Roche and Alnylam present positive results from the Phase II KARDIA-2 study of zilebesiran added to standard of care antihypertensives in patients with inadequately controlled hypertension

2024-04-07

The KARDIA-2 study met its primary endpoint demonstrating additive, placebo-adjusted systolic blood pressure reductions of up to 12.1 mmHg at month three. These results were statistically significant and clinically meaningful
Zilebesiran demonstrated an encouraging safety and tolerability profile when added to standard of care antihypertensives

Basel, 7 April 2024 - Roche (SIX: RO, ROG; OTCQX: RHHBY) and Alnylam today released detailed results from the Phase II KARDIA-2 study evaluating the efficacy and safety of a single subcutaneous dose of zilebesiran when added to one of three standard of care (SOC) antihypertensives. The data were presented as a late-breaking clinical trial at the 2024 American College of Cardiology (ACC) Annual Scientific Session and follow the positive KARDIA-2 topline results announced in March 2024.

The study achieved its primary endpoint showing statistically significant and clinically meaningful additive, placebo-adjusted systolic blood pressure (SBP) reductions of up to 12.1 mmHg at month three (assessed by 24-hour ambulatory blood pressure monitoring, ABPM) when adding zilebesiran to SOC antihypertensives including a thiazide-like diuretic (indapamide), calcium channel blocker (amlodipine) or angiotensin receptor blocker (olmesartan).

In addition, the study met its key secondary endpoint evaluated at month three, with a single dose of zilebesiran demonstrating clinically significant additive reductions in office SBP across all three independent cohorts. Zilebesiran also showed significant, sustained placebo-adjusted SBP reductions at month six when added to indapamide and amlodipine, despite the addition of rescue antihypertensives at month three. Overall, zilebesiran demonstrated clinically significant additive reductions in time-adjusted and placebo-adjusted office systolic blood pressure at month six across all three study cohorts, including the maximum dose of olmesartan.

“The KARDIA Phase II studies add to a growing body of evidence supporting the potential for zilebesiran to sustain lower blood pressure with twice-yearly dosing in combination with standard of care medicines,” said Levi Garraway, M.D., Ph.D., Roche’s Chief Medical Officer and Head of Global Product Development. “We look forward to continuing the zilebesiran study programme together with Alnylam in hopes of providing transformative impact for millions of people living with uncontrolled hypertension.’’

Hypertension, or high blood pressure, is the leading cause of cardiovascular disease worldwide and a major risk for premature mortality.¹ Hypertension represents a growing global health crisis, responsible for around 10 million deaths worldwide each year.² Approximately one in three adults are living with hypertension globally, and there remains a significant unmet medical need given the poor rates of adherence to existing treatments.³ Currently, up to 80% of people with hypertension have blood pressure that remains uncontrolled despite the availability of several classes of oral hypertension treatments; such individuals remain at an increased risk of cardiovascular, cerebrovascular, and renal disease.^4-8

The KARDIA-2 results build on the positive Phase II KARDIA-1 [NCT04936035] data, presented at the congress of the American Heart Association Scientific Sessions in November 2023, and published in JAMA in February 2024.^9,10 Roche and Alnylam have now initiated the global Phase II KARDIA-3 study [NCT06272487] designed to evaluate the efficacy of zilebesiran when added to two or more hypertension medications in people with uncontrolled hypertension at high cardiovascular risk.

About the KARDIA-2 study¹¹
The Phase II KARDIA-2 trial is a randomised, double-blind, placebo-controlled study designed to evaluate the efficacy and safety of zilebesiran, when added to a standard of care, in adults with mild-to-moderate hypertension. This global, multicentre trial enrolled 672 adults with hypertension. Patients who met all inclusion/exclusion criteria during a screening period were first randomised into three different cohorts to receive open-label therapy with olmesartan (maximum dose), amlodipine or indapamide as their protocol-specified background hypertension medication during a run-in period of at least four weeks. Following the run-in period, eligible patients with elevated SBP were randomised 1:1 in a blinded manner to receive one dose of zilebesiran 600 mg SC or placebo in addition to their protocol-specified background hypertension medication for six months.

As outlined in the study protocol, after three months of treatment, all patients were permitted to receive rescue antihypertensives as needed based on rescue response criteria. Across all cohorts, a higher percentage of placebo-treated patients required treatment with rescue antihypertensives compared to zilebesiran-treated patients.*

KARDIA-2 Study Results
The KARDIA-2 study results are as follows:

Key Endpoint	Indapamide (2.5 mg)	Amlodipine (5 mg)	Olmesartan (40 mg)
Primary Endpoint:
Change from Baseline to Month 3 in 24-Hour Mean SBP, Assessed by ABPM	-12.1 mmHg (p<0.001)	- 9.7 mmHg (p<0.001)	- 4.0 mmHg (p=0.036)
Key Secondary Endpoints:
Change from Baseline to Month 3 in Office SBP	- 18.5 mmHg (p<0.001)	- 10.2 mmHg (p<0.001)	- 7.0 mmHg (p<0.001)
*Time Adjusted Change from Baseline Through Month 6 in 24-Hour Mean SBP, assessed by ABPM	- 11.0 mmHg (p<0.001)	- 7.9 mmHg (p<0.001)	- 1.6 mmHg (p=0.26)
*Time Adjusted Change from Baseline Through Month 6 in Office SBP	- 13.6 mmHg (p<0.001)	- 8.6 mmHg (p<0.001)	- 4.6 mmHg (p<0.001)

The final key secondary endpoint evaluated the proportion of patients with 24-hour mean SBP assessed by ABPM <130 mmHg and/or reduction ≥20 mmHg without rescue antihypertensive medication at month six. As outlined in the study protocol, after three months of treatment, all patients were permitted to receive rescue antihypertensives as needed based on rescue response criteria. Across all cohorts, a higher percentage of placebo-treated patients required treatment with rescue antihypertensives compared to zilebesiran-treated patients. Additionally, the odds of meeting the SBP response criteria was significantly higher with zilebesiran in the indapamide and amlodipine cohorts, compared to placebo:

	Background Medication
	Indapamide (2.5 mg)		Amlodipine (5 mg)		Olmesartan (40 mg)
	Placebo(N=57)	Zilebesiran (N=53)	Placebo (N=102)	Zilebesiran (N=103)	Placebo (N=134)	Zilebesiran (N=117)
Response Criteria met	14.0%	64.2%	13.7%	39.8%	17.2%	26.5%
Odds Ratio 95% CI	12.4 (p<0.001)		5.1 (p<0.001)		1.8 (p=0.077)

Safety results
Zilebesiran demonstrated an encouraging safety and tolerability profile when added to standard of care antihypertensives. Most laboratory abnormalities of interest were mild, occurred in the first three months of treatment and resolved upon repeat measure within one to two weeks without intervention. No adverse events led to study discontinuation during the six-month double-blind period.

About zilebesiran
Zilebesiran is an investigational, subcutaneously administered RNAi therapeutic targeting angiotensinogen (AGT) in development for the treatment of hypertension in high unmet need populations. AGT is the most upstream precursor in the Renin-Angiotensin-Aldosterone System (RAAS), a cascade which has a demonstrated role in blood pressure regulation and its inhibition has well-established antihypertensive effects. Zilebesiran inhibits the synthesis of AGT in the liver, potentially leading to durable reductions in AGT protein and ultimately, in the vasoconstrictor angiotensin (Ang) II. Zilebesiran utilises Alnylam's Enhanced Stabilization Chemistry Plus (ESC+) GalNAc-conjugate technology, which enables infrequent subcutaneous dosing with increased selectivity and the potential to achieve tonic blood pressure control demonstrating consistent and durable blood pressure reductions throughout a 24-hour period, sustained up to six months after a single dose of zilebesiran. The safety and efficacy of zilebesiran have not been established or evaluated by the U.S. Food and Drug Administration, European Medicines Agency, or any other health authority. Zilebesiran is being co-developed and co-commercialised by Roche and Alynlam.

Zilebesiran Phase II clinical development overview:

Study	Overview of protocol
KARDIA-1 [NCT04936035]	Evaluated zilebesiran monotherapy in people with mild to moderate hypertension. Met primary endpoint.
KARDIA-2 [NCT05103332]	Evaluated zilebesiran when added to a standard of care hypertension medication in people with mild to moderate hypertension. Met primary endpoint.
KARDIA-3 [NCT06272487]	Designed to evaluate zilebesiran when added to two or more hypertension medications in people with uncontrolled hypertension at high cardiovascular risk.

About hypertension
More than one billion adults are living with hypertension worldwide, which is a major risk factor for cardiovascular disease and premature mortality.⁴ Early effects of hypertension can include subtle target organ damage such as left-ventricular hypertrophy and cognitive dysfunction.^12,13 Over time, uncontrolled hypertension can lead to cardiovascular disease including stroke (ischaemic and haemorrhagic), coronary artery disease, heart failure, peripheral artery disease, chronic kidney disease and end-stage renal disease, dementia, and Alzheimer’s disease.^5-8

There remains a significant unmet medical need, as poor rates of adherence to daily medications can result in inconsistent blood pressure control and an increased risk for stroke, heart attack, and premature death.³ In particular, there are a number of high unmet need settings where novel approaches to hypertension warrant additional development focus, including patients with high cardiovascular risk.¹⁴

About Roche
Founded in 1896 in Basel, Switzerland, as one of the first industrial manufacturers of branded medicines, Roche has grown into the world’s largest biotechnology company and the global leader in in-vitro diagnostics. The company pursues scientific excellence to discover and develop medicines and diagnostics for improving and saving the lives of people around the world. We are a pioneer in personalised healthcare and want to further transform how healthcare is delivered to have an even greater impact. To provide the best care for each person we partner with many stakeholders and combine our strengths in Diagnostics and Pharma with data insights from the clinical practice.

In recognising our endeavour to pursue a long-term perspective in all we do, Roche has been named one of the most sustainable companies in the pharmaceuticals industry by the Dow Jones Sustainability Indices for the fifteenth consecutive year. This distinction also reflects our efforts to improve access to healthcare together with local partners in every country we work.

Genentech, in the United States, is a wholly owned member of the Roche Group. Roche is the majority shareholder in Chugai Pharmaceutical, Japan.

For more information, please visit www.roche.com.

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References
[1] Mills KT, Stefanescu A, He J. The global epidemiology of hypertension. Nat Rev Nephrol. 2020;16:223-237. https://doi.org/10.1038/s41581-019-0244-2.
[2] World Heart Federation. Hypertension [Internet; cited February 2024]. Available from: https://world-heart-federation.org/what-we-do/hypertension/#:~:text=It%20affects%20an%20estimated%201.3,10%20million%20people%20every%20year.
[3] Burnier M, Egan BM. Adherence in Hypertension. Circ. Res. 2019;124:1124-1140. https://doi.org/10.1161/CIRCRESAHA.118.313220.
[4] World Health Organization. Hypertension [Internet; cited February 2024]. Available from: https://www.who.int/news-room/fact-sheets/detail/hypertension.
[5] Oparil S, et al. Hypertension. Nat Rev Dis Primers. 2018;4:18014. https://doi.org/10.1038/nrdp.2018.14.
[6] Nazarzadeh M, et al. JAMA Cardiol. Systolic Blood Pressure and Risk of Valvular Heart Disease: A Mendelian Randomization Study. 2019;4(8):788-795.
[7] Thorin E, Hypertension and Alzheimer Disease. J. Hypertens. 2015;65:36-38.
[8] Mennuni S, et al. Hypertension and kidneys: unraveling complex molecular mechanisms underlying hypertensive renal damage. J Hum Hypertens. 2014;28:74-79. doi: 10.1038/jhh.2013.55.
[9] Bakris GL, et al. Sustained Blood Pressure Reduction With the RNA Interference Therapeutic Zilebesiran: Primary Results From KARDIA-1, a Phase 2 Study in Patients With Hypertension. Presented at: American Heart Association Scientific Sessions; 2023 November 11-12; Philadelphia, Pennsylvania, USA. Abstract LBS.04.
[10] Bakris GL, et al. RNA Interference With Zilebesiran for Mild to Moderate Hypertension: The KARDIA-1 Randomized Clinical Trial. JAMA. Published online, February 16, 2024. doi:10.1001/jama.2024.0728.
[11] Clinicaltrials.gov. Zilebesiran as Add-on Therapy in Patients With Hypertension Not Adequately Controlled by a Standard of Care Antihypertensive Medication (KARDIA-2) [Internet; cited February 2024]. Available from: https://classic.clinicaltrials.gov/ct2/show/NCT05103332?term=Zilebesiran&draw=2.
[12] Bruno A, et al. Left ventricular hypertrophy in acute stroke patients with known hypertension. Clin Exp Hypertens. 2017;39:502-504. doi:10.1080/10641963.2016.1259328.
[13] Poon, IO. Effects of antihypertensive drug treatment on the risk of dementia and cognitive impairment. Pharmacotherapy. 2008;28:366-375. doi: 10.1592/phco.28.3.366.
[14] World Health Organization. Cardiovascular Death and Disability can be reduced more than 50 percent [Internet; cited February 2024]. Available from: https://www.who.int/news/item/17-10-2002-cardiovascular-death-and-disability-can-be-reduced-more-than-50-percent.

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