Hypertension: development of a new class of drugs

INTERVIEW - Firibastat, a new antihypertensive drug targeting a new pathway in the brain, has shown interesting results at the annual conference of the American Heart Association. Interview with Dr. Bruno Besse, Chief Medical Officer of Quantum Genomics, Chicago on the New Hope Study

Hypertension affects one in two people and the therapeutic needs remain unclear: more than 30% of patients remain difficult to treat and nearly 50% of them are not objectives, despite treatment sometimes involving 3 molecules.

Obesity, salt sensitivity, certain ethnicities ... have hypertension that remains poorly controlled due to variations in the metabolic processes involved in the onset of the disease: the pathways involved in their hypertension are not the same as in the others populations (eg, low renin activity), which compromises the effectiveness of current therapeutic strategies.

A new target in the brain

There is another renin angiotensin system that we know and it is located only in the brain. One of its fractions, angiotensin III, is one of the most potent peptides of brain-controlled arterial tone. This peptide helps to increase blood pressure through three different mechanisms: increased vasopressin concentration, increased sympathetic neuron activity associated with vessel vasoconstriction, and baroreflex inhibition.

An aminopeptidase A inhibitor

The firibastat is the "first inhibitor of cerebral aminopeptidases-A", and it inaugurates the class of BAPAI ("Brain Amino Peptidase A Inhibition") with an original mechanism of action in arterial hypertension.

What is indeed interesting compared to other antihypertensives today is that the firibastat acts only on the brain and not on the peripheral organs. We can therefore consider new possibilities of therapeutic association.

Firibastat is a small molecule that is administered orally as a prodrug and is therefore able to enter the brain and selectively inhibit brain aminopeptidase A. This selective inhibition will block the transformation of angiotensin II to angiotensin III and reduce the release of vasopressin and sympathetic activity, as well as improve the baroreflex response.

A validation study

New-Hope is a Phase II study of 218 hypertensive patients, including at-risk patients and at least 50% black-skinned and Hispanic, ethnic groups that are usually underrepresented in studies, while resistance to treatment are frequent there. It was conducted with an automated measurement of blood pressure, which is now the reference method and avoids disturbances of measurement (white coat effect, for example).

Interesting results

At 8 weeks of treatment, there was a significant decrease in blood pressure: the systolic blood pressure dropped by 9.7 mmHg (p <0.0001) and the diastolic by 4.3 mmHg (p <0.0001). It is, moreover, a consistent decline regardless of the type of patient and race. The tolerance was good, and without any neuropsychiatric effect in particular.

There is now a new therapeutic pathway in hypertension and this new pathway may be complementary to other metabolic pathways used by current therapies. It remains to specify the best methods of association to improve the treatment of patients difficult to treat.

Interview with Dr. Bruno Besse, Chief Medical Officer of Quantum Genomics on the New Hope Study