Hypertension Vaccine Safe, Well-Tolerated in Phase 2a Study

Susan Jeffrey

November 06, 2007

November 6, 2007 (Orlando) — Results of a phase 2 study suggest that an investigational vaccine against angiotensin II was safe and well tolerated in patients with mild to moderate hypertension. The vaccine produced a long-lived antibody response with a half-life of about 4 months.

"Treatment with the high dose produced a significant reduction of daytime ambulatory blood pressure [BP] and a marked reduction in the early morning hours, when most adverse cardiovascular events occur," study author Jürg Nussberger, MD, from Centre Hospitalier Université Vaudois, in Lausanne, Switzerland, told attendees at the American Heart Association 2007 Scientific Sessions here.

"Future studies will apply state-of-the-art formulations and treatment regimens to explore the full potential of this approach," he said.

Early Riser

Good control of hypertension has been undermined by problems of patient compliance with antihypertensive medications. Although many effective drugs are available, only about 25% of patients are optimally controlled, Dr. Nussberger said. "This has probably something to do with the fact that these drugs have to be taken daily and lifelong."

However, many of these drugs have a half-life of less than 24 hours, so if patients take them in the morning, the medications are at a trough in the early-morning hours, he said, just as the normal rise in blood pressure takes place and when most cardiovascular events occur.

"With a vaccine against angiotensin II, where there is a long-lasting effect with antibodies, you may not have this problem of peak-trough, and the patient has to come to the doctor maybe only 2 or 3 times a year," Dr. Nussberger said.

Previous work by Morris J. Brown and colleagues at the University of Cambridge, United Kingdom, had tested a vaccine against angiotensin I and shown some reduction of aldosterone, but no blood pressure–lowering effect.

The current study explored the safety and tolerability of CYT006-AngQb, a viruslike particle-based conjugate vaccine that targets angiotensin II in a placebo-controlled phase 2a sequential 2-dose comparison trial. In the study, 72 patients with mild to moderate hypertension, defined as a systolic pressure of 140 to 179 mm Hg and a diastolic pressure of 90 to 109 mm Hg, were enrolled; 5 patients dropped out for reasons unrelated to the study, he noted.

The study was done over 4 months; patients were given 100 µg or 300 µg of the antigen or placebo at time zero, then at 1 month and 3 months, after which they were followed for 8 months for safety. End points were safety and tolerability, with an "exploratory" look at efficacy with ambulatory blood pressure measurements and plasma renin concentrations.

Adverse events occurred in all patients in both groups, a finding that was not unexpected, since even placebo patients received an injection of aluminum hydroxide emulsion and so reported pain, erythema, or edema at the injection site. Headache was also more frequent in the vaccination group, but all of these effects occurred over the first 1 or 2 days and were reversible.

Adverse Events (AE) With CYT006-AngQb vs Placebo

End point
Placebo
100 µg
300 µg
Incidence of any AE (%)
100
100
100
Severity of AEs (% of events)

Mild
91
94
90
Moderate
8
5
8
Severe
1
1
2
Relationship to treatment (%)
70
83
86
Severe AEs related to treatment
0
0
0

 

Antibody titers showed a strong response against angiotensin II in all patients, evident after the first injection. At 1 month, the second injection showed a strong peak in titers, followed by a decrease to 3 months, when the third injection was given. The antibody response was significantly higher with the 300-µg dose, with a terminal half-life of 123 days, or about 4 months.

Ambulatory BP measurements at week 14 showed a significant reduction in daytime blood pressure with the 300-µg dose vs placebo; systolic BP was reduced by 5.6 mm Hg and the diastolic pressure by 2.8 mm Hg compared with baseline measures. The low dose showed some trend toward a reduction in BP but did not reach significance. "So the high dose, 300 µg, worked," Dr. Nussberger said.

Particularly, there appeared to be strong efficacy during the early-morning pressor surge. When measures were averaged for each hour of 5 AM to 8 AM, there was a differential between placebo and the 300-µg group of 25/13 mm Hg at week 14.

Several studies to investigate further the safety and efficacy of the vaccine are now being planned, Dr. Nussberger said.

Potential Benefit of Good BP Control

Asked for comment on this work by Medscape Neurology & Neurosurgery, session moderator John M. Flack, MD, from Wayne State University, in Detroit, Michigan, said he thinks there is significant potential for this kind of approach to treating hypertension.

"There are potential safety issues — for example, in pregnant women, where angiotensin II is needed for the development of the fetus," Dr. Flack said. "On the other hand, in appropriately selected populations, this really overcomes 1 significant barrier, and that is the daily compliance required to receive the full effect of antihypertensive treatment.

"I think that once the right doses are found and the immune response and its link to blood pressure is better understood, that this is a very promising branch point in our ability to treat hypertension, a chronic condition, over the long term," he said.

The study was funded by Cytos Biotechnology AG, Schlieren, Switzerland, developer of this vaccine. Dr. Nussberger reports he received funding from Cytos for performing biochemical analyses for this study.

American Heart Association Scientific Sessions 2007: Abstract 2519. Presented November 6, 2007.

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