Summary Basis of Decision for Natrecor

3.3.1 Pharmacodynamics

Bolus IV doses of 0.3-20 µg/kg and IV infusions of 0.003-0.1 µg/kg/min demonstrated dose-dependent reductions in pulmonary capillary wedge pressure (PCWP) and systemic vascular resistance accompanied by an increase in cardiac index. Reductions in systolic blood pressure, without an associated increase in heart rate, were also seen with the higher doses of nesiritide.

The hemodynamic effects of nesiritide following bolus administration were transient in nature. Reductions in PCWP post-administration were detectable for up to approximately 4 hours but any effect on other hemodynamic variables did not appear to last longer than 2-3 hours.

When nesiritide was administered as an infusion, the apparent beneficial clinical hemodynamic effects were maintained during the course of the infusion. On stopping, the time course of the loss of pharmacodynamic (PD) effect was similar to that following bolus administration as the hemodynamic parameters returned to baseline values. There was no evidence of adaptive tolerance following repeat bolus dosing or during infusion. The dosing regimen was refined to include the use of a small bolus dose before the infusion to reduce the time to steady-state pharmacokinetics.

Higher doses of nesiritide appeared to offer little additional benefit in exchange for a marked increase in the number of hypotensive episodes. Any small benefit obtained by administering infusions greater than 0.03 mg/kg/min would be outweighed by the increased potential to precipitate hypotension.

3.3.2 Pharmacokinetics

The concentration vs. time profile of hBNP after IV bolus dosing of nesiritide was described with a two-compartment open model. Approximately two-thirds of the drug exposure (AUC) was associated with the longer terminal phase of elimination. The arithmetic mean of the terminal elimination half-life of hBNP was approximately 18 minutes and the initial distribution elimination phase was approximately 2 minutes.

Mean values for volume of the central compartment (Vc) and the mean steady-state volume (Vss) of distribution were approximately 0.073 L/kg and 0.19 L/kg, respectively. The estimated value for Vc was just less than twice the plasma volume, and the estimated value for Vss was approximately the same as that of extracellular water. The estimated values for volume of distribution did not differ significantly among dose groups, suggesting that the volume of distribution was not dose-dependent.

Non-clinical studies suggest that the NP-C receptor and the NEP 24.11 and/or related peptidases may play a role in the metabolism of nesiritide.

Elimination of nesiritide has not been studied specifically in humans. Mean estimates of plasma clearance of hBNP were approximately 9.2 mL/min/kg. Age, gender, race/ethnicity, baseline endogenous hBNP concentration, severity of CHF (as indicated by  baseline PCWP, baseline cardiac index, or New York Heart Association classification) did not influence clearance. Clearance was found to vary proportionally with body weight. Clinical data suggest that the dose (weight-adjusted) of nesiritide does not need to be adjusted in patients with renal insufficiency.

3.3.3 Clinical Efficacy

The Natrecor clinical development program for heart failure (HF) comprised of a total of 10 completed studies. The studies that were potentially most relevant in terms of clinical efficacy and safety were the Long Infusion studies 311, 325, 326, 329, and 339. These studies were randomized, multicentre, placebo- or active-controlled studies (comparative agents included nitroglycerin, dobutamine, milrinone, nitroprusside, or dopamine) in which 772 patients with decompensated chronic HF received continuous infusions of Natrecor at doses ranging from 0.01 to 0.03 µg/kg/min. Of these patients, the majority (n=541, 70%) received the Natrecor infusion for at least 24 hours: 371 (48%) received Natrecor for 24-48 hours, and 170 (22%) received Natrecor for greater than 48 hours.

There was great variability in study design, number of patients recruited, dosage regimens, type of control, and endpoints in the Long Infusion studies. Studies 311, 325, and 339 (VMAC) were double-blind studies, while Studies 326 and 329 were both open-label. VMAC specifically studied the recommended standard infusion dose (0.01 mg/kg/min), with a small subset of patients receiving nesiritide titrated up to a maximum infusion dose of 0.03 mg/kg/min, a dose regimen consistent with the dose recommended in the Product Monograph.

The efficacy of nesiritide was demonstrated in VMAC and, to some extent, in Studies 325 and 311. Additional supportive efficacy data was provided by Study 329 and Study 326.

VMAC was the most relevant study in demonstrating efficacy since, as the largest study (n=489), with a broad range of acutely decompensated heart failure (ADHF) patients, its design reflected how nesiritide would be used in clinical practice. That study provided comparative data to placebo (up to 3 hours) but also to nitroglycerin, which was administered per physician's usual practice. It was focused on endpoints which reflect the immediate and early treatment objectives in the target population.

The primary endpoint for VMAC was the change from baseline in PCWP and change in baseline in dyspnea 3 hours after start of the study drug. Global Clinical Status (GCS), an overall measure of well-being, was a secondary endpoint. The reduction of PCWP achieved with nesiritide was greater compared to placebo and the results were statistically significant.

For the dyspnea analysis in the VMAC study (co-primary endpoint), patient responses were assigned a score from +3 (markedly better) to -3 (markedly worse). Patients receiving Natrecor in addition to 'standard of care' reported a greater improvement in their dyspnea at 3 hours than patients receiving placebo in addition to 'standard of care' (p = 0.034), with an improvement in dyspnea reported by 75% of Natrecor patients compared with 63% of placebo patients.

In a double-blind dose-response study (Study 325), patients receiving Natrecor (0.015 μg/kg/min preceded by an IV bolus of 0.3 μg/kg/min, and 0.03 μg/kg/min preceded by an IV bolus of 0.6 μg/kg/min) reported greater improvement in dyspnea at 6 hours than patients receiving placebo (p<0.001, with 57% and 53% for the two nesiritide arms and 13% for placebo).

A long-term clinical study with specific design requirements was recommended prior to reconsidering this submission for approval.The sponsor refiled the drug submission with a protocol for a new large clinical study, ASCEND-HF. ASCEND-HF is a Phase III, randomized, double-blind, placebo-controlled, parallel-group, multicentre study evaluating the efficacy and safety of nesiritide administered with standard of care compared with placebo administered with standard of care in patients with ADHF.

A copy of the completed study report from the confirmatory, Phase III study will be provided to Health Canada as soon as it is available. The design of the ASCEND-HF study should address Health Canada's concerns with respect to use of Natrecor for the proposed indication.

3.3.4 Clinical Safety

The safety of Natrecor was evaluated in the clinical program described in the Clinical Efficacy section. The overall safety database consisted of 941 HF patients that enrolled in IV bolus, Short Infusion, and Long Infusion studies.

The most common side effects included hypotension (asymptomatic and symptomatic), non-sustained ventricular tachycardia, headache, and nausea. A complete list of the adverse drug reactions is in the Product Monograph.

In the Long Infusion studies, asymptomatic and symptomatic hypotension events were reported with increased frequency with increased doses of nesiritide. However, in VMAC, symptomatic and asymptomatic hypotension events were reported by a similar percentage of patients treated with nitroglycerin, nesiritide 0.01 mg/kg/min, or the nesiritide adjustable dose group. Symptomatic hypotension led to a dose reduction or discontinuation of study drug more frequently in the 0.015 mg/kg/min (9%) and 0.03 mg/kg/min (15%) nesiritide dose groups.

In the VMAC 30-day follow-up period, 5 patients in the nitroglycerin group (2%) and 9 patients in the Natrecor group using the recommended dose (3%) required first-time dialysis. When Natrecor was initiated at doses higher than the recommended dose of 0.01 µg/kg/min (0.015 and 0.03 µg/kg/min), there was an increased rate of elevated serum creatinine over baseline compared with standard therapies, although the rate of acute renal failure and need for dialysis was not increased.

Natrecor has not been studied in a trial designed or powered to assess mortality as a primary or key secondary endpoint. Mortality data were collected during the study period, during the standard follow up period (up to 30 days), as well as at 6 months. In VMAC, a total of 273 patients received Natrecor and 216 patients received nitroglycerin. No patients died while receiving the study drug. The mortality rates at 30 days from any cause were 8.1% for patients treated with Natrecor and 5.1% for patients treated with nitroglycerin. The hazard ratio (nesiritide/nitroglycerin) was 1.56 (95% CI: 0.75--3.24). The mortality rates at 6 months for patients receiving Natrecor or nitroglycerin were 25.1% and 20.8%, respectively. The hazard ratio was 1.22 (95% CI: 0.83--1.79). In the absence of a prospective study that is adequately powered to estimate the relative risk of mortality at one month from treatment with nesiritide, with proper adjustment in the study design and data analyses for patients' severity of illness and other prognostic factors at baseline that may have an impact on mortality, the potential increase in mortality observed in pivotal study VMAC can neither be ruled out nor be ignored.

Further clinical studies are needed to clearly confirm the safety of nesiritide. Study ASCEND-HF should address Health Canada's safety concerns in relation to Natrecor for the proposed indication.

3.3.5 Outstanding Issues

In keeping with the provisions outlined in the Notice of Compliance with Conditions (NOC/c) Policy, the Sponsor has agreed to provide the following confirmatory study:

Phase III Study A093: A Double-Blind, Placebo-Controlled, Multicentre Acute Study of Clinical Effectiveness of Nesiritide in Subjects with Decompensated Heart Failure- ASCEND-HF.

• A copy of the completed study report for the confirmatory study will be provided to Health Canada as soon as it is available.
• The Sponsor will include monitoring and follow-up of adverse events from this study as well as events noted in post-marketing reporting and other major safety concerns identified.
• An independent Data and Safety Monitoring Committee (DSMC) will be established to be responsible for reviewing the progress of the study at regular intervals to ensure patient safety and trial integrity.

The Sponsor agrees to submit to Health Canada the Periodic Safety Update Reports semi-annually until the conditions have been fulfilled and removed from the NOC/c by Health Canada. In addition, the Sponsor will commit to post-marketing surveillance and reporting of adverse drug reactions in accordance with Guidance for Industry: Notice of Compliance with Conditions.