Baxdrostat does not meet primary endpoint for BP reduction, possibly due to nonadherence
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Key takeaways:
- In patients with uncontrolled hypertension, baxdrostat did not lower seated systolic or diastolic BP at 8 weeks compared with placebo.
- The placebo group had a greater-than-expected decline in BP.
- Some patients assigned to baxdrostat had very low levels of the drug in their serum, indicating nonadherence, and a post hoc analysis limited to adherent patients indicated that baxdrostat 2 mg per day did lower seated systolic BP at 8 weeks compared with placebo.
NEW ORLEANS — Baxdrostat, an aldosterone synthase inhibitor, did not lower systolic BP compared with placebo at 8 weeks in patients with uncontrolled hypertension, but nonadherence may have been a factor, researchers reported.
As Healio previously reported, in the phase 2 BrigHTN trial of baxdrostat (Cincor Pharma/AstraZeneca) vs. placebo at 12 weeks in patients with treatment-resistant hypertension, baxdrostat significantly lowered systolic BP at two different doses, 1 mg and 2 mg, compared with placebo. Cardiology Today Intervention Section Editor Deepak L. Bhatt, MD, MPH, FACC, FAHA, FESC, MSCAI, director of Mount Sinai Heart and the Dr. Valentin Fuster Professor of Cardiovascular Medicine at the Icahn School of Medicine at Mount Sinai, presented the results of the phase 2 HALO trial of baxdrostat vs. placebo in patients with uncontrolled hypertension at the American College of Cardiology Scientific Session.
The HALO trial included 249 patients with uncontrolled hypertension randomly assigned to one of four groups: baxdrostat 0.5 mg, baxdrostat 1 mg, baxdrostat 2 mg or placebo. Mean age in each group ranged from 59 to 61 years; the percentage of women in each group ranged from 44% to 60%. Mean systolic BP at baseline ranged from 146.3 mm Hg to 147.9 mm Hg.
The primary endpoint of placebo-corrected change in mean seated systolic BP at 8 weeks did not differ between the placebo group and any of the baxdrostat groups (placebo, –16.6 mm Hg; baxdrostat 0.5 mg, –17 mm Hg; baxdrostat 1 mg, –16 mm Hg; baxdrostat 2 mg, –19.8 mm Hg; P for baxdrostat 0.5 mg vs. placebo = .83; P for baxdrostat 1 mg vs. placebo = .79; P for baxdrostat 2 mg vs. placebo = .15), Bhatt said during a presentation.
Placebo-corrected change in mean seated diastolic BP at 8 weeks also did not differ between the groups, nor did percentage of patients achieving less than 130 mm Hg systolic BP at 8 weeks, he said, noting the systolic and diastolic BP decreases in the placebo group were larger than expected.
Baxdrostat lowered serum aldosterone levels and raised plasma renin activity compared with placebo, as expected, he said.
The rate of adverse events was similar across all groups, Bhatt said.
The researchers performed a post hoc analysis related to adherence.
“The baxdrostat levels in plasma were measured at week 8,” Bhatt said during the presentation. “Twenty patients, that is, 36% of the 54 patients who completed the 8-week treatment in the 2 mg arm, had baxdrostat levels that were less than 0.2 ng/mL, indicating nonadherence. That level was less than 1% of the expected level if the patient were actually taking that dose. Interestingly, nonadherence measured biochemically was discordant with the dosing records by pill count that the patient and site provided, which showed more than 95% adherence in all groups.”
In the post hoc analysis, for which the baxdrostat 2 mg group included only patients who had a plasma baxdrostat level of at least 0.2 ng/mL at week 8, baxdrostat 2 mg significantly reduced mean seated systolic BP at 8 weeks compared with placebo (difference, –7.9 mm Hg; P < .01), Bhatt said.
“Of course, this finding will need to be confirmed in an appropriately powered phase 3 trial,” he said.
Placebo effect and nonadherence
“The trial did not meet its primary endpoint. Period. However, I think there are two very important variables,” Cardiology Today Editorial Board Member Nanette K. Wenger, MD, MACC, MACP, FAHA, FASPC, emeritus professor of medicine (cardiology) at Emory University School of Medicine, consultant at Emory Heart and Vascular Center and founding consultant at Emory Women’s Heart Center, said during a discussion after the presentation. “One of them is the marked decrease in blood pressure in the placebo group, which tells us that going into another phase 3 trial, we will have to do very different approaches to measuring blood pressure. Secondly was the question of nonadherence. We all know that if we take the medicine out of the bottle and put it in a pill box, it may remain there rather than being ingested. So we will have to do something in a subsequent trial to see if we can coach patients, so we get reasonable adherence. A marked placebo effect and an intervention’s suboptimal adherence is guaranteed to torpedo a trial of hypertension therapy.”
Wenger added that she is “excited” about the drug because “hypertension is a major problem worldwide and poor hypertension control is a major problem worldwide. We have not had a new antihypertensive class of drugs in well over a decade. This drug ... seems to have a reasonable safety profile. This is another potential [agent] either to add to a regimen for patients with resistant hypertension or, should it be shown to be effective, possibly even as an upstream drug for patients with hypertension.”
Future research
Bhatt said the adherence problem was “clustered in a few sites” and indicates “we have to be really careful about site selection and to provide enough support for patients to navigate complex medical regimens.”
He said AstraZeneca, which bought the drug’s developer, Cincor Pharma, in February, has announced plans for a phase 3 trial of baxdrostat in patients with resistant hypertension.
“I believe [the post hoc observations] to be true,” Bhatt said. “I think we have good biological rationale and ... post hoc analyses that have provided clear relationships between the actual drug levels and the drug’s effect, as we could see previously in BrigHTN. A large phase 3 trial will give us a much more precise estimate of efficacy and also safety. But my prediction is, the resistant hypertension population [represents] such a great unmet need that [baxdrostat] will be a useful addition to our armamentarium.”
Perspective
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Manesh R. Patel, MD, FACC, FAHA, FSCAI
The HALO findings teach us about the importance of adherence to BP medications and show us that when we do placebo-controlled trials in patients with BP issues, adherence and the effect of placebo are tied to being on medications and being observed.
Despite the results, the therapy still has a lot of promise. In BrigHTN, there was a significant 11 mm Hg reduction in systolic BP, and a change in aldosterone. What is different in HALO is that this was a study of people with uncontrolled but not treatment-resistant hypertension, which is a broader population of people who theoretically have higher BP despite being on an ACE inhibitor/angiotensin receptor blocker or a thiazide-type diuretic. Surprisingly, there was a 16 mm Hg reduction in systolic BP in patients getting placebo, which could indicate that these patients are taking their BP medications better than they otherwise might have, which led to a nonsignificant difference compared with baxdrostat.
Interestingly, the aldosterone levels changed with baxdrostat, and the researchers found that 20 patients in the baxdrostat 2 mg arm had very low levels of baxdrostat, making us worry about adherence to the study medication. When they looked at patients who were adherent, they seemed to see benefit.
The message is that it is important to do placebo-controlled trials and to achieve adherence to these therapies. The drug has shown biologically that it does what we think it does, but we must show in trial populations that it makes a difference.
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Bhatt DL, et al. Featured Clinical Research I. Presented at: American College of Cardiology Scientific Session; March 4-6, 2023; New Orleans (hybrid meeting).
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