Therapeutics

Nilvadipine

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Overview

Name: Nilvadipine
Synonyms: Nilvad, Nivadil, ARC029
Therapy Type: Small Molecule (timeline)
Target Type: Other (timeline)
Condition(s): Alzheimer's Disease
U.S. FDA Status: Alzheimer's Disease (Inactive)
Company: Archer Pharmaceuticals, Inc.

Background

Nilvadipine is a dihydropyridine calcium channel blocker. It has been prescribed in Europe and Japan to treat hypertension since the 1990s and has accumulated a strong safety record. Nilvadipine is manufactured by Astellas Pharma US and sold as 8 mg prolonged-release capsules. After its patent expired, Archer Pharmaceuticals obtained intellectual property rights to develop it for Alzheimer's.

There is growing epidemiological evidence that chronic high blood pressure increases risk for dementia (AlzRisk database). Some studies have suggested promise for treatment with anti-hypertensive medications, but the evidence is mixed. It remains unclear which class of anti-hypertensive—e.g., calcium channel blockers, beta blockers, drugs targeting angiotensin, or diuretics—are most beneficial for symptomatic versus prophylactic treatment (Mar 2006 news story). Mid-life hypertension is widely viewed as causing neurovascular damage that impairs neurovascular homeostasis in late life, hence drugs that lower blood pressure may be counterindicated in aged people who have neurovascular disease or orthostatic hypotension (May 2014 news story; Dec 2013 Webinar).

One small Japanese study reported that nilvadipine prevented cognitive decline in people with mild cognitive impairment, and there are case reports of nilvadipine increasing cerebral blood flow in patients with early Alzheimer's and hypertension  (Hanyu et al., 2007; Matsuda et al., 2008; Sato et al., 2008).

An in vitro study reported that nilvadipine reduces Aβ accumulation, albeit at much higher doses than its reported effects on L-type calcium channels (see Jul 2011 news story; Paris et al., 2011; Cho et al., 1989). In other preclinical work, nilvadipine was reported to counteract cerebrovascular effects of Aβ in mice, and ischemia-induced memory impairment in rats (Paris et al., 2004; Iwasaki et al., 2007). Nivaldipine has also been reported to potentially increase clearance of Aβ from the brain (Bachmeier et al., 2001).

Findings

A six-week, open-label Phase 1/2a clinical study conducted in Ireland compared safety and tolerability of 8 mg/day of nilvadipine taken by 56 patients with mild to moderate Alzheimer's disease to placebo taken by 30 patients. Nivaldipine was reported to be well-tolerated in patients with and without orthostatic hypotension. This study also reported a treatment benefit on the MMSE and an executive function test called EXIT25 (Kenelly et al., 2010; Kenelly et al., 2011).

In 2013, NILVAD, an 18-month multicenter trial in nine European countries, began enrolling 500 people with mild to moderate Alzheimer's. This study compared a once-daily dose of 8 mg nilvadipine to placebo for its ability to generate a difference on standard outcome measures in AD clinical trials, the ADAS-cog, CDR-DB, and the DAD (for published protocol see Lawlor et al., 2014). In 2018, researchers reported no change in rates of decline on any of these measures (Sep 2018 news). This was funded by the European Commission (Jul 2011 news). Various substudies and posthoc analyses of this trial have been reported (e.g. Meulenbroek et al., 2016; de Heus et al., 2019; de Heus et al., 2019; de Jong et al., 2019; Dyer et al., 2020; Dyer et al., 2020; Dyer et al., 2020; Abdullah et al., 2020).

For other details on this trial, see ISRCTN, or clinicaltrials.gov.

Last Updated: 08 Feb 2023

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References

News Citations

  1. Nilvadipine Fails to Slow Cognitive Decline in AD Patients
  2. Search for AD Drugs Turns to a Hypertension Medicine
  3. No Pressure, But Could Hypertension Medication Prevent AD?
  4. It’s Not All About You, Neurons. Glia, Blood, Arteries Shine at Symposium

Webinar Citations

  1. Neurovascular Underpinnings of Alzheimer's Dementia

Paper Citations

  1. Kennelly SP, Abdullah L, Paris D, Parish J, Mathura V, Mullan M, Crawford F, Lawlor BA, Kenny RA. Demonstration of safety in Alzheimer's patients for intervention with an anti-hypertensive drug Nilvadipine: results from a 6-week open label study. Int J Geriatr Psychiatry. 2010 Oct 29; PubMed.
  2. Kennelly S, Abdullah L, Kenny RA, Mathura V, Luis CA, Mouzon B, Crawford F, Mullan M, Lawlor B. Apolipoprotein E genotype-specific short-term cognitive benefits of treatment with the antihypertensive nilvadipine in Alzheimer's patients-an open-label trial. Int J Geriatr Psychiatry. 2011 May 10; PubMed.
  3. Lawlor B, Kennelly S, O'Dwyer S, Cregg F, Walsh C, Coen R, Kenny RA, Howard R, Murphy C, Adams J, Daly L, Segurado R, Gaynor S, Crawford F, Mullan M, Lucca U, Banzi R, Pasquier F, Breuilh L, Riepe M, Kalman J, Wallin A, Borjesson A, Molloy W, Tsolaki M, Olde Rikkert M. NILVAD protocol: a European multicentre double-blind placebo-controlled trial of nilvadipine in mild-to-moderate Alzheimer's disease. BMJ Open. 2014 Oct 9;4(10):e006364. PubMed.
  4. Meulenbroek O, O'Dwyer S, de Jong D, van Spijker G, Kennelly S, Cregg F, Olde Rikkert M, Abdullah L, Wallin A, Walsh C, Coen R, Kenny RA, Daly L, Segurado R, Borjesson-Hanson A, Crawford F, Mullan M, Lucca U, Banzi R, Pasquier F, Breuilh L, Riepe M, Kalman J, Molloy W, Tsolaki M, Howard R, Adams J, Gaynor S, Lawlor B. European multicentre double-blind placebo-controlled trial of Nilvadipine in mild-to-moderate Alzheimer's disease-the substudy protocols: NILVAD frailty; NILVAD blood and genetic biomarkers; NILVAD cerebrospinal fluid biomarkers; NILVAD cerebral blood flo. BMJ Open. 2016 Jul 19;6(7):e011584. PubMed.
  5. de Heus RA, Donders R, Santoso AM, Olde Rikkert MG, Lawlor BA, Claassen JA, Nilvad Study Group. Blood Pressure Lowering With Nilvadipine in Patients With Mild-to-Moderate Alzheimer Disease Does Not Increase the Prevalence of Orthostatic Hypotension. J Am Heart Assoc. 2019 May 21;8(10):e011938. PubMed.
  6. de Heus RA, Olde Rikkert MG, Tully PJ, Lawlor BA, Claassen JA, NILVAD Study Group. Blood Pressure Variability and Progression of Clinical Alzheimer Disease. Hypertension. 2019 Nov;74(5):1172-1180. Epub 2019 Sep 23 PubMed.
  7. de Jong DL, de Heus RA, Rijpma A, Donders R, Olde Rikkert MG, Günther M, Lawlor BA, van Osch MJ, Claassen JA. Effects of Nilvadipine on Cerebral Blood Flow in Patients With Alzheimer Disease. Hypertension. 2019 Aug;74(2):413-420. Epub 2019 Jun 17 PubMed.
  8. Dyer AH, Murphy C, Lawlor B, Kennelly SP, NILVAD Study Group. Cognitive Outcomes of Long-term Benzodiazepine and Related Drug (BDZR) Use in People Living With Mild to Moderate Alzheimer's Disease: Results From NILVAD. J Am Med Dir Assoc. 2020 Feb;21(2):194-200. Epub 2019 Oct 8 PubMed.
  9. Dyer AH, Murphy C, Segurado R, Lawlor B, Kennelly SP, NILVAD Study Group. Is Ongoing Anticholinergic Burden Associated with Greater Cognitive Decline & Dementia Severity in Mild to Moderate Alzheimer Disease ?. J Gerontol A Biol Sci Med Sci. 2019 Oct 15; PubMed.
  10. Dyer AH, Lawlor B, Kennelly SP, NILVAD Study Group. Gait speed, cognition and falls in people living with mild-to-moderate Alzheimer disease: data from NILVAD. BMC Geriatr. 2020 Mar 30;20(1):117. PubMed.
  11. Abdullah L, Crawford F, Tsolaki M, Börjesson-Hanson A, Olde Rikkert M, Pasquier F, Wallin A, Kennelly S, Ait-Ghezala G, Paris D, Hendrix S, Blennow K, Lawlor B, Mullan M. The Influence of Baseline Alzheimer's Disease Severity on Cognitive Decline and CSF Biomarkers in the NILVAD Trial. Front Neurol. 2020;11:149. Epub 2020 Mar 6 PubMed.
  12. Hanyu H, Hirao K, Shimizu S, Sato T, Kiuchi A, Iwamoto T. Nilvadipine prevents cognitive decline of patients with mild cognitive impairment. Int J Geriatr Psychiatry. 2007 Dec;22(12):1264-6. PubMed.
  13. Matsuda H, Araki N, Kuji I, Ohkubo T, Imabayashi E, Shimazu K. Effect of nilvadipine on regional cerebral blood flow in a patient with early Alzheimer disease. Clin Nucl Med. 2008 Jan;33(1):34-5. PubMed.
  14. Sato T, Hanyu H, Akai T, Takasaki A, Sakurai H, Iwamoto T. [A patient with early Alzheimer's disease who showed improvement of cognitive function and cerebral perfusion by combined therapy of nilvadipine and PPAR gamma agonists]. Nihon Ronen Igakkai Zasshi. 2008 Jul;45(4):428-33. PubMed.
  15. Paris D, Bachmeier C, Patel N, Quadros A, Volmar CH, Laporte V, Ganey J, Beaulieu-Abdelahad D, Ait-Ghezala G, Crawford F, Mullan MJ. Selective antihypertensive dihydropyridines lower Aβ accumulation by targeting both the production and the clearance of Aβ across the blood-brain barrier. Mol Med. 2011 Mar-Apr;17(3-4):149-62. PubMed.
  16. Cho H, Ueda M, Shima K, Mizuno A, Hayashimatsu M, Ohnaka Y, Takeuchi Y, Hamaguchi M, Aisaka K, Hidaka T. Dihydropyrimidines: novel calcium antagonists with potent and long-lasting vasodilative and antihypertensive activity. J Med Chem. 1989 Oct;32(10):2399-406. PubMed.
  17. Paris D, Quadros A, Humphrey J, Patel N, Crescentini R, Crawford F, Mullan M. Nilvadipine antagonizes both Abeta vasoactivity in isolated arteries, and the reduced cerebral blood flow in APPsw transgenic mice. Brain Res. 2004 Feb 27;999(1):53-61. PubMed.
  18. Iwasaki K, Egashira N, Takagaki Y, Yoshimitsu Y, Hatip-Al-Khatib I, Mishima K, Fujiwara M. Nilvadipine prevents the impairment of spatial memory induced by cerebral ischemia combined with beta-amyloid in rats. Biol Pharm Bull. 2007 Apr;30(4):698-701. PubMed.
  19. Bachmeier C, Beaulieu-Abdelahad D, Mullan M, Paris D. Selective dihydropyiridine compounds facilitate the clearance of β-amyloid across the blood-brain barrier. Eur J Pharmacol. 2011 Jun 1;659(2-3):124-9. PubMed.

External Citations

  1. ISRCTN
  2. clinicaltrials.gov
  3. AlzRisk database

Further Reading

Papers

  1. Valenzuela M, Esler M, Ritchie K, Brodaty H. Antihypertensives for combating dementia? A perspective on candidate molecular mechanisms and population-based prevention. Transl Psychiatry. 2012;2:e107. PubMed.
  2. Yagami T, Kohma H, Yamamoto Y. L-type voltage-dependent calcium channels as therapeutic targets for neurodegenerative diseases. Curr Med Chem. 2012 Jul 25; PubMed.
  3. Nimmrich V, Eckert A. Calcium channel blockers and dementia. Br J Pharmacol. 2013 Jul;169(6):1203-10. PubMed.
  4. Dudenbostel T, Glasser SP. Effects of antihypertensive drugs on arterial stiffness. Cardiol Rev. 2012 Sep-Oct;20(5):259-63. PubMed.
  5. Kennelly S, Abdullah L, Kenny RA, Mathura V, Luis CA, Mouzon B, Crawford F, Mullan M, Lawlor B. Apolipoprotein E genotype-specific short-term cognitive benefits of treatment with the antihypertensive nilvadipine in Alzheimer's patients-an open-label trial. Int J Geriatr Psychiatry. 2011 May 10; PubMed.