Quantum Genomics SA made some noise at the Scientific Sessions of the American Heart Association meeting in Chicago with top-line results from its phase IIb NEW-HOPE trial of firibastat (QGC-001), a brain aminopeptidase A inhibitor (BAPAI) designed to treat arterial hypertension.
In a late-breaking oral presentation on Saturday, principal investigator Keith Ferdinand, professor at Tulane University School of Medicine, reported that eight weeks of treatment with firibastat led to a statistically significant decrease of 9.7 mmHg in systolic automatic office blood pressure (AOBP) from baseline (p<0.0001), the primary endpoint of the trial. Diastolic AOBP, a secondary endpoint, showed a reduction of 4.3 mmHg (p<0.0001).
Firibastat was effective in lowering blood pressure (BP) across subgroups by age, sex, ethnic origin and weight. Notably, a statistically significant decrease in systolic AOBP was found in individuals who were obese (-10,4 mmHg, p<0.0001) and in participants who were black (-10,5 mmHg, p<0.0001). Those subgroups represent high cardiovascular risk populations in which angiotensin-converting enzyme (ACE) inhibitors and angiotensin receptor blockers are not recommended as first-line monotherapy, according to current U.S. and European guidelines.
Quantum was seeking to achieve a minimum decrease of at least 7 mmHg in systolic AOBP, which represents a clinically relevant benchmark in difficult-to-treat hypertensive patients, according to Bruno Besse, chief medical officer of the Paris-based company. By exceeding that goal in NEW-HOPE, the company will seek a meeting with the FDA to discuss a pivotal phase III study that could begin in the second half of 2019.
"We need to propose the design of the phase III and also the statistical plan," said Besse, noting that the company has been working with the agency throughout the firibastat development program. Quantum plans to conduct the trial in the U.S. and, potentially, include sites in Europe.
Quantum is targeting a subgroup of patients with complicated hypertension in which drugs such as ACE inhibitors, which act by lowering renin levels, don't work well. Those patients typically include individuals of African, Asian and Hispanic ethnicity as well as older adults regardless of ethnicity.
The multicenter, open-label, dose-titrating NEW-HOPE study enrolled 256 patients, including 65 percent with at least grade 1 obesity (BMI=25 to 29.9) and primary hypertension. NEW-HOPE also sought to enroll at least half of trial participants from ethnic populations known to have increased incidence of treatment-resistant hypertension, achieving that goal, Besse said, with combined African American and Hispanic enrollment of 53 percent. More than one-third of trial participants also had type 2 diabetes.
Partnering efforts beginning in earnest
Minority populations, especially African Americans, are underrepresented in clinical trials, "and this is a major concern of the FDA," Besse told BioWorld. Exclusion of those subpopulations has led to a false sense of confidence in the efficacy of approved antihypertensives.
Quantum's drug is more likely to work in those patients, he said, because the mechanism of action can interfere with the mechanisms that influence blood pressure control in those with a hormonal profile characterized by low renin concentration and high vasopressin concentration.
BAPAI molecules target the brain renin-angiotensin system, or RAS – specifically, aminopeptidase A (APA), the enzyme responsible for producing angiotensin III (AngIII) from angiotensin II (AngII). Lead candidate firibastat is a prodrug of a compound called EC33 that delivers a selective and specific inhibitor of APA, preventing the production of AngIII in the brain.
Quantum in-licensed firibastat and is working in close alliance with the Institut national de la santé et de la recherche médicale (INSERM), the French national institute for public health and medical research, to advance it in the clinic. A research team headed by Catherine Llorens-Cortès of the Center for Interdisciplinary Research in Biology at the Paris-based Collège de France discovered the glutamyl aminopeptidase inhibitor and showed in animal models that halting the production of brain AngIII prevented three mechanisms that contributed, independently of each other, to increased blood pressure. Llorens-Cortès received the Prix Galien award for her work.
In the phase IIb, following a two-week washout period participants received oral firibastat for eight weeks, dosed at 250 mg twice daily for two weeks, then 500 mg twice daily if AOBP>140/90 mmHg. The study also allowed the addition of hydrochlorothiazide 25 mg once daily after one month if systolic AOPB≥160 mmHg and/or diastolic AOBP ≥100 mmHg.
In addition to meeting the primary endpoint, firibastat was well-tolerated in the trial. Skin reactions and headaches were most common adverse events, occurring in 4 percent and 3 percent of participants, respectively, or a rate similar to that observed with other antihypertensive classes, according to the company. No angioedema was reported, no changes in serum potassium or sodium levels were observed and blood glucose levels and renal function remained stable.
Quantum previously conducted a randomized, double-blind, placebo-controlled phase IIa study of firibastat in 34 individuals with grade I or II essential hypertension. Last year, the company reported at the European Society of Hypertension congress in Milan that, at day 28, the difference between the study drug and placebo in change from baseline in the primary endpoint of daytime ambulatory systolic BP was -2.7 (p=0.16). Those findings, in a small and more heterogeneous population, gave the company confidence to move into the larger phase IIb study with high-risk patients in whom approved BP-lowering agents are not effective, Besse explained.
Quantum scheduled a conference call at 10 a.m. Eastern Monday morning to discuss the findings in more detail but signaled its optimism that the NEW-HOPE data positioned the drug for a pivotal phase III trial in resistant hypertension.
Partnering efforts also will begin in earnest, although Quantum is prepared to run the phase III program on its own if a suitable alliance doesn't emerge in the meantime.
Shares of Quantum, which trades on the Euronext Paris as ALQGC, closed Friday at €3.08 (US$3.49) for a gain of €0.19, or 6.6 percent.