Roche and Alnylam report positive topline results from the Phase II
KARDIA-2 study in people with hypertension, demonstrating
clinically significant blood pressure reductions with zilebesiran
when added to standard of care
- KARDIA-2 study met its
primary endpoint, demonstrating clinically significant systolic
blood pressure reductions in each treatment arm at month
three
- Zilebesiran added to a
standard of care hypertension medication demonstrated an
encouraging safety and tolerability profile in adults with mild to
moderate uncontrolled hypertension, and results support the
potential for twice-yearly dosing
- Roche and Alnylam have
initiated the Phase II KARDIA-3 study in adults with uncontrolled
hypertension at high cardiovascular risk
- KARDIA-2 study results will
be presented as a late-breaking abstract in April at the 2024
American College of Cardiology Annual Scientific
Session
Basel, 05 March 2024 - Roche (SIX: RO, ROG; OTCQX: RHHBY) and
Alnylam announced today that the Phase II KARDIA-2 study
[NCT05103332] of zilebesiran, an investigational RNAi therapeutic
in development for the treatment of hypertension (high blood
pressure) - the leading cause of cardiovascular disease
worldwide1 - met its primary endpoint. People with mild
to moderate hypertension treated with zilebesiran added to a
standard of care hypertension medication experienced a clinically
and statistically significant reduction in systolic blood pressure
at month three. Zilebesiran added to a standard of care
demonstrated an encouraging safety and tolerability profile.
“With twice-yearly dosing in combination with standard of care
medication, zilebesiran has strong potential to sustain lower blood
pressure and reduce the risk of stroke, heart attack and death that
can result from inadequate treatment,” 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 Phase
II study programme with Alnylam as we seek to provide
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 It is 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, leaving them at an increased risk of cardiovascular,
cerebrovascular, and renal disease.4-8
The Phase II KARDIA-2 trial results will be presented as a
late-breaking abstract at the 2024 American College of Cardiology
Annual Scientific Session (6-8 April 2024, Atlanta, Georgia, USA).
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
randomised into three different cohorts to receive open-label
therapy with olmesartan, 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 were randomised 1:1 to receive zilebesiran 600 mg
or placebo in addition to their protocol-specified background
hypertension medication for six months.
The primary endpoint is the change from baseline mean systolic
blood pressure (SBP) at month three, assessed by 24-hour ambulatory
blood pressure monitoring (ABPM). Additional endpoints include the
change in 24-hour mean SBP after six months of treatment assessed
by ABPM, change in office SBP at months three and six, and change
in diastolic blood pressure measured by ABPM and office blood
pressure at months three and six. Safety will be assessed
throughout the study.
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 reduction 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.
All trademarks used or mentioned in this release are protected
by law.
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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