La Jolla’s Giapreza: Emergency Use Requests Sped US FDA Approval For Septic Shock

After publication of ATHOS-3 study results, agency received several requests from medical community for emergency use in hospitalized patients with shock and hypotension unresponsive to available therapy, spurring FDA to take an approval action two months ahead of user fee goal date.

An influx of emergency use requests for La Jolla Pharmaceutical Co.'s Giapreza (angiotensin II) following publication of positive Phase III results spurred the US FDA to expedite approval of the septic shock treatment more than two months ahead of the drug's user fee deadline.

FDA approved Giapreza (formerly known as LJPC-501) to increase blood pressure in adults with septic or other distributive shock on Dec. 21, just six months into FDA's eight-month priority review. (See sidebar for timeline.)

The approval was based on results from a single randomized, placebo-controlled trial, ATHOS-3, in which Giapreza demonstrated a treatment effect of 47% on the primary endpoint based on increase in mean arterial pressure (MAP) after three hours of dosing.

This effect size "is large and clinically meaningful on its face," Office of Drug Evaluation I Director Ellis Unger said in a Dec. 21 memorandum, adding that the results are "statistically persuasive and robust to any type of exploration."

The ATHOS-3 trial results were published online by the New England Journal of Medicine May 21 – a little more than a month before the Giapreza new drug application (NDA) was submitted. The study results appeared in the NEJM's print edition on Aug. 3.

On Aug. 8, La Jolla announced the initiation of a US expanded access program to provide LJPC-501 to patients with vasodilatory or distributive shock who cannot achieve target MAP despite adequate fluid resuscitation and treatment with currently available vasopressors – a condition the company described as "catecholamine-resistant hypotension" or "clinically refractory hypotension."

"Although we have granted priority review status to this application, we are taking steps so that we can act on this application well before the priority review action date of Feb. 28, 2018 so that the drug will be available through commercial channels for use in patients with distributive shock as quickly as possible." – FDA's Rose

After the ATHOS-3 results were published, FDA "received several requests from members of the medical community for emergency use of LJPC-501 in hospitalized patients with shock and hypotension who are unresponsive to available therapy," Cross-Discipline Team Leader Martin Rose said in a Dec. 16 memo.

"Septic shock, which constitutes about 90% of cases of distributive shock, has a high mortality rate even though most patients with this condition are treated in an Intensive Care Unit," Rose said. "Although we have granted priority review status to this application, we are taking steps so that we can act on this application well before the priority review action date of Feb. 28, 2018 so that the drug will be available through commercial channels for use in patients with distributive shock as quickly as possible."

Similarities To An Older Drug

Giapreza is a chemically synthesized 8-amino acid peptide (octapeptide) with a sequence identical to that of human angiotensin II, which upregulates blood pressure by directly stimulating arterial vasoconstriction and triggering synthesis and release of aldosterone from the adrenal cortex.

No human angiotensin II product has ever been marketed as a drug in the US. Ciba-Geigy Corp.'s (now Novartis AG) Hypertensin, an octapeptide that is identical in sequence to bovine angiotensin II, received US FDA approval in 1962 for treatment of shock. However, the NDA was withdrawn in 2009 for reasons unrelated to safety.

La Jolla submitted the Giapreza NDA on June 29 as a 505(b)(2) application, relying in part on FDA's safety and efficacy findings relative to Hypertensin. However, during the course of the review agency staff concluded that since bovine angiotensin II differs from the human peptide by one amino acid, LJPC-501 is considered a new molecular entity approvable under 505(b)(1).

Targeting A Pharmacodynamic Endpoint

La Jolla sought approval for "treatment of hypotension in adults with distributive or vasodilatory shock who remain hypotensive despite fluid and vasopressor therapy." The proposed indication tracks the characteristics of the population that was studied in ATHOS-3, the lone Phase III trial that provided the major source of efficacy and safety data for LJPC-501, Rose said. (See sidebar for reviewers.)

ATHOS-3 was a randomized, placebo-controlled trial of 344 adults with distributive shock and persistent hypotension (mean arterial pressure (MAP) of 55-70 mmHg) after treatment of specified intensity with fluids and vasopressors. The trial was conducted under a Special Protocol Assessment agreed to by FDA, with the agency accepting La Jolla's proposed pharmacodynamic primary endpoint of MAP response at three hours of randomized treatment.

"The proposed endpoint was consistent with the blood pressure endpoints that supported approval of other vasopressor agents used to treat shock, none of which had hard clinical outcomes data," Rose said. "These drugs include norepinephrine, epinephrine, vasopressin, phenylephrine, ephedrine, dopamine and metaraminol. All these agents are approved to raise blood pressure, except for dopamine, which is indicated to correct 'hemodynamic imbalances' in shock."

FDA has not required sponsors to show a benefit beyond increased blood pressure to support approval of drugs intended to treat hypotension in patients with shock, Rose noted. "We have accepted the belief prevalent in the medical community that treatment of hypotension in patients with shock will improve tissue perfusion and decrease death and serious morbidity, although this hypothesis has never been rigorously evaluated. However, given the high rate of death in patients with septic shock despite treatment, there is clearly an unmet need for additional safe and effective treatments."

In addition to concluding that effects on blood pressure could support approval for LJPC-501, FDA's cardio-renal review division "also accepted the applicant's proposal to proceed directly to their confirmatory trial without doing their own Phase I or II studies in patients with shock," Rose said.

However, FDA review documents take note of a published report of a randomized, placebo-controlled study of Bachem human angiotensin in 20 patients with shock. The ATHOS trial, which was sponsored by George Washington University, suggested that angiotensin II use was associated with reduced need for catecholamines to maintain blood pressure in the target range. The LJPC-501 dosing regimen used in ATHOS-3 was based on the regimen used in ATHOS.

Efficacy Data Impress, Survival Data Reassure

The ATHOS-3 modified intent to treat (mITT) population included 163 and 158 patients in the angiotensin II and placebo arms, respectively. Results for the primary endpoint of MAP response rate at three hours – with response defined as MAP of >75 mmHG or an increase from baseline of  >10 mmHG – strongly favored angiotensin II, with 114 (70%) vs. 37 (23%) responders in the angiotensin II and placebo arms, respectively. The odds ratio was 8, with a highly statistically significant p-value.

Similar results were observed in various sensitivity analyses performed, including the more conservative ITT analysis at three hours with response rates of 67% and 24% for the angiotensin II and placebo arms, respectively. "This is compelling evidence of efficacy for effects on blood pressure. Both arms had increases in MAP between baseline and three hours, but the mean increase in MAP was about 7 mmHg larger in the angiotensin II arm," Rose's review states. In addition, response rates at three hours favored angiotensin across a range of subgroups based on demographics, geography and disease-related characteristics.

Mortality numerically favored angiotensin II over placebo in the mITT population over the course of the study. Death rates at seven and 28 days favored angiotensin II over placebo, although the difference between the study arms was not statistically significant.

"While the study results do not show a statistically significant effect on mortality or indeed any other outcome, there is compelling evidence of an effect on blood pressure, and no evidence to support fatal harm," Rose said, concluding that the ATHOS-3 results were strong enough to provide substantial evidence of efficacy without the need for a second pivotal trial.

"One might make the argument that efficacy is supported by the efficacy of the previously marketed, closely related bovine angiotensin product, but the strength of the results of ATHOS-3 makes that unnecessary," he said.

Thrombosis Risk Expected And Manageable

The major safety concern identified in ATHOS-3 was thrombosis, with a higher incidence of venous and arterial thromboembolic events in the LJPC-301 arm compared to placebo (12.9% vs 5.1%).

FDA review documents observe that a prothrombotic effect of angiotensin II has been demonstrated in animals and healthy volunteers, and the target population for LJPC-301 is at high risk for thrombosis. Nevertheless, FDA concluded this risk could be addressed with a label warning and recommendation for use of anticoagulation during treatment with LJPC-301.

ODE I's Unger put the efficacy results and thrombosis risks into a number needed to treat/harm calculation.

"The study demonstrated that 47% of patients (in absolute terms) obtained a (mean) 7 mmHg increase in MAP. For this ~7 mmHg increase in MAP, the number needed to treat (NNT) is ~2," Unger said. "The single greatest safety concern is an increased risk of thrombotic events. If we assume that the absolute risk of thrombotic events is 4-8%, the number needed to harm is between 25 and 12. From the standpoint of thrombosis, therefore, the worst case is that for 12 patients treated, one will have a thrombotic event and six will increase their MAP by 7 mmHg."