Summary Basis of Decision for Zontivity

Clinical Pharmacology

Vorapaxar, the medicinal ingredient of Zontivity, is a selective and reversible inhibitor of the protease-activated receptor-1 (PAR-1) on platelets. Vorapaxar inhibits thrombin-induced platelet aggregation in in vitro studies. In addition, vorapaxar inhibits thrombin receptor agonist peptide (TRAP)-induced platelet aggregation without affecting coagulation parameters. Vorapaxar does not inhibit platelet aggregation induced by other agonists such as adenosine diphosphate (ADP), collagen or a thromboxane mimetic.

The clinical pharmacology included reports on the human pharmacodynamic and pharmacokinetic studies.

A population pharmacokinetic and exposure-response modelling of vorapaxar indicated that a 2.5 mg dose of vorapaxar was the lowest dose likely to provide ≥80% inhibition of TRAP-induced platelet aggregation in most patients; efficacy could be reduced at doses <2.5 mg. This study supported the proposed market dose of 2.5 mg once daily.

The clinical pharmacological data support the use of Zontivity for the recommended indication.

For further details, please refer to the Zontivity Product Monograph, approved by Health Canada and available through the Drug Product Database.

Clinical Efficacy

The efficacy of Zontivity in reducing atherothrombotic events in stable patients with a history of myocardial infarction (MI) was demonstrated through a single pivotal clinical trial, Thrombin Receptor Antagonist in Secondary Prevention of Atherothrombotic Ischemic Events (TRA 2^oP-TIMI 50), which was a randomized, double-blind, placebo‑controlled, fixed-dose, events-driven trial.

To participate in the TRA 2^oP-TIMI 50 trial, patients had to have evidence or a history of atherosclerosis involving the coronary, cerebrovascular or peripheral vascular systems as follows:

• Coronary artery disease (CAD) as indicated by a history of presumed spontaneous MI that occurred ≥2 weeks but ≤12 months before initiation of therapy;
• Ischemic (presumed thrombotic) cerebrovascular disease (CVD) as indicated by a history of ischemic stroke that occurred ≥2 weeks but ≤12 months before initiation of therapy; or
• Peripheral artery disease (PAD) as indicated by a history of intermittent claudication and a resting ankle brachial index (ABI) of <0.85 or amputation, peripheral bypass or peripheral angioplasty of the extremities secondary to ischemia.

The primary efficacy endpoint was a composite of cardiovascular death, MI, stroke and urgent coronary revascularization, while the key secondary efficacy endpoint was a composite of cardiovascular death, MI and stroke.

A total of 26,449 patients were randomized to receive orally either 2.5 mg vorapaxar sulfate (number of patients [n] = 13,224) or placebo (n = 13,225) once daily, in addition to acetylsalicylic acid (ASA), with or without clopidogrel. Of these 26,449 patients, 17,779 (67.2%) were assigned to the CAD stratum, 4,883 (18.5%) to the CVD stratum and 3,787 (14.3%) to the PAD stratum. The median duration of treatment was just over 2 years. However, following safety concerns (increased risk of intracranial hemorrhage [ICH]) identified in a double-blind, placebo-controlled Phase III trial, TRA-CER (Thrombin Receptor Antagonist for Clinical Event Reduction in Acute Coronary Syndrome [ACS]), patients with a history of stroke were excluded from the TRA 2^oP-TIMI 50 trial. Those encompassed 4,510 patients (2,948 receiving placebo and 2,262 receiving Zontivity) that had either a prior history of stroke (CVD stratum) or experienced a stroke endpoint during the study. Also excluded were all patients with a history of transient ischemic attack (TIA) and those who experienced a TIA during the trial.

The analysis of the treated PAD patients in the TRA 2^oP-TIMI 50 trial found insufficient statistical evidence of efficacy in the primary and key secondary efficacy endpoints, potentially due to the relatively low number of patients in this stratum of the trial.

In the CAD patients with no history of stroke or TIA, Zontivity added to ASA, with or without clopidogrel, significantly reduced the primary efficacy composite endpoint [HR 0.82; 95% CI 0.74-0.90; p<0.001] and the key secondary efficacy composite endpoint [HR 0.78; 95% CI 0.70-0.88; p<0.001]. The rate of reduction of MI was the major component that contributed to this reduction. The effect was similar regardless of the time from qualifying MI to the start of therapy with Zontivity and was maintained for the duration of the trial. However, there was an attenuation of the effect of Zontivity from Year 2 to Year 3, while bleeding risk remained and even increased over time with patient age and co-morbidities. Therefore, there is insufficient evidence to support long-term (life-long) treatment with Zontivity. Zontivity was also associated with a reduction in the incidence of recurrent events and definite stent thrombosis. There was a consistency of effect with Zontivity among subgroups that included age, sex, hypertension, use of antiplatelet agents and diabetes mellitus.

Compared to placebo, Zontivity prevented 71 cardiovascular death, non-fatal MI or ischemic stroke events per 10,000 patient-years, while causing 31 additional Global Utilization of Streptokinase and Tissue Plasminogen Activator for Occluded Arteries (GUSTO) Moderate bleeding events, 1 additional GUSTO Severe non-fatal non-ICH event and no fatal bleeding. From a number needed to treated (NNT) or number needed to harm (NNH) perspective, 140 patients would need to be treated for 1 year with Zontivity to prevent 1 non-bleeding cardiovascular death, MI or stroke event, while 1 in every 7,488 patients and 1 in every 325 patients treated for 1 year with Zontivity would have a GUSTO Severe non-fatal non-ICH event and a GUSTO Moderate bleeding event, respectively.

Indication

The original New Drug Submisssion (NDS) for Zontivity was filed with the following proposed indication:

“Zontivity (vorapaxar sulfate) is indicated for the reduction of atherothrombotic events in patients with a history of myocardial infarction (MI) or with peripheral arterial disease (PAD). Zontivity has been shown to reduce the rate of a combined endpoint of cardiovascular death, MI, stroke, and urgent coronary revascularization (UCR).”

The originally proposed dosage and administration statement referred to the use of Zontivity in combination with acetylsalicylic acid (ASA), with or without clopidogrel, with no specific recommendation on its combined use with prasugrel or ticagrelor due to lack of evidence. This lack of evidence, combined with a potentially increased risk of bleeding with these agents, led to the Health Canada’s decision to restrict the use of Zontivity with ASA, with or without clopidogrel.

Also, as the analysis of the treated PAD patients in the pivotal trial TRA 2^oP-TIMI 50 showed insufficient statistical evidence of efficacy, Health Canada only accepted the proposed indication for the reduction of atherothrombotic events in the post-MI patients. Hence, Health Canada approved the following indication:

Zontivity (vorapaxar sulfate), co-administered with acetylsalicylic acid (ASA) with or without clopidogrel, according to their standard of care, is indicated for the reduction of atherothrombotic events in adult high-risk patients with a history of myocardial infarction (MI).

All of the issues impacting the indication, contraindications, dosage and safety information for Zontivity, which led to issuing a Notice of Non-Compliance (NON) on October 6, 2015, were subsequently satisfactorily resolved and reflected appropriately in the various sections of the Zontivity Product Monograph. The submission was found to be in compliance with the Food and Drugs Act and Regulations and a Notice of Compliance (NOC) was issued.

For more information, refer to the Zontivity Product Monograph, approved by Health Canada and available through the Drug Product Database.

Clinical Safety

Zontivity was evaluated for safety in the Phase III clinical trial TRA 2°P‑TIMI 50 (described in the Clinical Efficacy section). Patients randomized to Zontivity received treatment for a median of 2.3 years with 2,187 patients treated for >3 years.

The safety analysis of the coronary artery disease (CAD) patients with no history of stroke or transient ischemic attack (TIA) included 16,856 patients. Of those, 8,412 received placebo and 8,444 received Zontivity. More than half of the patients (62.7% for placebo-treated and 61.9% for Zontivity-treated) were on treatment for ≥2 years. The duration of participation within each group was nearly identical between placebo- and Zontivity-treated patients. Of the 26,352 patients treated, 6,093 patients (23.0%) discontinued treatment (2,948 in the placebo group and 3,145 in the Zontivity group). More patients in the Zontivity group (n = 1,381) than in the placebo group (n = 1,299) discontinued treatment due to adverse experiences. Of the patients who discontinued treatment, approximately half (48.1% for the placebo group and 49.5% for the Zontivity group) discontinued treatment after ≥1 year.

The safety endpoints evaluated in the pivotal trial were measures of bleeding, including a composite of moderate and severe bleeding events according to the Global Utilization of Streptokinase and Tissue Plasminogen Activator for Occluded Arteries (GUSTO) classification, and clinically significant bleeding, defined as Thrombolysis in Myocardial Infarction (TIMI) Major or TIMI Minor bleeding, or bleeding that required unplanned medical treatment, surgical treatment or laboratory evaluation.

Bleeding Adverse Events

Bleeding risk was considered the major potential safety concern for Zontivity. Bleeding risk was found to be greater for patients in the Zontivity group as compared with patients in the placebo group. However, the rate of intracranial hemorrhage (ICH) was equivalent (0.5%) in both treatment groups. This was in contrast to patients with a history of stroke or TIA who had an increased risk of ICH. Zontivity did not significantly increase the rate of GUSTO Severe bleeding, TIMI Major bleeding, non-CABG (coronary artery bypass graft surgery)‑related major bleeding and ICH. The overall incidence of fatal bleeding was low and similar between Zontivity and placebo (0.1%). There was no increase in the risk of any of the bleeding endpoints in patients ≥65 years versus (vs.) <65 years and ≥75 years vs. <75 years.

In the overall population, the proportions of patients requiring transfusions following a bleeding event, a CABG surgery, or a non-CABG cardiac or vascular surgery were higher in the Zontivity group compared to the placebo group. However, in totality, Zontivity did not appear to be associated with any increased perioperative bleeding risk.

There were small percentages of serious bleeding events reported during treatment. More patients reported serious bleeding events in the Zontivity group compared to the placebo group. Gastrointestinal-related bleeding events were the most frequently reported serious bleeding events.

Discontinuation of treatment due to bleeding events was low, but higher in the Zontivity group compared to the placebo group. Epistaxis (nosebleed) was the most frequently reported bleeding event and was reported twice as often in the Zontivity group compared to the placebo group (7.2% vs. 3.6%). It was also the most frequently reported bleeding event that led to treatment discontinuation.

The lack of appropriate labelling to mitigate the increased risk of bleeding associated with Zontivity was the major safety concern that led to a NON for the original drug submission. In post-MI patients, the pivotal trial showed an attenuation of the efficacy of Zontivity after 2 years of treatment, while the bleeding risk in these patients remained high. The pivotal trial also showed that, in post-MI patients, relatively more bleeding events were seen in: patients weighing <60 kg vs. those weighing ≥60 kg; patients ≥65 years of age vs. those <65 years of age; patients with reduced renal function; and patients with reduced hepatic function. Appropriate measures were taken to mitigate these risks, including the need for a re-assessment of the risk/benefit balance for each patient after 2 years of treatment with Zontivity (stated in the Dosage and Administration section of the Product Monograph). The bleeding risks have been reflected appropriately in the Contraindications and Warnings and Precautions sections of the Zontivity Product Monograph.

Low body weight

In the TRA 2^oP‑TIMI 50 trial, patients weighing <60 kg had a higher rate of bleeding (measured by GUSTO Moderate or Severe, clinically significant, and ICH) compared to patients weighing ≥60 kg. For all bleeding endpoints, hazard ratios for patients <60 kg (n = 857) were higher by 18% ‑ 37% than those for patients ≥60 kg (n = 15,977). Although the numbers of events were small (≤76 events), this indicated an increased risk of bleeding for patients weighing <60 kg. Therefore, the Warnings and Precautions Section of the Product Monograph contains a warning that Zontivity should be used with caution in patients with a body weight <60 kg.

Older Age (≥65 years)

In the TRA 2°P‑TIMI 50 trial, 28.9% of post-MI patients without a history of stroke or TIA were ≥65 years of age and 7.3% were ≥75 years of age. Older subjects (≥65 years) had greater bleeding event rates in the placebo and Zontivity trial arms than did younger subjects (<65 years). The same observation was made for subjects aged ≥75 years vs. <75 years. Older patients are generally at a higher risk of bleeding and this intrinsic bleeding risk has been included in the Warnings and Precautions section of the Zontivity Product Monograph.

Renal impairment

Reduced renal function is a known risk factor for bleeding. In the TRA 2^oP-TIMI 50 trial, out of 16,987 CAD patients with no history of stroke or TIA randomized, only 101 patients had estimated Glomerular Filtration Rate (eGFR) <30 mL/min/1.73 m². Therefore, the underlying bleeding risk in patients with reduced renal function and the limited experience in patients with severe renal impairment or end-stage renal disease have been pointed out in the Warnings and Precautions section of the Zontivity Product Monograph.

Hepatic impairment

Severe hepatic impairment is a known risk factor for bleeding. In the TRA 2^oP-TIMI 50 trial, 98.2% of coronary artery disease (CAD) patients with no history of stroke or TIA had no prior history of hepatic disease. In addition, in a Phase I study to determine the effects of hepatic impairment on the pharmacokinetics of Zontivity, only 4 instead of 6 subjects with severe hepatic impairment were enrolled because one subject experienced a serious adverse event of gastrointestinal hemorrhage secondary to ruptured esophageal varices; this event was considered possibly related to the study drug. The Warnings and Precautions section of the Zontivity Product Monograph has included the underlying bleeding risk in patients with reduced hepatic function. Furthermore, Zontivity has been contraindicated in patients with severe hepatic impairment.

Concomitant use with other P2Y12 inhibitors – prasugrel or ticagrelor

In the TRA 2^oP‑TIMI 50 trial, only 0.2% (n = 38) of CAD patients with no history of stroke or TIA took prasugrel; no subject took ticagrelor. In addition, prasugrel and ticagrelor are more potent than clopidogrel and as such are expected to increase the risk of bleeding. Given the paucity of evidence of efficacy and safety of co-administering Zontivity with ASA and ticagrelor, or with ASA and prasugrel, Health Canada restricted its indication to co-administration with ASA, with or without clopidogrel.

Concomitant use with warfarin, other oral anticoagulants and heparin

There is very limited clinical experience with the concomitant use of Zontivity with warfarin, other oral anticoagulants and heparin, including low molecular weight heparin, but their concomitant use may increase the risk of bleeding. Therefore, an appropriate warning has been included in the Warnings and Precautions section of the Zontivity Product Monograph.

Non-bleeding Adverse Events

The pivotal TRA 2°P‑TIMI 50 trial showed no significant differences in non-bleeding adverse events between the two treatment groups. Anemia was reported slightly more frequently in the Zontivity group (2.5%) compared to the placebo group (1.9%); there was no evidence of an association between Zontivity treatment and non-bleeding causes of anemia, such as bone marrow suppression. Anemia was also the most frequently reported other adverse event that led to treatment discontinuation. The numbers of events that resulted in discontinuation of treatment were similar between the two treatment groups.

Conclusion

All of the issues impacting the indication, contraindications, dosage and safety information for Zontivity, which led to issuing a Notice of Non-Compliance (NON) on October 6, 2015, were subsequently satisfactorily resolved and reflected appropriately in the various sections of the Zontivity Product Monograph.

Based on the information provided for this submission, the benefit/risk ratio of Zontivity, co-administered with acetylsalicylic acid (ASA) with or without clopidogrel, for the reduction of atherothrombotic events in adult high-risk patients with a history of myocardial infarction (MI) is considered to be favorable. Appropriate warnings and precautions are in place in the approved Zontivity Product Monograph to address the identified safety concerns.

For more information, refer to the Zontivity Product Monograph, approved by Health Canada and available through the Drug Product Database.