FDA Approval of Angiotensin II for the Treatment of Hypotension in Adults With Distributive Shock

Fortunato Senatore; Gowraganahalli Jagadeesh; Martin Rose; Venkateswaran C. Pillai; Sudharshan Hariharan; Ququan Liu; McDowell Tzu-Yun; Mohan K. Sapru; Mary Ross Southworth; Norman Stockbridge

Disclosures

Am J Cardiovasc Drugs. 2019;19(1):11-20. 

In This Article

Regulatory Review

Chemistry

The drug substance in Giapreza® is the acetate salt of synthetic angiotensin II, an octapeptide identical to endogenous human angiotensin II. The active pharmaceutical ingredient, a synthetic Ile5-angiotensin II acetate (human sequence) of Giapreza® was classified as a New Molecular Entity because it did not have exactly the same amino acid sequence, chemical form and origin as the previously marketed Hypertensin® (synthetic Val5-angiotensin-II amide; NDA 12–791). Both the N- and the C-terminus of the sequence are unmodified.

  • Human angiotensin II: Asp1-Arg-Val-Tyr-Ile5-His-Pro-Phe8 (This sequence is identical to the recently approved product, Giapreza®).

  • Bovine angiotensin II: Asp1-Arg-Val-Tyr-Val 5-His-Pro-Phe8.

  • Hypertensin® (Ciba-Geigy): Asn 1-Arg-Val-Tyr-Val 5-His-Pro-Phe8) (Variation in the amino acid from human angiotensin II is shown in italic).

Angiotensin II injection for intravenous (IV) infusion drug product (Giapreza®) is a sterile, aqueous solution containing 2.5 mg/mL angiotensin II (equivalent to an average of 2.9 mg angiotensin II acetate) and 25 mg/mL mannitol in water, adjusted to pH 5.5, and is supplied in single-dose vials. Giapreza® is supplied in two strengths: 2.5 mg angiotensin II/vial (2.5 mg/mL) and 5 mg angiotensin II/vial (2.5 mg/mL). The drug product is diluted in 0.9% (volume/volume) sodium chloride solution prior to administration by IV infusion and is titrated to effect. Results from an inuse study demonstrate that the drug product is stable and compatible when diluted in normal saline IV bags of both the PVC and non-PVC bag types for up to 36 h at 25 °C. These worst-case scenario in-use stability data adequately support product administration instructions that state that diluted solution may be stored at room temperature or under refrigeration and should be discarded after 24 h. Regarding the undiluted product, the current stability data support a shelf-life of 18 months for the product when stored at 2–8 °C in the approved commercial container closure system.

Assessment of the Clinical Data

The approval of this NDA was based almost entirely on the ATHOS-3 trial that had undergone a special protocol assessment (SPA). The original hypothesis set forth by the Applicant was the potential catecholamine-sparing benefit associated with use of angiotensin II in patients with catecholamine-resistant distributive shock who have been administered high catecholamine doses. During the SPA and concomitant discussion with the Applicant, there was an agreement that the goal of the trial was to establish the efficacy of angiotensin II in raising MAP to a clinically adequate level. To accomplish this, the trial design was required to maintain all other pressors constant such that increases in MAP could be attributed to study drug during the first 3 h of treatment. After 3 h, the trial permitted titration of study drug and catecholamines in order to evaluate studydrug– induced maintenance of MAP while sparing the use of catecholamine.

The original NDA was based on the 505(b)(2) regulatory pathway. In a 505(b)(2) application, the applicant relies upon published literature or FDA's finding of safety and efficacy for one or more drugs on the FDA's list of approved drug products (available online at http://www.accessdata.fda.gov/scripts/cder/ob/). In a 505(b)(1) application, the applicant owns or has a right of reference to all the included information that is relied upon to support the safety and efficacy of the product. The Applicant submitted a dossier to support safety and efficacy including the full report of the ATHOS-3 trial as well as nine supportive clinical publications. Eight of these were small trials with sample sizes ranging from 6 to 50 for a total of 93 subjects (approximately 50% healthy and 50% in shock). These studies were conducted between 1966 and 2014. The ninth supportive publication was a systematic literature review of 31,281 subjects in 1124 studies published from 1941 to 2016.[14] These studies were not prospectively designed to collect safety data. Of these, 982 studies did not mention safety and 75 studies reported no adverse events. Eight studies reported dose reductions due to excess blood pressure responses, and the remaining 59 studies reported adverse events, most commonly headache, chest pressure/tightness, dyspepsia/nausea, bradycardia, and orthostatic hypotension.

The wide variability in time when the supportive studies were conducted led us to conclude that time-dependent standard of care may have confounded the assessment of safety. The lack of safety assessment in 87% of the studies comprising the systematic review led us to conclude that the supportive safety data was suboptimal. The NDA review team therefore assessed the ATHOS-3 trial as both essential and sufficient to support approvability of angiotensin II (Giapreza®). Because none of the publications were essential to support approval, the 505(b)(2) pathway was changed to a 505(b)(1) pathway.

ATHOS-3 Trial

The trial results were published in 2017.[15] This was a multicenter, placebo-controlled, double-blind, randomized clinical trial in 344 adults with refractory distributive shock, defined as persistent hypotension (MAP 55–70 mmHg) after treatment with fluids and high-dose vasopressors. Subjects were randomized 1:1 to receive angiotensin II starting at 20 ng/kg/min or placebo (saline), in addition to standard of care. Subjects were titrated on study drug until the endpoint response was achieved. The primary endpoint was the rate of response at 3 h of treatment with study drug, defined as either a 10-mmHg increase from baseline in MAP or an MAP of at least 75 mmHg. A logistic regression was used for the primary endpoint analysis adjusted by fixed covariates of baseline MAP (< 65 mmHg vs ≥ 65 mmHg), Acute Physiologic Assessment and Chronic Health Evaluation (APACHE) II score, vasopressin use over the 6 h prior to randomization (yes vs no), and average norepinephrine equivalent dose (NED) over the 6 h prior to randomization, using the modified intent-to-treat (mITT) population, defined as randomized patients who received at least one dose of the study drug.

There were two study periods: period 1 covered baseline to 3 h, and period 2 covered 3–48 h. Study drug (placebo or angiotensin II) was initiated at hour 0 and titrated to restore MAP during period 1. Study drug administration continued during period 2 with mandatory down-titration and discontinuation at hour 48. However, the protocol provided for optional re-initiation of angiotensin II from hours 48–168. The trial hypothesis focused on period 1, during which background vasopressor and fluid dosing were not changed. In period 2, the catecholamine doses were down-titrated to evaluate whether angiotensin II could maintain MAP with lower catecholamine doses. However, the trial was not designed to evaluate the catecholamine-sparing effect.

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