New Blood-Thinner Zontivity: Expanded Comparative Safety Research Profile

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Drugs Covered: BRILINTA, EFFIENT, PLAVIX, heart in patients with previous myocardial infarction (heart ZONTIVITY attack) or blockages in the arteries to the legs. Zontivity is contraindicated for use in patients with a history of stroke Classes Covered: Platelet aggregation inhibitors excl. or transient ischemic attack (TIA), as there was substantially heparin increased risk of intracranial hemorrhage (ICH) paired with Indications Covered: Myocardial Infarction, Stroke, no apparent benefit of treatment in this subset of patients in Thromboembolic Events Zontivity’s clinical trial. Mechanism of Action Covered: Thrombin Inhibitors Like other antiplatelets (e.g. Brilinta, Effient, Plavix), Zontivity has been shown to increase patient risk for potentially fatal bleeding, which has been reflected in Actionable Intelligence: AdverseEvents, Inc. (AEI) the Boxed Warning included in the drug’s prescribing analyzed Zontivity (vorpaxar, Merck), the newly approved information. The use of this drug is restricted to certain high- antiplatelet agent indicated for the reduction of heart attack, risk patient populations due to its proclivity for inducing stroke, and CV death in patients with history of heart attack serious bleeding and intracranial hemorrhage (ICH). or blockages in the arteries to the legs. We compared the existing safety profile of Zontivity to the antiplatelet agents Zontivity is the first FDA-approved drug in the class of Brilinta (ticagrelor), Plavix (clopidogrel), and Effient protease-activated receptor-1 (PAR-1) antagonists, and (prasugrel). Based on our analysis, we believe that Zontivity works by decreasing platelets’ ability to clot. Clinical trial has a riskier safety profile compared to other antiplatelet data showed that patients taking Zontivity experienced medications currently on the market as Zontivity displayed reduced risk of a composite of events which includes heart elevated rates of intracranial hemorrhage in clinical trials, attack, stroke, cardiovascular death, and urgent coronary and Zontivity’s half-life lasts significantly longer compared revascularization by 1.7% compared to placebo. AEI to existing antiplatelet drugs. Zontivity’s label contains a compared the prescribing information for Zontivity to the Black Box warning highlighting this increased bleeding risk branded antiplatelet drug Brilinta (ticagrelor), and analyzed and limits Zontivity’s usage to patients who have not had potential safety concerns for this newly approved blood a prior stroke or prior transient ischemic attack (TIA). We thinning medication. will monitor incoming adverse event reports for Zontivity as they become available to determine the extent this drug Safety Comparison to Existing Treatments should be covered by payers in the future. Efficacy ofZontivit y was based on clinical trial data from a study which included over 26,000 patients diagnosed with On May 8th, 2014, Zontivity (vorpaxar, Merck) was prior myocardial infarction (MI), prior ischemic stroke, or approved as a novel oral antiplatelet drug indicated to reduce established peripheral artery disease (PAD). Individuals the risk of heart attack, stroke, cardiovascular (CV) death, were randomly assigned to receive either Zontivity or and need for procedures to restore the blood flow to the www.adverahealth.com © 2015 Advera Health Analytics 1 placebo, and were stratified based on their intended use of clopidogrel (brand namePlavix ). All patients also received their background standard of care treatments. The primary endpoint was the composite of first occurrence of CV death, MI, stroke, or urgent coronary revascularization (UCR). The secondary endpoint was a composite of first occurrence of CV death, MI, or stroke. Results showed that Zontivity decreased chances of reaching the primary and secondary endpoints by 1.7% and 1.6%, respectively. It is important to note that safety considerations were changed mid-way through the Zontivity study, due to serious bleeding events and ICH in patients with prior incidence of stroke or TIA. No benefit for vorpaxar treatment was shown for patients with prior history of stroke or TIA. It is also important to note that patients with history of TIA but not stroke experienced increased rate of stroke during the study. Zontivity was approved with a Boxed Warning stating that this medication should not be used in patients with a history of stroke, transient ischemic attack (TIA), or intracranial hemorrhage (ICH), or active pathological bleeding. Effient is the only other antiplatelet drug that includes this particular warning. The Boxed Warning also reflects the increased risk for bleeding (including ICH and fatal bleeding) that affects patients taking antiplatelet agents.

TheZontivity drug label lists the following risks: Anemia, Bleeding, Fatal bleeding, Depression, Diplopia, Eruptions, Erythema, Gastrointestinal Bleeding, Hemodynamic compromise, Hypotension, Intracranial hemorrhage, Oculomotor disturbances, Rash, Retinal Disorder, Retinopathy, and Severe bleeding.

Below is a safety comparison between AEs listed on Zontivity’s drug label and three other antiplatelet drugs currently on the market. Case counts and ROR1 values for each AE x Drug pair are included.

www.adverahealth.com © 2015 Advera Health Analytics 2 The top 10 adverse reactions with highest case counts for thePlatelet Aggregation Inhibitor (excl. heparins) class of drugs are listed below. For comparative purposes, we omitted any adverse reactions that appeared on Zontivity’s drug label.

We will monitor Zontivity case report data when it becomes available to identify whether an RxSignal2 exists for Zontivity, and whether AEs that appear with other antiplatelet drugs are more or less prevalent with Zontivity. We utilized our proprietary RxSignal disproportionality analysis (DA) tool to calculate scores for the following AEs below, as they have been identified as key events that the FDA takes into consideration for Safety labeling Changes. We identified multiple serious AEs for Plavix and one for Brilinta that are not currently listed on the prescribing information for these drugs. Typically, an adverse event with a DA score above 2 that is not already on the drug label is in indication that a warning or label change from the FDA may be forthcoming. You will be alerted once we obtain adverse event data for Zontivity and whether we identify any AEs that contribute to an RxSignal. Plavix

Brilinta

Like other antiplatelet blood thinning drugs, Zontivity does not have any approved antidote. The prescribing information for Zontivity states, “There is no known treatment to reverse the antiplatelet effect of Zontivity. Significant inhibition of platelet aggregation remains 4 weeks after discontinuation.” Plavix, Effient, and Brilinta have been noted as possessing half-lives of 30 minutes, 7 hours, and 9 hours, respectively. Based on this information, Zontivity has a substantially longer half-life compared to other antiplatelet agents currently on the market.

www.adverahealth.com © 2015 Advera Health Analytics 3 In a press release, Merck stated that Zontivity will be available in the third quarter of 2014. The first FOIA data for this medication should be available on the AE Explorer platform 3 to 4 months after the launch of Zontivity.

Boxed Warning Zontivity was approved with a Boxed Warning stating that patients taking this medication are at an increased risk for serious bleeding events, including ICH and fatal bleeding. The Warning alto states that Zontivity should not be used in patients with a history of stroke, transient ischemic attack (TIA), ICH, or active pathological bleeding.

Brilinta and Effient also carry Boxed Warnings relaying increased risk for potentially fatal bleeding, and are contraindicated for use in patients with active pathological bleeding, history of intracranial hemorrhage, or patients undergoing coronary artery bypass graft surgery.Plavix’s Boxed Warning does not convey bleeding risks, though bleeding is listed other sections of the prescribing information for this drug. A summary of hemorrhage-related adverse event terms for Brilinta, Plavix, and Effient are listed below.

Zontivity, Brilinta, Plavix, and Effient are all required to have Medication Guides as part of their drug label, which contain a summary of safety information that patients should read before taking the drug and every time they get a prescription refill, as safety information may be updated periodically. TheFDA requires Medication Guides be included in certain prescription medications to help patients avoid serious adverse events that are specific to said drugs. Med Guides are required when the FDA determines 1) certain information is necessary to prevent serious adverse events, 2) patient decision-making should be informed by information about a known serious side effect with a product, or 3) patient adherence to directions for the use of a product are essential to its effectiveness.

REMS Program Zontivity does not have a post-market clinical trial requirement under the REMS program.

www.adverahealth.com © 2015 Advera Health Analytics 4 RxScore We will alert you once we have the initial RxScore3 for Zontivity, 3 to 4 months after the drug becomes available on the market. Below is the RxScore figure for all of the otherplatelet inhibiting drugs. Of these drugs, Effient (prasugrel) has the highest RxScore of 81.13. This follows the conclusion from ourrecent research report which found that prasugrel may have higher safety risks compared to other antiplatelet agents.

Clinical Trials Clinical efficacy for Zontivity was supported by a randomized, double-blind, placebo-controlled trial including 13,225 patients treated with Zontivity and 13,224 patients treated solely with standard of care (placebo group). The primary endpoint was a composite of CV death, MI, stroke, and urgent coronary revascularization (UCR). The secondary endpoint was a composite of CV death, MI, and stroke. Study results showed that Zontivity was more effective than placebo at decreasing both primary and secondary endpoints (10.1% vs 11.8%, and 7.9% vs 9.5%, respectively). In post- MI or peripheral arterial disease patients who survived an on-study efficacy event, the incidence of later events was lower when patients were treated with Zontivity. Hemorrhage data defined Global Utilization of Streptokinase and Tissue Plasminogen Activator for Occluded Arteries (GUSTO) severe bleeding as fatal, intracranial, or bleeding with hemodynamic compromise requiring intervention. Data was aggregated from 10,059 patients treated with Zontivity and 10,049 patients assigned to the placebo group. The prescribing information states that Zontivity increased GUSTO moderate or severe bleeding by 55%. Breakdowns for bleeding events for Zontivity vs placebo are as follows: 1.3% vs 1.0% for severe bleeding; 3.7% vs 2.4% for moderate or severe bleeding; 27.7% vs 19.8% for any GUSTO bleeding; 0.2% vs 0.2% for fatal bleeding; 0.6% vs 0.4% for intracranial hemorrhage; 15.5% vs 10.9% for clinically significant bleeding; and 4.7% vs 3.5% for gastrointestinal bleeding. Clinical efficacy for Brilinta was determined through a randomized, double-blind study of patients with acute coronary syndrome. Participants were randomized to receive aspirin plus standard therapy combined with either Brilinta (N = 9,333) or clopidogrel (Plavix) (N = 9,291). Patients were treated for at least 6 months and up to 12 months. The primary endpoint was composite of first occurrence of CV death, non-fatal MI (excluding silent MI), or non-fatal stroke. Secondary endpoint was each of these components individually assessed. Results for the primary endpoint showed that Brilinta lowered patient risk of CV death, MI, or stroke by 1.9% compared to Plavix (9.8% vs 11.7%). Secondary endpoints for Brilinta vs Plavix yielded better outcomes in CV death (4.0% vs 5.1%), MI (5.8% vs 6.9%), and all-cause mortality (4.5% vs 5.9%), but not in stroke (1.5% vs 1.3%).

1ROR is a disproportionality analysis known as the Reporting Odds Ratio. An ROR score greater than 1 indicates that there is a higher than normal reporting rate for a given AE / drug combination. While there is no widely accepted benchmark regarding the numerical level at which disproportionality analysis yields a “safety signal,” many in the drug industry assume that results above 2.0 warrant attention.

2RxSignal uses a refined version of disproportionality analysis (DA) in order to make predictions regarding future FDA advisory actions. The key issue for developing a relevant signaling platform is being able to properly identify, and track, which AEs are of significant interest to FDA. RxSignal was developed by identifying key AEs from hundreds of prominent FDA alerts issued over the past 12 years.

3RxScore is a proprietary algorithmic scoring model based predominantly on FAERS data. The score is presented on a 100-point scale and is derived by differentially weighing FAERS categories such as “Outcome,” “Event Seriousness,” “Report Type,” and “Reporter Type,” a disproportionality measure, and existing FDA warnings and DEA risk classifications. The score is also negatively adjusted by factoring in both “Indication Seriousness” and a patient’s existing comorbidities. A score of 100 indicates the highest potential adverse event risks.

AdverseEvents Explorer provides the highest quality, standardized and sourced data on post approval drug effects from FAERS, as well as access to proprietary data via Freedom of Information Act (FOIA) requests.

RxSuite includes:

• RxFilter® provides complete data optimization of the FAERS dataset through a 17-step algorithmic process to make it completely accessible and searchable.

• RxCost® is the first standardized methodology to determine direct costs of adverse drug events, enabling decisions to be made based on total cost of care.

• RxSignal® is a predictive algorithm that alerts users to emerging and/or previously unidentified side effect threats that may prompt a future FDA regulatory action (warnings, Black Box designations, product withdrawal or recalls, etc).

• RxScore® is the first drug safety scoring system that quickly summarizes comprehensive post-approval drug safety issues, like a FICO credit score

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