Roche and Alnylam report positive topline results from Phase 2 study KARDIA-1 of zilebesiran, an investigational RNAi therapeutic in development to treat hypertension in patients at high risk of cardiovascular disease
September 07 2023 - 7:00AM
Roche and Alnylam report positive topline results from Phase 2
study KARDIA-1 of zilebesiran, an investigational RNAi therapeutic
in development to treat hypertension in patients at high risk of
cardiovascular disease
- Zilebesiran
met primary endpoint demonstrating greater than 15 mmHg
reduction of systolic blood pressure at three months of treatment
compared to placebo
- Study met key secondary
endpoints showing consistent and sustained reductions of systolic
blood pressure at six months
- Zilebesiran
demonstrated an encouraging safety and tolerability profile
in adult patients with mild-to-moderate hypertension
- Full study results to be
presented at an upcoming scientific conference
Basel, 7 September 2023 - Roche (SIX: RO, ROG; OTCQX: RHHBY) and
Alnylam announced today that the Phase 2 study KARDIA-1 of
zilebesiran, an investigational RNAi therapeutic targeting
liver-expressed angiotensinogen (AGT), met the primary endpoint.
Zilebesiran demonstrated a clinically significant reduction in
24-hour mean systolic blood pressure (SBP) at month three,
achieving a placebo-subtracted reduction greater than 15 mmHg with
both 300 and 600 mg doses (p < 0.0001). The study also met key
secondary endpoints showing consistent and sustained reductions of
SBP at six months supporting quarterly or biannual dosing. In
addition, the study showed that zilebesiran was associated with a
potent and durable reduction of serum AGT levels through month six
while demonstrating an encouraging safety and tolerability
profile.
“These early results indicate the potential for zilebesiran to
achieve sustained blood pressure reduction with quarterly or
biannual dosing,” said Levi Garraway, M.D., Ph.D., Roche’s Chief
Medical Officer and Head of Global Product Development. “Also,
these data underscore the potential of this investigational
medicine to provide transformative impact for many people living
with uncontrolled hypertension.’’
The Phase 2 trial KARDIA-1 is a randomised, double-blind,
placebo-controlled, multi-centre global dose-ranging study designed
to evaluate the efficacy and safety of zilebesiran as monotherapy
in adults with mild-to-moderate hypertension. The study enrolled
394 adults representing a diverse patient population with untreated
hypertension or who were on stable therapy with one or more
anti-hypertensive medications (after a washout period).
Hypertension is a growing global health crisis responsible for
around 10 million deaths worldwide each year. Approximately one in
three adults are living with hypertension globally, with up to 80%
of individuals remaining uncontrolled despite the availability of
several classes of oral anti-hypertensive treatments leaving them
at an increased risk of cardiovascular, cerebrovascular and renal
disease.
Earlier this year, Roche entered the partnership with Alnylam to
co-develop and co-commercialise zilebesiran. The KARDIA study
program also includes the Phase 2 study KARDIA-2 of zilebesiran
used in combination with one of three standard classes of
anti-hypertensive medications which completed enrollment in June
2023. The topline results of KARDIA-2 are expected in early
2024.
About the KARDIA-1 studyThe
Phase 2 KARDIA-1 trial enrolled 394 adults with untreated
hypertension or who were on stable therapy with one or more
anti-hypertensive medications. Any patients taking prior
anti-hypertensive medications completed at least a two- to
four-week wash-out before randomisation. Patients were randomised
to one of five treatment arms during a 12-month double blind (DB)
period and DB extension period: 150 mg zilebesiran subcutaneously
once every six months; 300 mg zilebesiran subcutaneously once every
six months; 300 mg zilebesiran subcutaneously once every three
months; 600 mg zilebesiran subcutaneously once every six months; or
placebo. Patients who received placebo were randomised to one of
the four initial zilebesiran dose regimens beginning at Month 6.
The primary endpoint is defined as the change from baseline in SBP
at Month 3, assessed by 24-hour ambulatory blood pressure
monitoring (ABPM). Key secondary and exploratory endpoints in this
study include additional measures of blood pressure reduction at
six months, time-adjusted change in blood pressure, and change in
daytime average and night-time average blood pressure.
The study met the primary endpoint demonstrating a
dose-dependent, clinically significant reduction in 24-hour mean
systolic blood pressure (SBP) measured by ABPM at month 3,
achieving a placebo-subtracted reduction greater than 15 mmHg (p
< 0.0001) with both 300 mg and 600 mg doses. The study also met
key secondary endpoints including change in 24-hour mean SBP as
measured by ABPM at month 6 as well as change in office SBP at
month 3 and month 6, for all zilebesiran arms, compared to
placebo.
About zilebesiranZilebesiran
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
(BP) regulation and its inhibition has well-established
anti-hypertensive 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 Stabilisation Chemistry
Plus (ESC+) GalNAc-conjugate technology. It 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 FDA, EMA or any other health authority.
Zilebesiran is being co-developed and co-commercialized by Alnylam
and Roche.
About hypertensionHypertension, or high blood
pressure, is the leading cause of cardiovascular disease worldwide,
and a major risk for premature mortality. Early effects of
hypertension can include subtle target organ damage such as
left-ventricular hypertrophy and cognitive dysfunction. 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.
There remains a significant unmet medical need, especially given
the poor rates of adherence to existing daily oral medications,
resulting in inconsistent blood pressure control and an increased
risk for stroke, heart attack and premature death. 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. 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 thirteenth 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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