Innovative Treatment for Hypertension: One Shot Every Quarter or Even Six Months

Alnylam Pharmaceuticals and Ionis Pharmaceuticals are developing drugs designed to treat hypertension that cannot be treated with existing hypotensive medications.

• There are strong indications that the therapeutic efficacy of future drugs will be maintained with a very infrequent dosing regimen: one subcutaneous injection every three or even six months. In the future, these drugs may evolve into oral tablets or capsules.

 

Why It Matters

Arterial hypertension is a complex multifactorial disease manifested by elevated blood pressure.

One in four men and one in five women on the planet, over 1.13 billion people in all, suffer from hypertension.

Hypertension is one of the leading causes of death.

Despite the availability of effective hypotensive medications, the therapy of hypertension leaves much to be desired. At the same time, half of the patients who adhere to chronic pharmacotherapy of hypertension do not manage to reach the target levels of blood pressure. This increases the risk of developing or worsening cardiovascular disease and brain circulation disorders (atherosclerosis, myocardial infarction, stroke), and also contributes to the progression of chronic kidney disease (CKD).

The situation is complicated by the fact that many patients with hypertension do not adhere strictly to a treatment regimen involving the daily administration of oral hypotensive drugs.

 

Alnylam Pharmaceuticals and Pioneering Treatments for Hypertension

Alnylam is developing an experimental drug, zilebesiran (ALN-AGT), built on the increasingly popular RNA interference technology.

 

Zilebesiran: How It Works

Experimental zilebesiran (ALN-AGT) is targeted against angiotensinogen (AGT), the earliest precursor of angiotensin (AGT), an oligopeptide hormone that causes vasoconstriction and high blood pressure. Angiotensin is part of the renin-angiotensin-aldosterone system (RAAS), a cascade that has been reliably proven to play a determining role in blood pressure regulation and whose suppression is accompanied by well-known hypotensive effects.

Zilebesiran is based on RNA interference (RNAi) therapy, a natural mechanism of silencing (suppression of expression) of genes at the stage of transcription, translation, deadenylation, or degradation of matrix RNA (mRNA) using small interfering RNAs (miRNAs)

Zilebesiran interferes with mRNA of AGT gene, which leads to its silencing. The subsequent inhibition of AGT synthesis in the liver results in a sustained decrease of angiotensin and ultimately angiotensin II (Ang II) levels. As a consequence, blood pressure is decreased, since the latter both has a vasoconstrictor effect on its own and does so by stimulating vasopressin synthesis.

Constructively, zilebesiran consists of two parts: a chemically modified miRNA against AGT and an N-acetylgalactosamine (GalNAc) ligand that binds asialoglycoprotein receptor 1 (ASGPR) on hepatocytes for targeting drug delivery.

Zilebesiran appeals to the proprietary Enhanced Stabilization Chemistry Plus (ESC+) GalNAc-conjugate technology, which allows for very infrequent dosing of the subcutaneously administered drug coupled with its high selectivity and broad therapeutic index.

 

Zilebesiran: What Came Out

The NCT03934307 phase 1 (randomized, double-blind, placebo-controlled) clinical trial enrolled adult participants (n=60) with elevated systolic blood pressure (mild-to-moderate hypertension with 130 to 165 mmHg) who were not taking any hypotensive medications (who had not previously treated hypertension at all or had refused such drugs).

Participants received one subcutaneous dose of either placebo or zilebesiran (in different doses).

After a single injection of zilebesiran at a dose of 200 mg, the results, taken after 8 weeks, are as follows:

• A drop in serum angiotensinogen levels of more than 90% persisted for 3 months.
• Over 8 weeks, the average reduction in blood pressure was 11±2 and 8±1 mmHg for systolic and diastolic blood pressure, respectively, with some subjects having maximum reductions of 19 and 12 mmHg.
• No serious adverse events in response to zilebesiran administration were reported.

The results recorded after 12 weeks after a single injection of zilebesiran are as follows:

• Patients who received zilebesiran at a dose of 100 mg or higher showed a sustained reduction in serum angiotensinogen levels of more than 90%, with a 96%–98% drop in the 800-mg dose cohort.
• Administration of zilebesiran at a dose of 100 mg or higher provided a reduction in systolic blood pressure of at least 10 mmHg, with a reduction of more than 15 mmHg in the 800-mg dose cohort.
• No serious problems with the safety profile of zilebesiran were noted.

The results demonstrated after 24 weeks following a single injection of zilebesiran are as follows:

• At week 3 of follow-up, the use of zilebesiran at a dose of 100 mg or higher resulted in a decrease in serum angiotensinogen levels of more than 90%, which was sustained for 12 weeks.
• In the 800-mg dose cohort, this reduction was sustained for 24 weeks.
• At week 8 of follow-up, administration of zilebesiran at a dose of 200 mg or higher resulted in a decrease in systolic blood pressure of at least 10 mmHg and continued to maintain its clinically significant drop until week 24.
• At week 24 of follow-up in the 800-mg dose cohort, its decline exceeded 20 mmHg, and in 6 of 8 patients this was achieved without any additional hypotensive medication.
• Zilebesiran at a dose of 200 mg and above provided a stable and sustained reduction of systolic and diastolic blood pressure during the day and night, indicating the ability to achieve tonic pressure control over a long period.
• No serious problems with the safety profile of zilebesiran have been identified.

Alnylam further studied the 800-mg dose of zilebesiran on a low-salt diet or the concomitant daily administration of 300 mg of irbesartan.

Testing zilebesiran on a low-salt diet was necessary to ascertain treatment tolerance because of the depletion of body fluid due to sodium loss caused by a low-salt diet and could lead to hypotensive events. Such a diet has been found to have an additional effect in the form of an increased reduction in blood pressure. The conclusions are as follows: a high-salt diet may be helpful in preventing likely hypotensive events.

The addition of irbesartan resulted in additional reductions in systolic and diastolic blood pressure of 6.4 and 3.2 mmHg, respectively, with no clinically significant changes in serum creatinine and potassium levels.

 

Zilebesiran: What’s Next

In the wake of the success of an early-phase clinical trial of zilebesiran, Alnylam has launched two new clinical studies of the drug candidate. The trials are examining the use of zilebesiran in different regimens: 300 mg once every 3 months, 150 mg once every 6 months, 300 mg once every 6 months, and 600 mg once every 6 months.

Therapeutic efficacy endpoints were established by changes in systolic and diastolic blood pressure after 3 and 6 months of treatment.

The KARDIA-1 (NCT04936035) phase 2 (randomized, double-blind, placebo-controlled, multicenter) clinical trial is testing monotherapy with zilebesiran in adult patients (n=375) with moderate-to-severe hypertension (mean daily systolic blood pressure between 135 to 160 mmHg) who have not previously been treated for hypertension or are following a stable course of hypotensive medications. In either case, the subjects would not take the latter during the study.

During a 6-month double-blind period, participants receive zilebesiran or placebo. At a subsequent 6-month double-blind period, patients in the placebo group are switched to zilebesiran. Upon completion of KARDIA-1, participants can move on to a double-blind extension period of up to 12 months.

Four dosing options have been established for zilebesiran: 150, 300, or 600 mg every 6 months, 300 mg every 3 months.

The KARDIA-2 (NCT05103332) phase 2 (randomized, double-blind, placebo-controlled, multicenter, international) clinical trial is testing the addition of zilebesiran (600 mg every 6 months) to hypotensive therapy in adult patients (n=800) with hypertension that is not controlled by medication.

Among the inclusion criteria: an average daily systolic blood pressure of 155–180 mmHg or 145–180 mmHg (for previously untreated and treated hypertension, respectively), which should decrease to 130–160 mm Hg after the introductory study period.

An introductory 4-week period involves taking some hypotensive medication (olmesartan, amlodipine, or indapamide). In the subsequent 6-month period, participants receive zilebesiran or placebo — on the background of the previously selected hypotensive medication (after 3 months, additional ones may be added if hypertension is not controlled). After completion, patients may be eligible to participate in a separate zilebesiran open-label extension (OLE) study of up to 12 months.

 

Zilebesiran: What’s the Outlook

The consensus view is that a reduction in blood pressure of more than 5 mmHg is clinically significant, and therefore the success of zilebesiran seems encouraging. The commercial success of the drug is mainly due to its dosing regimen, as patient adherence to pharmacotherapy for hypertension is decidedly lacking.

Because zilebesiran is selectively targeted against angiotensinogen production in the liver, its altering effects on renal angiotensin II are minimal. In other words, renal compensatory mechanisms are not affected. This improves the therapeutic index, allowing zilebesiran to be prescribed at higher doses without the fear of developing adverse events such as hypotension, hyperkalemia, and acute renal failure that those taking standard RAAS blockers face because they target downstream components of the RAAS signaling pathway relative to AGT.

Again, zilebesiran would eliminate excessive prescribing of different classes of hypotensive drugs.

• Presumably, Alnylam will position zilebesiran to treat uncontrolled hypertension (blood pressure spikes, insufficient reduction at night, poor adherence to therapy) that is resistant to the prescription of three to four hypotensive drugs. It is possible that patients with heart failure or diabetic nephropathy will then be added. Overall, zilebesiran is quite capable of becoming the new standard of treatment for primary hypertension.

 

Zilebesiran: Where Is Evidence

In favor of the fact that Alnylam’s technological approach will work in the task of treating hypertension, the three RNAi-based drugs it has put on the commercial rails against rare diseases are evidence of this:

• Onpattro (patisiran) is intended to treat hereditary transthyretin amyloidosis (hATTR) with polyneuropathy (hATTR-PN), also known as familial amyloid polyneuropathy (FAP).

• Givlaari (givosiran) is focused on the treatment of acute hepatic porphyria (AHP).

• Oxlumo (lumasiran) is the first drug for the treatment of primary hyperoxaluria type 1 at any age.

All of these drugs are used by injection and in infrequent dosing regimens: once every three weeks, month and quarter, respectively.

In addition, Novartis has launched Leqvio (inclisiran), an RNAi drug designed to potently lower low-density lipoprotein (LDL) cholesterol through a single injection every six months. Behind the original idea of Leqvio is Alnaylam.

 

Ionis Pharmaceuticals and Advanced Hypertension Treatment

Ionis Pharmaceuticals is working on an experimental IONIS-AGT-L_Rx, which, similar to zilebesiran, is targeted against angiotensinogen in the liver and is designed to treat hypertension that cannot be treated with standard heart drugs.

 

IONIS-AGT-L_Rx: Mechanism of Action

Subcutaneously administered IONIS-AGT-L_Rx is an antisense oligonucleotide that inhibits angiotensinogen synthesis in the liver. IONIS-AGT-L_Rx, being exactly complementary to mRNA encoding AGT, binds to its non-translated site, thus leading to its own destruction by ribonuclease. As a result, translation is prevented and angiotensinogen synthesis is stopped.

Preclinical studies of IONIS-AGT-L_Rx in rodent models with hypertension or acute renal failure demonstrated a sustained reduction in blood pressure and a 90% drop in circulating AGT levels.

If Ionis commercializes IONIS-AGT-L_Rx, its injections will be given once or twice a month.

 

IONIS-AGT-L_Rx: Clinical Results

Ionis has completed two phase 2 (randomized, double-blind, placebo-controlled, multicenter) clinical trials that tested the therapeutic feasibility of prescribing IONIS-AGT-L_Rx during the treatment of resistant hypertension.

The NCT03714776 clinical trial enrolled adult patients (n=25) with primary hypertension on a stable course of hypotensive medications: two medications — one an angiotensin-converting enzyme inhibitor (ACEi) or angiotensin II receptor blocker (ARB), and one a beta blocker, calcium channel blocker, or diuretic.

Subjects’ systolic blood pressure had to fall within the range of 140–165 mmHg.

For 6 weeks, participants who discontinued all hypotensive medications were given an 80-mg dose of IONIS-AGT-L_Rx or placebo by subcutaneous injection once a week.

The results are as follows:

• Serum angiotensinogen levels in the IONIS-AGT-L_Rx group decreased by 54.0±24.8% — versus an increase of 12.6±23.3% in the placebo group (p<0.001), with a statistically significant difference starting on day 8 and remaining so until day 78.
• Administration of IONIS-AGT-L_Rx resulted in numerically greater (but statistically insignificant) drops in systolic and diastolic blood pressure: at an average of −8 mmHg (95% CI: −17 to +2) and −1 mmHg (95% CI: −8 to +5), respectively.
• In the IONIS-AGT-L_Rx group, a greater proportion of patients than in the control group showed systolic and diastolic blood pressure reductions of at least 5, 10, or 15 mmHg and reached targets below 140 and 90 mmHg, respectively.
• The safety profile of IONIS-AGT-L_Rx was characterized by acceptability: no hypotensive events, hyperkalemia, or renal dysfunction were reported.

The NCT04083222 clinical trial (randomized, double-blind, placebo-controlled, multicenter) enrolled adult patients (n=26) with primary hypertension who were following a stable course of hypotensive medications that were not helping them.

Participants must continue to follow a two- to three-drug hypotensive therapy involving administration of an ACEi or ARB along with one to two additional medications, such as a beta blocker, calcium channel blocker, or diuretic (not a potassium-sparing). 65% of the subjects took two hypotensive drugs and 35% took three.

Patients received an 80-mg dose of IONIS-AGT-L_Rx or placebo by subcutaneous injection once a week for 8 weeks.

The results collected are as follows:

• Serum angiotensinogen levels in the IONIS-AGT-L_Rx group decreased by 67,0±14,1% — versus an increase of 3,4±17,8% in the placebo group (p<0.001), with a statistically significant difference starting on day 8 and remaining so until day 92.
• Administration of IONIS-AGT-L_Rx resulted in numerically greater (but statistically insignificant) drops in systolic and diastolic blood pressure: at an average of −12 mmHg (95% CI: −21 to −4) and −6 mmHg (95% CI: −11 to −1), respectively.
• In the IONIS-AGT-L_Rx group, a greater proportion of patients than in the control group showed systolic and diastolic blood pressure reductions of at least 5, 10, or 15 mmHg and reached targets below 140 and 90 mmHg, respectively.
• There were no significant differences between outcomes depending on whether patients were taking two or three hypotensive drugs.
• The safety profile of IONIS-AGT-L_Rx was characterized by acceptability: no hypotensive events, hyperkalemia, or renal dysfunction were reported.

 

IONIS-AGT-L_Rx: What’s Next

Ionis has launched a pair of phase 2b ( randomized, double-blind, placebo-controlled, multicenter) clinical trials that are testing the weekly administration of IONIS-AGT-L_Rx at different doses and in different patient populations:

• The ASTRAAS (NCT04714320) clinical trial is examining IONIS-AGT-L_Rx in uncontrolled resistant hypertension among patients already taking three or more hypotensive medications.
• The ASTRAAS-HF (NCT04836182) clinical trial is evaluating IONIS-AGT-L_Rx in patients with chronic heart failure with reduced ejection fraction (HFrEF).

Ionis has also started the NCT04731623 phase 1 (randomized, double-blind, placebo-controlled) clinical study, which is trialing IONIS-AGT-2.5-L_Rx (ION904), the next generation of the antisense oligonucleotide inhibiting angiotensinogen synthesis, which is more than 10 times stronger than IONIS-AGT-L_Rx. It is possible that the drug can be prescribed even less frequently and will be implemented in an oral formulation.

 

IONIS-AGT-L_Rx: Where Is Evidence

We can safely hope for the success of antisense therapy for hypertension, because Ionis has already commercialized three drugs made within this technological modality:

• Spinraza (nusinersen) is intended to treat spinal muscular atrophy in children and adults.
• Tegsedi (inotersen) is focused on the therapy of adult patients with hATTR-PN (FAP).
• Waylivra (volanesorsen) is used as adjunctive therapy to diet in adult patients with a genetically confirmed diagnosis of familial chylomicronemia (FCS) and a high risk of pancreatitis if response to diet and lipid-lowering medications is insufficient.

 

Extras

Alnylam Pharmaceuticals. KARDIA: Zilebesiran phase 2 clinical development overview. [PDF]

Durable reductions in circulating angiotensinogen and blood pressure 6 months after single doses of ALN-AGT, an RNA interference therapeutic targeting hepatic angiotensinogen synthesis, in hypertensive patients. AHA 2021. [PDF]

Safety and tolerability of ALN-AGT, an RNA interference therapeutic targeting hepatic angiotensinogen synthesis, in hypertensive patients during sodium depletion or irbesartan coadministration. AHA 2021. [PDF]

Safety, pharmacodynamics, and blood pressure effects of ALN-AGT, an RNA interference therapeutic targeting angiotensinogen, in a randomized single ascending dose study of hypertensive adults. ESH-ISH 2021. [PDF]

Dose-related reductions in blood pressure with a RNA interference (RNAi) therapeutic targeting angiotensinogen in hypertensive patients: interim results from a first-in-human phase 1 study of ALN-AGT01. [PDF]

Alnylam Pharmaceuticals. ALN-AGT: in development for the treatment of hypertension. June 23, 2020. [PDF]

Blood pressure lowering and safety improvements with liver angiotensinogen inhibition in models of hypertension and kidney injury. Hypertension. 2017 Sep;70(3):566-576. [source]

Antisense inhibition of angiotensinogen with IONIS-AGT-L_Rx: results of phase 1 and phase 2 studies. JACC Basic Transl Sci. 2021 Jun; 6(6): 485–496. [source]

Ionis Pharmaceuticals. Cardiovascular franchise webcast. September 2, 2020. [PDF]

Ionis Pharmaceuticals. Investor Day 2020. December 7, 2020. [PDF]

Targeting angiotensinogen with RNA-based therapeutics. Curr Opin Nephrol Hypertens. 2020 Mar;29(2):180-189. [source]