response after discussing the overall phase 3 findings. The phase 3 program consisted of 2 randomized, double-blind, placebo-controlled studies. TRACER enrolled 12944 subjects with acute coronary syndromes, and it showed an 8% risk reduction in cardiovascular death, myocardial infarction, hospitalization for recurrent ischemia, and urgent coronary revascularization; p=0.072. There is no claim stemming from this study. TRA-2P enrolled 26449 subjects who were 2 weeks to a year from their index cardiovascular event and followed them for a mean of 2.2 years. Randomization was stratified by entering diagnosis—prior myocardial infarction, prior stroke, or peripheral arterial disease. Background included aspirin (94%), clopidogrel (61%), beta blocker (69%), ACE inhibitor (60%), statin (90%), and PPI (25%). Follow-up was pretty good—about 2% loss in both groups over 2 years—and not considered to be a critical factor in TRA-2P’s interpretation. The statistical review comments extensively on an interim analysis that resulted in curtailing the enrollment of subjects with a prior history of stroke, but neither I nor Dr. Marciniak consider this to be problematic. I show the ITT results below (subjects with events, not annualized rates). Unlike the reviewers’ tables, this shows component events at any time, not just as first events: Placebo Vorapaxar N=13224 N=13225 Primary 10.7% 9.5% RRR=12%; p<0.001 Cardiovascular death 2.4% 2.2% Myocardial infarction 5.1% 4.3% Stroke 2.5% 2.4% Urgent revascularization 2.4% 2.1% The key secondary end point omitted urgent revascularization; it is also highly statistically significant, as are analyses of the primary and key secondary end points restricted to subjects with no prior history of stroke or only those with prior myocardial infarction. PPI use had an impact1. Placebo event rates were 12.1% among subjects on any PPI for at least 7 days vs 9.9% if not. For use of omeprazole or esomeprazole, the corresponding rates were 13.7% vs. 10%. Treatment differences were directionally the same regardless of PPI use, but smaller among subjects not taking PPIs. Vorapaxar adds something to effective clopidogrel, but more to subjects not taking effective clopidogrel. The primary safety end point was GUSTO moderate or severe bleeding. I show those data below (again as subjects with any event). Placebo Vorapaxar N=13224 N=13225 GUSTO moderate/severe 2.5 4.1 Moderate 1.1 1.7 1 This information comes from the TRA2P study report. I did not see any discussion in any review. C:\Users\STOCKBRIDGEN\Documents\NDA\N204886 Vorapaxar\ZontivityDivMemo.doc Last saved 2 10:57 Friday, April 25, 2014 Reference ID: 3495840 Divisional memo NDA 204886 Zontivity (secondary prevention in cardiovascular disease) Severe 1.4 2.6 CABG-related 0.1 0.1 ICH2 0.4 0.7 Most of the subgroup analyses for benefit or bleeding are not concerning. However, a fair amount of effort went into characterizing these by weight, at best a modest predictor of exposure. Despite treatments of the issue in reviews by clinical pharmacology, biostatistics, the clinical review, and CDTL memo, what was analyzed differed (<60 vs >60; by 10-kg increment; by median; or by quintile), and where there was nominally the same description, proportions of subjects with events differ from one review to the next by a fraction of a percent. The CDTL memo (analyses by quintile) at least gives both the primary end point and the principal bleeding end point event rates by what one hopes is a consistent methodology. As Dr. Marciniak did, I discount the cited p-value for interaction in the <60 vs. >60 analysis, as the cut-point was not prespecified and not more sensible than any other value. There is in these data some trend for bleeding rates to decrease on both placebo and vorapaxar with increasing weight. There is also a trend for primary event rates to increase with weight, but only in the placebo group. One has to worry that weight is confounded with other risk factors; Dr. Marciniak performs a logistic regression—with a set of cofactors he does not justify—and weight is not significant3. I do not find the analyses by weight particularly compelling, and other subgroup analyses by age and aspirin dose are less so. All need to be exposed in the label, but, I think, without advice as to interpretation, other than to be skeptical of subgroup analyses whether they show differences or not. Whether to include peripheral arterial disease in the claim has some of the same properties; you can make arguments against or in favor of including it. I do not think that anyone would have considered excluding it had the prior stroke/TIA population not been excluded forsafety reasons. 2 Note that hemorrhagic strokes are also counted in the primary efficacy end point. 3 Even if one could justify a set of cofactors or show that a variety of such analyses similarly explained the effect of weight, I would not know whether the model appropriately incorporated weight, since all of the action—if there is any—is in the tail of the weight distribution. C:\Users\STOCKBRIDGEN\Documents\NDA\N204886 Vorapaxar\ZontivityDivMemo.doc Last saved 3 10:57 Friday, April 25, 2014 Reference ID: 3495840 --------------------------------------------------------------------------------------------------------- This is a representation of an electronic record that was signed electronically and this page is the manifestation of the electronic signature. --------------------------------------------------------------------------------------------------------- /s/ ---------------------------------------------------- NORMAN L STOCKBRIDGE 04/25/2014 Reference ID: 3495840 DAIOP Medical Officer’s Review of NDA 204886 Request for Consultation from Consultation from Division of Cardiovascular and Renal Products (DCaRP) NDA 204886 SDN-044 Date of Document: November 8, 2013 SDN-052 Date of Document: November 22, 2013 Date of Review: April 18, 2014 Applicant: Schering Corporation 2000 Galloping Hill Road Kenilworth, NJ 07033 Drug: voraxapar sulfate (SCH 530348) Pharmacologic Category: thrombin receptor antagonist Comments/Special Instructions: 1. VACUOLIZATION An original consultative review was completed by DTOP on 10/29/13. SCH 530348 is a PAR-1 antagonist that inhibits human and primate platelet aggregation and smooth muscle cell proliferation induced by thrombin.
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