The article delves into the groundbreaking impact of zilebesiran, an innovative RNA interference therapy. It demonstrates its potential to effectively lower blood pressure for up to six months with just a single injection. 

In the phase 2 dose-ranging KARDIA-1 study, adults with mild to moderate hypertension saw an effective 6-month reduction in blood pressure with a single injection of the investigational antihypertensive drug zilebesiran (Alnylam Pharmaceuticals), with an encouraging side-effect profile.

These findings suggest that zilebesiran may enhance drug compliance, lowering the risk of cardiovascular disease in hypertensive individuals. At the recent American Heart Association (AHA) Scientific Sessions 2023, held in Philadelphia, on November 11, the KARDIA-1 research was presented.

Zilebesiran

1. Zilebesiran is an RNAi therapy under research that targets angiotensinogen (AGT) and is delivered subcutaneously. It is being developed for the treatment of hypertension in populations with high unmet needs.
2. In the Renin-Angiotensin-Aldosterone System (RAAS), the most upstream precursor is AGT. This cascade has been shown to have a function in regulating blood pressure (BP), and inhibiting it has been shown to have anti-hypertensive effects.
3. Zilebesiran prevents the liver's production of AGT, which may result in long-lasting decreases in AGT protein and, eventually, in the vasoconstrictor angiotensin II.
4. Utilising Alnylam's Enhanced Stabilisation Chemistry Plus (ESC+) GalNAc-conjugate technology, zilebesiran can be used to achieve tonic blood pressure control with infrequent subcutaneous dosing and increased selectivity.
5. Zilebesiran has been shown to consistently and durably lower blood pressure over 24 hours, with the effects lasting up to six months following a single dose.

Despite the availability of effective antihypertensives, many individuals with hypertension go untreated, and up to 80% of cases of uncontrolled hypertension worldwide are associated with morbidity and death.

With a strong affinity for the hepatic asialoglycoprotein receptor, zelebesiran is a subcutaneous RNA interference therapy that reduces the production of angiotensinogen, the only precursor to all angiotensin peptides. Its hepatocyte-targeted administration is thought to sustain extrahepatic angiotensinogen expression, potentially reducing off-target effects in the kidney and other organs.

In patients with mild to moderate hypertension (systolic blood pressure of 135–160 mm Hg), either untreated or on stable treatment with up to two antihypertensive medicines, the KARDIA-1 study examined the safety and effectiveness of various zilebesiran dosages.

394 individuals with an average baseline systolic blood pressure of 142 mm Hg were involved in the trial and were randomly allocated to receive either a placebo or one of four zilebesiran dosages (150 mg, 300 mg, or 600 mg once every six months or 300 mg once every two months). There were 377 patients in the final study (56% male and 25% Black).

Throughout the 6-month follow-up period, the results revealed consistent reductions in serum angiotensinogen (between 88% and 98%).

All zilebesiran regimens substantially reduced ambulatory systolic blood pressure assessed over a 24-hour period. The mean reduction from baseline to month six was about 10 mm Hg in the three highest dosages evaluated, and approximately 14 mm Hg when compared with placebo.

At six months, patients on zilebesiran had a higher chance of achieving 24-hour average systolic blood pressure readings < 130 mm Hg.

Furthermore, systolic blood pressure decreases throughout the day and at night was consistently considerably larger for individuals in all four zilebesiran groups.

In the zilebesiran groups, there were four non-serious adverse events that resulted in withdrawal: two cases of orthostatic hypotension, one blood pressure increase, and one injection site response.

While 6% of individuals had hyperkalemia adverse effects, the majority of these were moderate, did not need intervention, and usually went away with repeat measurements; none of these were linked to acute renal damage or required stopping study medication. According to Bakris, there were few hypotension occurrences and no clinically significant alterations in hepatic or renal function.

A patient using 300 mg of zilebesiran every three months had one fatality from cardiopulmonary arrest; nevertheless, this was not considered a drug-related event.

In the current KARDIA-2 phase 2 trial, zelebesiran is being further assessed as an adjunct medication for the treatment of hypertension.

It's also crucial to remember that some patients may not come back for further doses, although subcutaneous dosage may allow for at-home administration.

According to this research, we may now focus on angiotensinogen, the first stage in the renin-angiotensin system. This looks to result in a significant and sustained reduction in blood pressure for up to six months, which should enhance adherence.

Considering that only 50% of patients still taking antihypertensive medications a year later, improving adherence will boost effectiveness and maybe prevent some target organ damage."

Disclaimer- The views and opinions expressed in this article are those of the author and do not necessarily reflect the official policy or position of M3 India.

About the author of this article: Dr Monish Raut is a practising super specialist from New Delhi.