Anavex Life Sciences Corp (AVXL)

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Amyloid ß oligomers constrict human capillaries in Alzheimer’s disease via signaling to pericytes
Ross Nortley1, Nils Korte1,*, Pablo Izquierdo1,*, Chanawee Hirunpattarasilp1,*, Anusha Mishra2,*, Zane Jaunmuktane3,4,*, Vasiliki Kyrargyri1,*,†, Thomas Pfeiffer1, Lila Khennouf1, Christian Madry1,‡, Hui Gong1, Angela Richard-Loendt3, Wenhui Huang5, Takashi Saito6, Takaomi C. Saido6, Sebastian Brandner3,7, Huma Sethi8, David Attwell1,§
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Science 20 Jun 2019:

Cerebral blood flow is reduced early in Alzheimer’s disease (AD). Because most of the vascular resistance within the brain is in capillaries, this could reflect dysfunction of contractile pericytes on capillary walls. Here we used live and rapidly-fixed biopsied human tissue to establish disease-relevance, and rodent experiments to define mechanism. We found that, in humans with cognitive decline, amyloid ß (Aß) constricts brain capillaries at pericyte locations. This was caused by Aß generating reactive oxygen species, which evoked the release of endothelin-1 (ET) that activated pericyte ETA receptors. Capillary, but not arteriole, constriction also occurred in vivo in a mouse model of AD. Thus, inhibiting the capillary constriction caused by Aß could potentially reduce energy lack and neurodegeneration in AD.

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Anavex Life Sciences Corp. (“Anavex” or the “Company”) (Nasdaq: AVXL), a clinical-stage biopharmaceutical company developing differentiated therapeutics for the treatment of neurodegenerative and neurodevelopmental diseases today reports that the peer-reviewed scientific journal The Journal of Clinical Hypertension [1] has published a post-hoc analysis of blood pressure data collected during the Phase 2a study in mild-to-moderate Alzheimer’s disease patients demonstrating that ANAVEX®2-73 seems to normalize systolic blood pressure (SBP) in a patient population with risk for hypertension.

Statistical analyses including paired t-testing and multivariable linear mixed effects modeling (adjusted for time of measurement, gender, age, body mass index, and use of antihypertensives) indicate a normalization of SBP from the first reading (baseline) of 143.3 mmHg to the subsequent readings after ANAVEX®2-73 administration of 132.5 mmHg (p=0.048) at day 25 and of 135.3 mmHg (p=0.008) at day 36, respectively.

High blood pressure, or hypertension, occurs when either systolic or diastolic pressure remains elevated over time. High blood pressure is dangerous because it makes the heart work too hard and its extra force can damage arteries. Uncontrolled high blood pressure can lead to heart disease, kidney damage or stroke. New evidence also links high blood pressure to increased risk of cognitive decline and dementia. [2]

Thirty-two mild-to-moderate Alzheimer’s disease patients took part in the ANAVEX2-73 Phase 2a study. Mean age was 69.5 years, 60% were male, mean body mass index was 26.5 kg/m2, and 50% were on antihypertensive medication. No patients reported any changes in their antihypertensive regimen while taking part in the study.

Raymond R. Townsend, MD, Professor of Medicine and Director of the Hypertension Program at the Hospital of the University of Pennsylvania, the senior author of the paper, notes “Intriguingly, systolic blood pressure was selectively normalized, the mediation of which is key in reducing the likelihood of heart attack, stroke and other cardiovascular issues in older patients.”

“The systolic blood pressure findings may be quite clinically meaningful. There are properties of the medication that support a compelling mechanism for how it can lower high blood pressure,” states Jordana B. Cohen, MD, MSCE, Instructor of Medicine in the Renal-Electrolyte and Hypertension Division at the University of Pennsylvania and lead author of the paper. “Nonetheless, given that the Phase 2a study was not designed to measure changes in blood pressure over time, the results require further corroboration.”

“While in a previously reported Phase 1 study ANAVEX2-73 did not affect blood pressure in healthy subjects, who demonstrated normal blood pressure levels at baseline, the results of the post-hoc analysis of the Phase 2a study in mild-to-moderate Alzheimer’s disease patients with majority of patients with elevated blood pressure, warrant cautious interpretation. Blood pressure measurement was not a primary goal of this trial, however, the potential beneficial effect of sigma-1 receptor activation restoring homeostasis on blood pressure normalization merits further investigation in future clinical studies,” stated Christopher U. Missling, PhD, President and Chief Executive Officer of Anavex.

https://www.anavex.com/anavex-life-sciences-reports-potential-normalization-of-hypertension-with-anavex2-73-published-in-the-journal-of-clinical-hypertension/

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