Rocheがひとまず3億ドル超を突っ込んで一役買うAlnylam Pharmaceuticals社のRNA干渉薬zilebesiran（ジレベシラン）単独投与のPh2試験KARDIA-1で目当ての収縮期血圧（SBP）低下効果が認められました。
24時間のSBP平均値の3か月時点での低下がプラセボを差し引きで15 mmHg超上回りました。
試験には軽～中等度高血圧症の成人およそ4百人（394人）が参加しました。
RocheはzilebesiranをAlnylam社と共同で開発して共同で売る権利を有します。
同剤と定番の降圧薬3つのうちのどれかとの併用Ph2試験KARDIA-2の被験者組み入れがこの6月に完了しており、その結果は来年の早くに判明する見込みです。
今回のzilebesiran単独投与Ph2試験結果詳細は後に学会で発表されます。
zilebesiranは肝臓のアンジオテンシノーゲン（AGT）のmRNAを減らしてAGT生成を阻止することで血圧を下げます。
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
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 study
The 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 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 (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.
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