Single, triple-combo pill hits BP target in two phase III trials

GMRx2, a novel low-dose single pill containing three antihypertensive drugs – telmisartan, amlodipine, and indapamide – achieves all efficacy endpoints in two pivotal phase III trials presented at ESC 2024.

“Globally, most people treated for high blood pressure (BP) do not achieve adequate control, primarily due to continued use of low-efficacy regimens including monotherapy,” noted principal investigator Professor Anthony Rodgers of the George Institute for Global Health, University of New South Wales in Australia, in the ESC press release. “Single-pill combinations of different low-dose drugs hold promise for improving hypertension management by virtue of additive benefits, rapid action, and a low risk of adverse events (AEs).”

GMRx2 was developed to deliver the synergistic benefits of triple therapy while maintaining tolerability in a single pill that may improve patient adherence, Rodgers noted during the ESC press conference.

“[We evaluated GMRx2] in a placebo-controlled trial to assess the product as a whole and in a trial against three different dual therapies to assess each component one by one. We are encouraged by the clinically meaningful BP improvements observed … All safety and efficacy endpoints were met in both trials,” he continued.

GMRx2 is composed of telmisartan, amlodipine, and indapamide at ultra-low (GMRx2 triple quarter; 10/1.25/0.625 mg), low (GMRx2 triple half; 20/2.5/1.25 mg), or standard doses (GMRx2 triple standard; 40/5/2.5 mg). [Rodgers, et al, ESC 2024]

GMRx2 vs placebo

The placebo-controlled trial evaluated GMRx2 at quarter and half doses in 295 hypertensive adults (average age 50 years, ~20 percent Asian) on 0–1 BP-lowering drugs. After a 2-week placebo run-in phase, those with home systolic BP (SBP) of 130–154 mm Hg were eligible for randomization in a 2:2:1 ratio to GMRx2 quarter or half dose or placebo. After the run-in phase, mean clinic BP was 138/86 mm Hg.

At week 4, the placebo-corrected changes in home SBP with the GMRx2 quarter and half doses were −7.4 and −8.5 mm Hg, respectively. “Almost all the effects were apparent within 2 weeks of starting [treatment and were] highly statistically significant for all measures at all timepoints,” said Rodgers during his presentation.

The percentage of participants achieving clinic BP control <140/90 mm Hg was twofold higher with GMRx2 than placebo at week 4 (65 percent [GMRx2 quarter] and 70 percent [GMRx2 half] vs 30 percent; p<0.001 for both).

The rates of treatment withdrawals due to AEs with GMRx2 were low, with none in the quarter-dose arm and 5 percent in the half-dose arm. With placebo, the corresponding rate was 2 percent.

GMRx2 vs dual combos

In the active-controlled trial, GMRx2 was compared against dual combinations of its components. This included 1,385 adults (mean age 59 years, ~52 percent female, 48 percent Asian) with hypertension receiving 0–3 BP-lowering drugs with screening SBP of 140–179 (participants on 0 drugs) to 110–150 mmHg (on 3 drugs).

During a 4-week active run-in period, existing medications were switched to GMRx2 half dose. Participants were then randomized 2:1:1:1 to continue their GMRx2 regimen or to each possible dual combo at half doses: telmisartan 20 mg/amlodipine 2.5 mg (TA), telmisartan 20 mg/indapamide 1.25 mg (TI), or amlodipine 2.5 mg/indapamide 1.25 mg (AI). At week 6, doses were doubled across all arms unless clinically contraindicated.

At screening, mean clinic BP was 142/85 mm Hg. This dropped to 133/81 mm Hg after the run-in phase.

By week 12, the reductions in home SBP was lower with GMRx2 than TA, TI, or AI (–5.4, –2.5, and –4.4 mm Hg, respectively; p<0.0001 for all comparisons). Nearly three-quarters of participants on GMRx2 achieved clinic BP <140/90 mm Hg; with TA, TI, and AI, the corresponding percentages were 54, 61, and 61 percent (p<0.0001 for all comparisons).

Treatment withdrawal rates due to AEs were low across all arms (2 percent with GMRx2 and 1 percent with each combo).

“[The findings show that] GMRx2 reduced BP quickly in mild-to-moderate hypertension and more effectively than dual therapy in a broad, large hypertensive population, without safety concerns,” said Rodgers.

May transform hypertension treatment landscape

Both trials showed the superior efficacy of the single triple-combo pill vs placebo and each dual combination by all BP measures. “The clinical and public health significance of these findings is considerable, given the continuing global disease burden of hypertension,” Rodgers said.

“With evidence increasingly showing the value of lower BP targets, the potential of an effective, low-dose, triple combination with a good safety profile for the early treatment of hypertension should not be underestimated,” Rodgers said. “The availability of a single-pill combination could help reduce the current therapeutic inertia, helping patients achieve BP control quickly in a small number of steps, with potential benefits for improved adherence.”

Thus, GMRx2 provides a potential new therapeutic alternative for hypertension – as a novel agent for initial or early treatment or in later steps of therapy. “[GMRx2 may] help address an unmet need to improve existing low rates of BP control, using effective, simple, tolerable combinations … [GMRx2 may] transform hypertension management,” Rodgers concluded.